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University of Groningen

Coronary risk stratificationGeluk, Christiane Anneliese

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Coronary risk stratificationFrom PREVEND to the prevention of coronary events

Christiane A. Geluk

Financial support by the Netherlands Heart Foundation and the Netherlands Kidney Foundation for the publication of this thesis is gratefully acknowlegded.

CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG

Geluk, C.A.Coronary risk stratification. From PREVEND to the prevention of coronary events.Proefschrift Groningen. Met literatuuropgave en samenvatting in het Nederlands.

ISBN 978-90-367-3259-8

© Copyright 2007, C.A. Geluk All rights reserved. No part of this publication may be reproduced, or transmitted in any form or by any means, without permission ot the author.

Layout: Helga de Graaf, Studio Eye Candy (www.proefschrift.info), Groningen.Printed by: Printpartners Ipskamp, Enschede.

RIJKSUNIVERSITEIT GRONINGEN

Coronary risk stratificationFrom PREVEND to the prevention of coronary events

Proefschrift

ter verkrijging van het doctoraat in de Medische Wetenschappen

aan de Rijksuniversiteit Groningenop gezag van de

Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op

woensdag 16 januari 2008 om 14:45 uur

door

Christiane Anneliese Gelukgeboren op 29 september 1977

te Rotterdam

Promotores: Prof. dr. F. Zijlstra Prof. dr. W.H. van Gilst

Prof. dr. H.L. Hillege

Beoordelingscommissie: Prof. dr. M. Oudkerk Prof. dr. J.G.P. Tijssen

Prof. dr. E.E. van der Wall

Paranimfen: Mw. drs. T. Svilaas Dr. M. Rienstra

The publication of this thesis was financially supported by:

the University of Groningen, the University Medical Center Groningen, the Groningen University Institution for Drug Explaration (GUIDE), Wetenschapsfonds Medisch Centrum Leeuwarden, Servier Nederland BV, Sanofi-Aventis BV, Astra Zeneca BV, Bristol Meyers Squibb BV, Boehringer Ingelheim BV, Dade Behring BV, Medtronic BV, Pfizer BV, Siemens, Schering-Plough, Novartis.

Aan Valérie

Contents

Chapter 1 Introduction to the thesis

Chapter 2 Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study Netherlands Heart Journal. 2007;15(4):133-41

Chapter 3 C-Reactive protein and angiographic characteristics of stable and unstable coronary artery disease – Data from the prospective PREVEND cohortAtherosclerosis. 2006 [Epub ahead of print]

Chapter 4 The predictive value of adding urinary albumin excretion and high-sensitive C-reactive protein to the Framingham risk score

Submitted

Chapter 5 Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention TrialEuropean Heart Journal. 2005;26(13):1314-20

Chapter 6 Measurement of coronary calcium scores or exercise testing as initial screening tool in asymptomatic subjects with ST-T changes on the resting ECG: an evaluation studyBMC Cardiovasular Disorders. 2007;7:19

Chapter 7 Measurement of coronary calcium scores or exercise testing as initial diagnostic tool in low-risk patients with suspected coronary artery diseaseEuropean Radiology. 2007 [Epub ahead of print]

Chapter 8 Summary, implications and future perspectives

List of abbreviations

Nederlandse samenvatting

Dankwoord

Curriculum Vitae

List of publications

11

27

45

65

83

99

117

135

141

143

149

155

157

Chapter 1

Introduction tothe thesis

12

Chapter 1

Background

Coronary artery disease is a major component of cardiovascular disease and the main cause of death in industrialized countries. The disease is characterized by a long asymptomatic period of atherogenesis, which results in plaque growth, and may be followed by a symptomatic period of anginal complaints or a clinical coronary event. It has been shown that intervention, such as lipid- or blood pressure lowering treatment, during the asymptomatic period may alter the progression of atherosclerosis into unstable plaques and consequently symptomatic coronary events.1;2 Therefore, coronary artery disease is an obvious candidate for screening programs.3 Optimization of these programs is currently challenged by the developing insight in coronary atherogenesis as well as new imaging techniques visualizing coronary artery disease. It has been recognized that vascular inflammation and endothelial dysfunction play a key role in atherogenesis. High-sensitive C-reactive protein, a marker of vascular inflammation, is associated with the formation, progression and rupture of coronary plaques.4-6 Furthermore, increased levels of C-reactive protein has been associated with worse clinical outcome.7 Urinary albumin excretion is recognized not only as an indicator of early renal dysfunction but also as a surrogate of endothelial dysfunction, a preclinical phase of the atherosclerotic process.8 Coronary calcifications represent the calcified coronary plaques, which represents about one fifth of total coronary plaque volume.9 Calcified plaques are easily detected by electron beam computed tomography or multidetector computed tomography and are related with coronary luminal stenosis as well as future coronary events.10-12 Therefore, these measures of coronary artery disease may apply for inclusion in strategies for coronary risk stratification in clinical practice.

The remaining part of this introduction provides a review of the evidence on the potential role of C-reactive protein, urinary albumin excretion and coronary calcium in coronary risk stratification and aims of this thesis.

Issues on the pathway from coronary risk association to risk stratification

On the pathway from risk association to risk stratification, several issues need to be addressed before a risk measure can be implemented in a clinical decision strategy. The ideal candidate is a risk measure strongly associated with atherogenesis and coronary risk but minimally associated with the current standard of risk evaluation, prevalent in a substantial part of the population, can easily be measured with high reproducibility, improves individual risk prediction, clinical management and survival.13-15 An overview of these issues with regard to C-reactive protein, urinary albumin excretion and coronary calcium is given in table 1 and explained below.

13

Introduction to the thesis

Chap

ter 1

Is the risk measure associated to the atherosclerotic process?The first issue deals with the association between the risk measure and coronary atherogenesis. This is of importance, since the process of coronary atherogenesis proceeds the occurrence of events and alteration of this process may alter outcome. With regard to urinary albumin excretion, the pathophysiologic mechanisms which relate urinary albumin excretion to the atherosclerotic process are still to be elucidated. Currently, there is no hard evidence that increased levels of urinary albumin excretion are causally linked to the atherosclerotic process. The Steno hypothesis considered transvascular leakage of albumin as predisposition for leakage of atherogenic lipoprotein particles in the arterial wall, but consistent evidence for this hypothesis is lacking.16-18 Some have argued that moderately increased levels of urinary albumin excretion (microalbuminuria) represents endothelial dysfunction, the early phase of atherogenesis.8 However, this is a complex relationship. Coronary risk factors may precede endothelial dysfunction and chronic inflammation, and result in atherogenesis and urinary albumin excretion, which may introduce confounding in the association between microalbuminuria and atherogenesis.8;19-24 Only one cross-sectional study evaluated the association between microalbuminuria and angiographic evidence of coronary artery disease, with a positive result.25

The contribution of C-reactive protein to coronary atherogenesis may be explained through its association with systemic processes involved in coronary atherosclerosis, such as insulin resistance and obesity, infections and a pro-thrombotic state.26 Some have argued for a direct causative association with coronary atherosclerosis, although this view has been denied by others.27-29 Observations in favor of the first view is a direct contribution of C-reactive protein to atherogenesis by promoting the uptake of oxidized LDL cholesterol by macrophages.28 Furthermore, C-reactive protein is a potent stimulator of tissue factor production by macrophages.29 C-reactive protein has been associated with angiographically detected coronary plaque growth30 and

Table 1. Issues on the pathway from risk association to risk stratification.*

The risk measure: UAE† CRP CC

-is associated with the atherosclerotic process ± + +

-adds independent information about coronary risk + + +-accounts for a large proportion of coronary risk ± ± +-can be tested in routine clinical practice + + ±-equates or improves the current standard for risk prediction ? ± ?1/±2

-improves patient outcome compared with other available ways of identifying and treating coronary risk

? ? ?

-changes clinical management ? ± ±1/+2

-is a target for intervention - ? -

*The listed issues are adapted from Manolio13, Greenland14 and Cook15. Explanation of symbols: current evidence is to the advantage (+) or disadvantage (-) of the statement; is is inconclusive (±) or not available yet (?) with regard to the risk measure. 1 compared to exercise testing; 2 compared to currently used prediction models such as the Framingham risk score. †applies to non-diabetic populations.UAE = Urinary albumin excretion, CRP = C-Reactive protein, CC = Coronary calcium.

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instability.4;31;32 Most of these studies, however, are limited by a cross sectional design. Coronary calcification is highly specific for and intimately associated with coronary atherosclerosis.33;34 Coronary atherosclerosis results from a consecutive process of endothelial dysfunction, development of fatty streaks (type I-III plaque according to AHA/ACC criteria I-VI) and of atheroma including a lipid core (type IV plaque) and fibrotic and/or calcified tissue (type V plaque).35 These stages of progression yield periods of plaque instability and plaque rupture, which are followed by plaque stabilization and growth, and are be associated with the deposition of calcium.9;36;37 Although the precise mechanism of calcium deposition is regarded as complex and largely unknown, it has been shown that matrix glycoproteins play a part in this process.38 The amount of coronary calcifications correlates linearly with total plaque volume and tend to be related to the presence of healed plaque ruptures.9 Therefore coronary calcifications have been regarded as a reflection of total plaque burden.39 A spotty pattern of calcifications has been detected by intravascular ultrasound in vulnerable plaques of patients with an acute coronary syndrome.40 However, a role of calcifications in plaque instability seems small since calcifications are more frequently present in hard than in soft plaques.41 In addition, amounts of coronary calcifications detected by electron beam tomography (measured as calcium score) are associated with the presence of obstructive coronary artery disease at coronary angiography, although the calcium score does not translate in a one-to-one fashion into direct luminal narrowing.10;12 The association between coronary calcifications and atherosclerosis has been corroborated by the low likelihood (<5%) of obstructive coronary artery disease or a coronary event when coronary calcifications are absent. 42-45

Does the risk measure add independent information about coronary risk? The second issue deals with coronary risk assessment. Elevated urinary albumin excretion levels independently predict coronary risk in patients with hypertension46, diabetes47 and in the general population at large.48-52 C-reactive protein has consistently been shown that the association between C-reactive protein and the occurrence of coronary events is independent from traditional risk factors.53-63 Patients suffering from an acute ischemic event have significantly higher calcium scores than age-matched controls.64 The association with coronary events is derived from the observation that high calcium scores represent advanced stages of coronary artery disease, with many sites of (calcified or non-calcified) non-obstructive plaques, from which the major portion of acute coronary events occur.65 A strong association between coronary calcifications and coronary risk has been found in large prospective studies of mostly asymptomatic subjects at various risk levels.66;67 This association has been proven to be stronger than and largely independent from standard cardiovascular risk factors, such as cholesterol, blood pressure and smoking.11;67

Does the risk measure account for a large proportion of coronary risk? This issue deals with the prevalence of the risk measure in the population as well as its contribution to coronary risk. Urinary albumin excretion levels have been found to be

15


Chap

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present in 3-15% of the general population and up to 38% of diabetic or hypertensive populations.47;49;50 Elevated urinary albumin excretion (microalbuminuria) was associated with increased cardiovascular risk and multivariable adjusted relative risks ranged between 1.3 and 2.3.68 Elevated C-reactive protein (as defined by >3 mg/L)56;60;62;69;70 is a frequently occurring risk factor, which has been reported to be present in 20-30% of study populations free of previous documented coronary artery disease.57;70-73 Multivariable adjusted relative risks of about 1.5 in most studies have been reported.53

The prevalence of coronary calcifications parallels the prevalence of atherosclerosis, with increased values in the elderly and in men when compared to women. Coronary calcifications increases significantly after 50 years of age, being present in at least 50% and 75% of male subjects in the age categories 50-60 and 60-70 years, respectively.45 There is a slight gender variation, with lower scores in the early decade in women, which is eliminated in the 65- to 70-years of age group.45 Coronary calcium scores over 100 are present in at least 25% of male and female subjects in the age categories 50-60 and over 65, respectively.45 High multivariate relative risks are associated with coronary calcifications. In a meta-analysis of large asymptomatic populations, coronary calcium scores 1-100 and >400 were associated with relative risks of 2.1 and 4.3-17.0, respectively, after adjustment for established risk factors.66;67 These relatives risks were confirmed in a recent meta-analysis.11

Can tests be applied in routine clinical practice? Direct urinary albumin excretion can be quantified by immunochemical techniques, for which inexpensive assays with low intra- and inter-assay coefficients of variation are available.74 Timed 24-hour urine collection has been the gold standard for quantifying urinary protein excretion and levels of 30-300 mg/24h have been defined as microalbuminuria.74;75 The intraindividual variation of urinary albumin excretion has been shown to range between 30 and 50% and depends on several factors, among which exercise, cardiac failure, acute illness, pregnancy, low urinary tract infections and nephrologic diseases.74;75 Despite this intraindividual variation, the presence of elevated urinary albumin excretion in a single urine sample is associated with increased coronary risk.49;50 Modifications to the 24-hour collection have been shown to accurately predict microalbuminuria in subsequent 24-hour urine collections.76 These include a timed shorter collection time or first morning void or spot albumin/ceatinine ratio.74;75 C-reactive protein can be measured with several standardized, validated, and inexpensive high-sensitivity assays.77 The variability of C-reactive protein measurement has been shown to be similar to that of total cholesterol.53;77;78 C-reactive protein levels remain stable over long periods of time without circadian variations.57 Accurate measurement of calcium scores can be performed by electron beam computed tomography (EBCT) as well as by the current types of multi detector computed tomography (MDCT). This a patient friendly procedure, not requiring intravenous access or contrast administration, and can be performed within 1-2 breath holds. Electron beam computed tomography and MDCT use low radiation doses of 0.7mSv

16

Chapter 1

and 1.0 mSv, respectively. Since most clinical evidence on the association between calcium scores and coronary risk was based on EBCT, similar validation is still lacking for MDCT. Strong correlations79 and variabilities in calcium scores of about 20%,80;80-82 however, favor MDCT for measurement of calcium scores. A disadvantage is that these imaging tools are not yet widely available and attention has to be paid to radiation exposure.

Does the risk measure equate or improve the current standard for risk prediction? The clinical use of a risk measure becomes evident if the risk measure performs at least as good as the current standard of risk prediction, or if the risk measure is able to improve the current standard for risk prediction. For global coronary risk estimation, the main current standards are based on the Framingham risk score and SCORE.1;83 However, these risk equations fall short in discrimination between those who are versus who are not at risk of a coronary event.84-90 In the evaluation of novel risk measures and their additive value to the current standards, these risk measures require to be strongly associated with coronary risk and to be poorly associated to the established risk factors of the current standard. So far, no studies have compared the additive value of urinary albumin excretion to prediction models such as the Framingham risk score. Few studies have evaluated the additive role of C-reactive protein to the Framingham risk score, with conflicting results.60-62 In a new risk sum prediction model using individual Framingham risk parameters refitted in the Womens Health Study, a preference for inclusion of C-reactive protein in a risk sum prediction model was demonstrated.91;92 As stated above, the coronary calcium score has been shown to add to the risk associated with traditional cardiovascular risk factors. So far, only few prospective studies have investigated the additional value of the calcium score to Framingham risk estimation, with conflicting results.93;94 Additional investigations are underway.95 In many hospitals in Europe and the USA, the current standard for diagnostic testing for evaluation of coronary risk is exercise testing. Although experts have suggested that measurement of coronary calcifications has the potential to equate or improve detection of high risk subjects when compared to exercise testing, concrete evidence has been lacking so far.96;97

Does identification of the risk measure improve patient outcomes compared with other available ways of identifying and treating coronary risk? So far, no clinical data are available in which patient groups are randomized to risk assessment by different risk measures, prediction models or tests, treated according to current guidelines and subsequently evaluated for clinical outcome.

Does identification of the risk measure change clinical management? The American NCEP ATPIII guidelines, and the European, as well as the Dutch guidelines, are used for the clinical management of subjects at risk of a coronary event.1;98;99;100 These guidelines categorize individuals in low to (very) high risk groups, based on the Framingham risk score and SCORE, respectively, taking into account the presence

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Chap

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of risk factors included or not included in the risk scores. Initiation of lifestyle advices or medical treatment depends on the risk category applied. Therefore, when inclusion of a novel risk measure would change an individual from one to another risk category, clinical management may change thereafter. With regard to urinary albumin excretion, so far no data have been published evaluating a change in clinical management by inclusion of urinary albumin excretion in the prediction model. Concerning C-reactive protein, in the Women’s Health Study, a new risk prediction model was developed and validated, including C-reactive protein. This model was associated with a reclassification of the predicted risk in many women, however, the specific contribution of C-reactive protein was not presented.92

With regard to coronary calcium, an interesting secondary analysis of subjects with an intermediate Framingham risk score from four study populations demonstrated that a calcium score >400 reclassified these subjects into a higher risk category.101;102 Since this category requires a higher standard of preventive treatment, this observation has clinical implications. The main advantage of measurement of coronary calcium in subjects without documented coronary artery disease, lies in its ability to obviate further diagnostic testing when coronary calcium is absent, due to a high negative predictive value for future coronary events. However, so far, most studies addressing exercise testing and measurement of coronary calcium have studied symptomatic populations in whom coronary angiography was indicated. Only one study has evaluated the effect of adding measurement of coronary calcium to a positive exercise test in subjects without documented coronary artery disease and showed that this strategy may lead to a lower number of coronary angiographies.103

Is the risk measure a target for intervention? In the PREVEND Intervention Trial, urinary albumin excretion levels were lowered by fosinopril, but not statin treatment.104 In this trial, a trend towards a protective cardiovascular effect was shown for treatment with fosinopril. Since ACE-inhibitors or angiotensin receptor blockers not only lower urinary albumin excretion, but also blood pressure levels, a definite answer on the question whether lowering of urinary albumin excretion by itself reduces cardiovascular risk remains to be answered.104;105 Drugs that specifically target microalbuminuria may throw new light upon this issue. So far it has not been studied whether a subgroup of subjects with microalbuminuria at increased coronary risk, as defined by the presence of the frequently concomitant metabolic syndrome, may clinically profit from treatment with statin treatment. With regard to C-reactive protein, a large body of evidence has shown a lowering effect by statin treatment, while some studies focused on the effects of peroxisome proliferator-activated receptor gamma agonists.106-110 It is currently unclear whether C-reactive protein reduction improves outcomes over and above the improvement provided by reduction of LDL cholesterol levels, as was suggested by the results of a secondary prevention trial.106 So far, primary prevention trials have not demonstrated that lowering of C-reactive protein improves clinical outcome.107;108 Future studies

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evaluating the effects of C-reactive protein -inhibitors on clinical outcome will give new insight in this issue.111

With regard to measurements of coronary calcifications, a large randomised trial could not establish reductions of coronary calcifications by intensive statin treatment during a follow up time of 1 year, despite a favorable effect on LDL cholesterol levels.112 These results were in contrast to previous reports.113;114 Adequately powered trials with longer follow up times should be carried out to provide a definite answer to this question.

Aims of the thesis

The aims of this thesis are to study some of the unresolved issues on the pathway from coronary risk association to risk stratification. The contribution of C-reactive protein and urinary albumin excretion to angiographic evidence of coronary artery disease, as well as to clinical outcome and prediction of coronary events are studied. Furthermore, the measurement of coronary calcium by a novel imaging tool, electron beam computed tomography, in coronary risk stratification in subjects at increased coronary risk is evaluated. The main part of this thesis, chapters 2-6, is based on data of the Prevention of REnal and Vascular ENdstage Disease (PREVEND) study, a large population based cohort study in Groningen, the Netherlands. The initial purpose of the PREVEND study is to assess the value of urinary albumin excretion in relation to cardiovascular and renal risk in the general population. In 1997, 8,592 subjects were included, of whom the large majority (n=8,139) had no previous documented coronary artery disease. Collected data include medical history, urine- and blood laboratory measurements, an electrocardiogram and information on follow up events. In Chapter 2 the number of coronary events and invasive procedures in the PREVEND study during 5 years of follow up are given, reflecting last decade’s routine clinical practice and incidence of coronary events. Chapter 3 evaluates the association between C-reactive protein, in relation to other coronary risk measures, and angiographic characteristics of stable and unstable coronary artery disease. Chapter 4 shows the potential additive role of C-reactive protein and urinary albumin excretion in the prediction of coronary events in relation to the Framingham risk score. Chapter 5, a substudy of the PREVEND Intervention Trial, answers the question whether microalbuminuric subjects with the metabolic syndrome have a better outcome when treated with statins. Chapters 6 and 7 evaluate the role of non-invasive measurement of coronary calcifications in relation to exercise testing as initial diagnostic test in asymptomatic subjects at increased coronary risk and in low risk subjects with suspected coronary artery disease. Finally, chapter 8 will describe the summary, implications and future perspectives.

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39. Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation. 1995;92:2157-2162.

40. Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D, Nakamura Y, Yamashita H, Yamagishi H, Takeuchi K, Naruko T, Haze K, Becker AE, Yoshikawa J, Ueda M. Spotty Calcification Typifies the Culprit Plaque in Patients With Acute Myocardial Infarction. An Intravascular Ultrasound Study. Circulation. 2004.

41. Baumgart D, Schmermund A, Goerge G, Haude M, Ge J, Adamzik M, Sehnert C, Altmaier K, Groenemeyer D, Seibel R, Erbel R. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol. 1997;30:57-64.

42. Budoff MJ, Diamond GA, Raggi P, Arad Y, Guerci AD, Callister TQ, Berman D. Continuous probabilistic prediction of angiographically significant coronary artery disease using electron beam tomography. Circulation. 2002;105:1791-1796.

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44. Georgiou D, Budoff MJ, Kaufer E, Kennedy JM, Lu B, Brundage BH. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol. 2001;38:105-110.

45. Wong ND, Budoff MJ, Pio J, Detrano RC. Coronary calcium and cardiovascular event risk: evaluation by age- and sex-specific quartiles. Am Heart J. 2002;143:456-459.

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49. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

50. Hillege HL, Fidler V, Diercks GF, Van Gilst WH, De Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, De Jong PE. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777-1782.

51. Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjaer H. Microalbuminuria and all-cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-up study. The Nord-Trondelag Health Study (HUNT), Norway. Am J Kidney Dis. 2003;42:466-473.

52. Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, Wareham NJ. A prospective study of microalbuminuria and incident coronary heart disease and its prognostic significance in a British population: the EPIC-Norfolk study. Am J Epidemiol. 2004;159:284-293.


54. Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB, Sr., Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380-385.

55. Wilson PW, Nam BH, Pencina M, D’Agostino RB, Sr., Benjamin EJ, O’Donnell CJ. C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study. Arch Intern Med. 2005;165:2473-2478.

56. Roivainen M, Viik-Kajander M, Palosuo T, Toivanen P, Leinonen M, Saikku P, Tenkanen L, Manninen V, Hovi T, Manttari M. Infections, inflammation, and the risk of coronary heart disease. Circulation. 2000;101:252-257.

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57. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813-1818.

58. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843.

59. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.

60. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation. 2004;109:1349-1353.

61. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.

62. van der Meer I, de Maat MP, Kiliaan AJ, van der Kuip DA, Hofman A, Witteman JC. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study. Arch Intern Med. 2003;163:1323-1328.

63. Miller M, Zhan M, Havas S. High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors: the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2005;165:2063-2068.

64. Vliegenthart R, Oudkerk M, Song B, van der Kuip DA, Hofman A, Witteman JC. Coronary calcification detected by electron-beam computed tomography and myocardial infarction. The Rotterdam Coronary Calcification Study. Eur Heart J. 2002;23:1596-1603.


66. O’Malley PG, Taylor AJ, Jackson JL, Doherty TM, Detrano RC. Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations. Am J Cardiol. 2000;85:945-948.

67. Pletcher MJ, Tice JA, Pignone M, Browner WS. Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. Arch Intern Med. 2004;164:1285-1292.

68. Diercks GF, van Boven AJ, Hillege JL, De Jong PE, Rouleau JL, Van Gilst WH. The importance of microalbuminuria as a cardiovascular risk indicator: A review. Can J Cardiol. 2002;18:525-535.

69. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003;107:391-397.

70. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, Sharrett AR. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837-842.


72. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144:537-547.

73. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237-242.

74. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-266.

75. Mogensen CE, Vestbo E, Poulsen PL, Christiansen C, Damsgaard EM, Eiskjaer H, Froland A, Hansen KW, Nielsen S, Pedersen MM. Microalbuminuria and potential confounders. A review and some

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observations on variability of urinary albumin excretion. Diabetes Care. 1995;18:572-581. 76. Gansevoort RT, Verhave JC, Hillege HL, Burgerhof JG, Bakker SJ, de ZD, De Jong PE. The validity of

screening based on spot morning urine samples to detect subjects with microalbuminuria in the general population. Kidney Int Suppl. 2005;S28-S35.

77. Ledue TB, Rifai N. Preanalytic and analytic sources of variations in C-reactive protein measurement: implications for cardiovascular disease risk assessment. Clin Chem. 2003;49:1258-1271.

78. Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E. Variability and classification accuracy of serial high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem. 2001;47:444-450.

79. Becker CR, Kleffel T, Crispin A, Knez A, Young J, Schoepf UJ, Haberl R, Reiser MF. Coronary artery calcium measurement: agreement of multirow detector and electron beam CT. AJR Am J Roentgenol. 2001;176:1295-1298.

80. Detrano RC, Anderson M, Nelson J, Wong ND, Carr JJ, Nitt-Gray M, Bild DE. Coronary calcium measurements: effect of CT scanner type and calcium measure on rescan reproducibility--MESA study. Radiology. 2005;236:477-484.

81. Daniell AL, Wong ND, Friedman JD, Ben-Yosef N, Miranda-Peats R, Hayes SW, Kang X, Sciammarella MG, de YL, Germano G, Berman DS. Concordance of coronary artery calcium estimates between MDCT and electron beam tomography. AJR Am J Roentgenol. 2005;185:1542-1545.

82. Weintraub WS. Coronary artery calcium and cardiac events: is electron-beam tomography ready for prime time? Circulation. 2003;107:2528-2530.

83. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Cats VM, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2003;10:S1-S10.

84. Brindle P, Emberson J, Lampe F, Walker M, Whincup P, Fahey T, Ebrahim S. Predictive accuracy of the Framingham coronary risk score in British men: prospective cohort study. BMJ. 2003;327:1267.

85. D’Agostino RB, Sr., Grundy S, Sullivan LM, Wilson P. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286:180-187.

86. Empana JP, Ducimetiere P, Arveiler D, Ferrieres J, Evans A, Ruidavets JB, Haas B, Yarnell J, Bingham A, Amouyel P, Dallongeville J. Are the Framingham and PROCAM coronary heart disease risk functions applicable to different European populations? The PRIME Study. Eur Heart J. 2003;24:1903-1911.

87. Haq IU, Ramsay LE, Yeo WW, Jackson PR, Wallis EJ. Is the Framingham risk function valid for northern European populations? A comparison of methods for estimating absolute coronary risk in high risk men. Heart. 1999;81:40-46.

88. Menotti A, Puddu PE, Lanti M. Comparison of the Framingham risk function-based coronary chart with risk function from an Italian population study. Eur Heart J. 2000;21:365-370.

89. Orford JL, Sesso HD, Stedman M, Gagnon D, Vokonas P, Gaziano JM. A comparison of the Framingham and European Society of Cardiology coronary heart disease risk prediction models in the normative aging study. Am Heart J. 2002;144:95-100.

90. Neuhauser HK, Ellert U, Kurth BM. A comparison of Framingham and SCORE-based cardiovascular risk estimates in participants of the German National Health Interview and Examination Survey 1998. Eur J Cardiovasc Prev Rehabil. 2005;12:442-450.

91. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 2006;145:21-29.

92. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611-619.

93. Detrano RC, Wong ND, Doherty TM, Shavelle RM, Tang W, Ginzton LE, Budoff MJ, Narahara KA. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation. 1999;99:2633-2638.

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94. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210-215.

95. McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation. 2006;113:30-37.

96. Greenland P, Gaziano JM. Clinical practice. Selecting asymptomatic patients for coronary computed tomography or electrocardiographic exercise testing. N Engl J Med. 2003;349:465-473.

97. O’Rourke RA, Brundage BH, Froelicher VF, Greenland P, Grundy SM, Hachamovitch R, Pohost GM, Shaw LJ, Weintraub WS, Winters WL, Jr., Forrester JS, Douglas PS, Faxon DP, Fisher JD, Gregoratos G, Hochman JS, Hutter AM, Jr., Kaul S, Wolk MJ. American College of Cardiology/American Heart Association Expert Consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease. Circulation. 2000;102:126-140.


99. Burgers JS, Simoons ML, Hoes AW, Stehouwer CD, Stalman WA. [Guideline ‘Cardiovascular Risk Management’]. Ned Tijdschr Geneeskd. 2007;151:1068-1074.

100. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr., Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr., Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.


102. Greenland P, Bonow RO, Brundage BH, Budoff MJ, Eisenberg MJ, Grundy SM, Lauer MS, Post WS, Raggi P, Redberg RF, Rodgers GP, Shaw LJ, Taylor AJ, Weintraub WS, Harrington RA, Abrams J, Anderson JL, Bates ER, Grines CL, Hlatky MA, Lichtenberg RC, Lindner JR, Pohost GM, Schofield RS, Shubrooks SJ, Jr., Stein JH, Tracy CM, Vogel RA, Wesley DJ. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). Circulation. 2007;115:402-426.

103. Lamont DH, Budoff MJ, Shavelle DM, Shavelle R, Brundage BH, Hagar JM. Coronary calcium scanning adds incremental value to patients with positive stress tests. Am Heart J. 2002;143:861-867.

104. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, De Zeeuw D, De Jong PE, van Veldhuisen DJ, Van Gilst WH. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004;110:2809-2816.

105. Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wan Y. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension. 2005;45:198-202.

106. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28.

107. Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292-2297.

108. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM, Jr. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary

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111. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature. 2006;440:1217-1221.

112. Schmermund A, Achenbach S, Budde T, Buziashvili Y, Forster A, Friedrich G, Henein M, Kerkhoff G, Knollmann F, Kukharchuk V, Lahiri A, Leischik R, Moshage W, Schartl M, Siffert W, Steinhagen-Thiessen E, Sinitsyn V, Vogt A, Wiedeking B, Erbel R. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial. Circulation. 2006;113:427-437.

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Chapter 2

Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study

C.A. Geluk, R.A. Tio, J.G.P. Tijssen, R.B. van Dijk, W.A. Dijk, H.L. Hillege, P.E. de Jong, W.H. van Gilst, F. Zijlstra.

Nederlands Heart Journal. 2007;14(4):133-141

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Abstract

BackgroundThe use of invasive procedures has mostly been studied in retrospective (multi)national registries. Limited evidence exists on the association between microalbuminuria and coronary artery disease (CAD).

Methods and resultsThe incidence of major adverse cardiac events (MACE) and invasive cardiac procedures was registered between 1997-2003 in 8,139 subjects, without prior documented CAD, in the PREVEND cohort study (the Netherlands), which focus is on microalbuminuria and cardiovascular risk. Qualitative coronary angiographic analysis was performed. During 5.5 years of follow up, a first MACE occurred in 271 (3.3%), and a first coronary angiography (CAG) was performed in 264 (3.2%) subjects. Of these, 216 CAGs were available for qualitative angiographic analysis. Indications for CAG were stable angina in 129, acute coronary syndrome (ACS) in 55 and ST-elevation myocardial infarction (STEMI) in 32 subjects. Obstructive coronary artery disease was present in respectively 61, 53 and 30 subjects. A revascularization was performed in, respectively, 50 (39%), 50 (91%) and 25 (78%) subjects. Microalbuminuria was associated with a first MACE, after adjustment for established risk factors. Microalbuminuria was present at baseline in 9% of subjects with normal coronary arteries, in 21% of subjects with 1- and 2-vessel CAD and in 39% of subjects with 3-vessel or left main CAD at CAG during follow up (Ptrend=0.005).

ConclusionsThis large cohort study shows that two-thirds of diagnostic CAGs for stable angina were not followed by a revascularization, in contrast to CAGs for STEMI or ACS. Furthermore, this study shows that microalbuminuria is associated with CAD.

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Cardiac events and coronary angiographic findings in PREVEND

Chap

ter 2

Introduction

Most of our knowledge related to the incidence and consequences of invasive procedures in patients with suspected coronary artery disease (CAD) is derived from large (multi)national registries or randomized controlled trials, which are based on a retrospective design and selection of participating hospitals or patient groups. These registries have shown that the increase in numbers of percutaneous coronary interventions (PCI) has been almost two times the increase in the number of coronary angiographies (CAG).1 In spite of this increase, an underuse of coronary revascularizations has been reported in appropriate candidates for a revascularization procedure.1-3 Furthermore, it was shown that up to 50% or more of CAGs is not followed by a revascularization procedure.1,4 A prospective cohort analysis may provide additional information, since it allows insight in baseline clinical variables and the assessment of events and procedures in patients with suspected CAD, reflecting routine clinical practice. We therefore performed an additional analysis of the prospective Prevention of REnal and Vascular ENdstage Disease (PREVEND) cohort study, which focus is on microalbuminuria and cardiovascular risk in the general population, to assess the number of invasive procedures following major adverse cardiac events (MACE). Our second purpose was to assess the indications for CAGs and the incidence of subsequent revascularization procedures in subjects with suspected CAD. Thirdly, we assessed the association between microalbuminuria and CAD.

Methods

Study population The principle purpose of the Prevention of REnal and Vascular ENdstage Disease (PREVEND) study is to assess the value of microalbuminuria in relation to cardiovascular and renal risk in the general population. During the period 1997–1998, all inhabitants of the city of Groningen, The Netherlands aged between 28 and 75 years were asked to answer a short questionnaire and to send in a morning urine sample. Insulin treatment and pregnancy were exclusion criteria. Altogether 40,856 subjects responded. All subjects with a morning urinary albumin concentration of at least 10 mg/L (n=7,768) and a random sample of subjects with a morning urinary albumin concentration less than 10 mg/L were invited to an outpatient clinic. The screening program was completed by 8,592 subjects, including 6,000 subjects with and 2,592 subjects without an elevated morning urinary albumin concentration. Collected baseline data at the outpatient clinic included medical history, demographics, biometric data, urine- and blood collections and laboratory measurements. For the current analysis, only subjects without prior documented CAD were included. Prior documented CAD was defined as history of myocardial infarction, revascularization procedure or obstructive coronary artery disease prior to inclusion in the PREVEND

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Chapter 2

study. A history of myocardial infarction was based on a subjects’ medical history, including structured questionnaire, and the information on previous CAD was complemented by review of the medical report. In tables baseline demographics and laboratory parameters from the baseline visit of the PREVEND cohort are given. For details on the PREVEND study design we refer to earlier publications.5 The PREVEND study was approved by the medical ethics committee and conducted in accordance with the guidelines of the declaration of Helsinki. All subjects gave written informed consent.

Definition of end points and follow up Cardiac events and revascularization procedures during follow up were counted in PREVEND subjects without prior documented CAD at baseline. The end point of this study was defined as cardiovascular death (ICD-10 I01-99), cardiac events (ICD-9 410, 411), PCI and coronary artery bypass graft surgery (CABG). The vital status of all subjects was evaluated through the municipal register until December 31st 2003. Causes of death were obtained from the Central Bureau of Statistics according to ICD-10 codes (I01-I99 for cardiovascular disorders). Information related to cardiac events and revascularization procedures were obtained from the national hospital information system (Prismant, Utrecht, the Netherlands). Cardiac events were reviewed by a clinical event committee and divided into ST-elevation myocardial infarctions (STEMI) or non-ST-elevation acute coronary syndromes (ACS). ST-elevation myocardial infarction was defined as chest pain and ST-elevation over 1 mm in at least 2 contiguous leads.6 To evaluate therapeutic consequences after STEMI, subjects with STEMI were divided into those presenting within or over 24 hours after the onset of chest pain. Non-ST-elevation acute coronary syndrome was defined as chest pain with positive cardiac markers (troponin or creatinin kinase) and/or dynamic ST-segment changes.7 Major adverse cardiac event was defined as cardiovascular death, STEMI, ACS or revascularization procedure.

Assessment of coronary angiographyThe incidence of coronary angiographies was obtained from the Catheterisation Laboratory registries of the two hospitals in the Groningen region, namely the University Medical Center Groningen (UMCG) and the Martini Hospital Groningen (MHG) and was completed with information on CAG obtained from the national hospital information system (Prismant, Utrecht, the Netherlands). In case a PCI was performed during the same session as the CAG, PCI and CAG were counted as separate procedures. All CAGs performed in the UMCG or MHG were requested in order to perform qualitative angiographic analysis and to evaluate the therapeutic consequences as decided by the UMCG Thoraxcenter multidisciplinary team. For all subjects in whom CAG is performed in the UMCG or MHG, the UMCG Thoraxcenter multidisciplinary team takes decisions to perform revascularization procedures or to continue conservative treatment. The team has extensive experience with the RAND-UCLA criteria8,9 and takes decisions in accordance with the European Society of Cardiology guidelines.10 Indications for CAG were divided into STEMI presenting

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within or over 24 hours after the onset of chest pain, ACS or stable angina. Stable angina was defined as angina or angina-like symptoms. Indications for CAG and peri- and post-procedural events were reviewed by a senior cardiologist.

Qualitative angiographic analysisWe performed qualitative angiographic analysis of all available first CAGs for all indications (STEMI, ACS or stable angina). Qualitative coronary angiographic analysis was performed by a senior cardiologist (RT), who had no knowledge of the clinical indications for CAG or of the subjects’ clinical status. Analysis of CAGs included the identification of obstructive lesions (at least 50% stenosis) or minor lesions (less than 50% stenosis) in the left main stem, left anterior descending artery, left circumflex artery and/or right coronary artery. In case an obstructive lesion was found in a coronary vessel, additional minor lesions present in this vessel were not recorded. In case of absence of any lesion, the coronary arteries were graded as normal. An interobserver agreement of 95% was found in a random sample of 44 coronary angiographies (20%) which were analysed by a senior cardiologist (FZ) unaware of the prior analyses.

Data handling and definitionsRisk factors were defined as follows or as given in tables. Hypertension was defined as blood pressure equal to or above 140/90 mm Hg or use of antihypertensive medication. Hypercholesterolemia was defined as total cholesterol above 6.5 mmol/L or use of lipidlowering treatment. Abdominal obesity was defined a waist circumference equal to or above 102 cm in men and equal to or above 88 cm in women.11 Low HDL cholesterol was defined as HDL-cholesterol below 1.04 mmol/L in men and below 1.30 mmol/L in women.11 Diabetes was defined as fasting plasma glucose levels above 6.9 mmol/L, or non-fasting plasma glucose levels above 11.0 mmol/L or the use of oral anti-diabetic drugs.12 High age was defined as age >60 years. High hs-C-reactive protein (CRP) was defined as hs-CRP>3.0 mg/L.13

Analytical methodsSystolic and diastolic blood pressure measurements were calculated as the mean of the last two out of ten consecutive measurements with an automatic Dinamap XL model 9300 series device (Johnson-Johnson Medical INC, Tampa, Florida). Serum total cholesterol were determined by Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, New York, U.S.A.). HDL-cholesterol was determined by MEGA (Merck, Darmstadt, Germany). The urinary albumin excretion was measured as the mean of two 24h-urine collections. Urinary albumin concentrations were determined by nephelometry with a threshold of 2.3 mg l-1 and intra- and inter-assay coefficients of variation of less than 2.2% and 2.6%, respectively (Dade Behring Diagnostic, Marburg, Germany). High sensitive CRP was measured by nephelometry with a threshold of 0.18 mg/L and intra-and interassay coefficients of variation of <4.4 and <5.7% respectively (BNII, Dade Behring Diagnostic, Marburg, Germany).

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Statistical analysisContinuous data are given as means (standard deviation). In case of a skewed distribution the median (interquartile range) was used. Differences between groups were evaluated by Chi-square tests, when appropriate. P-values were two-sided and needed to be <0.05 to be significant. Probability weighted Cox’ proportional hazard analyses were performed to adjust for the survey weights based on non-random inclusion of subjects with and without elevated morning urinary albumin concentration levels at the PREVEND cohort study entry. Models were fitted to evaluate the univariate impact of microalbuminuria, and after adjustment for age and sex, and after adjustment for established risk measures, namely smoking status, diabetes, obesity, hypertension, hypercholesterolemia, low HDL-cholesterol and high hs-CRP. Event-free survival time for subjects was defined as the period from the date of the outpatient clinic baseline assessment to the date of first MACE or CAG, or death from any cause until 31 December 2003, or 31 December 2002 until which date information regarding specific causes of death follow up information was available. If a person had moved away from the city of Groningen or to an unknown destination, or died due to a non-cardiovascular cause, the person was censored on the last available contact date or date of death. All calculations were performed with SPSS version 11.0 software (SPSS, Chicago, IL, USA).

Results

Baseline characteristicsOf the initial 8,592 subjects included, 8,139 had no prior documented CAD (94.7%), and were included in the current analysis. The population consisted of middle-aged subjects and included an equal number of males and females. More than one third were current smokers and only a small number had diabetes (table 1).

Incidence of MACEDuring a mean of 5.5 years of follow up, 271 subjects (3.3%) experienced a first MACE. During follow up, 747 subjects (9%) left the area and 186 subjects (2%) died from a non-cardiovascular cause and were therefore censored. Incidence of all and first MACEs, respectively, are shown in table 2. Kaplan Meier survival curves for subjects who remained free from cardiovascular death, STEMI, ACS or revascularization procedures show a gradual decrease in event free survival (figure 1).

Number of invasive procedures following a first MACEThe number of invasive procedures and therapeutic consequences after a first MACE is shown in figure 2a (flowchart). Of the 50 patients presenting with STEMI as a first cardiac event, 37 subjects presented within 24 hours after onset of symptoms. Twenty-two of these subjects (59%) received thrombolytic therapy. In 2 subjects (5%) contraindications for thrombolytic therapy were present, but primary PCI was

33


Chap

ter 2

Table 1. Baseline characteristics of 8,139 PREVEND participants without prior documented CAD.

Characteristics n=8,139

Age, mean (SD), y 49 (12)

Male gender, No. (%) 3,979 (49)

Body mass index, mean (SD) kg/m2 26 (4)

Blood pressure, mean (SD), mm Hg

Systolic 129 (20)

Diastolic 74 (10)

Smoking status, No. (%)

Current 2,786 (34)

Past 2,880 (35)

Diabetes, No. (%) 270 (3)

Cholesterol, mean (SD), mmol/L

Total 5.6 (1.1)

HDL 1.33 (0.40)

Albuminuria, median (interquartile range), mg/24h 9.17 (6.24-16.88)

hs-CRP, median (interquartile range), mg/L 1.24 (0.54-2.87)

Medication, No. (%)

Lipidlowering 875 (5)

Antihypertensive 389 (11)

Abbreviations: CAD, coronary artery disease; hs-CRP, high sensitivity- C-reactive protein; HDL, high density lipoprotein.SI conversion factor: to convert mg/dL tot mmol/L, divide values for total cholesterol and HDL cholesterol by 0.0259.

Table 2. Incidence of MACE in 8,139 PREVEND participants without prior documented CAD (1997-2003).

Abbreviations: MACE, major adverse cardiac event; CAD, coronary artery disease. Major adverse cardiac event is defined as a composite end point comprising, respectively, any (†) and the first of any (‡) of these events: revascularization procedure, non-ST-elevation acute coronary syndrome, ST-elevation myocardial infarction, or cardiovascular death.

Outcome All Events, No. (%) First Events, No. (%)

Major adverse cardiac event 419† (5.1) 271‡ (3.3)

Revascularization procedure 181 (2.2) 70 (0.9)

Percutaneous coronary intervention 115 (1.4) 40 (0.5)

Coronary artery bypass surgery 66 (0.8) 30 (0.5)

Non-ST-elevation acute coronary syndrome 133 (1.6) 118 (1.4)ST-elevation myocardial infarction, time delay after onset of chest pain 51 (0.6) 50 (0.6)

‹ 24 hours 38 (0.5) 37 (0.5)

› 24 hours 13 (0.2) 13 (0.2)

Cardiovascular mortality 54 (0.7) 33 (0.4)

34

Chapter 2

Figure 1.

Follow up time (months)

0 2 0 4 0 6 0

Surv

ival

80

0,00

0,10

0,95

0,96

0,97

0,98

0,99

1,00

upper curve: without cardiovascular deathsecond curve: without the above + ST-elevation myocardial infarctionthird curve: without all of the above + non-ST-elevation acute coronary syndromelowest curve: without all of the above + revascularization procedure

Figure 1. Kaplan Meier survival curves of 8,139 PREVEND subjects without prior documented CAD who remained free from cardiovascular death, ST-elevation myocardial infarction, non-ST-elevation acute coronary syndrome, or revascularization procedure.

Figure 2.

(a)

(b)

40 PCI

30 CABG

33 cardiovascular death

13 STEMI (› 24h)

37 STEMI (‹ 24h)

118 ACS

‹ 24h24h:

: 13 primary PCI (22 thrombolytic therapy)

› ‹3 months: 13 C A Gs (11 revascularizations)

› 3 months: 2 C A G s (1 revascularization)

8,592 8,139

Without

Prior CAD

264

First

CAG

18 STEMI (‹ 24h)

21 STEMI (‹ 24h)

73 ACS

152 stable angina

18

No. of CAGs Available

for Analysis:

No. of Subsequent

revascularizations:

Indications for CAG:

gfshsh

129

55

14

18

7

50

50

‹ 3 months: 4 C A G s (2 revascularizations)

› 3 months: 7 C A G s (5 revascularizations)

‹ 3 months: 57 CA G s (54 revascularizations)

› 3 months: 19 CA G s (13 revascularizations)

N o. of Invasive Procedures F ollowing F irst MACE:

271

First

MACE

8,139

Without

Prior CAD

No . of First MACE:

8,592

PREVEND

Participants

PREVEND

Participants

A

B

Figure 2. Flow chart for the incidence of first major adverse cardiac events and subsequent invasive procedures (A) and for the incidence and indications of first coronary angiographies and subsequent revascularization procedures (B).

Abbreviations: CAD, coronary artery disease; MACE, major adverse cardiac event; STEMI, ST-elevation myocardial infarction; ACS, non-ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; CAG, coronary angiography.

35


Chap

ter 2

not performed. In 13 subjects (35%) primary PCI was performed. Of the 118 subjects with ACS, in 57 subjects (48%) CAG was performed within 3 months, which was followed by a revascularization procedure in 54 subjects (46%). In a later stadium, more invasive procedures were performed in an additional number of subjects. This resulted in a total of 76 CAGs (64%) and 67 revascularization procedures (57%), including 45PCIs (38%) and 32 CABGs (27%), during the entire follow up period.

Incidence of coronary angiographiesTwo-hundred-and-sixty-four subjects (3.2%) underwent a first CAG after inclusion in the PREVEND study (incidence 0.6% per year). In 48 subjects (18.2%) this was followed by a second CAG (incidence 0.1% per year). The incidence of CAGs was stable during follow up (data not shown). Indications for 264 first CAGs were STEMI in 39 subjects (15%), following an ACS in 73 subjects (28%) and stable angina in 152 subjects (58%), respectively, as shown in figure 2b (flowchart).

Coronary angiographic findings and subsequent revascularization procedures Of 264 first CAGs, 240 CAGs were performed in the UMCG or MHG and 216 of these were available for angiographic analysis (90%). The angiographic findings and revascularization procedures following these 216 first CAGs according to indications are given in table 3.Of 129 subjects with a first CAG for stable angina, 61 subjects had obstructive CAD, while in 68 subjects normal coronary arteries or nonobstructive coronary artery disease was present. Of 61 subjects with obstructive CAD, in 50 subjects a revascularization procedure was performed, while in 11 subjects conservative treatment was continued (due to a coronary anatomy not suitable for intervention in 9 subjects, and angina being secondary to other causes in 2 subjects). Of 68 subjects without obstructive CAD, reasons for CAG were in 13 subjects the evaluation of aortic valve disease, atrial septum defect or electrophysiology. All subjects had angina or angina-like symptoms. In 26 subjects a CAG was performed because of stable angina, without evidence of

Table 3. Indications and findings of first CAG in 216 PREVEND participants without prior documented CAD in whom CAG was available for analysis.

n

Normal coronary arteries

n(%)

Nonobstructive CAD

n(%)

1-vessel CAD

n(%)

2-vessel CAD

n(%)

3-vessel CAD or LM lesion

n(%)

STEMI (<24 h) 18 0 (0) 0 (0) 11 (61) 5 (28) 2 (11)

STEMI (>24 h) 14 1 (8) 1 (8) 6 (46) 6 (39) 0 (0)

ACS 55 0 (0) 2 (4) 24 (44) 16 (29) 13 (24)

Stable Angina* 129 34 (26) 34 (26) 21 (16) 23 (18) 17 (13)

Abbreviations: ACS, non-ST-elevation acute coronary syndrome; CAD, coronary artery disease; CAG, coronary angiography; STEMI, ST-elevation myocardial infarction. * Stable angina is defined as angina or angina-like symptoms.

36

Chapter 2

ischemia based on electrocardiographic exercise testing or myocardial perfusion imaging, in order to eliminate diagnostic uncertainty. In 15 subjects an abnormal electrocardiographic exercise test result, and in 14 subjects a reversible myocardial perfusion defect were the reasons to perform CAG.All subjects who underwent acute CAG for STEMI <24 hours had obstructive CAD and were treated with primary PCI. In 14 subjects in whom a CAG was performed for STEMI >24 hours, in 12 subjects obstructive CAD was found, followed by a revascularization procedure in 7 and conservative treatment in 5 subjects. In 53 out of 55 subjects with a first CAG following an ACS obstructive CAD was found. In 50 out of these 55 subjects (91%) a subsequent revascularization procedure was performed. In 3 subjects with obstructive CAD a revascularization procedure was not indicated and conservative treatment was continued.

The association between microalbuminuria and CADThe association between microalbuminuria and the occurrence of a first MACE during follow up is shown in table 4. In univariate analysis and after adjustment for established coronary risk factors, microalbuminuria was associated with a first MACE.

Table 4. Risk of a first MACE in 8,139 PREVEND participants without prior documented CAD according to the presence of microalbuminuria * .

Model 1 Model 2 Model 3

HR (95% CI) HR (95% CI) HR (95% CI)

Microalbuminuria 3.03 (2.68-3.43) 1.83 (1.60-2.08) 1.24 (1.06-1.45)

Abbreviations: CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiac event*Microalbuminuria is defined as urinary albumin excretion levels › 30 mg/24h. Model 1 includes microalbuminuria. Model 2 includes microalbuminuria, age and sex. Model 3 includes microalbuminuria, age, sex, smoking, obesity, hypertension, diabetes, hypercholesterolemia, low HDL cholesterol, and elevated hs-CRP levels. For definitions please see methods section.

Table 5. Severity of CAD at CAG according to the presence of microalbuminuria at baseline of the PREVEND cohort study*.

Normal coronary arteries

n=32

Nonobstructive, 1- or 2-vessel CAD

n=143

3-vessel or left main CAD

n=31Ptrend

Normoalbuminuria, n (%) 29 (91) 113 (79) 19 (61)0.005

Microalbuminuria, n (%) 3 (9) 30 (21) 12 (39)

*in 206 subjects in whom CAG and urinary albumin excretion levels were availableMicroalbuminuria was defined as urinary albumin excretion › 30 mg/24hAbbreviations: CAD, coronary artery disease; CAG, coronary angiography

37


Chap

ter 2

As shown in table 5, microalbuminuria was present at baseline in 9% of subjects with normal coronary arteries, in 21% of subjects with 1- and 2-vessel CAD and in 39% of subjects with 3-vessel or left main CAD at CAG during follow up (Ptrend=0.005).

Discussion

This is the first report to describe the clinical and angiographic characteristics of subjects without a history of CAD undergoing a first CAG after inclusion in a prospective population based cohort study. We performed the current analysis since most of the insight in the incidence of CAGs and revascularization procedures result from registries with a retrospective design. This type of study uses a selection of hospitals and subject groups. A prospective cohort analysis has major advantages, since it allows insight in baseline clinical variables and the assessment of events and procedures in subjects with suspected CAD, reflecting routine clinical practice.

Invasive procedures after a first MACEThe low number of primary PCIs in subjects with STEMI, namely in one-third only, reflects the clinical practice between 1997-2003, since in this time period thrombolytic therapy was still accepted as first-line treatment in these subjects. This number will have increased from then, since primary PCI has been accepted as a first line treatment in subjects presenting with STEMI.14 The number of CAGs in subjects with ACS (48% within 3 months, 64% during total follow up) was in line with the European Heart Survey (52%). The numbers of PCIs and CABGs (27% and 38%) in PREVEND were higher than the rates in European and American Surveys (25-33% and 5-12%, respectively), probably due to a longer follow up time.15-17 The number of revascularizations was comparable to the ICTUS trial. In ICTUS, high risk ACS subjects were randomized to an early invasive or conservative strategy under modern antiplatelet therapy.18 Early CAG was followed by a revascularization procedure in 79%, versus 54% of the “conservative” patients. These data confirm the need for a revascularization procedure in many subjects with ACS in the days or weeks following the acute presentation.

Coronary angiographic findings and subsequent revascularization proceduresCoronary angiographies in subjects with STEMI or ACS were mostly followed by a revascularization procedure. This was not the case for CAGs in subjects with stable angina, which was defined as angina or angina-like symptoms and the indication for most first CAGs. The high number (61%) of these CAGs not followed by a revascularization procedure is in line with a large European registry.1 This high number is worrisome, since CAG is associated with considerable costs, and a small, but significant risk of major complications. There are two potential explanations for this phenomenon. First, it has been reported that some subjects with an indication for a revascularization

38

Chapter 2

procedure, receive conservative treatment. This issue has been evaluated by several studies,2,8,9,19 in one of which the UMCG Thoraxcenter has also participated.8,9 The relevance of this issue has been highlighted by the observation that in appropriate candidates for a revascularization procedure, an underuse of revascularization procedures was associated with a worse clinical outcome.2,20 In PREVEND, a decision to perform a revascularization procedure was taken by the UMCG Thoraxcenter multidiciplinary team for 90% of subjects with obstructive CAD. In the other subjects performance of a revascularization procedure was discussed, but conservative treatment was continued, due to presence of contraindications for a revascularization procedure. Second, current clinical guidelines advise the performance of non-invasive tests for the detection of myocardial ischemia prior to CAG.4;21 Although we have not included the results of non-invasive tests in the current analysis, the high number of CAGs for stable angina in the absence of any coronary lesion, which is in line with previous reports,22 raises the suspicion that currently available non-invasive tests have a limited ability to differentiate between subjects at high versus low coronary risk. Perhaps that new imaging modalities that provide anatomical information on CAD, such as electron beam computed tomography or multislice detector computed tomography, may improve risk stratification prior to CAG. Future studies are needed to evaluate the implications of such a strategy on the incidence on CAG.

Impact of microalbuminuria on CADMicroalbuminuria has been found to be present in 3-15% of the general po pulation 23-25 and has been associated with increased coronary risk.23,24,26,27 The pathophysiologic link between microalbuminuria and increased coronary risk still needs to be elucidated. Microalbuminuria may imply a vulnerability for atherosclerosis due to its association with inflammatory and prothrombotic changes involved in endothelial dysfunction.28-

35 There is conflicting evidence that microalbuminuria reflects a systemic transvascular leakage of albumin, which may be associated with leakage of lipoproteins and other macromolecules.36-38 Finally, microalbuminuria has been regarded as marker of generalized atherosclerosis, but this hypothesis has been denied previously.39 In our study, an association between microalbuminuria and MACE was demonstrated, which confirms earlier evidence on the impact of microalbuminuria on cardiovascular risk. Furthermore, in line with an earlier angiographic study,40 microalbuminuria was most frequently present in subjects who had severe CAD at CAG during follow up. Whether microalbuminuria can be regarded as appropriate screening tool in asymptomatic populations is subject to future investigation.

Limitation The generalizability of our results may be somewhat limited since a part of our study population was selected for the presence of microalbuminuria. Our cohort may therefore represent a population with an increased cardiovascular risk profile when compared to a general population based cohort. We realize that the subjects

39


Chap

ter 2

of the PREVEND study were selected for a different reason than the observation of the incidence and therapeutic consequences of coronary angiographies. Therefore for example the number of diabetes subjects is not representative for a population undergoing CAG. Furthermore, our study was a single center study, and limited by a low number of coronary events. However, the advantage of a cohort study lies in its prospective design and its population based approach may better reflect routine clinical practice than multinational registries on the incidence of invasive procedures. Furthermore, the uniqueness of our study lies herein that we included only subjects without prior documented CAD.

Conclusions

This large cohort study shows that two-thirds of diagnostic CAGs for stable angina were not followed by a revascularization, in contrast to CAGs for STEMI or ACS. Furthermore, this study confirms the association between microalbuminuria and CAD.

40

Chapter 2

Reference list

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2. Hemingway H, Crook AM, Feder G, Banerjee S, Dawson JR, Magee P, et al. Underuse of coronary revascularization procedures in patients considered appropriate candidates for revascularization. N Engl J Med 2001;344:645-54.

3. Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, et al. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004;292:2096-104.

4. Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 1999;33:1756-824.

5. Smilde TD, Asselbergs FW, Hillege HL, Voors AA, Kors JA, Gansevoort RT, et al. Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy. Am J Hypertens 2005;18:342-7.

6. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24:28-66.

7. Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002;23:1809-40.

8. Rigter H, Meijler AP, McDonnell J, Scholma JK, Bernstein SJ. Indications for coronary revascularisation: a Dutch perspective. Heart 1997;77:211-8.

9. Meijler AP, Rigter H, Bernstein SJ, Scholma JK, McDonnell J, Breeman A, et al. The appropriateness of intention to treat decisions for invasive therapy in coronary artery disease in The Netherlands. Heart 1997;77:219-24.

10. Smith SC, Jr., Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, et al. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 2001;37:2215-39.

11. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

12. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.

13. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, III, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.

14. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, et al. Guidelines for percutaneous coronary interventions: the task force for percutaneous coronary interventions of the European society of cardiology. Eur Heart J 2005;26:804-47.

15. Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, et al. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004;292:2096-104.

16. Fox KA, Goodman SG, Anderson FA, Jr., Granger CB, Moscucci M, Flather MD, et al. From guidelines

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to clinical practice: the impact of hospital and geographical characteristics on temporal trends in the management of acute coronary syndromes. The Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1414-24.

17. Hasdai D, Behar S, Wallentin L, Danchin N, Gitt AK, Boersma E, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002;23:1190-201.

18. de Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095-104.

19. Shekelle PG, Kahan JP, Bernstein SJ, Leape LL, Kamberg CJ, Park RE. The reproducibility of a method to identify the overuse and underuse of medical procedures. N Engl J Med 1998;338:1888-95.

20. Filardo G, Maggioni AP, Mura G, Valagussa F, Valagussa L, Schweiger C, et al. The consequences of under-use of coronary revascularization; results of a cohort study in Northern Italy. Eur Heart J 2001;22:654-62.

21. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003;107:149-58.

22. Phibbs B, Fleming T, Ewy GA, Butman S, Ambrose J, Gorlin R, et al. Frequency of normal coronary arteriograms in three academic medical centers and one community hospital. Am J Cardiol 1988;62:472-4.

23. Hillege HL, Fidler V, Diercks GF, Van Gilst WH, De Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002;106:1777-82.

24. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol 1999;19:1992-7.

25. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med 1997;157:1413-8.

26. Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001;249:519-26.

27. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet 1988;2:530-3.

28. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989;32:219-26.

29. Barzilay JI, Peterson D, Cushman M, Heckbert SR, Cao JJ, Blaum C, et al. The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. Am J Kidney Dis 2004;44:25-34.

30. Stehouwer CD, Gall MA, Twisk JW, Knudsen E, Emeis JJ, Parving HH. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 2002;51:1157-65.

31. Stehouwer CD, Nauta JJ, Zeldenrust GC, Hackeng WH, Donker AJ, den Ottolander GJ. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992;340:319-23.

32. Festa A, D’Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int 2000;58:1703-10.

33. Clausen P, Jensen JS, Jensen G, Borch-Johnsen K, Feldt-Rasmussen B. Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects.

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Circulation 2001;103:1869-74. 34. Clausen P, Feldt-Rasmussen B, Jensen G, Jensen JS. Endothelial haemostatic factors are associated

with progression of urinary albumin excretion in clinically healthy subjects: a 4-year prospective study. Clin Sci (Lond) 1999;97:37-43.

35. McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001;86:713-8.

36. Furtner M, Kiechl S, Mair A, Seppi K, Weger S, Oberhollenzer F, et al. Urinary albumin excretion is independently associated with carotid and femoral artery atherosclerosis in the general population. Eur Heart J 2005;26:279-87.

37. Jensen JS. Renal and systemic transvascular albumin leakage in severe atherosclerosis. Arterioscler Thromb Vasc Biol 1995;15:1324-9.

38. Jensen JS, Feldt-Rasmussen B, Borch-Johnsen K, Jensen KS, Nordestgaard BG. Increased transvascular lipoprotein transport in diabetes: association with albuminuria and systolic hypertension. J Clin Endocrinol Metab 2005;90:4441-5.

39. Jager A, Kostense PJ, Ruhe HG, Heine RJ, Nijpels G, Dekker JM, et al. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Arterioscler Thromb Vasc Biol 1999;19:617-24.

40. Tuttle KR, Puhlman ME, Cooney SK, Short R. Urinary albumin and insulin as predictors of coronary artery disease: An angiographic study. Am J Kidney Dis 1999;34:918-25.

Chapter 3

C-reactive protein and angiographic characteristics of stable and unstable coronary artery disease – Data from the prospective PREVEND cohort

C.A. Geluk, W. J. Post, H.L. Hillege, R.A. Tio, J.G.P. Tijssen, R.B. van Dijk, W. A. Dijk, S.J.L. Bakker, P.E. de Jong, W.H. van Gilst, F. Zijlstra.

Atherosclerosis 2006 [Epub ahead of print]

46

Chapter 3

Abstract

BackgroundHigh sensitive-C-reactive protein (hs-CRP) is associated with coronary risk, which may be explained by an association with (unstable) coronary artery disease (CAD). Until now, histopathological and angiographic studies have failed to consistently demonstrate a strong relationship. However, most of these studies were limited by a cross-sectional design. Our aim was to prospectively evaluate the association between hs-CRP and plaque instability. Therefore, firstly, we investigated the relation between hs-CRP measured long before coronary angiography (CAG) and angiographic characteristics of stable and unstable CAD. In addition, we investigated the association with coronary events during follow up in the total PREVEND population.

Methods and resultsOf the population based Prevention of REnal and Vascular ENdstage Disease (PREVEND) study, 8,139 subjects without previous documented CAD were followed for the incidence of CAG and coronary events from 1997-2003. For the qualitative angiographic analysis, 216 CAGs were available. Mean time to CAG was 37±19 months. The 864 coronary vessels were graded as follows: 436 coronary vessels as normal, 175 as non-obstructive CAD, 179 as stable obstructive CAD and 74 as unstable obstructive CAD. Multilevel ordinal regression analysis was performed to study associations between baseline clinical variables and angiographic findings. Hs-CRP contributed significantly to the multivariate model after adjustment for age, gender, smoking, lipids and blood pressure. In 8,139 subjects, two-hundred-and-one (2.5%) first coronary events occurred during follow up. Cox survival analysis showed age- and sex- adjusted hazard ratios for hs-CRP 1-3 mg/L and >3 mg/L of, respectively, 1.26 (95% CI 0.67-2.40) and 3.16 (95% CI 1.26-3.16), relative to hs-CRP <1 mg/L.

ConclusionsIn the prospective PREVEND study of subjects without previous documented CAD, hs-CRP levels at baseline were associated with angiographic characteristics and clinical consequences of plaque instability during follow up. This observation supports the concept that hs-CRP significantly contributes to coronary atherogenesis.

47

C-Reactive protein and coronary artery disease

Chap

ter 3

Introduction

High sensitive-C-reactive protein (hs-CRP) has been shown to be an independent predictor of future coronary risk.1 Elevated levels of hs-CRP are present in many patients with an acute ischemic event,2 and have been associated with a poor prognosis.3 It has been suggested that elevated hs-CRP in these patients reflects the extent of plaque burden,4;5 or presence of multiple unstable coronary plaques, 2;4-6 associated with an adverse outcome.7 Conflicting evidence exists on the active biological role of hs-CRP in atherogenesis.8-10 Until now, angiographic, histopathological and other studies have failed to consistently demonstrate a strong relationship between hs-CRP levels and coronary plaque burden. Correlations with extent of stable coronary plaque burden were small4 or absent.5;11;12 Correlations with unstable plaques were weak and diminished after adjustment for other risk factors,4;8;12;13 or were only present in patients presenting with acute coronary syndromes,2;4;5;8;14 with the exception of one study.6 However, most of these studies have been based on a cross-sectional design. Hs-CRP and other variables were measured simultaneously with coronary angiography (CAG) for stable or unstable angina,2;4-6;12;14 or were derived from post-mortem serum evaluation.8 The hs-CRP levels may have been elevated due to the acute phase responses present in patients with ischemic symptoms, which limits any conclusion on an association of causality between hs-CRP and coronary plaque burden. Therefore, we aimed to investigate whether in subjects without clinical evidence of atherosclerosis, levels of hs-CRP and other clinical variables, measured at time of inclusion in a prospective population based cohort study, are associated with angiographic characteristics of stable and unstable coronary artery disease (CAD), as documented by a first CAG during 5.5 years of follow up. This aim was studied in PREVEND participants who underwent CAG during follow up. Additionally, in the total PREVEND population, we prospectively evaluated the association between hs-CRP and the occurrence of a first coronary event.

Methods

Study populationThe Prevention of REnal and Vascular ENdstage Disease (PREVEND) study is a population-based cohort study in Groningen, the Netherlands, which primary aim is to assess the value of urinary albumin excretion in relation to cardiovascular and renal risk. During the period 1997–1998, all inhabitants of the city of Groningen, The Netherlands aged between 28 and 75 years were asked to answer a short questionnaire and to send in a morning urine sample. Insulin treatment and pregnancy were exclusion criteria. Altogether 40,856 subjects responded. All subjects with a urinary albumin excretion (UAE) of at least 10 mg/L (n=7,768) and a random sample of subjects with UAE less than 10 mg/L were invited to an outpatient clinic. The screening program was completed by 8,592 subjects. Collected baseline data at the

48

Chapter 3

outpatient clinic included medical history, including the presence of a malignancy and liver disease, but no information was obtained on the presence of rheumatoid arthritis or other inflammatory diseases. Further collected baseline data included demographics, use of medications, biometric data, urine- and blood collections and laboratory measurements. In case of flu and/or a febrile temperature, blood collection was postponed to a later time when participants had recovered. Of 8,592 subjects included, 8,139 participants were without previous documented CAD and were included in the current analysis. Previous documented CAD was defined as history of myocardial infarction, revascularisation procedure or obstructive coronary artery disease, prior to inclusion in the PREVEND study. A history of myocardial infarction was based on a subjects’ medical history, including structured questionnaire, and the information on previous CAD was complemented by review of the medical report. For details on the PREVEND study design we refer to earlier publications.15 The PREVEND study was approved by the medical ethics committee and conducted in accordance with the guidelines of the declaration of Helsinki. All participants gave written informed consent.

Coronary angiographyDuring 1997-2003, all CAGs performed in the only two hospitals in the Groningen region, namely the University Medical Center Groningen and the Martini Hospital Groningen, were collected in order to perform qualitative angiographic analysis. Of 240 performed first CAGs during 5.5 years of follow up, 216 CAGs were available for angiographic analysis (90%). CAGs for all indications were included in the analysis. These indications were reviewed by a clinical event committee and divided into stable angina, non-ST-elevation acute coronary syndrome (defined as chest pain with positive cardiac markers (troponin or creatinin kinase) and/or dynamic ST-segment changes),16 and ST-elevation myocardial infarction (defined as chest pain and ST-elevation over 1 mm in at least 2 contiguous leads).17

Qualitative angiographic analysisQualitative coronary angiographic analysis was performed by a senior cardiologist (RT), who had no knowledge of the clinical indications for CAG or of the patients’ clinical status. By angiographic analysis, the severity of CAD was assessed in all four coronary vessels, namely the left main stem, left anterior descending artery, left circumflex artery and right coronary artery. Severity of CAD was graded as follows: normal coronary arteries (absence of any coronary plaque), non-obstructive CAD (less than 50% stenosis), stable obstructive CAD (at least 50% stenosis) and unstable obstructive CAD. Plaques were considered unstable if they caused at least 50% stenosis and had two or more of the following morphologic features: an intraluminal filling defect consistent with thrombus, defined as abrupt vessel cut-off with persistence

of contrast, or an intraluminal filling defect in a patent vessel within or adjacent to a stenotic region with surrounding homogeneous contrast opacification; plaque ulceration, defined by the presence of contrast and hazy contour beyond the vessel lumen; plaque irregularity, defined by irregular margins or overhanging edges; and

49


Chap

ter 3

impaired flow.7 Plaques were considered stable if less than two of these morphologic features were present.7 In case 2 or more coronary plaques were found in a coronary vessel, the most severe angiographic plaque was registered. An interobserver agreement of 95% was found in a random sample of 44 CAGs (20%) which were analysed by a second senior cardiologist (FZ) unaware of the prior analyses. To evaluate whether the group of patients with normal coronary arteries would be representative for PREVEND participants without a CAG or coronary event during follow up, the baseline characteristics of both groups were compared.

Coronary eventsAll 8,139 participants were followed for 5.5 years for the occurrence of coronary events, defined as myocardial infarction or cardiovascular death. The vital status of all participants was evaluated through the municipal register until December 31st 2003. Causes of death were obtained from the Central Bureau of Statistics according to ICD-10 codes (I01-I99 for cardiovascular disorders). Information related to myocardial infarctions (ICD-9 410, 411) were obtained from the national hospital information system (Prismant, Utrecht, the Netherlands). All cardiac events were reviewed by a clinical event committee.

Analytical methods and definitionsSystolic and diastolic blood pressure measurements were calculated as the mean of the last two out of ten consecutive measurements with an automatic Dinamap XL model 9300 series device (Johnson-Johnson Medical INC, Tampa, Florida). Fasting serum total cholesterol was determined by Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, New York, U.S.A.). HDL-cholesterol was determined by MEGA (Merck, Darmstadt, Germany). High sensitive C-reactive protein (hs-CRP) was measured by nephelometry with a threshold of 0.18 mg/L and intra- and interassay coefficients of variation of <4.4 and <5.7% respectively (BNII, Dade Behring, Marburg, Germany). The urinary albumin excretion was measured as the mean of two 24h-urine collections. Urinary albumin concentrations were determined by nephelometry with a threshold of 2.3 mg l-1 and intra- and inter-assay coefficients of variation of less than 2.2% and 2.6%, respectively (Dade Behring, Marburg, Germany). Renal dysfunction was defined as creatinin clearance <60 ml/min/1.73 m2. Smoking status included current and past smoking. Ever smoking is defined as current or past smoking. Antihypertensive medication included diuretics, betablockers, ACE-inhibitors and angiotensin receptor blockers.

Statistical analysis

Baseline characteristicsContinuous data were given as means (standard deviation). In case of a skewed distribution the median (interquartile range) are presented. Differences between

50

Chapter 3

groups were evaluated by Chi-square tests or analysis of variance. Differences in hs-CRP levels between subjects with stable and unstable CAD were tested after logarithmic transition by one-way ANOVA with Bonferroni correction. P-values were two-sided and needed to be <0.05 to be significant. SPSS version 11.0 software (SPSS, Chicago, IL, USA) was used for these analyses.

Association between hs-CRP and coronary plaque characteristics in PREVEND participants who underwent CAG during follow upCox survival analysis Cox proportional hazard models were fitted to evaluate associations between clinical variables at baseline and time to CAG showing an obstructive coronary plaque, and an unstable obstructive coronary plaque, respectively, in 216 patients (at a patient level). The proportional hazard assumption was assessed for every predictor variable using graphical approaches. Proportional hazard was assumed when the log-log-survival curve was found constant over time. Hs-CRP was log transformed for this analyses because the relationship between hs-CRP levels and the endpoint was not of linear nature. A stepwise model was used, introducing a variable if p<0.15, first entering the variables with the highest Wald statistics. If p>0.10, a variable was excluded from the model. The variables introduced in the model were age, sex, smoking status, total cholesterol, diastolic blood pressure, HDL cholesterol, hs-CRP, diabetes, microalbuminuria and waist circumference. Moreover, a variable was introduced which represented one of the factors reported in the PREVEND database which may have influenced hs-CRP levels, namely renal dysfunction, malignancy, liver disorder, antihypertensive or lipid lowering medication or aspirin. Event-free survival time for participants was defined as the period beween inclusion in the study and CAG. SPSS version 11.0 software (SPSS, Chicago, IL, USA) was used for these analyses.Multilevel ordinal logistic regression analysis Multilevel ordinal logistic regression analysis is appropriate for hierarchical data to take into account the clustering of angiographic plaques per vessel in a patient. We performed this analysis in order to evaluate associations between clinical variables at baseline and severity of CAD on a vessel level, after adjustment for the patient level. In our dataset, each subject (higher level; n=216) has four coronary vessels (lower level; n=864). The multilevel ordinal logistic model evaluates the association of baseline clinical variables with the type of angiographic plaque per vessel, expressed as outcome variable in 4 categories (no CAD, non-obstructive CAD, obstructive stable CAD and obstructive unstable CAD). Multilevel ordinal logistic regression analysis was performed in all patients in whom all clinical variables of interest had been measured. The modelling strategy was to first enter demographic variables (p<0.05). Secondly, other clinical variables were entered and were retained in the model in case of significance (p<0.05). These included smoking status, total cholesterol, diastolic blood pressure, HDL cholesterol, hs-CRP, diabetes, microalbuminuria, waist circumference and time between inclusion to PREVEND and performance of CAG. Moreover, as was done for the Cox survival analysis, a variable was introduced which represented one of the factors reported in the PREVEND database which may have influenced hs-CRP levels, namely renal

51


Chap

ter 3

dysfunction, malignancy, liver disorder, antihypertensive or lipid lowering medication or aspirin. The proportional odds assumption was satisfied for all clinical variables, except for smoking status. From the 3 logits the cumulative response probabilities of the categorical outcome variable (angiographic types of plaque) were estimated (2nd order PQL estimation). MlwiN, version 2.0, was used for the multilevel analysis.

Association between hs-CRP and the occurrence of a first coronary event in the total PREVEND populationCox survival analysis Probability weighted Cox proportional hazard models were fitted to evaluate independent predictors of time to a first coronary event taking into account adjustment for the non-random inclusion of subjects with and without elevated UAE at study entry. The proportional hazard assumption was assessed using graphical approaches. Hs-CRP was introduced as a categorical variable 18 after adjustment for age and sex. Event-free survival time for participants was defined as the period from the date of the outpatient clinic baseline assessment to the date of first coronary event, or death from any cause until 31 December 2003, or 31 December 2002 until which date information regarding specific causes of death follow up information was available. If a person had moved away from the city of Groningen or to an unknown destination, the person was censored on the last available contact date. STATA version 10.0 software (STATA, College Station, Texas, USA) was used for this analysis.

Results

Baseline characteristicsIn 216 PREVEND participants a first CAG was available for angiographic analysis. Mean time between inclusion into PREVEND and performance of first CAG was 37±19 months. Severity of CAD in 216 patients and in their 864 coronary vessels, respectively, is shown in table 1. Of 216 patients, 35 patients had normal coronary arteries. In 42 patients, non-obstructive CAD was found. In 139 patients, obstructive CAD was present, of whom at least one unstable plaque was present in 60 patients. Of 864 coronary vessels, 436 vessels were free from CAD. In 175 vessels non-obstructive CAD was found. In 179 stable coronary plaques were found, while in 74 vessels unstable CAD was present. Unstable plaques contained thrombi in 84%, impaired flow in 56%, irregularity in 80% and ulceration in 31%. Baseline characteristics according to severity of CAD are shown in table 2. Age, male gender, blood pressure, total cholesterol, HDL cholesterol, smoking status at baseline, and clinical presentation were significantly different between the groups, while hs-CRP levels showed a trend (P

trend=0.079). The hs-CRP levels of subjects with stable and

unstable CAD were not significantly different (2.54 and 2.39 (p=1.00)). Patients with unstable CAD had an adverse risk profile at baseline, while only few were receiving lipidlowering and/or antihypertensive medication. Microalbuminuria was not significantly different between the groups. All patients with normal coronary

52

Chapter 3

arteries had undergone CAG for symptoms compatible with stable angina. Indications for CAG in patients with obstructive unstable plaques were non-ST-elevation acute coronary syndrome or ST-elevation myocardial infarction in 75% of cases. Regarding the baseline characteristics, the reference group (35 patients with normal coronary arteries) was comparable to the control group (7,916 PREVEND participants without CAG or cardiac event during follow up) (table 3).

Association between hs-CRP and coronary plaque characteristics in PREVEND participants who underwent CAG during follow upCox survival analysis In 200 out of 216 PREVEND participants of whom the first CAG was available for angiographic analysis, all clinical variables of interest had been measured at baseline and were included in the analyses. Multivariate Cox regression analyses showed that hs-CRP levels at a subject level were associated with time to CAG showing an obstructive coronary plaque, and an obstructive unstable coronary plaque, respectively (table 4). Of all variables introduced in the model, the variables mentioned in table 4 significantly added to the model. There was no interaction with hs-CRP. Multilevel ordinal regression analysis Additionally, the multilevel ordinal logistic regression analysis in 800 vessels of these 200 patients showed that hs-CRP, age, sex, smoking status, total cholesterol, diastolic blood pressure and HDL cholesterol at baseline were significantly associated with the angiographic outcome variable, measured at CAG during follow up. The other variables introduced were not associated with the angiographic outcome variable. There was no interaction with hs-CRP. The multilevel regression model allows the estimation of absolute probabilities and odds ratios for an angiographic type of plaque (i.e. no CAD, non-obstructive CAD, obstructive stable CAD and obstructive unstable CAD) in the presence of certain clinical variable. In figure 1, the absolute probabilities and odds ratios for the presence

Table 1. Angiographic characteristics in 216 PREVEND participants and in their 864 coronary vessels.

Angiographic characteristics (in 216 patients) No. (%)

≥1 unstable obstructive plaque 60/216 (28)

≥1 stable obstructive plaque 79/216 (37)

≥1 non-obstructive plaque 42/216 (19)

Without coronary artery disease 35/216 (16)

Angiographic characteristics (in 864 coronary vessels) No. (%)

≥1 unstable obstructive plaque 74/864 (9)

≥1 stable obstructive plaque 179/864 (20)

≥1 non-obstructive plaque 175/864 (20)Without coronary artery disease 436/864 (51)

53


Chap

ter 3

Tabl

e 2.

Bas

elin

e ch

arac

teri

stic

s of

216

PRE

VEN

D pa

rtic

ipan

ts a

ccor

ding

to a

ngio

grap

hic

char

acte

rist

ics

of c

oron

ary

arte

ry d

isea

se*.

Refe

renc

e Gr

oup

(nor

mal

coro

nary

art

erie

s)n=

35

Non

-obs

truc

tive

coro

nary

art

ery

dise

ase

n=42

Stab

le o

bstr

ucti

ve

coro

nary

art

ery

dise

ase

n=79

Uns

tabl

e ob

stru

ctiv

e co

rona

ry a

rter

y di

seas

en=

60Pt

rend

Age,

mea

n (S

D), y

53(1

2)60

(10)

59(1

0)60

(9)

0.00

7M

ale

gend

er, N

o. (%

)13

(37)

23(5

5)61

(77)

41(6

8)0.

001

Bloo

d pr

essu

re, m

ean

(SD)

, mm

Hg

Syst

olic

128

(19)

144

(24)

140

(21)

142

(21)

0.00

4Di

asto

lic74

(10)

80(1

0)79

(8)

81(9

)0.

001

Smok

ing

stat

us, N

o. (%

)0.

045

Curr

ent

15(4

2)13

(31)

38(4

8)31

(52)

Past

11(3

1)16

(38)

29(3

7)24

(40)

Diab

etes

, No.

(%)

2(6

)2

(5)

2(3

)5

(8)

0.59

3W

aist

cir

cum

fere

nce,

cm

89(1

1)94

(13)

98(1

2)95

(11)

0.00

3Ch

oles

tero

l, m

ean

(SD)

, mm

ol/L

Tota

l5.

9(1

.1)

6.0

(1.1

)6.

3(0

.9)

6.6

(1.2

)0.

003

HDL

1.27

(0.3

7)1.

17(0

.35)

1.11

(0.3

1)1.

09(0

.35)

0.01

2Al

bum

inur

ia, m

edia

n (i

nter

quar

tile

rang

e),

mg/

24h

9.1

(6.4

-17.

9)10

.7(8

.4-4

1.5)

14.0

(8.3

-33.

8)15

.0(7

.1-2

8.1)

0.95

3

hs-C

RP, m

edia

n (i

nter

quar

tile

rang

e), m

g/L

1.59

(0.7

0-2.

58)

1.98

(1.1

8-3.

53)

2.54

(1.1

4-5.

24)

2.39

(1.2

4-7.

19)

0.07

9M

edic

atio

n, N

o. (%

)Li

pidl

ower

ing

3(9

)5

(12)

10(1

3)5

(8)

0.93

4An

tihy

pert

ensi

ve†

4(1

1)14

(33)

24(3

0)12

(20)

0.60

0AC

E in

hibi

tors

/ an

giot

ensi

n re

cept

or b

lock

ers

3(9

)4

(10)

9(1

1)3

(5)

0.61

0As

piri

n0

(0)

2(5

)8

(10)

5(8

)0.

078

Clin

ical

pre

sent

atio

n, N

o. (%

)‹ 0

.001

Stab

le a

ngin

a35

(100

)38

(90)

44(5

6)15

(25)

Non

-ST-

elev

atio

n ac

ute

coro

nary

syn

drom

e0

(0)

2(5

)18

(23)

29(4

8)ST

-ele

vati

on m

yoca

rdia

l inf

arct

ion

0(0

)2

(5)

17(2

1)16

(27)

*Bas

elin

e ch

arac

teri

stic

s w

ere

mea

sure

d du

ring

incl

usio

n in

PRE

VEN

D co

hort

stu

dy. M

ean

tim

e be

twee

n in

clus

ion

and

coro

nary

ang

iogr

aphy

dur

ing

follo

w u

p w

as 3

7±19

m

onth

s. †

incl

udin

g AC

E in

hibi

tors

and

ang

iote

nsin

rece

ptor

blo

cker

s. A

bbre

viat

ions

: HDL

, hig

h de

nsit

y lip

opro

tein

; hs-

CRP,

hig

h se

nsit

ivit

y- C

-rea

ctiv

e pr

otei

n.SI

con

vers

ion

fact

or: t

o co

nver

t mm

ol/L

to m

g/dL

, div

ide

valu

es fo

r tot

al c

hole

ster

ol a

nd H

DL c

hole

ster

ol b

y 0.

0259

.

54

Chapter 3

Table 3. Comparison of baseline characteristics of the reference group without coronary artery disease (n=35) versus a control group of PREVEND participants (n=7,916) who remained free from coronary angiography or coronary event during follow up.

Reference group (normal coronary arteries at coronary angiography)

(n=35)

PREVEND control group

(n=7,916)

P

Age, mean (SD), y 53 (12) 49 (12) 0.054Male gender, No. (%) 13 (37) 3836 (49) 0.181Blood pressure, mean (SD), mm Hg

Systolic 128 (19) 128 (20) 0.812Diastolic 74 (10) 74 (10) 0.811

Smoking status, No. (%)Current 15 (42) 2684 (34) 0.272Ever 26 (74) 5482 (70) 0.540

Diabetes, No. (%) 2 (6) 25 (3) 0.435Cholesterol, mean (SD), mmol/L

Total 5.9 (1.1) 5.6 (1.1) 0.141HDL 1.27 (0.37) 1.33 (0.40) 0.319

Albuminuria, median (interquartile range), mg/24h 9.1 (6.4-17.9) 9.23 (6.3-16.8) 0.833

hs-CRP, median (interquartile range), mg/L 1.59 (0.70-2.58) 1.21 (0.54-2.83) 0.274Medication, No. (%)

Lipidlowering 3 (9) 366 (5) 0.258Antihypertensive 4 (11) 28 (11) 0.821

Abbreviations: HDL, high density lipoprotein; hs-CRP, high sensitivity- C-reactive protein.SI conversion factor: to convert mmol/L to mg/dL, divide values for total cholesterol and HDL cholesterol by 0.0259.

Table 4a. Univariate- and multivariate predictors for the presence of an obstructive plaque (by Cox survival analysis).

Univariate analysis Multivariate analysis

RR (95% CI) P RR (95% CI) PMale versus female sex 1.38 (0.96-2.00) 0.084 1.15 (1.02-2.24) 0.038Hs-CRP, per log mg/L 1.22 (1.02-1.48) 0.027 1.24 (1.04-1.48) 0.015

Table 4b. Univariate- and multivariate predictors for the presence of an obstructive unstable plaque (by Cox survival analysis).

Univariate analysis Multivariate analysis

RR (95% CI) P RR (95% CI) PAge, per year 1.03 (1.00-1.05) 0.049 1.03 (1.00-1.06) 0.051Total cholesterol, per mmol/L 1.32 (1.03-1.69) 0.029 1.38 (1.05-1.80) 0.019Diastolic blood pressure, per mmHg 1.03 (1.00-1.06) 0.077 1.03 (1.00-1.06) 0.059Hs-CRP, per log mg/L 1.38 (1.06-1.60) 0.017 1.39 (1.03-1.86) 0.031

Abbreviation: hs-CRP, high sensitivity- C-reactive protein.

55


Chap

ter 3

of a stable and unstable plaque are shown. E.g. males have a higher probability of stable and unstable coronary artery disease compared to females. With increasing age, the probabilities of stable and unstable plaques increase from 7% to 18% and from 3% to 9%, respectively. Smoking was only associated with non-obstructive coronary artery disease. With increasing total cholesterol levels, the probabilities of stable and unstable plaques increase from 13% to 26% and from 3% to 9%, respectively. Increasing hs-CRP levels are associated with an increase in the probabilities of stable and unstable coronary plaques from 19% to 26% and from 5% to 8%, respectively. Figure 1 shows that the highest probabilities for stable and unstable coronary plaques are related to age and high total cholesterol, and the lowest to elevated hs-CRP.

Figure 1.

13% 3%

Male †

Female †

66%

49%

17%

7%22%

22%

Age 38 years †

Age 59 years †

Age 80 years †

Non-Smoker †

(Ex-)Smoker †

Diastolic blood pressure 61 mmHg †



55%

55%

5%19%

12%

60%

50%

6%

40%

23%

21%

5%

28%

4%3%7% 121%

70%19%

5%5%11%22%55%

28%

22%

9%9%18% 28%

40%

33%

Figure 1. Absolute probabilities of unstable (black), stable (dark grey), non-obstructive (light grey) and no coronary artery disease (white) according to the magnitude of risk factors (mean value ±2 standard deviations).**except for hs-CRP: the 5th, 50th and 95th percentiles are presented for hs-CRP due to skewness of the distribution. †at the mean of other covariates.

56

Chapter 3

Association between hs-CRP and the occurrence of a first coronary event in the total PREVEND populationCox survival analysis. During 5.5 years of follow up, 201 (2.5%) coronary events occurred. In 7,722 (95%) subjects, hs-CRP had been measured and in 184 of these subjects a coronary event occurred. Coronary events occurred in 34 (1.0%) of 3,320 subjects with hs-CRP<1 mg/L; in 75 (2.9%) of 2,554 subjects with hs-CRP 1-3 mg/L; and in 75 (4.1%) of 1,848 subjects with hs-CRP>3 mg/L. Cox survival analysis showed that hs-CRP was significantly associated with the occurrence of a first coronary event. Age- and sex- adjusted hazard ratios for hs-CRP 1-3 mg/L and >3 mg/L were, respectively, 1.26 (95% CI 0.67-2.40) and 3.16 (95% CI 1.26-3.16), relative to hs-CRP <1 mg/L.

Discussion

Principal findingsIn the PREVEND population based cohort study, in patients without previous documented CAD, hs-CRP levels at baseline were independently associated with angiographic characteristics of stable and unstable CAD at a first CAG during 5.5 years of follow up. Our results support the concept that hs-CRP significantly contributes to coronary atherogenesis. Furthermore, our results imply that the increased coronary risk due to hs-CRP is, at least in part, associated with coronary plaque burden. The association between hs-CRP and plaque instability was corroborated by the significant association between hs-CRP and the occurrence of a first coronary event.

Hs-CRP and coronary plaque burdenIn the last decade, inflammation parameter hs-CRP has been proven to be an independent predictor of coronary risk.1;3;19-21 Although hs-CRP may be related to various systemic processes, such as insulin resistance and obesity,22 infections,23 and a prothrombotic state,24 recent studies have suggested an active biological role in atherogenesis.9 Hs-CRP has been found present in advanced atherosclerotic plaques.8;25 Hs-CRP has been shown to promote the uptake of oxidized LDL cholesterol.26 Furthermore, hs-CRP has pro-inflammatory and protrombotic effects on the vessel wall, implying a role in plaque vulnerability.9;25 However, the evidence on the role of hs-CRP in atherogenesis is conflicting.10 Angiographic and histopathological studies could not consistently demonstrate an association with the extent of coronary plaque burden and unstable coronary plaques,2;4-6;8;11;13;27 making the association with coronary plaque burden a controversial issue. Furthermore, the increased coronary risk associated with elevated hs-CRP levels was independent from the extent of atherosclerotic plaque burden.4;5 Whether hs-CRP should be regarded as marker of CAD activity in patients with stable or unstable angina is therefore not yet clear. Additionally, none of these studies have been performed in patients without clinically established atherosclerosis. However, we question the design chosen in most of these studies, since these are cross-

57


Chap

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sectional data, which lack time dependency. The uniqueness of our study design is characterised by two aspects. First, the study population consists of patients previous documented CAD. Second, the measurements of hs-CRP and other clinical variables have been performed at a mean time period of 3 years before the performance of a first CAG. The angiographic outcome variable chosen was a combination of severity of luminal stenosis and characteristics of plaque instability, ranging from no or non-obstructive CAD to obstructive stable or unstable CAD. Unexpectedly, hs-CRP levels in subjects with stable and unstable CAD were of the same magnitude. This may be due to the fact that inflammatory processes are not only associated with plaque instability, but also play a role in plaque growth. Furthermore, our small sample size may have played a role. Since subjects with unstable CAD had an adverse coronary risk profile at baseline, we included established coronary risk factors and use of medication in the regression analyses, in order to evaluate whether these factors could have influenced the association between hs-CRP and the outcome variable. By use of multilevel regression analysis, it turned out that hs-CRP was independently associated with angiographic characteristics of stable and unstable coronary plaque burden. Therefore, our results confirm the hypothesis that hs-CRP is a marker of CAD activity in a population without prior documented CAD. Beside the uniqueness of our study design, another new aspect of our study is that we were able to estimate the absolute probability on a certain type of coronary plaque by use of the multilevel regression model. These probabilities reflect the clinical relevance of the parameter. Figure 1 illustrates that dependent on the magnitude of risk factors at baseline, the absolute probability of a stable coronary plaque could range between 7 and 34%, while the probability of an unstable obstructive plaque could range between 3 and 15%. The ranges of the probabilities given in figure 1 show that hs-CRP is statistically and clinically associated with the angiographic outcome variable. This observation confirms that atherosclerosis is a multifactorial process, in which inflammation plays an independent role. Our data are restricted to subjects who underwent CAG during follow up, but seem generalizable to the whole study population, since the patients with normal angiographic findings were comparable to subjects who remained free from CAG or major adverse cardiac event during follow up. We realise that the reference group is a somewhat more homogenous sample due to the selection of subjects with a CAG when compared to the control group, which is reflected by the wider dispersion of hs-CRP levels present in the control group. The association between hs-CRP and coronary plaque characteristics as indicators for plaque instability was corroborated by the significant association between hs-CRP and occurrence of a first coronary event in the total PREVEND study population. This is of importance, since a coronary event most frequently results from coronary plaque instability.

Hs-CRP, coronary plaque burden and causality A first question that remains to be answered is whether our results imply a causal relationship with coronary atherogenesis. Our results contribute to some of the criteria for causality as have been defined by Hill.28 First, in the association between

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hs-CRP and angiographic CAD, hs-CRP was measured before the performance of CAG, thereby fulfilling the criterion of temporality. Second, the association found was independent from other risk factors, thereby contributing to the criterion of strength. Furthermore, elevated hs-CRP levels were associated with a higher probability of angiographic characteristics of stable and unstable CAD, supporting a of dose-response relationship. Our results are in line with another prospective study, which included patients with a first CAG and showed that hs-CRP was associated with progression of CAD,27 thereby contributing to the criterion of consistency. Additionally, our results confirm recent studies that have suggested that hs-CRP may play an active biological role in atherogenesis and plaque vulnerability,8;9;23;25;26 thereby contributing to the criteria of plausibility and coherence.Our study design does not allow to comment the other criteria. It is not clear yet whether lowering hs-CRP levels will result in a reduction of CAD, although recent trials have shown promising results.29;30 Furthermore, we did not study analogous factors or specificity of the effect. Therefore, our results favour some of the criteria supporting a causal relationship, but do not provide a definite answer.

Hs-CRP, coronary plaque burden and coronary riskA second question that remains to be answered is whether our results imply that the increased coronary risk associated with hs-CRP is due to its association with coronary plaque burden. Our results support the association with coronary plaque burden. However, morphologic coronary plaque characteristics and clinical outcome are not always closely related. Although autopsy studies have reported a heterogeneity in types of unstable coronary plaques in patients with a fatal myocardial infarction, in some patients the coronary arteries were characterised by an absence of unstable plaque characteristics.31;32 Most unstable plaques are found in patients with acute myocardial infarction and unstable angina.7;33 However, unstable plaques are also found in patients with symptoms compatible with stable angina, albeit less frequently.34 Furthermore, a time delay up to several weeks has been demonstrated between the occurrence of plaque rupture and first symptoms of acute myocardial infarction.35 Even, it has been shown that in many cases ruptured plaques do not cause symptoms at all, but heal silently.36 Therefore, whether plaque instability leads to a clinical ischemic event may depend on the interaction between morphologic coronary plaque characteristics and systemic factors, such as factors involved in inflammation, coagulation and fibrinolysis,24 lipids and blood pressure,32 physical activity,31 and diet.37 Since it is known that hs-CRP is associated with some of these processes, the impact of hs-CRP on coronary risk may depend on its association with plaque burden as well as on its association with the systemic processes involved in atherothrombosis. Our results therefore support that the increased coronary risk due to hs-CRP is at least in part dependent on its association with coronary plaque burden.

LimitationsIn PREVEND, diabetes was not associated with the angiographic outcome variables. This observation may be explained by the fact that only very few diabetes patients

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were included. Furthermore, only type 2 diabetes patients and mostly female subjects, not using insulin were included, reflecting a low coronary risk when compared to diabetes patients in general. In the multilevel ordinal model, smoking status was only associated with non-obstructive CAD, in contrast to obstructive CAD. It should be studied whether this observation can be confirmed in future studies. High-sensitive CRP may also be associated with plaque instability in other vascular regions, but the focus of the current manuscript has been on coronary artery disease. We included subjects who underwent CAG for stable and unstable presentations of coronary disease during follow up, to be able to include a wide range of types and severity of coronary plaques. Unfortunately, subgroups were too small to allow a stratified analysis. In our analyses we were able to adjust for most, but unfortunately not all, factors which could have influenced hs-CRP levels at time of study entry. Coronary angiography, although very useful in coronary risk stratification, can not be regarded as a true gold standard for identifying advanced CAD and unstable plaques, as it only shows the intravascular lumen, and not the diseased vessel wall. Coronary angiography is limited by the fact that early atherosclerosis may result in positive remodelling of the coronary artery, which may be missed by CAG since narrowing of the coronary lumen only occurs in more advanced atherosclerosis. Coronary angiography is not suitable to detect unstable characteristics of non-obstructive lesions, which is illustrated by the observation that acute coronary events may occur due to rapid progression of lesions that have been shown to be non-obstructive on a previous CAG. Nevertheless, for an evaluation of CAD in a prospective cohort study CAG is at this moment in time the most suitable technique, although non-invasive techniques such as multidetector computed tomography coronary angiography will become more important in the near future. Furthermore, the clinical impact of severity of CAD as detected by CAG is very well documented.38

Conclusion

This substudy of the PREVEND study shows that in subjects without previous documented CAD hs-CRP is associated with angiographic characteristics of stable and unstable coronary plaque burden.

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Reference list


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3. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000;343:1139-1147.

4. Zebrack JS, Muhlestein JB, Horne BD, Anderson JL. C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina. J Am Coll Cardiol. 2002;39:632-637.

5. Arroyo-Espliguero R, Avanzas P, Cosin-Sales J, Aldama G, Pizzi C, Kaski JC. C-reactive protein elevation and disease activity in patients with coronary artery disease. Eur Heart J. 2004;25:401-408.

6. Katritsis D, Korovesis S, Giazitzoglou E, Parissis J, Kalivas P, Webb-Peploe MM, Ioannidis JP, Haliassos A. C-Reactive protein concentrations and angiographic characteristics of coronary lesions. Clin Chem. 2001;47:882-886.

7. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med. 2000;343:915-922.

8. Burke AP, Tracy RP, Kolodgie F, Malcom GT, Zieske A, Kutys R, Pestaner J, Smialek J, Virmani R. Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation. 2002;105:2019-2023.

9. Jialal I, Devaraj S, Singh U. C-reactive protein and the vascular endothelium: implications for plaque instability. J Am Coll Cardiol. 2006;47:1379-1381.

10. Taylor KE, Giddings JC, van den Berg CW. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol. 2005;25:1225-1230.

11. Azar RR, Aoun G, Fram DB, Waters DD, Wu AH, Kiernan FJ. Relation of C-reactive protein to extent and severity of coronary narrowing in patients with stable angina pectoris or abnormal exercise tests. Am J Cardiol. 2000;86:205-207.

12. Avanzas P, Arroyo-Espliguero R, Cosin-Sales J, Quiles J, Zouridakis E, Kaski JC. Multiple complex stenoses, high neutrophil count and C-reactive protein levels in patients with chronic stable angina. Atherosclerosis. 2004;175:151-157.

13. Avanzas P, Arroyo-Espliguero R, Cosin-Sales J, Aldama G, Pizzi C, Quiles J, Kaski JC. Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes. Heart. 2004;90:847-852.

14. Zairis MN, Lyras AG, Bibis GP, Patsourakos NG, Makrygiannis SS, Kardoulas AD, Glyptis MP, Prekates AA, Cokkinos DV, Foussas SG. Association of inflammatory biomarkers and cardiac troponin I with multifocal activation of coronary artery tree in the setting of non-ST-elevation acute myocardial infarction. Atherosclerosis. 2005;182:161-167.

15. Smilde TD, Asselbergs FW, Hillege HL, Voors AA, Kors JA, Gansevoort RT, Van Gilst WH, De Jong PE, van Veldhuisen DJ. Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy. Am J Hypertens. 2005;18:342-347.

16. Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, De Feyter PJ, Specchia G, Ruzyllo W. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2002;23:1809-1840.

17. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on

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the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003;24:28-66.

18. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC, Jr., Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511.

19. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237-242.



22. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003;107:391-397.

23. Kaski JC, Cox ID. Chronic infection and atherogenesis. Eur Heart J. 1998;19:366-367. 24. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part I:

evolving concepts. J Am Coll Cardiol. 2005;46:937-954. 25. Montero I, Orbe J, Varo N, Beloqui O, Monreal JI, Rodriguez JA, Diez J, Libby P, Paramo JA. C-reactive

protein induces matrix metalloproteinase-1 and -10 in human endothelial cells: implications for clinical and subclinical atherosclerosis. J Am Coll Cardiol. 2006;47:1369-1378.

26. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001;103:1194-1197.

27. Zouridakis E, Avanzas P, rroyo-Espliguero R, Fredericks S, Kaski JC. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation. 2004;110:1747-1753.

28. HILL AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295-300. 29. Ray KK, Cannon CP, Cairns R, Morrow DA, Rifai N, Kirtane AJ, McCabe CH, Skene AM, Gibson CM,

Ridker PM, Braunwald E. Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005;46:1417-1424.

30. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292:1307-1316.

31. Burke AP, Farb A, Malcom GT, Liang Y, Smialek JE, Virmani R. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA. 1999;281:921-926.

32. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276-1282.

33. Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002;106:804-808.

34. Maehara A, Mintz GS, Bui AB, Walter OR, Castagna MT, Canos D, Pichard AD, Satler LF, Waksman R, Suddath WO, Laird JR, Jr., Kent KM, Weissman NJ. Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound. J Am Coll Cardiol. 2002;40:904-910.

35. Rittersma SZ, van der Wal AC, Koch KT, Piek JJ, Henriques JP, Mulder KJ, Ploegmakers JP, Meesterman M, de Winter RJ. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: a pathological thrombectomy study in primary percutaneous coronary intervention. Circulation. 2005;111:1160-1165.

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36. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, Virmani R. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001;103:934-940.

37. Casscells W, Naghavi M, Willerson JT. Vulnerable atherosclerotic plaque: a multifocal disease. Circulation. 2003;107:2072-2075.

38. Proudfit WJ, Bruschke AV, MacMillan JP, Williams GW, Sones FM, Jr. Fifteen year survival study of patients with obstructive coronary artery disease. Circulation. 1983;68:986-997.

Chapter 4

The predictive value of adding urinary albumin excretion and high-sensitive C-reactive protein to the Framingham risk score

C.A. Geluk, F. W. Asselbergs, S.J.L. Bakker, R.T. Gansevoort, P.E. de Jong, W.H. van Gilst, D.E. Grobbee, F. Zijlstra, H.L. Hillege.

Submitted

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Abstract

BackgroundEndothelial dysfunction and vascular inflammation play a key role in atherosclerosis and their measurement may provide information on coronary risk. We examined the extent to which urinary albumin excretion and C-reactive protein, add independently to coronary risk prediction based on the Framingham risk score.

Methods and resultsThe population-based cohort PREVEND study included 7,089 Dutch subjects without previous documented coronary artery disease. Probability weighted logistic regression models were fitted to determine the association between the Framingham risk score, urinary albumin excretion and C-reactive protein and the occurrence of a first coronary event. From 1997 to 2003, 209 (3.0%) first coronary events occurred. In regression analyses, besides the Framingham risk score, also urinary albumin excretion and C-reactive protein were significantly associated with a first coronary event. The goodness of fit (Akaike’s Information Criterion (AIC)) and predictive ability (area under the receiver-operating-characteristic curve (AUC)) of the Framingham risk score did not and, respectively, marginally change (p=0.056 and p=0.047), when urinary albumin excretion or C-reactive protein were added (AIC=1343 versus 1342 and 1341; AUC=0.81 versus 0.82 and 0.82). In a second analysis, the Framingham risk factors were refitted with and without inclusion of urinary albumin excretion and C-reactive protein. In this model, C-reactive protein was selected with a modest improvement of risk prediction (AUC=0.84; AIC=1275).

ConclusionsThe addition of urinary albumin excretion and C-reactive protein does not materially improve the predictive ability of the Framingham risk score. However, the use of C-reactive protein may have a modest impact on risk prediction when the Framingham risk factors are refitted to a new population.

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Urinary albumin, C-reactive protein and Framingham risk

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Introduction

Coronary atherosclerosis is attributable to a variety of factors and has several clinical manifestations. It is increasingly recognized that endothelial dysfunction and vascular inflammation are crucial processes in atherogenesis and may serve as final common pathways through which many conventional risk factors lead to atherosclerotic lesion formation, progression and symptomatic cardiovascular events.1 Increased levels of urinary albumin excretion (UAE) not only indicate early renal dysfunction but also provide a surrogate of endothelial dysfunction.2 C-reactive protein (CRP) was first identified as a critical factor in cellular immunity and inflammation. Increasing evidence suggests that CRP plays is intimately associated with cardiovascular disease progression.3;4 Accordingly, these markers of endothelial dysfunction and inflammation have been proposed to provide additional information about coronary risk and prognosis.5-11 However, in order to be useful in clinical risk prediction novel markers of risk need to add predictive capacity to commonly available multifactorial prediction model like the well established Framingham Risk Score (FRS) algorithm.12 Only few studies have reported on the added predictive ability of CRP to FRS and have shown conflicting results.13-15 To our knowledge there are no published data on the predictive impact of adding both CRP and UAE to the FRS. We prospectively investigate the added value of UAE and CRP in predicting first coronary events using the FRS in a large population based cohort study. In an additional analyses, the potential contribution of the individual risk factors of the FRS and UAE and CRP was examined in a model refitted to the population.

Methods

The analyses were done using data from the Prevention of REnal and Vascular ENdstage Disease (PREVEND) population based cohort study of which details have been published previously.16 The initial purpose of the PREVEND study was to determine the value of UAE measurements in relation to cardiovascular and renal risk in the general population. During the period 1997–1998, all inhabitants of the city of Groningen, The Netherlands aged between 28 and 75 years were asked to answer a short questionnaire and to send in a morning urine sample. Insulin treatment and pregnancy were exclusion criteria. Altogether 40,856 subjects responded. All subjects with UAE concentrations of at least 10 mg/L (n=7,768) and a random sample of subjects with UAE concentrations less than 10 mg/L (n=3,395) were invited to an outpatient clinic. The screening program was completed by 8,592 subjects. Collected baseline data at the outpatient clinic included medical history, demographics, biometric data, urine- and blood collections and laboratory measurements. Previous documented coronary artery disease was defined as history of myocardial infarction, revascularization procedure or obstructive coronary artery disease prior to inclusion in the PREVEND study. A history of myocardial infarction was based on a subjects’

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medical history, including structured questionnaire, and the information on previous coronary artery disease was complemented by review of the medical report. The PREVEND study was approved by the medical ethics committee and conducted in accordance with the guidelines of the declaration of Helsinki. All participants gave written informed consent.

Definition of end points and follow upThe participants were followed for 5 years for a first coronary event, defined as coronary death, myocardial infarction or revascularization procedure after the baseline screening. The vital status of all participants was recorded until December 31st 2003. Data on mortality was received through the municipal register. Cause of death was obtained by linking the number of the death certificate to the primary cause of death as coded by the Dutch Central Bureau of Statistics. Information on hospitalisation for cardiac morbidity was obtained from PRISMANT, the Dutch national registry of hospital discharge diagnoses. All data were coded according to the International classification of diseases, 9th revision and the classification of interventions. For this study cardiac events were defined as the following; acute myocardial infarction (ICD-code 410), acute and subacute ischemic heart disease (411), coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. In case a person had moved to an unknown destination, the date on which the person was removed from the municipal registry was used as censoring date.

MeasurementsSystolic and diastolic blood pressure measurements were calculated as the mean of the last two out of ten consecutive measurements with an automatic Dinamap XL model 9300 series device (Johnson-Johnson Medical INC, Tampa, Florida). Serum total cholesterol were determined by Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, New York, U.S.A.). HDL-cholesterol was determined by MEGA (Merck, Darmstadt, Germany). The urinary albumin excretion (UAE) was measured from the mean of two 24h-urine collections. Urinary albumin concentrations were determined by nephelometry with a threshold of 2.3 mg l-1 and intra- and inter-assay coefficients of variation of less than 2.2% and 2.6%, respectively (Dade Behring, Marburg, Germany). High sensitive C-reactive protein (CRP) was measured by nephelometry with a threshold of 0.18 mg/L and intra-and interassay coefficients of variation of <4.4 and <5.7% respectively (BNII, Dade Behring, Marburg, Germany).

Data analysisThe 10-year Framingham coronary risk scores (FRS) were estimated according to Wilson et al.17 Framingham risk score based 10-year risk prediction was classified as very low risk (FRS <5%), low risk (FRS 5%-10%), intermediate risk (FRS 10%-20%) and high risk (FRS >20%).18 Urinary albumin excretion was categorized as low-normal (UAE <15 mg/24h), high-normal (15-30 mg/24h), microalbuminuria (UAE 30-300 mg/24h) and macroalbuminuria (UAE >300 mg/24h).6 Due to the small numbers of subjects with UAE>300 mg/24h, subjects with UAE>30 mg/24h were

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considered one category in the current analyses. C-reactive protein was categorized as low (CRP<1.0 mg/L), intermediate (1.0-3.0 mg/L) and high (>3.0 mg/L).19 Continuous data are given as means (standard deviation). Categorical data are presented as per group percentages. In case of a skewed distribution the median (interquartile range) was used. Differences between groups were evaluated by Student t-tests, Mann-Whitney U tests, or Chi-square tests, when appropriate. Endpoint analyses were conducted using the Stata survey procedures, to adjust for the survey weights based on non-random inclusion of subjects with and without elevated UAE concentrations at the PREVEND cohort study entry.6

Of 8,592 subjects initially included, 440 subjects were excluded for missing C-reactive protein (CRP) levels, 15 subjects for missing urinary albumin excretion (UAE) levels, 371 subjects for missing data on one of the Framingham risk score (FRS) variables or morning urine albumin concentration measurement and 178 subjects were excluded due to previous documented coronary artery disease. Complete 5-year follow up was not obtained in 499 of the remaining 7,588 PREVEND participants. Therefore, 7,089 subjects were included for the current analysis.

Analysis of the added value of UAE and CRP to FRS based coronary risk predictionProbability weighted logistic regression analyses were performed. Models were fitted for the association between FRS, UAE and CRP with the occurrence of a first coronary event. To estimate the added value of UAE and CRP to FRS based prediction of coronary events FRS, UAE and CRP were categorized according to cut-off levels given above as well as according to the 1, 5, 25, 50, 75, 95, and 99 percentile ranks. A stepwise model selection was used at which the Schwartz Criterion reaches its minimum (http://www2.sas.com/proceedings/sugi28/275-28.pdf). The goodness of fit of the different prediction models were assessed by estimation of Akaike’s Information Criterion (AIC), which adjusts for the number of variables in the model.20 Lower values indicate better fit. The predictive ability (diagnostic yield) of the prediction models were expressed by the area under the receiver operating characteristic (ROC) curve (AUC).21

Analysis of the added value of UAE and CRP to a model of Framingham risk factors refitted to the populationWe evaluated the contribution of UAE and CRP by means of probability weighted logistic regression analyses to a model refitted to the population including the individual risk factors of the FRS, namely age, gender, smoking status, diabetes, systolic blood pressure, total cholesterol and HDL cholesterol. In addition, cholesterol lowering and antihypertensive medication were entered in the model. Fractional polynomials were used to determine the functional form for continuous variables.22;23 As an alternative to the AUC, to visually display the predictive abilities of the FRS and the exploratory model refitted to the population, respectively, the predicted probabilities of a first coronary event were compared to the observed probabilities.24 Finally, the individual risk estimated by the FRS and, secondly, by the model of individual Framingham risk factors refitted to the population, was classified into the

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therapeutic clinical meaningful risk categories below or equal 20%, and above 20% 10-year coronary risk.12 This analysis was repeated after inclusion of UAE, and CRP, respectively, and the numbers of subjects who were reclassified between below or equal 20% and above 20% 10-year coronary risk were estimated.25

SPSS version 12.0 software (SPSS, Chicago, IL, USA, STATA version 10.0 software (STATA, College Station, Texas, USA) and SAS version 9.1 Software (Unix, SAS Institute Inc) were used for these analyses. P-values are two-sided.

Results

Baseline characteristicsBaseline characteristics of the study population are given in table 1. During a follow up of 5 years, 209 first coronary events occurred. Subjects with a first coronary event were older, more frequently male and smoking; had higher blood pressure levels and an adverse lipid profile; elevated UAE and CRP and more frequently used lipid lowering or antihypertensive medication, when compared to those who remained free from a coronary event. Most subjects (42%) were in the lowest FRS category of coronary risk, while 21%, 19% and 17% were at low, intermediate and high coronary risk.

Risk of a first coronary event according to FRS, UAE and CRP categoriesFor subjects with a very low, low, intermediate and high predicted FRS based coronary risk profile, the absolute 5-year probabilities of a first coronary event stratified within the four FRS subgroups are shown in figure 1. The extrapolated 10-year risks of a first coronary event were, 0.8%, 1.8%, 8.2% and 10.0% in these subjects, respectively. The observed extrapolated 10-year coronary risk in the FRS category <5% of 0.8% was not affected by UAE levels. In the FRS category 5-10%, the extrapolated 10-year risk, stratified into UAE levels <15 mg/24h, 15-30 mg/24h and >30 mg/24h, was 1.6%, 5.7% and 1.0%, respectively. In subjects with an intermediate FRS score of 10-20%, the overall risk was 8.2%, and UAE levels did not affect coronary risk. In the FRS category >20%, the overall risk was 16.8%, 29.0% and 23.6% in subjects with UAE 0-15mg/24h, 15-30 mg/24h and >30 mg/24h, respectively. In the FRS categories <5% and 5-10%, the observed extrapolated 10-year coronary risk regarding different CRP levels did not affect coronary risk. In subjects with an intermediate FRS score of 10-20%, the overall risk stratified into CRP levels <1 mg/L, 1-3 mg/L and > 3 mg/L, was 2.2%, 8.8% and 10.4%, respectively. In the FRS category >20%, the overall risk was 16.2%, 17.9% and 24.6% in subjects with CRP levels <1 mg/L, 1-3 mg/L and > 3 mg/L, respectively. In the univariate analyses evaluating the relative risks of a first coronary event associated with FRS, UAE and CRP separately, all three parameters were significantly associated with a first coronary event (table 2a). Goodness of fit (AIC) was lower and predictive ability (AUC values) was higher for FRS (AIC

FRS 1343; AUC

FRS =0.81) when

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Table 1. Baseline characteristics of 7,089 PREVEND participants without prior coronary heart disease with and without a coronary event during 5 years follow up.

CharacteristicsWith

Coronary Event(n=209)

Without Coronary Event

(n=6,880)P

Age, mean (SD), y 60 (10) 49 (12) < 0.001Male gender, No. (%) 159 (76) 3,316 (48) < 0.001Blood pressure, mean (SD), mm Hg

Systolic 145 (24) 128 (20) < 0.001Diastolic 80 (9) 74 (10) < 0.001

Smoking status, No. (%) < 0.001Current 97 (46) 2,274 (33)Past 113 (54) 4,605 (67)

Diabetes, No. (%) 20 (10) 219 (3) < 0.001Cholesterol, mean (SD), mg/dL

Total 6.2 (1.2) 5.6 (1.1) < 0.001HDL, ,mg/dL 1.11 (0.33) 1.33 (0.40) < 0.001

Triglycerides, median (interquartile range), mg/dL 1.60 (1.10-2.29) 1.15 (0.84-1.66) < 0.001

UAE, median (interquartile range), mg/24h 18.3 (8.4-45.5) 9.2 (6.22-16.72) < 0.001CRP, median (interquartile range), mg/L 2.63 (1.27-5.70) 1.22 (0.54-2.85) < 0.001Medication, No. (%)

Lipidlowering 36 (17) 397 (6) < 0.001Antihypertensive 62 (30) 736 (11) < 0.001

Abbreviations: hs-CRP, high sensitivity- C-reactive protein; HDL, high density lipoprotein; UAE, urinary albumin excretion. SI conversion factor: to convert mg/dL to mmol/L, multiply values for total cholesterol and HDL cholesterol with 0.0259; and for triglycerides with 0.0113.

FRS<5% FRS 5-10% FRS 10-20% FRS >20%

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10

12

14

16

18

20

No. of events/N 11/2,987 19/1,500 52/1,366 127/1,236 11/2,987 19/1,500 52/1,366 127/1,236

A B

Figure 1. Absolute probability (standard error) of a first coronary event according to Framingham risk score subgroups, urinary albumin excretion (A) and C-reactive protein (B) during 5 years of follow up. From left to right the grey colors represent urinary albumin excretion <15, 15-30 and >30 mg/24h and C-reactive protein <1, 1-3 and >3 mg/L, respectively.

72

Chapter 4

compared to UAE (AICUAE

=1544; AUCUAE

=0.60, p<0.0001) or CRP (AICCRP

=1542; AUC

CRP =0.64; p<0.0001). Graphic presentation of the ROC curves is given in figure

2. The FRS ROC curve showed superior predictive ability when compared to the UAE and CRP ROC curves, respectively, independent of the cut-off value classification of the variables (figure 2a and b).

Added value of UAE, CRP to FRS based coronary risk predictionWe determined the added predictive ability of UAE and CRP to FRS in clinically meaningful categories, using AUC analysis. In multivariate analyses, UAE and CRP

Table 2a. Relative risk of a first coronary event. Results from probability weighted univariate (a) and multivariate (b) Cox’ proportional hazard analyses.

Univariate ModelsFactor Events/n HR (95% CI) P value

FRS, % <<0.0001<5 11/2,987 Reference

5-10 19/1,500 2.50 (1.17 - 5.33)10-20 52/1,366 11.60 (6.21 -21.67)

<>20 127/1,236 29.99 (16.38 - 54.90)AIC 1343

AUC 0.81UAE, mg/24h <<0.0001

<<15 87/5,041 Reference15-30 50/1,032 2.82 (1.87 - 4.27)

<>30 72/1,016 3.58 (2.29 - 5.61)AIC 1544

AUC 0.60

CRP, mg/L <<0.0001

<<1 38/3,024 Reference1-3 81/2,340 2.20 (1.48 - 3.29)<>3 90/1,725 3.56 (2.39 - 5.31)AIC 1542

AUC 0.64

Table 2b.Model With FRS and UAE Model With FRS and CRP

Factor HR (95% CI) P value HR (95% CI) P value

FRS, % <0.001 FRS, % <<0.001<<5 Reference <<5 Reference

5-10 2.44 (1.14 - 5.21) 5-10 2.44 (1.14 – 5.22)10-20 11.04 (5.90 - 20.66) 10-20 10.81 (5.75 – 20.32)

<>20 26.77 (14.48 - 49.51) <>20 26.59 (14.32- 49.38)

UAE, mg/24h CRP, mg/L<<15 Reference 0.056 <<1 Reference 0.047

15-30 1.62 (1.06 - 2.48) 1-3 1.14 (0.75 – 1.72)<>30 1.41 (0.88 - 2.25) <>3 1.62 (1.07 - 2.46)

AIC 1342 AIC 1341AUC 0.82 AUC 0.82

Abbreviations: AIC, Akaike Information Criterium; AUC, Area Under the Curve; CRP, C-Reactive Protein; FRS, Framingham Risk Score; UAE, Urinary Albumin Excretion.

73


Chap

ter 4

were not, or only marginally significantly (p=0.056 and p=0.047), associated with the occurrence of a first coronary respectively (table 2b). Addition of UAE and CRP to the model with FRS did not materially change the predictive ability of FRS (AUC

FRS =0.81;

AUCFRS+UAE

=0.82; AUCFRS+CRP

=0.82). As suggested by the AIC levels, the fit of the models were almost similar. The corresponding ROC curves are shown in figures 2c and d.

Refitted model with individual Framingham risk factors, UAE and CRPSecond, a new risk model was estimated by refitting the individual FRS risk factors in this population together with UAE and CRP. CRP was selected in this model and contributed significantly. The model did not significantly improve by adding UAE, HDL cholesterol, systolic blood pressure, diabetes and antihypertensive medication (Table 3). Graphic representation of the predictive abilities, plotted by deciles of

1-specificity0,0 0,2 0,4 0,6 0,8 1,0

sens

itiv

ity

0,0

0,2

0,4

0,6

0,8

1,0

Framingham risk scoreUrinary albumin excretionC-reactive protein

1-specificity0,0 0 ,2 0 ,4 0 ,6 0 ,8 1 ,0

sens

itiv

ity

0,0

0,2

0,4

0,6

0,8

1,0

Framingham risk scoreUrinary albumin excretionC-reactive protein

A B

1-specificity0,0 0,2 0,4 0,6 0,8 1,0

sens

itiv

ity

0,0

0,2

0,4

0,6

0,8

1,0

Framingham risk scoreUrinary albumin excretionFramingham risk score and urinary albumin excretion

1-specificity0,0 0 ,2 0 ,4 0 ,6 0 ,8 1 ,0

sens

itiv

ity

0,0

0,2

0,4

0,6

0,8

1,0

Framingham risk scoreC-reactive proteinFramingham risk score and C-reactive protein

DC

Figure 2. Univariate (A and B) and combined (C and D) receiver operator characteristic curves for the Framingham risk score, urinary albumin excretion and C-reactive protein. The following categories were used: (A) Framingham risk score <5, 5-10, 10-20 and >20%; urinary albumin excretion <15, 15-30 and >30 mg/24h; C-reactive protein <1, 1-3 and >3 mg/L; (B, C and D) all variables divided by eight equal categories.

74

Chapter 4

Tabl

e 3.

Rel

ativ

e ri

sk o

f a fi

rst c

oron

ary

even

t. M

ulti

vari

ate

resu

lts

from

refit

ted

Fram

ingh

am ri

sk fa

ctor

s w

ith

and

wit

hout

incl

usio

n of

UAE

and

CRP

.

Odds

Rat

io

(95%

Con

f. In

terv

al)

zP>

>⎟z⎟

Odds

Rat

io

(95%

Con

f. In

terv

al)

ZP>

>⎟z⎟

AUC

AIC

Age

per 1

0 ye

ars

1.90

(1.5

0-2.

42)

5.24

< 0.

001

1.87

(1.4

7-2.

38)

5.09

< 0.

001

0.73

-M

ale

3.61

(2.0

5-6.

37)

4.45

< 0

.001

3.82

(2.9

-6.6

4)4.

73<

0.00

10.

79-

Smok

ing

3.05

(1.9

6-4.

75)

4.93

< 0

.001

2.92

(1.8

7-4.

57)

4.71

< 0.

001

0.82

-

Tota

l cho

lest

erol

per

1 m

g/dL

1.26

(1.0

8-1.

46)

2.98

0.00

31.

26(1

.08-

1.46

)2.

990.

003

0.83

-

Chol

este

rol l

ower

ing

med

icat

ion

1.95

(1.0

8-3.

51)

2.23

0.02

61.

94

(1.0

9-3.

47)

2.24

0.02

50.

83-

HDL

cho

lest

erol

per

0.1

mg/

dL0.

92(0

.86-

0.99

)-2

.20

0.02

80.

93(0

.86-

1.00

)-1

.93

0.05

30.

84-

Syst

olic

blo

od p

ress

ure

per 1

0 m

mH

g1.

13(1

.00-

1.28

)1.

890.

059

1.12

(0.9

9-1.

27)

1.76

0.07

80.

84-

Diab

etes

1.58

(0.7

3-3.

42)

1.16

0.24

51.

51(0

.69-

3.36

)1.

030.

303

0.84

-

Anti

hype

rten

sive

med

icat

ion

1.03

(0.6

2-1.

71)

0.12

0.90

41.

01(0

.61-

1.69

)0.

050.

958

0.84

1284

UAE

per

30

mg/

24h

1.01

(0.9

9-1.

08)

1.02

0.30

70.

84-

C-re

acti

ve p

rote

in p

er 3

mg/

L1.

13(1

.05-

1.23

)3.

110.

002

0.84

1275

75


Chap

ter 4

risk, of the FRS, and, secondly, the refitted model of Framingham risk factors, is given in Figure 3. Visually, a better calibration was obtained by the refitted model of the Framingham risk factors and CRP (Figure 3b).

Reclassification of coronary riskIn the FRS risk category above 20%, adding UAE or CRP to the FRS was associated with a reclassification of 560 (65.3%) and 539 (62.8%) subjects to the lower FRS risk category below or equal to 20% (Table 4). The observed risks on a coronary event in these reclassified groups were 16.8 and 17.4%, respectively. No subjects were reclassified from the category below or equal to 20% to the higher risk category above 20%. Compared to the refitted model of individual Framingham risk factors, addition of UAE to the model reclassified in total 5 (0.0%) subjects, whereas addition of CRP reclassified in total 63 (0.9%) subjects. Forty subjects from the risk category below or equal to 20% were reclassified to the higher risk category, while 23 subjects were reclassified from the risk category above 20% to the lower risk category, respectively. Almost 50% of the group reclassified in the higher risk category suffered a cardiac event during follow up, whereas no subjects reclassified in the lower risk category suffered an event.

Deciles of Predicted Risk by the Framingham Risk Score

0 1 2 3 4 5 6 7 8 9 10

Num

ber o

f Fir

st C

oron

ary

Even

ts

0

20

40

60

80

100

Predicted RiskObserved Risk

Deciles of Predicted Risk in Model With Individual Framingham Risk Factors and CRP

0 1 2 3 4 5 6 7 8 9 10

Num

ber o

f Fir

st C

oron

ary

Even

ts

0

20

40

60

80

100

Predicted RiskObserved Risk

BA

Figure 3. Figures showing risk of acute coronary events occurring within 5 years of follow-up in observed against those predicted by the Framingham Risk Score (A) and the refitted prediction model including individual Framingham risk factors with CRP (B). Calibration refers to the accuracy of the score in predicting the probability of a coronary event. Observed risk is plotted against the predicted risk with the line of identity indicating perfect calibration.

76

Chapter 4

Discussion

In the present prospective cohort study involving 7,089 male and female participants aged 28 to 75, 209 coronary occurred. Markers of endothelial dysfunction and vascular inflammation, urinary albumin excretion (UAE) and C-reactive protein (CRP), were associated with the occurrence of a first coronary event. In terms of global fit and predictive ability, adding UAE to the Framingham Risk Score (FRS) did not improve risk prediction, while CRP had a marginal positive effect. By adding UAE or CRP, almost two-thirds of subjects in the Framingham risk category above 20% were reclassified to the lower risk category, but the observed extrapolated 10 year coronary risk was still over 15%. When a new model of individual FRS risk factors was refitted in this population, CRP showed a modest improvement in prediction in terms of global fit, predictive ability and calibration. In this model, inclusion of CRP improved overall risk stratification by almost 1%. To appreciate these findings, some aspects of the PREVEND cohort study need to be addressed. Strength of the study is that measurement of UAE was performed by the use of two 24-h urinary collections for measurement of UAE, which is the standard of reference for measurement of UAE. Also, both males and females were included, allowing generalization to populations of both sexes. Thirdly, we have chosen to define the endpoint as coronary event. We believe that this is an appropriate endpoint, since the Framingham score was validated on coronary but not cardiovascular events. 17 A consequence of this choice is the relatively low number of endpoints. A limitation of the study with respect to the present analyses is that the original aim was to evaluate

Table 4. Reclassification of risk by adding urinary albumin excretion and C-reactive protein to the Framingham risk score (in categories) (left panel) and to a model of Individual Framingham risk factors refitted in this population (continuously) (right panel).

Framingham Risk ScoreRefitted Model of

Framingham Risk Factors

+UAE +CRP +UAE +CRP

0 – 20% > 20% 0 – 20% > 20% 0 – 20% > 20% 0 – 20% > 20%

Predicted Risk 0-20%n (%)

6231(87.9)

0(0.0)

6231(87.9)

0(0.0)

6776(95.6)

3(0.0)

6738(95.0)

40(0.6)

Observed Risk (%) 2.6 - 2.6 - 3.8 0.0 3.4 49.8

Predicted Risk > 20%n(%)

560(7.9)

298(4.2)

539(7.6)

319(4.5)

2(0.0)

308(4.4)

23(0.3)

288(4.1)

Observed Risk (%) 16.8 26.1 17.4 24.6 40.0 24.6 0.0 26.6

77


Chap

ter 4

the potentials of UAE and CRP in coronary risk prediction. As a consequence selection into the cohort was based on a non-random inclusion of subjects with and without elevated UAE concentrations. We addressed this by using probability weighted logistic regression analysis. Insulin dependent diabetes was an exclusion criterion for the PREVEND cohort. The number of diabetes patients in PREVEND was therefore low, and characterized by a lower than expected coronary risk. This probably explained the absence of contribution of diabetes to the model refitted to the population with the individual FRS risk factors. In the current study, markers of endothelial dysfunction (UAE) and vascular inflammation (CRP) were strongly related to the occurrence of clinical outcomes. However, UAE and CRP showed little added value when combined with the FRS to predict cardiovascular risk. Interestingly, substantial percentages of subjects were reclassified from the risk category over 20% to the lower risk category by adding UAE or CRP to the FRS based coronary risk prediction. However, although reclassification of risk may have therapeutical consequences,12;25 these may be limited in this group of reclassified subjects, since the observed extrapolated 10 year risk in the group of reclassified subjects was still over 15%. This study is the first to explore the additive value of UAE to FRS risk prediction and adds to recent evidence showing that an elevated albumin-to-creatinine ratio could not improve the predictive ability of a model based on traditional risk factors.26 Two previous studies, the Rotterdam and MONICA Augsburg study, have studied the added value of CRP to the predictive ability of FRS.14;15 The PREVEND study population, a large sample of the general population, was younger than the subjects in the Rotterdam study, which included only elderly subjects, and the MONICA Augsburg study. Furthermore, PREVEND included both males and females in contrast to the MONICA Augsburg study, in which only males were included. The coronary risk profile was therefore lower in PREVEND than in the other studies, which was reflected by the high (42%) number of subjects in the lowest coronary risk category, and the low (17%) number of subjects at high coronary risk. The Rotterdam study could not document any added value of using CRP in combination with the FRS whereas the MONICA Augsburg study showed a minimal increase in AUC in the total study population and in the subgroup at intermediate coronary risk. We showed in PREVEND a modest contribution of CRP and no relationship of UAE using clinically acceptable cut-off value of FRS. This finding could be explained by the overall lower risk in PREVEND due to the young age of the study participants. The higher prevalence of conventional cardiovascular risk factors in the study participants in the Rotterdam study may have attenuated the sensitive role of UAE and CRP as marker of endothelial dysfunction and vascular inflammation. Our second analysis was based on a new model comprising the individual Framingham risk factors in combination with UAE and CRP, refitted in this population. This risk model showed a better fit and predictive ability when compared to the FRS already when based on the Framingham risk factors only. The performance of the model was further improved when CRP was added where the ability to correctly reclassify was increased in 0.9% of subjects. Interestingly, in the subjects reclassified to the risk category above

78

Chapter 4

20%, a high incidence of almost 50% of first coronary events was observed. These results confirm that this marker of vascular inflammation can potentially contribute to coronary risk prediction and may enhance risk assessment, which is in line with the results of the Women’s Health Study, when refitted to the particular population.27;28 However, the number of reclassified subjects was rather small and the implications for risk assessment and management are limited. Also, the generalizability of the model to other populations needs to be determined which reduces the utility relative to simple application of the original FRS. Recommendations for routine measurement of CRP for coronary risk stratification in a primary prevention setting are therefore premature.

Conclusions

In conclusion, the results of the present study show that the addition of urinary albumin excretion and C-reactive protein do not materially improve the predictive ability of the Framingham risk score. When the Framingham risk factors are refitted to a new population, adding CRP may, however, improve risk prediction.

79


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Reference list

1. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340:115-126. 2. Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: Analysis of

potential mechanisms. J Am Soc Nephrol. 2006;17:2106-2111. 3. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human

endothelial cells. Circulation. 2000;102:2165-2168. 4. Lagrand WK, Visser CA, Hermens WT, Niessen HW, Verheugt FW, Wolbink GJ, Hack CE. C-reactive

protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96-102.

5. Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion. An independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992-1997.

6. Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D, De Jong PE. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249:519-526.


8. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet. 1988;2:530-533.





13. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-1565.

14. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation. 2004;109:1349-1353.

15. van der Meer I, de Maat MP, Kiliaan AJ, van der Kuip DA, Hofman A, Witteman JC. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study. Arch Intern Med. 2003;163:1323-1328.

16. Smilde TD, Asselbergs FW, Hillege HL, Voors AA, Kors JA, Gansevoort RT, Van Gilst WH, De Jong PE, van Veldhuisen DJ. Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy. Am J Hypertens. 2005;18:342-347.

17. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.

18. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-266.

19. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC, Jr., Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American

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Heart Association. Circulation. 2003;107:499-511. 20. Burnham, K. P. and Anderson, D. R. Model selection and inference: a practical information-theoretic

approach. New York, NY: Springer; 1998:43-48. 21. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging

the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol. 2004;159:882-890.

22. Royston P, Altman DG. Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. Appl Statistics. 1994;43:429-467.

23. Sauerbrei W, Meier-Hirmer C, Benner A, Royston P. Multivariable regression model building by using fractional polynomials: Description of SAS, STATA and R programs. Computational Statistics & Data Analysis. 2006;50:3464-3485.

24. Hosmer DW, Hosmer T, Le Cessie S, Lemeshow S. A comparison of goodness-of-fit tests for the logistic regression model. Stat Med. 1997;16:965-980.

25. Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation. 2007;115:928-935.

26. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, D’Agostino RB, Vasan RS. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355:2631-2639.

27. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 2006;145:21-29.

28. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611-619.

Chapter 5

Impact of statins in microalbuminuric subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial

C.A. Geluk, F.W. Asselbergs, H.L. Hillege, S. J.L. Bakker, P.E. de Jong, F. Zijlstra, W.H. van Gilst.

European Heart Journal. 2005;26(13):1314-20

84

Chapter 5

Abstract

BackgroundMicroalbuminuria frequently clusters with the metabolic syndrome and may identify subjects at increased coronary risk. Statin treatment may reduce the incidence of major adverse cardiac events in subjects with the Metabolic syndrome, but evidence is limited. We evaluated the impact of pravastatin treatment on the incidence of major adverse cardiac events in microalbuminuric subjects with the metabolic syndrome.

Methods and resultsThis substudy of the PREVEND Intervention Trial (a randomized, placebo-controlled trial with a 2x2 factorial design) included 864 microalbuminuric subjects, who were randomized to fosinopril 20 mg or matching placebo and pravastatin 40 mg or matching placebo (mean follow-up 46 months). The metabolic syndrome was defined according to the NCEP ATPIII-report. Subjects with versus without the metabolic syndrome were characterised by a higher age, male sex and increased albuminuria. The incidence of major adverse cardiac events in subjects with the metabolic syndrome (9.1% (95% confidence interval (CI) 6.0-13.0%)) was increased versus those without (3.6% (95% CI 2.3-5.5%; p=0.007). Pravastatin treatment lowered the incidence of major adverse cardiac events in subjects with the metabolic syndrome after adjustment for age and sex (HR=0.39 (95% CI 0.17-0.89) p=0.025).

ConclusionsThis study supports the use of statins in microalbuminuric subjects with the metabolic syndrome to reduce the incidence of major adverse cardiac events.

85

Statins in microalbuminuric subjects with the metabolic syndrome

Chap

ter 5

Introduction

Microalbuminuria may reflect generalized vascular dysfunction1 and identify subjects at increased coronary risk.2;3 Microalbuminuria frequently clusters with the metabolic syndrome, which is characterized by a constellation of risk factors, among which insulin resistance, dyslipidemia, hypertension, obesity and endothelial dysfunction.4-7 Presence of the metabolic syndrome is associated with increased risk for coronary heart disease.8-12 Since a considerable part of the western population is affected by the metabolic syndrome,13;14 prevention guidelines have advocated risk reduction in these subjects for the prevention of cardiovascular disease.15;16 Large statin trials have shown coronary risk reduction in a primary prevention setting.17-20 The effects of statin therapy in high risk subjects with the metabolic syndrome have been promising, but equivocal.8;20-23 Recently, the PREVEND Intervention Trial has evaluated the effects of interventional treatment on cardiovascular disease incidence in microalbuminuric subjects.24 Pravastatin treatment did not lower the incidence of coronary events in the total study cohort, but the treatment effect has not yet been described in a subgroup of microalbuminuric subjects with the metabolic syndrome. We therefore have performed a supplemental analysis of the PREVEND Intervention Trial (PREVEND IT) for the effects of pravastatin on major adverse cardiac events in microalbuminuric subjects stratified according to presence or absence of the metabolic syndrome.

Methods

PatientsThis study is a supplemental analysis of the PREVEND Intervention Trial (PREVEND IT), which is a substudy of the PREVEND program. The objective of the PREVEND program is to assess the value of microalbuminuria as an indicator of increased cardiovascular and renal risk in the general population.2;25 Details of the PREVEND IT objectives, design and methods have been reported previously.25 Planned additional analyses in the PREVEND program include the Framingham Risk score,26 hs-CRP, intima media thickness27 and the metabolic syndrome. In summary, the PREVEND IT was an investigator driven, single-center, double-blind, randomized, 2x2 factorial design, placebo-controlled trial. The intentional follow up time of 4 years was the same for each subject. The median follow up duration was 47.4 months (interquartile range 46.7-47.9 months). Eight-hundred and sixty-four subjects were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The key entry criteria were persistent microalbuminuria (once a urinary albumin concentration > 10 mg/l in an early morning spot urine and at least once 15-300 mg/24 hours in 2x24-hour urine samples), blood pressure (BP) < 160/100 mm Hg without the use of antihypertensive medication and total cholesterol < 8.0 mmol/l without the use of lipid lowering drugs.24 The metabolic syndrome was defined as the presence of at least three out of five risk determinants according to

86

Chapter 5

the NCEP ATP-III report (increased waist circumference (men >102 cm; women > 88 cm), fasting triglycerides (TG) > 1.69 mmol/L, low HDL-cholesterol (HDL-C) (men < 1.03 mmol/L, women < 1.29 mmol/L), systolic RR ≥130 and/or diastolic RR ≥85 mm Hg and fasting plasma glucose level ≥6.1 mmol/L).16 The primary endpoint was defined as the occurrence of major adverse cardiac events, consisting of total mortality and cardiovascular morbidity at 4 yars. Total mortality was defined as all-cause mortality. Cardiovascular morbidity was defined as hospitalization for documented non-fatal myocardial infarction (MI) or myocardial ischemia.24 Non-fatal MI was defined as a non-fatal event accompanied by at least two out of four of the following which should include either new Q waves (3) and /or enzyme elevation(4): 1. Presence or history of typical or atypical chest pain of at least 15 minutes duration. 2. ECG detection of ST segment changes of at least 0.1mV and/or T wave inversion in at least 2 out of 12 leads. 3. ECG detection of new significant Q waves in at least 2 out of 12 leads. 4. Elevation of measurements of total CPK and/or its isoenzyme CPK-MB in at least two samples drawn within 48 hours of development of chest pain. CPK levels should be >2x the upper limit of normal local laboratory range and/or CPK-MB/CPK ratio > 10%.24 Myocardial ischemia was defined as ischemic events accompanied by the appearance of a ST segment change of >0.1mV and/or T wave inversion in at least 2 of 12 leads or objective evidence by other means than ECG or a need for revascularisation (PCI/ CABG) and severe enough to justify immediate hospital admission.24 Since all ischemic events were accompanied by a revascularisation procedure these events are reported as revascularisations. This substudy of the PREVEND IT reports the incidence of major adverse cardiac events by pravastatin treatment, and does not focus on the fosinopril component of the trial. In the text, the group without pravastatn treatment is labelled as “control group”. The study was approved by the Institutional Review Board and conducted in accordance with the guidelines of the declaration of Helsinki. Informed consent was obtained from all subjects before randomization.

Analytical methodsThe urinary albumin excretion was measured as the mean of two 24h-urine collections. Urinary albumin concentrations were determined by nephelometry with a threshold of 2.3 mg l-1 and intra- and inter-assay coefficients of variation of less than 2.2% and 2.6%, respectively (Dade Behring Diagnostic, Marburg, Germany). Systolic and diastolic BP measurements were calculated as the mean of the last two out of ten consecutive measurements with an automatic Dinamap XL model 9300 series device (Johnson-Johnson Medical INC, Tampa, Florida). Blood glucose, serum total and LDL-cholesterol (LDL-C) were determined by Kodak Ektachem dry chemistry (Eastman Kodak, Rochester, New York, U.S.A.). In text and tables glucose levels are reported as plasma glucose concentrations.28 Blood glucose levels were therefore converted to equivalent plasma glucose concentrations by factor (1.125*whole blood glucose)-0.4375 according to the procedure proposed by Passing and Bablok.29;30

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Statistical analysisAll analyses were performed on an intention-to-treat basis and p-values were two-sided and needed to be <0.05 to be significant. Baseline characteristics are given as means (± standard deviation). In case of a skewed distribution the median (interquartile range) was used. Differences between groups were evaluated by Student t-test or Wilcoxon two sample test, when appropriate. A subject was considered compliant when more than 75% of the supplied study medication was taken during the period of the trial. Log rank statistics are used to test differences in the incidence of major adverse cardiac events between subjects with and without the metabolic syndrome. Because of inequality in distribution of age and sex in the study population, the significance of the difference in major adverse cardiac events between treatment groups was tested by Cox regression analysis after adjustment for age and sex. In addition, adjustment for fosinopril treatment was performed. The significance of the difference in major adverse cardiac events was additionally tested in subjects with the metabolic syndrome who were compliant users of pravastatin, non-diabetics and free of prior coronary heart disease (CHD) respectively. Results are summarized by hazard ratios (HR) with 95% confidence intervals. Times to first major adverse cardiac events are presented as Kaplan-Meier estimates or Cox-adjusted survival curves. Finally, the effect of pravastatin and the metabolic syndrome was tested, taking into account the interaction between the pravastatin treatment group and the metabolic syndrome. Plots of the distribution of the residuals against time and log-log survival curves were used to evaluate adherence of the Cox proportional hazard model assumptions. All calculations were performed with SPSS version 11.0 software (SPSS, Chicago, IL, USA).

Results

Baseline characteristics Thirty-three percent of the subjects (n=286) fulfilled the criteria for the metabolic syndrome, while 67% (n=578) did not have three or more of the qualifying characteristics. Table 1 reports baseline characteristics and the qualifying characteristics of the metabolic syndrome. Levels of albuminuria, total and LDL-C levels were increased in subjects with metabolic syndrome. Subjects with the metabolic syndrome were characterised by a higher age, male sex and a higher prevalence of diabetes. Furthermore, they were more often prescribed medication at baseline. The number of prior cardiovascular events was low and not significantly different between the two groups. Statin use by the control group was 3.5% and comparable in subjects with versus without the metabolic syndrome (p=0.587). In subjects with the metabolic syndrome, those who were treated with pravastatin (n=147) versus controls (n=139) were older. No other significant differences in baseline characteristics were found between the treatment groups (Table 2). In subjects without the metabolic syndrome, no baseline differences were present in the pravastatin (n=286) versus control group (n=292) except for medication (Table 2).

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Table 1. Baseline characteristics and qualifying characteristics of the metabolic syndrome of 864 subjects in the PREVEND IT divided according to the presence of the metabolic syndrome.*

Metabolic syndrome

Baseline characteristics: present (n=286) absent (n=578) P value

Age years 55 (11) 50 (12) <0.001Male gender % 70 62 0.020Caucasian % 96 97 0.381Body mass index kg/m2 29.3 (4.5) 24.9 (3.5) <0.001Current smoking % 39 40 0.186Total cholesterol mmol/L 6.1 (1.0) 5.7 (1.0) <0.001LDL cholesterol mmol/L 4.2 (1.0) 4.0 (0.9) 0.012Albuminuria mg/24h 28.5 (18.8-51.9) 21.0 (14.6-38.2) <0.001Diabetes Mellitus % 20.3 1.9 <0.001Prior cardiovascular disease† % 3.9 3.1 0.571Medication‡ % 8.7 4.0 0.004

Qualifying characteristics of the metabolic syndrome:

Systolic BP mm Hg 140 (15) 126 (17)Diastolic BP mm Hg 81 (9) 74 (9)Increased BP % 82 34Waist cm 102 (11) 87 (11)Abdominal obesity % 64 13HDL-C mmol/L 0.85 (0.19) 1.11 (0.34)Low HDL-C % 96 58TG mmol/L 1.99 (1.69-2.81) 1.08 (0.78-1.44)Elevated TG % 75 15Glucose mmol/L 5.7 (1.7) 4.8 (0.6)

Elevated glucose levels % 33 3

* Values are mean (SD) or median (interquartile range) for albuminuria and TG which were skewed distributed. To convert values for cholesterol to mg/dl, divide by 0.02586. To convert values for TG to mg/dl, divide by 0.01129. Please see text for the definition of the metabolic syndrome.†myocardial infarction, angina pectoris, coronary angioplasty or bypass, heart failure or cerebrovascular accident. ‡aspirin and anti-platelet agents, beta-blockers, nitrate, diuretics, calcium channel blockers or digoxin. Figure 1.

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Figure 1. Reductions in LDL-C (left panel) and BP (right panel) in the pravastatin and control group according to the presence of the metabolic syndrome. *p=0.037.

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The use of fosinopril was equally divided in the pravastatin and control groups: in those with the metabolic syndrome 51.7% and 45.3% (p=0.281), respectively, and in those without the metabolic syndrome 49.0% and 52.1% (p=0.456), respectively.

LDL-C and systolic BP measurements during study follow upLDL-C and BP measurements were performed at consecutive timepoints during study follow up: at baseline, after 3 months and after 1, 2, 3 and 4 years (Figure 1). Owing to premature discontinuation of the study24 and technical failure of 5 baseline LDL-C measurements26 some data are missing. In subjects treated with pravastatin, LDL-C after 3 months was higher in subjects with versus without the metabolic syndrome (p=0.037), although reductions in LDL-C after 3 months were similar (respectively -1.19±0.71 and -1.18±0.79 mmol/L; p=0.927). No significant differences at other timepoints were found. In the control group, no significant differences were found in LDL-C in subjects with the metabolic syndrome when compared to those without (Figure 1; left panel). No significant effect of pravastatin treatment was found on HDL-C and TG levels in those with or without the metabolic syndrome. Systolic BP levels in those with or without the metabolic syndrome were similar in those treated with or without pravastatin or with placebo at all timepoints (Figure 1; right panel).

Table 2. Baseline characteristics of 286 subjects with the metabolic syndrome (upper panel) and 578 subjects without the metabolic syndrome (lower panel) in the PREVEND IT in the pravastatin and control group.*

Pravastatin Control P valueMetabolic syndrome present: n=147 n=139Age years 56 (11) 53 (11) 0.015Male gender % 75 66 0.083Current smoking % 44 33 0.060Systolic BP mm Hg 139 (17) 140 (13) 0.809LDL-C mmol/L 4.2 (1.0) 4.2 (1.0) 0.989HDL-C mmol/L 0.85 (0.18) 0.84 (0.20) 0.575Albuminuria mg/24h 28.0 (18.4-50.9) 29.4 (19.2-53.5) 0.488Medication† % 6.1 11.5 0.107Metabolic syndrome absent: n=286 n=292Age years 50 (12) 19 (12) 0.496Male gender % 64 61 0.403Current smoking % 59 60 0.707Systolic BP mm Hg 125 (17) 126 (17) 0.382LDL-C mmol/L 4.0 (0.9) 4.0 (0.9) 0.602HDL-C mmol/L 1.1 (0.3) 1.1 (0.4) 0.388Albuminuria mg/24h 19.8 (14.1-38.2) 21.3 (15.0-38.5) 0.407Medication† % 2.1 5.7 0.022

* Values are mean (SD) or median (interquartile range) for albuminuria which was skewed distributed. To convert values for cholesterol to mg/dl, divide by 0.02586. †aspirin and anti-platelet agents, beta-blockers, nitrate, diuretics, calcium channel blockers or digoxin.

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The incidence of major adverse cardiac events according to the presence of the metabolic syndrome The incidence of major adverse cardiac events was increased in subjects with the metabolic syndrome versus those without: 9.1% (95% CI 6.0-13.0%) versus 3.6% (95% CI 2.3-5.5%) (p=0.007). The Kaplan-Meier survival curves are shown in Figure 2.

The incidence of major adverse cardiac events in microalbuminuric subjects according to the metabolic syndrome and treatment In subjects with the metabolic syndrome, the incidence of major adverse cardiac events at 4 years was 12.2% in the control group and 6.1% in the pravastatin group. The distribution of the separate components of major adverse cardiac events was similar in the control group when compared with the pravastatin group: 5 versus 2 MIs, 7 versus 4 revascularisations and 7 versus 4 deaths, respectively. The incidence of these single components was not significantly different between the two groups. However, regarding the composite endpoint, pravastatin treatment showed a significant beneficial effect on the incidence of major adverse cardiac events (Figure 3). In an unadjusted model, treatment with pravastatin tended to reduce the hazard ratio for major adverse cardiac events two-fold (HR 0.48 (95% CI 0.21-1.07) p=0.074). After adjustment for age and sex pravastatin treatment significantly lowered the hazard ratio for major adverse cardiac events (HR 0.39 (95% CI 0.17-0.89) p=0.025). Additional adjustment for fosinopril treatment did not affect the results (HR 0.39 (95% CI 0.17-0.89) p=0.026). The effect of pravastatin treatment on the incidence of major adverse cardiac events was significant in compliant pravastatin users (HR=0.35 (95% CI 0.15-0.82) p=0.015), in non-diabetics (HR=0.28 (95% CI 0.11-0.74) p=0.010), and in subjects without prior CHD (HR=0.38 (95% CI 0.16-0.89) p=0.027). In subjects without the metabolic syndrome, the incidence of major adverse cardiac events at 4 years was 3.1% in the control group and 4.2% in the pravastatin group.

Figure 2. Kaplan Meier estimates of the incidence of major adverse cardiac events according to the presence of the metabolic syndrome.

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Treatment with pravastatin did not significantly reduce the incidence of major adverse cardiac events (HR=1.40 (95% CI 0.59-3.31) p=0.45) in an unadjusted model, neither after adjustment for age and sex (HR=1.31 (95% CI 0.55-3.12) p=0.54) or additionally adjusted for fosinopril treatment (HR=1.32 (95% CI 0.56-3.15) p=0.53).The interaction between pravastatin treatment and the metabolic syndrome on the incidence of major adverse cardiac events, adjusted for age, sex and fosinopril, was statistically significant (p=0.040).

Discussion

This substudy of the PREVEND Intervention Trial shows that in microalbuminuric subjects in whom the metabolic syndrome was present, the incidence of major adverse cardiac events at four years was increased when compared to subjects without the metabolic syndrome. Pravastatin treatment effectively lowered the incidence of major adverse cardiac events in subjects with the metabolic syndrome. The importance of the metabolic syndrome as a risk factor for coronary heart disease has been recognized by both the NCEP ATPIII 16 and the European Third Joint Task Force prevention guidelines.15 Large statin trials have shown coronary risk reduction in subjects without clinically overt atherosclerosis.8;17-23 In these trials, distinct inclusion criteria were employed, such as an adverse lipid profile, hypertension, CHD, diabetes or vascular disease, all identifying subjects at increased CHD risk. However, the number of trials which focussed on subjects with the metabolic syndrome is limited and the results are not consistent. Some trials showed superior or equal risk reduction in patients with features of the metabolic syndrome,17;18;21-23 while one study did not

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Figure 3. Cox-adjusted survival curves of the incidence of major adverse cardiac events according to pravastatin treatment in subjects with (left panel) and without the metabolic syndrome (right panel). Asterisk indicates age and sex adjusted P-values.

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show a clinical benefit of statin treatment in patients with the metabolic syndrome.20 The PREVEND Intervention Trial was designed to study the incidence of cardiovascular events in microalbuminuric subjects treated by pravastatin or fosinopril in a 2x2-design.24 This supplemental analysis of the PREVEND Intervention Trial shows that the presence of both the metabolic syndrome and microalbuminuria identifies a group of subjects at high coronary risk who are candidates for statin treatment to reduce the incidence of major adverse cardiac events. Our results are in concordance with previous reports that showed that statin treatment was most effective in diabetes patients and in non-diabetic subjects with features of the metabolic syndrome (substudies of the WOSCOPS, 4S trial and CARE trial).8;20-23

The WOSCOPS has evaluated the effects of pravastatin treatment (40 mg) versus placebo in 6595 hypercholesterolemic men in a primary prevention setting.19 Twenty six percent of the total study population had the metabolic syndrome. The incidence of coronary death and MI was similarly reduced in subjects with the metabolic syndrome (HR= 0.73 (95% CI 0.53-1.01)) when compared to those without (HR=0.69 (95% CI 0.54-0.89)).8

The 4S trial reported the effects of simvastatin (20 or 40 mg) versus placebo in CHD patients with elevated LDL-C levels.21;31 In one substudy, patients were divided by presence of the lipid triad (high TG, low HDL-C and high LDL-C), which was accompanied by features of the metabolic syndrome.21 The relative risk reduction of major adverse cardiac events was significant in 458 subjects with the lipid triad (RR=0.48 (95% CI 0.33-0.69)), but no significant risk reduction was observed in 545 patients with isolated high LDL-C (RR=0.86 (95% CI 0.59-1.26)). Another substudy of the 4S trial confirmed the benefit of statin treatment in patients with impaired glucose tolerance.23

The CARE trial studied the effects of pravastatin 40 mg versus placebo in 3553 non-diabetic CHD patients.22 Patients with impaired glucose tolerance (n=342) and a concomitant disadvantageous cardiovascular risk profile suffered more recurrent MIs than 3104 patients with normal glucose tolerance during 5 years of follow up. Although relative risk reductions by pravastatin treatment were equal in both groups, absolute risk reduction was greater in those with impaired glucose tolerance. The WOSCOPS, 4S trial and the CARE trial therefore provide evidence on the use of statin treatment in subjects with features of the metabolic syndrome. Only 3% of our study group had a history of cardiovascular disease. The four year incidence of major adverse cardiac events was 12.2% in microalbuminuric subjects with the metabolic syndrome in the PREVEND IT (control group), which was comparable to the event rate in the metabolic syndrome WOSCOPS substudy (five year placebo event rate 10.4%), but much lower when compared to the 35.9% five year major adverse cardiac events incidence in patients with the lipid triad in the 4S study (on placebo) and the 34.7% five year event incidence (CHD death, MI and revascularisation procedure) in patients with impaired glucose tolerance in the CARE trial (on placebo).21;22 Since the incidence of major adverse cardiac events was affected by statin treatment in subjects with the metabolic syndrome only, our substudy of

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PREVEND IT supports the use of statins in subjects with microalbuminuria, in whom the presence of the metabolic syndrome reveals a high CHD risk. This study therefore contributes to the current knowledge on the benefit of statin therapy in subjects with the metabolic syndrome. This is in contrast with the results from the ASCOT-LLA substudy on the metabolic syndrome. The ASCOT-LLA investigated the effects of atorvastatin 10 mg (versus placebo) on the incidence of major adverse cardiac events in 10,305 hypertensive subjects with 3 additional cardiovascular risk factors, but without previous CHD or hypercholesterolemia.20 The event rate (non fatal MI plus fatal CHD) was 3.1% in 3926 subjects with the metabolic syndrome (on placebo) during 3.3 years of follow up, which is similar to the event rate in our study. In contrast with our study results, atorvastatin treatment did not result in clinical benefit in subjects with the metabolic syndrome. The beneficial effects of statin therapy in subjects with the metabolic syndrome may be partly explained by its lipid independent effects. In our study, equal reductions of LDL-C were found in subjects with and without the metabolic syndrome. Reductions in BP were equal in the pravastatin and control group and could therefore not account for the event reduction in subjects with the metabolic syndrome. Urinary albumin, HDL-C and TG levels were not altered by pravastatin therapy.24 Besides lipid lowering, statins may reduce cardiovascular burden through plaque stabilization or through beneficial effects on the vasculature, e.g. NO mediated vasodilatation, a decrease in inflammation and an improvement of fibrinolytic balance.32-35 All of these processes are harmed in an insulin resistant state, which is the fundamental disorder of the metabolic syndrome.36 The link between microalbuminuria and insulin resistance is not fully known.2;3;37 In our study, microalbuminuric subjects with the metabolic syndrome had higher levels of urinary albumin than those without. Our study results are in agreement with previous studies, that showed that levels of urinary albumin were associated with metabolic risk factors.38-40 Microalbuminuria has also been associated to parameters of vascular dysfunction, that may accompany the metabolic syndrome.41-43 Additionally, microalbuminuria may reflect the atherosclerotic burden present in patients with the metabolic syndrome.1;44 Therefore, one may hypothesise that subjects with the metabolic syndrome and microalbuminuria are among the most vulnerable for development of atherosclerotic processes. This may be improved by statin treatment. However, as participants in our study were selected for microalbuminuria, our study design does not allow us to assess the clinical impact of statin therapy in normoalbuminuric subjects with the metabolic syndrome.

LimitationsThe PREVEND IT was limited by an unexpected small number of events, resulting in an insufficient power to detect an effect of pravastatin treatment on the incidence of major adverse cardiac events in subjects without the metabolic syndrome. It should be addressed that no specific information was available regarding microalbuminuric subjects in the design phase of this intervention study. However, our results are in line with results of earlier clinical trials, which showed that in subjects at increased risk of CHD, LDL-C lowering resulted in a reduction of CHD risk. 8;17-23 We therefore feel

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that our results are generalizable to patients with microalbuminuria who are at high risk of CHD, such as due to the presence of the metabolic syndrome. In the PREVEND IT, subjects with a BP over 160/100 mm Hg were excluded. This may have led to an underestimation of the prevalence of the metabolic syndrome. However, we assume that the benefit of pravastatin in microalbuminuric subjects with the metabolic syndrome at higher BP levels is not significantly different from the subjects included in our study.

Conclusion

This study supports the prescription of statin treatment in microalbuminuric subjects with the metabolic syndrome to reduce the incidence of major adverse cardiac events.

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Chapter 6

Measurement of coronary calcium scores or exercise testing as initial screening tool in asymptomatic subjects with ST-T changes on the resting ECG: an evaluation study

C.A. Geluk, R. Dikkers, J.A. Kors, R.A. Tio, R.H.J.A. Slart, R. Vliegenthart, H.L Hillege, T.P. Willems, P.E. de Jong, W.H. van Gilst, M. Oudkerk, F. Zijlstra.

BMC Cardiovasular Disorders. 2007;7:19

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Abstract

Background Asymptomatic subjects at intermediate coronary risk may need diagnostic testing for risk stratification. Both measurement of coronary calcium scores and exercise testing are well established tests for this purpose. However, it is not clear which test should be preferred as initial diagnostic test. We evaluated the prevalence of documented coronary artery disease (CAD) according to calcium scores and exercise test results.

Methods and resultsAsymptomatic subjects with ST-T changes on a rest ECG were selected from the population based PREVEND cohort study and underwent measurement of calcium scores by electron beam tomography and exercise testing. With calcium scores ≥10 or a positive exercise test, myocardial perfusion imaging (MPS) or coronary angiography (CAG) was recommended. The primary endpoint was documented obstructive CAD (≥50% stenosis). Of 153 subjects included, 149 subjects completed the study protocol. Calcium scores ≥400, 100-399, 10-99 and <10 were found in 16, 29, 18 and 86 subjects and the primary endpoint was present in 11 (69%), 12 (41%), 0 (0%) and 1 (1%) subjects, respectively. A positive, nondiagnostic and negative exercise test was present in 33, 27 and 89 subjects and the primary endpoint was present in 13 (39%), 5 (19%) and 6 (7%) subjects, respectively. Receiver operator characteristics analysis showed that the area under the curve, as measure of diagnostic yield, of 0.91 (95% CI 0.84-0.97) for calcium scores was superior to 0.74 (95% CI 0.64-0.83) for exercise testing (p=0.004).

Conclusions Measurement of coronary calcium scores is an appropriate initial non-invasive test in asymptomatic subjects at increased coronary risk.

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Introduction

In selected asymptomatic subjects with an intermediate coronary risk profile, non-invasive testing may be required for coronary risk stratification.1-5 Guidelines recommend the use of exercise testing 2;6;7 and measurement of coronary calcium scores,8 since the predictive values of both non-invasive tests for future coronary events have been well established in asymptomatic subjects at intermediate risk.7;9-11 However, guidelines do not recommend one of these tests as initial screening tool in these subjects. Although an abnormal exercise test result is widely accepted as indication for coronary angiography (CAG),12 the indications for an invasive diagnostic or therapeutic procedure have not yet been defined for subjects with high calcium scores. This may be of particular importance for subjects with calcium scores ≥400, since these subjects are at a high annual risk of cardiac events of 4.8%.9 So far, no head to head studies have compared exercise testing with measurement of calcium scores as initial tool in the evaluation of coronary artery disease (CAD).Our aim was to investigate the diagnostic yield of coronary calcium scores and exercise testing in asymptomatic subjects with an intermediate coronary risk profile. Therefore, in a population based cohort study, all 12-lead rest ECGs with ST depression (defined as Minnesota codes 4.1-2 (>0.5 mm ST-junctional depression)), T-wave inversion (codes 5.1-2 (T wave inversion ≥1.0 mm)) or with an abnormal frontal T-axis (-180° to -15° and 105° to 180°)13-17 were selected, after exclusion of the ECGs with non-interpretable ST segments during the exercise test by a clinical cardiologist.7 These subjects are representative for a study population at intermediate coronary risk, due to the selection from a low risk population and in the presence of ≥1 high risk characteristic.13-18 First, we investigated the prevalence of documented CAD. Second, we investigated the invasive therapeutic implications according to coronary calcium scores and exercise test results.

Methods

Subjects Asymptomatic male and female subjects with ST-T changes on a 12-lead resting ECG were selected from the prospective population based Prevention of REnal and Vascular ENdstage Disease (PREVEND) cohort study in Groningen, the Netherlands. The primary aim of this cohort study is to assess the value of urinary albumin excretion in relation to cardiovascular and renal risk. In addition to the ECG, collected data include medical history, demographics, biometric data, urine- and blood collections and laboratory measurements. The first visit has taken place between 1997-1998. Subjects for the current study were selected after the second visit (2001-2003). Exclusion criteria were previous manifestations of coronary heart disease (myocardial infarction, revascularization procedure, or Q waves on the ECG) or coronary angiography (CAG); age >70 years; and subjects in whom the ST-T segment was not interpretable during

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the exercise test due to atrial fibrillation or left bundle branch block (LBBB) or ST depression >1mm at 80 msec after the J point.7 For details on the PREVEND study design we refer to earlier publications.19 All participants underwent measurement of calcium scores by EBT and exercise testing. This PREVEND substudy was approved by the medical ethics committee and conducted in accordance with the guidelines of the declaration of Helsinki. All participants have given written informed consent.

Electrocardiography Standard 12-lead ECGs were recorded with Cardio Perfect equipment (Cardio Control, Delft, The Netherlands), stored digitally, and classified according to the Minnesota code, using the computer program MEANS (Modular ECG Analysis System).20 Signal analysis and classification of MEANS have been extensively evaluated.21;22 ST-T segment changes were defined by Minnesota codes 4.1-2 (ST-junctional depression ≥0.5 mm) and 5.1-2 (negative T-wave ≥1 mm) or abnormal mean frontal T-axis (-180° to -15° and 105° to 180°).13-18 T axes were computed from vectorcardiographic X, Y and Z leads, which can, in good approximation, be reconstructed from the standard ECG leads.23 The mean spatial axis was obtained by vectorially adding the instantaneous heart vectors during the T wave. The mean frontal T axis is the angle between the X axis and the projection of the mean spatial T axis on the frontal XY plane. Q waves were defined by Minnesota codes 1.1-1.3.17 All ECGs were reviewed by a senior clinical cardiologist in order to exclude the ECGs of which the ST-T segment was not interpretable during the exercise test.

Measurement of coronary calcium scores Coronary calcium was measured using electron beam tomography (EBT) (e-Speed, GE Medical Systems, South San Francisco, USA). According to subjects’ weight and size the beam speed was set to 50 ms (for small or slender patients) or 100 ms (for larger patients). Prospective ECG triggering was used and set at 42% of the R-R interval. Scans were made without the use of a contrast agent with 130 kV and 895 mAs. A single collimation of 3.0 mm and an increment of 3.0 mm was applied. Total radiation exposure was <1 mSv for each patient. The coronary calcium score was obtained by multiplying each area of interest with a factor indicating peak density within the individual area, as was proposed by Agatston.24

Exercise testing As is common practice in the Netherlands, all exercise tests were performed on a bicycle. Exercise tests were performed in accordance with the guidelines for exercise testing.6;7 All exercise tests were independently reviewed by a cardiologist (RT) and a research physician (CG), who reached consensus in all cases. Exercise test end points were defined as follows: positive, in case of ECG evidence of myocardial ischemia (≥1.0 mm horizontal shift of the ST segment at 80 msec after the J point compared to the baseline ECG) and/or in case of 30 mmHg decrease in systolic blood pressure and/or ventricular arrhythmia and/or typical angina; intermediate, in case of <1.0 mm ST depression as compared to baseline and/or aspecific anginal complaints in

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the absence of ECG evidence of ischemia; negative, in the absence of any of the above mentioned criteria; and non-interpretable, if <85% of the age- and sex- predicted heart rate or a rate pressure product <18,000 was achieved. Intermediate and non-interpretable results are considered as “nondiagnostic test results”.

Protocol All patients underwent measurement of coronary calcium scores by EBT and exercise testing. Test performance was evaluated according to the decision protocol as given in figure 1. In case of calcium scores ≥10, or positive exercise test result, CAG or MPS was recommended to evaluate the presence of obstructive CAD (figure 1). In subjects with calcium scores <10 and a negative or nondiagnostic exercise test result, a test to document obstructive CAD was not recommended. In this population the presence of obstructive CAD is almost fully excluded due to the high negative predictive value of low calcium scores on CAD.9;10;25 In subjects with calcium scores <10 and a positive exercise test and in subjects with calcium scores 10-99, the first choice recommended test was myocardial perfusion scintigraphy (MPS), followed by CAG in case of abnormal results. In subjects with calcium scores 100-399 and in subjects with calcium scores ≥400, the first choice recommended test was CAG.

Endpoints The primary endpoint was defined as documented CAD, i.e. presence of obstructive significant CAD (≥50% luminal obstruction), based on CAG, or MPS, in case CAG was not available. Myocardial perfusion scintigraphy was performed as previously

Calcium score <10

Calcium score 10-99 + any exercise test result

Calcium score ≥100 + any exercise test result

EBCT + exercise test

Nondiagnostic exercise test

MPS ± CAG

CAG ± MPS

Follow up

(n=149)

(n=86)

(n=18)

Positive exercise test

Negative exercise test

(n=9)

(n=10)

(n=67)

(n=45)

Figure 1. Decision protocol**see text for explanationAbbreviations: CAG, coronary angiography; MPS, myocardial perfusion scintigraphy.

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described.26 All CAGs were re-analysed by a senior cardiologist (FZ), without knowledge of the clinical data. By qualitative analysis the coronary arteries were graded as follows: normal coronary arteries, defined as the absence of any coronary lesion; non-obstructive CAD, if maximal luminal obstructions were <50%; and obstructive CAD, if lesions obstructed the lumen ≥50% (i.e. documented CAD). The secondary endpoint was a class I or IIa indication for a revascularization procedure (percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG)) according to the ESC and ACC/AHA guidelines for PCI and CABG.27-29 Decisions to perform a revascularization procedure were taken by the Thoraxcenter multidisciplinary heart team. In case of obstructive CAD (≥50% luminal stenosis), either MPS, or fractional flow reserve (FFR) measurement30;31 was performed to guide the decision for a revascularization procedure. An FFR <0.75 was an indication for a revascularization procedure. All subjects were followed for the occurrence of cardiac events, i.e. myocardial infarction or coronary death. Cardiac events were collected by review of the subject’s medical record, questionnaire or telephone interview.

Statistical analysis Continuous data are expressed as mean ± standard deviation. Hypertension was defined as a systolic blood pressure >140 mmHg and/or diastolic >90 mmHg or use of antihypertensive medication. Left ventricular hypertrophy (LVH) on the ECG was defined according to the Cornell voltage-duration product.19 Framingham risk estimations were calculated according to Wilson et al32 Since HDL cholesterol was not measured during the second visit, HDL cholesterol data of the first visit were used for the Framingham risk estimations. Significance was reached when p<0.05. To compare the diagnostic yield of calcium scores with exercise test results, receiver operating characteristic (ROC) curve analysis was performed. We compared the area under the curves of both tests for the primary and the secondary endpoints. For the ROC analysis, subjects with calcium scores <10 and a negative or nondiagnostic exercise test and in whom MPS or CAG was not performed, were assumed to have no endpoints. Calculations were performed using the statistical package SPSS version 12.0 (SPSS, Chicago, USA) and STATA 9.0 (College Station, Texas, USA).

Results

Baseline characteristics In 6,804 (99%) of 6,894 subjects participating in PREVEND between 2001-2003, a 12-lead resting ECGs was recorded. Of 481 (7%) subjects with ST-T changes on the ECG, 291 subjects had any of the following characteristics, namely previous manifestation of coronary heart disease; age >70 years; atrial fibrillation; LBBB or ST depression >1.0 mm at 80 msec after the J point. Of 190 subjects invited, 153 responded (81%) and were included. Baseline characteristics of the participants are shown in table 1. Of the 11 subjects with ECG criteria for LVH, 5 had calcium scores

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of 0 and 6 between 16 and 1313. The 10-year estimated Framingham risk was <10% in 49%, 10-20% in 22% and >20% in 29% of subjects.

Test results Eighty-six (58%) participants had low calcium scores (<10), 18 (12%) had calcium scores 10-99, 29 (19%) participants had calcium scores 100-399 and 16 (11%) participants had high calcium scores (≥400). Exercise test characteristics are shown in table 2. Significant ST depression occurred in 19% of subjects and angina was present in 2%. Eighty-nine (60%) participants had a negative exercise test result, while 27 (18%) had a nondiagnostic and 33 (22%) had a positive exercise test result.

Endpoints Four patients refused to undergo CAG or MPS as recommended by the decision protocol, namely one patient with calcium scores <10 and a positive exercise test; one patient with calcium scores 10-99 and a positive exercise test; one patient with

Table 1. Baseline characteristics.

Characteristics n=153

Age, mean (SD), y 56 (9)Male gender, No. (%) 88 (58)Blood pressure, mean (SD), mm Hg

Systolic 133 (23)Diastolic 76 (10)

Hypertension, No. (%) 75 (49)Current smoking, No. (%) 30 (20)Diabetes, No. (%) 15 (10)History of Cerebrovascular accident, No. (%) 3 (2)History of Peripheral Arterial Disease, No. (%) 2 (1)History of Valvular Heart Disease, No. (%) 0 (0)Total cholesterol, mean (SD), mmol/L 5.5 (1.1)Albuminuria, median (interquartile range), mg/24h 8.7 (5.9-17.3)Medication, No. (%)

Lipidlowering 29 (19)Antihypertensive medication 62 (41)

Diuretics 37 (24)Betablockers 24 (16)ACE/AII blockers 30 (20)Calciumantagonists 8 (5)

Aspirin 13 (9)Antidiabetic treatment 15 (10)

Left ventricular hypertrophy criteria, No. (%) 11 (7)

Abbreviations: HDL, high density lipoprotein.SI conversion factor: to convert mmol/L to mg/dL, divide values for total cholesterol and HDL cholesterol by 0.0259 and divide values for triglycerides by 0.0113.

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calcium scores 10-99 and a negative exercise test; and one patient with calcium scores ≥400 and positive exercise test result. Therefore, outcome was obtained in 149 participants (100%) during 14±3 months of follow up. No cardiac events occurred during follow up. The primary endpoint (documented CAD) was present in 24 (16%) participants. In 16 (11%) participants, the secondary endpoint, a Class I or IIa indication for revascularization procedure, was present according to the ESC and ACC/AHA guidelines for PCI and CABG in asymptomatic patients.27-29

The diagnostic yield of coronary calcium scores compared to the exercise test Results are shown in table 3 and figure 2. The primary and secondary endpoints were present in, respectively, 69% and 63% of 16 subjects with calcium scores ≥400 and in, respectively, 39% and 27% of 33 subjects with a positive exercise test. In 37% of the 33 subjects with a positive exercise test, the absence of CAD was confirmed by a low calcium score and/or normal coronary arteries at CAG. A false negative test result was observed in 1% of 86 subjects with calcium scores <10 and in 7% of 89 subjects with a negative exercise test result. The subject with calcium scores <10, a positive exercise test and obstructive CAD was a non-diabetic, male 56-year old subject, a past smoker, who underwent a revascularization procedure for a left main stenosis. With regard to the primary endpoint, ROC statistics show an increased diagnostic yield of calcium scores above exercise testing: the area under the curve is 0.91 (95% CI 0.84-0.97) for calcium scores versus 0.74 (95% CI 0.64-0.83) for exercise testing

Table 2. Exercise test characteristics*.

Rest

Heart rate, per minute 75 (13)Systolic blood pressure, mmHg 142 (23)Diastolic blood pressure, mmHg 83 (11)

Exercise

Heart rate, per minute 147 (27)Systolic blood pressure, mmHg 205 (32)Diastolic blood pressure, mmHg 90 (16)Exercise capacity, Watt 151 (57)Rate pressure product 30,141 (7,381)Significant ST depression, No. (%)† 29 (19)>30 mmHg decrease in blood pressure, No. (%) 3 (21)Ventricular arrhythmia, No. (%) 5 (3)Angina, No. (%) 3 (2)

Recovery

Heart rate, per minute 97 (21)Systolic blood pressure, mmHg 145 (37)Diastolic blood pressure, mmHg 76 (19)

*Values are given in mean (SD) unless indicated. †for definition please see methods section.

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Table 3. Endpoints.

Calcium score Exercise test result No. (%) No. of

CAG*No. ofMPS*

No. with primary

endpoint†

No. with secondary endpoint‡

<10 (n=86) Positive 10/86 (12%) 3 7 1 1Nondiagnostic 9/86 (10%) - - 0 0

Negative 67/86 (8%) - - 0 0

10-99 (n=18) Positive 2/18 (11%) 1 1 0 0

Nondiagnostic 8/18 (44%) 4 4 0 0

Negative 8/18 (44%) 2 6 0 0

100-399 (n=29) Positive 14/29 (48%) 11 3 6 2


Negative 10/29 (34%) 7 3 4 2

≥400 (n=16) Positive 7/16 (44%) 7 0 6 6


Negative 4/16 (25%) 4 0 2 2

Abbreviations: CAG, coronary angiography; MPS, myocardial perfusion scintigraphy.*MPS was used for endpoint grading when CAG was not available.†primary endpoint, documented significant coronary artery disease.‡secondary endpoint, Class I or IIa indication for a revascularization procedure in asymptomatic patients.

A

0%

10%

20%

30%

40%

50%

60%

70%

Neg. Nond. Pos. <10 11-99 100-399 ≥400

Coronary Calcium Scores Exercise Testing

B

0%

10%

20%

30%

40%

50%

60%

70%

<10 11-99 100-399 ≥400

Coronary Calcium Scores

Neg. Nond. Pos.

Exercise Testing

Figure 2. Endpoints according to coronary calcium scores and exercise test results. (A) primary endpoint (documented significant obstructive coronary artery disease). (B) secondary endpoint (Class I or IIa indication for revascularization procedure).Abbreviations: neg., negative; nond., nondiagnostic; pos., positive.

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(p=0.004; figure 3). With regard to the secondary endpoint, ROC statistics show a similar pattern, albeit not statistically significant: the area under the curve is 0.90 (95% CI 0.78-1.00) for calcium scores versus 0.73 (95% CI 0.52-0.93) for exercise testing (p=0.170; figure 3).

A0.

000.

250.

500.

751.

00Se

nsit

ivit

y

0.00 0.25 0.50 0.75 1.00

1-Specificity


Exercise Testing

p=0.004

B

0.00

0.25

0.50

0.75

1.00

Sens

itiv

ity

0.00 0.25 0.50 0.75 1.00

1-Specificity


Exercise Testing

p=0.170

Figure 3. Receiver operator characteristic curves.(A) primary endpoint (documented significant obstructive coronary artery disease). Area under the curve for coronary calcium scores 0.91 (95% CI 0.84-0.97); Area under the curve for exercise test 0.74 (95% CI 0.64-0.83).(B) secondary endpoint (Class I or IIa indication for revascularization procedure)Area under the curve for coronary calcium scores 0.90 (95% CI 0.78-1.00); Area under the curve for exercise test 0.73 (95% CI 0.52-0.93)

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Discussion

Principal findings Our results show that the diagnostic yield of measurement of coronary calcium scores for documented obstructive CAD is clearly superior to exercise testing in asymptomatic subjects at increased coronary risk. Furthermore, compared to exercise testing, high calcium scores identified a higher number of subjects with a class I or IIa indication for a revascularization procedure according to the ESC and ACC/AHA guidelines for PCI and CABG.

General comments Non-invasive testing, such as measurement of coronary calcium scores and exercise testing, have become well established tests for risk stratification in selected asymptomatic subjects encountered in clinical practice.1;2;6-8 Both tests provide fundamentally different diagnostic information. Coronary calcifications are highly specific for atherosclerosis and a strong correlation with total plaque burden has been demonstrated.33;34 Coronary calcifications parallel the development of atherosclerosis, with higher values present in men and in the elderly.35 Higher amounts of coronary calcium have been associated with more severe CAD.33;34;36;37 Coronary calcifications have been associated with hard as well as with soft plaques.38 In ultrasound studies the sensitivity for the detection of soft plaques is lower than for hard plaques.38 However, since the absence of coronary calcium has been associated with a negative predictive value of >95% for future coronary events39;40, (soft) plaques maybe missed by EBCT have a limited clinical importance.5 Absolute coronary calcium scores, as well as age- sex- specific percentiles, have been associated with the occurrence of future coronary events. 35;39-41 Measurement of coronary calcium scores therefore focuses on the detection of CAD, while the exercise test focuses on the detection of myocardial ischemia. The “anatomic approach” has the advantage that certainty on the absence of clinically important CAD is obtained when calcium scores equals zero. This is of clinical importance since many subjects at intermediate risk (a probability of a coronary event between 1-2% per year due to the presence of at least one high risk characteristic or based on Framingham scores 4;5) do not have CAD.42-44 In asymptomatic populations, guidelines traditionally focus on long-term risk assessment and prevention of future manifestations of coronary disease, while the role of invasive diagnostic and therapeutic procedures is hardly discussed.8;45 Although high risk criteria on stress testing in asymptomatic subjects are accepted as indications for CAG12, direct referral to CAG based on high calcium scores is generally believed to be inappropriate.12;46 However, several arguments favor an invasive strategy in subjects with high calcium scores. A clear association has been demonstrated between calcium scores and the amount of myocardial ischemia47-49 as well as the severity of CAD,33;34;36 which are the principle components of guideline recommendations for a revascularization procedure.27-29 In addition, event free survival was decreased in asymptomatic subjects with high calcium scores and an abnormal myocardial perfusion test.49 Clearly, all subjects with high calcium scores require aggressive secondary prevention, including

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treatment with cholesterol lowering, antihypertensive medications and aspirin. Our research protocol recommended performance of CAG in case of calcium scores ≥400 or positive exercise test result. The decision to perform a revascularization procedure when a non-invasive stress test had not been performed prior to CAG, was guided by fractional flow reserve measurement during CAG.12;30;31 Alternative diagnostic strategies may be the performance of CAG only after documentation of myocardial ischemia by non-invasive stress testing,46 or in combination with current generation CT-angiography. We agree that an invasive strategy is associated with a risk of complications and inappropriate revascularizations. The recent COURAGE trial has shown that some patients with stable CAD can be managed conservatively,50 and future guidelines may therefore be adapted. Our multidisciplinary study was based on the former ESC and ACC/AHA guidelines for PCI and CABG,27-29 and identified a substantial number of subjects with a class I or IIa indication for a revascularization procedure. Twenty-nine subjects had a calcium score between 100-399. When compared to subjects with calcium scores ≥400, less subjects had a primary endpoint (41% vs 68%) or an indication for a revascularization procedure (17% vs 63%). This finding is in line with previous findings on the increasing number of abnormal stress tests in case of higher calcium scores, namely in 18-60% of subjects with calcium scores ≥400, compared to 7-23% of subjects with calcium cores of 100-399.47-49 Since the finding of myocardial ischemia in asymptomatic subjects with calcium scores >100 affects clinical outcome, 49 non-invasive stress testing is warranted. This may be followed by an invasive strategy in case of abnormal test results, in addition to appropriate medical treatment. Further studies with larger numbers of patients are needed to evaluate these issues.

Remarks and limitations Thirthy-two patients (21.5%) used betablockers or calcium antagonists at the time of exercise testing. These medications may affect the maximal exercise heart rate.51 This may have contributed to a non-interpretable result found in one case (0.7%). With regard to the exercise test, information on the Duke score and ST-T hysteresis were not measured. Unfortunately, individual FFR values were not registered. We used EBT to measure calcium scores. Due to recent improvements in ECG gating software, shorter scan times and higher resolutions, current generation multi detector CT also provides accurate calcium scores measurements with a radiation dose of 1.0 mSv.52 Since multidetector CT scanners are more widely available than EBT, our results, when extended to multidetector CT scanners, may therefore influence clinical practice. The sensitivity of the exercise test was somewhat lower than expected from large symptomatic populations undergoing exercise testing and coronary angiography.53 However, the test characteristics of our study were very comparable to the studies including only asymptomatic subjects.7;54-56 The specificity for high calcium scores to detect significant CAD in our study population is similar to studies comparing calcium scoring and CAG in symptomatic patients.36;37 This observation implies that

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the association between calcium scores and severity of CAD at CAG may be extendable to asymptomatic populations. The current study population was derived from the PREVEND population of subjects without previous documented coronary heart disease, which can be regarded as a low risk population since 3.3% experienced a first coronary event during 5.5 years of follow up.57 The presence of ST-T changes on the resting ECG is a clear additional high risk characteristic, and therefore our population can be classified as intermediate risk.13-18 The prevalence of coronary calcium scores, in particular with regard to the 30-50% of subjects having calcium scores <10, was comparable to other asymptomatic populations with at least one risk factor.42;43 Our results are therefore applicable in asymptomatic populations, who are candidates for risk stratification, based on the presence of ≥1 high risk characteristic.

Conclusions Measurement of coronary calcium scores is an appropriate initial non-invasive test in asymptomatic subjects at increased coronary risk. Furthermore, invasive diagnostic and therapeutic procedures are indicated in a high number of subjects with coronary calcium scores ≥400.

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18. Ashley EA, Raxwal VK, Froelicher VF. The prevalence and prognostic significance of electrocardiographic abnormalities. Curr Probl Cardiol. 2000;25:1-72.

19. Smilde TD, Asselbergs FW, Hillege HL, Voors AA, Kors JA, Gansevoort RT, Van Gilst WH, De Jong PE, Van Veldhuisen DJ. Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy. Am J Hypertens. 2005;18:342-347.

20. Kors JA, van HG, Wu J, Zhang Z, Prineas RJ, van Bemmel JH. Validation of a new computer program for Minnesota coding. J Electrocardiol. 1996;29 Suppl:83-88.

21. Willems JL, Abreu-Lima C, Arnaud P, van Bemmel JH, Brohet C, Degani R, Denis B, Gehring J, Graham I, van Herpen G, . The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med. 1991;325:1767-1773.

22. van Bemmel JH, Kors JA, van Herpen G. Methodology of the modular ECG analysis system MEANS. Methods Inf Med. 1990;29:346-353.

23. Kors JA, van Herpen G, Sittig AC, van Bemmel JH. Reconstruction of the Frank vectorcardiogram from standard electrocardiographic leads: diagnostic comparison of different methods. Eur Heart J. 1990;11:1083-1092.

24. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Jr., Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832.

25. Budoff MJ, Shokooh S, Shavelle RM, Kim HT, French WJ. Electron beam tomography and angiography: sex differences. Am Heart J. 2002;143:877-882.

26. Slart RH, Bax JJ, Sluiter WJ, Van Veldhuisen DJ, Jager PL. Added value of attenuation-corrected Tc-99m tetrofosmin SPECT for the detection of myocardial viability: comparison with FDG SPECT. J Nucl Cardiol. 2004;11:689-696.

27. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, Hart JC, Herrmann HC, Hillis LD, Hutter AM, Jr., Lytle BW, Marlow RA, Nugent WC, Orszulak TA. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 2004;110:e340-e437.

28. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines for percutaneous coronary interventions: the task force for percutaneous coronary interventions of the European society of cardiology. Eur Heart J. 2005;26:804-847.

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29. Smith SC, Jr., Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO, Gibbons RJ, Alpert JP, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith SC, Jr. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001;37:2215-2239.

30. Berger A, Botman KJ, MacCarthy PA, Wijns W, Bartunek J, Heyndrickx GR, Pijls NH, De Bruyne B. Long-term clinical outcome after fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. J Am Coll Cardiol. 2005;46:438-442.

31. Bech GJ, De Bruyne B, Pijls NH, de Muinck ED, Hoorntje JC, Escaned J, Stella PR, Boersma E, Bartunek J, Koolen JJ, Wijns W. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation. 2001;103:2928-2934.

32. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847.

33. Simons DB, Schwartz RS, Edwards WD, Sheedy PF, Breen JF, Rumberger JA. Noninvasive definition of anatomic coronary artery disease by ultrafast computed tomographic scanning: a quantitative pathologic comparison study. J Am Coll Cardiol. 1992;20:1118-1126.


35. Wong ND, Budoff MJ, Pio J, Detrano RC. Coronary calcium and cardiovascular event risk: evaluation by age- and sex-specific quartiles. Am Heart J. 2002;143:456-459.



38. Baumgart D, Schmermund A, Goerge G, Haude M, Ge J, Adamzik M, Sehnert C, Altmaier K, Groenemeyer D, Seibel R, Erbel R. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol. 1997;30:57-64.

39. Arad Y, Spadaro LA, Goodman K, Lledo-Perez A, Sherman S, Lerner G, Guerci AD. Predictive value of electron beam computed tomography of the coronary arteries. 19-month follow-up of 1173 asymptomatic subjects. Circulation. 1996;93:1951-1953.

40. Shaw LJ, Raggi P, Schisterman E, Berman DS, Callister TQ. Prognostic value of cardiac risk factors and coronary artery calcium screening for all-cause mortality. Radiology. 2003;228:826-833.

41. Raggi P, Cooil B, Callister TQ. Use of electron beam tomography data to develop models for prediction of hard coronary events. Am Heart J. 2001;141:375-382.

42. Church TS, Levine BD, McGuire DK, Lamonte MJ, Fitzgerald SJ, Cheng YJ, Kimball TE, Blair SN, Gibbons LW, Nichaman MZ. Coronary artery calcium score, risk factors, and incident coronary heart disease events. Atherosclerosis. 2007;190:224-231.

43. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210-215.

44. Taylor AJ, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O’Malley PG. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol. 2005;46:807-814.

45. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421.

46. Hecht HS, Budoff MJ, Berman DS, Ehrlich J, Rumberger JA. Coronary artery calcium scanning:

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Clinical paradigms for cardiac risk assessment and treatment. Am Heart J. 2006;151:1139-1146. 47. Berman DS, Wong ND, Gransar H, Miranda-Peats R, Dahlbeck J, Hayes SW, Friedman JD, Kang X, Polk

D, Hachamovitch R, Shaw L, Rozanski A. Relationship between stress-induced myocardial ischemia and atherosclerosis measured by coronary calcium tomography. J Am Coll Cardiol. 2004;44:923-930.

48. He ZX, Hedrick TD, Pratt CM, Verani MS, Aquino V, Roberts R, Mahmarian JJ. Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia. Circulation. 2000;101:244-251.

49. Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, Lipkin D, Lahiri A. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Eur Heart J. 2006;27:713-721.

50. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med. 2007.

51. Herbert WG, Dubach P, Lehmann KG, Froelicher VF. Effect of beta-blockade on the interpretation of the exercise ECG: ST level versus delta ST/HR index. Am Heart J. 1991;122:993-1000.


53. Ashley EA, Myers J, Froelicher V. Exercise testing in clinical medicine. Lancet. 2000;356:1592-1597.

54. Borer JS, Brensike JF, Redwood DR, Itscoitz SB, Passamani ER, Stone NJ, Richardson JM, Levy RI, Epstein SE. Limitations of the electrocardiographic response to exercise in predicting coronary-artery disease. N Engl J Med. 1975;293:367-371.

55. Uhl GS, Hopkirk AC, Hickman JR, Fisher J, Medina A. Predictive implications of clinical and exercise variables in detecting significant coronary artery disease in asymptomatic men. J Cardiac Rehab. 1984;4:245-252.

56. Barnard RJ, Gardner GW, Diaco NV, Kattus AA. Near-maximal ECG stress testing and coronary artery disease risk factor analysis in Los Angeles City fire fighters. J Occup Med. 1975;17:693-695.

57. Geluk CA, Tio RA, Tijssen JGP, van Dijk RB, Dijk WA, Hillege HL, De Jong PE, Van Gilst WH, Zijlstra F. Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study. Netherlands Heart Journal. 2007;15:133-141.

Chapter 7

Measurement of coronary calcium scores by electron beam computed tomography or exercise testing as initial diagnostic tool in low-risk patients with suspected coronary artery disease

C.A. Geluk, R. Dikkers, P.J. Perik, R.A. Tio, M.J.W. Götte, H.L. Hillege, R. Vliegenthart, J. B. Houwers, T.P. Willems,M. Oudkerk, F. Zijlstra.

Eur Radiol. 2007 Sep 28; [Epub ahead of print]

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Abstract

BackgroundWe determined the efficiency of a screening protocol based on coronary calcium scores (CCS) compared to exercise testing in patients with suspected coronary artery disease (CAD), a normal ECG and troponin levels.

Methods and resultsThree-hundred-and-four patients were enrolled in a screening protocol including CCS by electron beam computed tomography (Agatston score), and exercise testing. Decision making was based on CCS. When CCS≥400, coronary angiography (CAG) was recommended. When CCS<10, patients were discharged. Exercise tests were graded as positive, negative or nondiagnostic. The combined endpoint was defined as coronary event or obstructive CAD at CAG. During 12±4 months, CCS≥400, 10-399 and <10 were found in 42, 103 and 159 patients and the combined endpoint occurred in 24 (57%), 14 (14%) and 0 patients (0%), respectively. In 22 patients (7%) myocardial perfusion scintigraphy was performed instead of exercise testing due to the inability to perform an exercise test. A positive, nondiagnostic and negative exercise test result was found in 37, 76 and 191 patients, and the combined endpoint occurred in 11 (30%), 15 (20%) and 12 patients (6%), respectively. Receiver operator characteristics analysis showed that the area under the curve of 0.89 (95% CI 0.85-0.93) for CCS was superior to 0.69 (95% CI 0.61-0.78) for exercise testing (p<0.0001).

ConclusionIn conclusion, measurement of CCS is an appropriate initial screening test in a well-defined low-risk population with suspected CAD.

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Coronary calcium vs exercise testing in low-risk patients

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Introduction The management of patients presenting with chest pain remains a major challenge. Although the majority is at low risk of an acute coronary syndrome (ACS), obstructive coronary artery disease (CAD) is present in 20% of patients.1 Furthermore, at least 2% of patients with ACS are mistakenly discharged, resulting in increased mortality.2

Clinical assessment, an electrocardiogram (ECG), and cardiac markers, such as troponin, allow initial discrimination between a high- and low-risk of ACS.3 However, risk stratification often requires additional diagnostic testing. Exercise testing and measurement of CCS are frequently used for coronary risk stratification.4-9 However, exercise testing has a sensitivity and specificity for obstructive CAD of 68% and 77%, respectively, while sensitivity for left main/three-vessel CAD is 86%.10 Therefore, exercise testing does not detect all patients with (severe) obstructive CAD and the finding of a negative test does not rule out the presence of CAD.1 Measurement of coronary calcium scores (CCS) may provide more effective triage. The finding of any coronary calcium has a 93-99% sensitivity and 23-75% specificity for obstructive CAD, while the negative predictive value ranges from 95-100%.7;8;11-16 A few studies have studied the value of CCS at the emergency department and have shown promising results.6-8 However, studies comparing CCS and exercise tests have included only patients selected by abnormal exercise tests17 or the need of coronary angiography.18;19 We therefore evaluated a screening protocol based on CCS in low-risk patients suspected of CAD and compared these findings to exercise test results.

Methods

Patients Consecutive low-risk patients with chest pain or other symptoms of CAD were included. Low-risk was defined as a normal 12-lead ECG, normal troponin, no hemodynamic instability and no abnormalities on physical examination or chest roentgenogram. Coronary risk factors were assessed by history and review of the medical record. Typical angina was defined as the presence of retrosternal pain, increasing with effort and responding to rest or nitroglycerin. If less than 3 of these characteristics were fulfilled, or a patient suffered from dyspnea, these patients were regarded as having atypical complaints. Other symptoms suggestive of CAD were arrhythmia, history of collaps or referral for screening. Patients with previously documented CAD were excluded. The pretest probability of significant CAD was assessed according to the method by Pryor and colleagues.20 A high, and low test probability was defined as a probability of equal to or higher than, and below 44%, respectively.20

Measurement of coronary calcium scores Coronary calcium was measured using EBCT (e-Speed, GE Medical Systems, South San Francisco, USA). According to patients’ weight and size the beam speed was set

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to 50 ms (for small or slender patients) or 100 ms (for larger patients). Prospective electrocardiographic triggering was used and set at 42% of the R-R interval. Scans were made without the use of a contrast agent with 130 kV and 895 mAs. A single collimation of 3.0 mm and an increment of 3.0 mm was applied. Radiation exposures were 0.3 mSv and 0.6 mSv for the 50 ms and 100 ms protocols, respectively. Individual exposures were not measured. Assessment of all CCS was performed by one reviewer blinded to the clinical data and the exercise test results. The CCS was obtained by multiplying each area of interest with a factor indicating peak density within the individual area, as was proposed by Agatston.21

Exercise testing Bicycle exercise tests were performed in accordance with the guidelines.22;23 All tests were independently reviewed by a cardiologist (RT) and a research physician (CG), who reached a consensus in case of discriminative results. Exercise test end points were defined as follows: positive, in case of ECG evidence of myocardial ischemia (0.1 mV horizontal shift of the ST segment at 80 msec after the J point); intermediate, in case of 30 mmHg decrease in systolic blood pressure and/or ventricular arrhythmia and/or <0.1 mV ST depression and/or anginal complaints in the absence of ECG evidence of ischemia; negative, in the absence of any of the above mentioned criteria; and non-interpretable, if <85% of the predicted heart rate or a rate pressure product <18,000 was achieved. The predicted heart rate was corrected for length, age and sex, making use of a standardized table.24 Intermediate and non-interpretable results are considered as “nondiagnostic results”. In case exercise testing was not possible, myocardial perfusion imaging was performed.

Myocardial perfusion scintigraphy Six-hundred MBq of 99mTc-tetrofosmin was injected at rest and the next day after adenosine or bicycle stress. SPECT images were acquired one hour after tracer administration using a double headed gammacamera (Siemens E.Cam) equipped with low-energy high-resolution collimators. The camera heads were in perpendicular position. Other acquisition parameters were: 32 steps rotation, 20 sec per step, 128 x 128 matrix size, rotation from the 45º right anterior oblique to the 135º left posterior oblique position with the patient laying supine. The scans were reconstructed after filtered-back-projection using a Butterworth 0.30/6 filter. All data were reorientated in order to produce short-axis (SA), horizontal long-axis (HLA) and vertical long-axis (VLA) sections. The perfusion images were scored on CAD by using a 17-segment polar map.

Screening protocol The former screening protocol for low-risk patients with chest pain included exercise testing. In the current study, measurement of CCS was added. Exercise testing and measurement of CCS were performed in random order. Decision making was based on CCS (figure 1). In case of a low CCS, defined as CCS<10, patients were discharged and followed for the occurrence of cardiac events. In case of a high CCS, defined as

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CCS≥400, coronary angiography (CAG) was recommended to evaluate the presence of obstructive CAD. In case of an intermediate CCS, defined as CCS 10-399, primary prevention measures were recommended, and the decision to perform additional testing was left to the judgment of the treating cardiologist. Both EBCT and exercise testing were performed during office hours. Therefore, in some patients the tests were performed directly after presentation, while others were discharged first and underwent the tests within 3 weeks at the outpatient clinic. Follow up was obtained in all patients to determine the clinical status at least 4 months after the measurement of CCS by review of the patient’s medical record, telephone interviews of patients or general practitioners. The project is part of a continuous quality-improvement program of the Thoraxcenter, initiated by the board of directors of the University Medical Center Groningen. The protocol was approved by the Institutional Review Board. Informed consent was given by all patients.

Angiographic analysis All CAGs were analyzed by a senior cardiologist (FZ), blinded to the clinical data. By qualitative analysis the coronary arteries were graded as follows: normal coronary arteries, defined as the absence of any coronary lesion; non-obstructive CAD, if maximal luminal obstructions were <50%; and obstructive CAD, if lesions obstructed the lumen ≥50%.

suspected coronary heartdisease?

delta ECG or ↑ Troponin?yes

Exercise test and EBCT (Agatston score)

< 10

10-399 at least primary prevention measures required

follow up visits discouraged

≥ 400 coronary angiography recommended

no

exclusion

previous documented CAD?yes

exclusion

yes

no

Figure 1. Flow chart.Abbreviations: CAD, coronary artery disease; EBCT, electron beam computed tomography.

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Endpoints The combined endpoint was defined as a combination of the angiographic endpoint and a cardiac event. The angiographic endpoint was defined as obstructive CAD at CAG (≥50% luminal obstruction). Cardiac events were defined as a revascularization procedure, myocardial infarction or coronary death. Myocardial infarction was defined as ST-elevation myocardial infarction (chest pain and ST-elevation over 1 mm in at least 2 contiguous leads) or non-ST-elevation acute coronary syndrome (defined as chest pain with positive cardiac markers (troponin or creatinin kinase) and/or dynamic ST-segment changes).25;26 Revascularization procedures included percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG). Decisions to perform a revascularization procedure were taken by the Thoraxcenter multidisciplinary heart team, which has extensive experience with the RAND-UCLA criteria and takes decisions in accordance with the ESC and ACC/AHA guidelines for PCI and CABG.27-31

Statistical analysis Continuous data are expressed as mean ± standard deviation. Significance was reached when p<0.05. To compare the diagnostic yield of CCS with exercise test results, receiver operating characteristic (ROC) curve analysis was performed, and positive and negative predictive values were measured. We compared the area under the curves of both tests for the combined endpoint in all patients and after exclusion of subjects with typical angina. Additional analysis on clinical outcome was performed in those patients in whom exercise testing was not possible and myocardial perfusion scintigraphy was performed, and in those with CCS≥400 in whom the cardiologist decided not to perform CAG. Calculations were performed using the statistical package SPSS version 12.0 (SPSS, Chicago, USA) and STATA 9.0 (College Station, Texas, USA).

Results

Baseline characteristics From May 2004 till September 2005, 304 patients were consecutively enrolled. Of all exercise tests performed during this period in patients without previous CAD, 90% were included in the study. Clinical characteristics are shown in table 1. Most patients (n=225) underwent diagnostic testing for atypical complaints. Typical anginal complaints were present in 59 patients, while in 20 patients diagnostic testing was performed for routine screening (n=10), collapse (n=3) or arrhythmia (n=7). The large majority (84%) had a low pretest probability of significant CAD. In 22 patients (7%) myocardial perfusion scintigraphy was performed instead of exercise testing due to the inability to perform an exercise test. The study population represented 90% of the exercise tests performed in new patients.

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Follow-up Follow up was obtained in all 304 patients (100%). During 12±4 months, 83 CAGs were performed. In 38 patients obstructive CAD was found, followed by a revascularization procedure in 28 patients (21 PCIs and 11 CABGs) (Tables 2,3). No myocardial infarctions or deaths occurred.

Coronary calcium scores by computed tomography Low, intermediate and high CCS were detected by EBCT in 159 (52%), 103 (34%) and 42 (14%) patients, respectively. In one patient (0.3%) the CCS quantification failed due to respiration artifacts. In this patient calcium was visible in all coronary arteries and was graded to be of intermediate amount.

Table 1. Baseline characteristics.

Characteristics n=304

Age, mean (range), y 55 (26-85)

Male gender, No. (%) 169 (56)Current Smoking, No. (%) 109 (38)Diabetes, No. (%) 37 (13)Blood pressure, mean (SD), mm Hg

Systolic 141 (81)Diastolic 81 (12)

Cholesterol, mean (SD), mg/dLTotal 208 (46)LDL 124 (39)HDL 54 (14)

Glucose, mean (SD), mmol/L 5.8 (1.9)Hypertension, No. (%) 113 (38)Hypercholesterolemia, No. (%) 128 (44)Positive family history, No. (%) 157 (54)Medication, No. (%)

ASA 59 (19)Betablocker 75 (25)Statin 75 (25)

Anginal complaints, No. (%)Typical angina 59 (19)Atypical complaints 225 (74)Other* 20 (7)

Pretest probability of obstructive CAD, ** (%) 15 (0-36)Pretest probability of obstructive CAD, No.(%)High (≥44%) 49 (16)Low (<44%) 255 (84)

Abbreviations: LDL, low density lipoprotein; HDL, high density lipoprotein.*see text for explanation; ** median (p25-p75).

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Calcium score ≥ 400 In 42 patients with a high CCS, positive, negative and nondiagnostic exercise test results were present in 13, 15 and 14 patients, respectively. These results are presented in table 2. In 37 patients a CAG was performed, showing one- or two-vessel disease in 15 (40%) and three-vessel or left main disease in 9 (24%) patients (table 3). In 5 patients CAG was not performed because symptoms disappeared with anti-ischemic medication. All patients with CAD received pharmacologic therapy, a revascularization procedure was performed in 17 patients. No myocardial infarctions or deaths occurred. The combined endpoint was observed in 24 of 42 (57%) patients.

Table 2. Numbers of angiographic endpoints and cardiac events during follow-up*†.

Calcium score Result of exercise test

No. (%)No. of Angiographic Endpoint

No. of Cardiac Event

≥400 (n=42) Positive 13/42 (31%) 7 7 (revascularization)Negative 15/42 (36%) 8 5 (revascularization)Nondiagnostic 14/42 (33%) 9 5 (revascularization)

10-399 (n=103) Positive 9/103 (9%) 4 4 (revascularization)Negative 63/103 (61%) 4 3 (revascularization)Nondiagnostic 31/103 (30%) 6 4 (revascularization)

<10 (n=159) Positive 15/159 (9%) 0 0Negative 113/159 (71%) 0 0Nondiagnostic 31/159 (20%) 0 0

*within a follow up time of 12±4 months.†Definitions of endpoints: angiographic endpoint: ≥50% luminal obstruction at coronary angiography; cardiac event: coronary death, myocardial infarction or revascularization procedure.

Table 3. Coronary angiographic findings*.

Calcium scoreCAG, No.

Normal coronary

arteries, No. (%)

Non-obstructive

CAD, No. (%)

One-vessel disease, No.

(%)

Two-vessel disease, No.

(%)

Three-vessel or left main disease, No.

(%)

≥400 (n=42) 37 1 (3) 12 (33) 9 (24) 6 (16) 9 (24)

10-399 (n=103) 33 5 (15) 14 (43) 10 (30) 2 (6) 2 (6)

<<10 (n=159) 13 11 (85) 2 (15) 0 0 0

*CAG=coronary angiography; CAD=coronary artery disease.

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Calcium score 10-399 In 103 patients with an intermediate CCS, most patients had negative (n=63) or nondiagnostic (n=31) exercise test results, while the remainder (n=9) had positive exercise test results (table 2). In 33 patients a CAG was performed, showing obstructive CAD in 14 patients (tables 2,3). In these 14 patients the CCS ranged from 23-379. All patients with CAD received pharmacologic treatment, a revascularization procedure was performed in 9 patients. One patient presented with unstable angina 4 months after PCI due to in-stent-restenosis and underwent repeat PCI. One patient underwent re-PCI for stable angina. No myocardial infarctions or deaths occurred. The combined endpoint occurred in 14 of 103 (14%) patients.

Calcium score <10 In 159 patients with a low CCS, the majority had a negative exercise test result (n=113), but positive and nondiagnostic tests were present in, respectively, 15 and 31 patients. In 13 patients CAG was performed for the following reasons: abnormal exercise test or myocardial perfusion scintigraphy (n=7); typical angina (n=2) and miscellaneous reasons (n=4). In none of these patients obstructive CAD was found (tables 2,3). The combined endpoint therefore occurred in 0 (0%) patients.

Comparison with exercise testing A positive, nondiagnostic and negative exercise test was present in 37 (12%), 76 (25%) and 191 patients (73%), respectively. The rates of high, intermediate and low CCS in these groups were, respectively, 35%, 24% and 41% (positive exercise test); 18%, 41% and 41% (nondiagnostic exercise test); and 8%, 33% and 59% (negative exercise test). The rates of the combined endpoint in the groups with positive and negative exercise test results were, respectively, 30% (11/37) and 6% (12/191). A combined endpoint occurred in 15 (20%) of the 76 subjects with an intermediate exercise test result, namely in 9 of 39 subjects with a nondiagnostic test results and in 6 of 37 subjects with an non-interpretable exercise test result. The rates of the combined endpoint according to CCS and exercise test results are shown in figure 2. ROC statistics show an area under the curve of 0.89 (0.85-0.93) for CCS and 0.69 (0.61-0.78) for exercise testing (p<0.0001; figure 3). A CCS>400 yielded a positive predictive value of 57% (41-72%), while the negative predictive value of a CCS<10 was 100% (98-100%). The positive predictive vale of a positive exercise test was 30% (16-47%; p>0.05 compared to CCS>400). The negative predictive value of a negative exercise test result was 94% (89-97%; p<0.05 compared to CCS<10). The area under the curve for CCS and exercise testing were 0.90 (0.86-0.95) and 0.67 (0.57-0.77) for subjects with a low pretest probability of CAD , and 0.81 (0.68-0.94) and 0.88 (0.76-0.99) for subjects with a high pretest probability of CAD, respectively. After exclusion of 59 patients with typical angina, ROC analysis showed an area under the curve of 0.93 (0.88-0.97) for CCS and 0.64 (0.51-0.78) for exercise testing (p<0.001). Additional analysis was performed in 277 patients, after exclusion of 5 patients with CCS ≥400 without CAG and 22 patients with myocardial perfusion imaging instead of exercise testing. The combined endpoint occurred in 21 (64%)

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of 33 patients with CCS ≥400; in 11 (12%) of 93 patients with CCS 10-400, and in 0 (0%) of 151 patients with CCS <10. The combined endpoint occurred in 8 (32%) of 25 patients with positive exercise test results, in 15 (20%) of 74 patients with nondiagnostic exercise test results, and in 9 (5%) of 178 patients with negative exercise test results. ROC statistics show an area under the curve of 0.91 (0.86-0.95) for CCS and 0.72 (0.62-0.82) for exercise testing (p<0.001).

0%

10%

20%

30%

40%

50%

60%

CCS <10; 11-399; ≥400 negative; nondiagnostic; positiveexercise test

30%

20%

6%

57%

14%

0%

Figure 2. Outcome according to CCS and exercise testing. The percentage of patients with the combined endpoint are shown per group. Abbreviations: CCS, coronary calcium score.

Exe rcise test

CCS

0

20

40

60

80

100

100-specificity (%)

Sens

itiv

ity

(%)

Exercise test AUC=0.69 (95% CI 0.61-0.78) CCS AUC=0.89 (95% CI 0.85-0.93)

0 2 0 4 0 6 0 8 0 1 00

Figure 3. Receiver operating characteristic curves of CCS (<10, 10-399 and ≥400) and exercise testing (negative, nondiagnostic, positive) for the combined endpoint. The difference in AUCs of both tests show the incremental diagnostic yield of measurement of CCS when compared to exercise testing (p<0.0001). Abbreviations: AUC, area under the curve; CCS, coronary calcium score; CI, confidence interval

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Discussion

The results of this study confirm that measurement of CCS provides effective triage in a well-defined patient group with suspected, but low risk of coronary artery disease. In addition, our results indicate that the diagnostic yield of CCS is superior to exercise testing. We included only low-risk patients, which was defined as the absence of prior evidence of CAD, an abnormal 12-lead ECG or elevated serum cardiac markers. The major clinical advantage of our strategy has been facilitation of safe discharge from the hospital in a majority (52%) of these patients, as defined by a low CCS derived from CT. The diagnostic efficacy of our strategy is further demonstrated by high rates of obstructive CAD (especially three-vessel and left main disease) and revascularization procedures in patients with a high CCS.Measurement of CCS and exercise testing provide fundamentally different diagnostic information. The first test provides information on the amount of calcium in the coronary arteries, while the second test’s purpose is to detect myocardial ischemia. Both an “anatomical” and “functional” approach as initial diagnostic tests in patients with suspected CAD may lead to effective risk stratification.1;4 The few studies on risk stratification based on CCS in low-risk patients with chest pain have shown promising results.6-8 However, studies comparing CCS with exercise testing have not yet been performed in low-risk populations.18;19 The former approach at our institution was exercise testing. This was replaced by a protocol in which all patients underwent both exercise testing and CT, and decision making was based on CCS. The efficiency of the current protocol was confirmed by the following observations. First, during a mean follow up of 12±4 months, no single hard event (myocardial infarction or death) occurred. Second, a large majority (57%) of patients with CCS ≥400 had obstructive CAD, and 21% had three-vessel or left main disease. In a majority of these patients a revascularization procedure was necessary according to the ESC and ACC/AHA guidelines for PCI and CABG.27-31 In subjects with a CCS < 10 no coronary events occurred during follow up. This contrasts with the exercise test results, with 6% of patients with negative exercise test results having obstructive CAD. The high negative predictive value of a low CCS is in concert with many earlier studies.8;11;14 Another major advantage of measurement of CCS may become the detection of minor degrees of CAD. In, respectively, 34% and 25% of our study population, an intermediate amount of coronary calcium and a nondiagnostic exercise test result was present. In patients with CCS 10-399, the presence of CAD has been confirmed and therefore the initiation of primary prevention measures such as life style modification, aspirin and/or statin treatment, can be initiated. In contrast to intermediate CCS findings, when exercise testing provides nondiagnostic results, uncertainty with regard to the presence of CAD remains. Some issues remain to be answered. Due to recent technical improvements CCS can now also be measured by multi detector computed tomography.32-40 Differences between CCS measurements on EBCT and multidetector CT have been shown to be similar to the reported individual EBCT and multidetector CT interscan variabilities of around 20%.32;35 Exclusion of coronary calcium by multidetector CT is as feasible

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as by EBCT.41;42 Comparative studies in low-risk patients with suspected CAD at our department, and in large populations of asymptomatic subjects,32 are currently underway. We propose to use measurement of CCS as gatekeeper for additional invasive and non-invasive testing.43 Our protocol enabled us to differentiate between high (CCS>400) and low risk (<100) subjects. However, one third of our study population had an intermediate CCS (10-399) and obstructive CAD was found in 14% of these subjects. Ideally, in this patient category, a test with high sensitivity for myocardial ischemia should guide the decision to perform CAG, in addition to pharmacologic treatment, as stated above. However, so far, the evidence for use of a clinical protocol in such patients is lacking. Exercise testing can not fulfill this task. Stress echocardiography, myocardial perfusion scintigraphy or stress cardiac magnetic resonance imaging may be better options.44 Another option is MDCT coronary angiography, which may be clinically useful an may may obviate the need of CAG when luminal stenoses are ruled out.45 The need for optimization of the current protocol was highlighted by the observation that of the 83 CAGs performed obstructive CAD was found in 38 (46%). Finally, is CCS more accurate than MDCT coronary angiography? So far, the role of MDCT coronary angiography in the evaluation of patients with suspected CAD has not become established. Compared to measurement of CCS, the advantage of MDCT coronary angiography lies in its information on luminal stenosis.45;46 This probably led to a higher number of patients that could be discharged in the evaluation of chest pain in case of negative results (68% with minimal or no stenoses47 versus 52% with CCS<10 in the current study). However, since very low CCS are associated with a high negative predictive value, performance of MDCT coronary angiography in such patients cannot be justified. We believe that CT coronary angiography may play a role in subjects with CCS>10. A recent study showed that, in a population scheduled for CAG, the diagnostic yield of MDCT coronary angiography was superior to exercise testing.48 Further studies are needed to establish the role of MDCT coronary angiography in low risk subjects. In addition, cost-effectiveness should be taken in mind, since in patients with a high probability of CAD, direct CAG may be more cost-effective than a strategy with MDCT coronary angiography.49

Remarks and limitations We have chosen a follow-up study design. Our design was limited by the absence of a gold standard in every patient, since the procedure to determine the endpoints was influenced by the test results. The absolute numbers of obstructive CAD or clinical events according to exercise test results may therefore have been somewhat biased, since the screening protocol was based on CCS. Furthermore, in patients with low CCS CAG was not performed, thereby decreasing the likelihood of detecting CAD. Our follow up design restricted the evaluation of cost-effectiveness, which is a limitation, since it was shown that CCS measurement may not be cost-effective.49 Further studies

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should be performed to evaluate this issue. Obstructive CAD was measured by qualitative coronary analysis, which is less accurate when compared to quantitative coronary analysis. For this low risk population without previous CAD, symptoms by itself during exercise testing cannot be classified as a positive exercise test. Therefore, symptoms without ECG changes were classified as an intermediate test result. We did not report the intermediate and non-interpretable exercise test results separately, but presented these as one (“nondiagnostic”) group, since both test outcomes do not provide diagnostic certainty and clinical outcome was similar.

Conclusion In patients with suspected CAD, with a normal ECG and normal cardiac markers, a screening protocol based on coronary calcium scores provides effective triage.

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Reference list

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2. Pope JH, Aufderheide TP, Ruthazer R, Woolard RH, Feldman JA, Beshansky JR, Griffith JL, Selker HP. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:1163-1170.

3. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;337:1648-1653.

4. Amsterdam EA, Kirk JD, Diercks DB, Lewis WR, Turnipseed SD. Immediate exercise testing to evaluate low-risk patients presenting to the emergency department with chest pain. J Am Coll Cardiol. 2002;40:251-256.

5. Polanczyk CA, Johnson PA, Hartley LH, Walls RM, Shaykevich S, Lee TH. Clinical correlates and prognostic significance of early negative exercise tolerance test in patients with acute chest pain seen in the hospital emergency department. Am J Cardiol. 1998;81:288-292.

6. McLaughlin VV, Balogh T, Rich S. Utility of electron beam computed tomography to stratify patients presenting to the emergency room with chest pain. Am J Cardiol. 1999;84:327-8, A8.

7. Laudon DA, Vukov LF, Breen JF, Rumberger JA, Wollan PC, Sheedy PF. Use of electron-beam computed tomography in the evaluation of chest pain patients e emergency department. Ann Emerg Med. 1999;33:15-21.

8. Georgiou D, Budoff MJ, Kaufer E, Kennedy JM, Lu B, Brundage BH. Screening patients with chest pain in the emergency department using electron beam tomography: a follow-up study. J Am Coll Cardiol. 2001;38:105-110.

9. Becker CR, Majeed A, Crispin A, Knez A, Schoepf UJ, Boekstegers P, Steinbeck G, Reiser MF. CT measurement of coronary calcium mass: impact on global cardiac risk assessment. Eur Radiol. 2005;15:96-101.

10. Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A, McArthur D, Froelicher V. Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation. 1989;80:87-98.


12. Detrano R, Hsiai T, Wang S, Puentes G, Fallavollita J, Shields P, Stanford W, Wolfkiel C, Georgiou D, Budoff M, Reed J. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol. 1996;27:285-290.

13. Kajinami K, Seki H, Takekoshi N, Mabuchi H. Noninvasive prediction of coronary atherosclerosis by quantification of coronary artery calcification using electron beam computed tomography: comparison with electrocardiographic and thallium exercise stress test results. J Am Coll Cardiol. 1995;26:1209-1221.

14. Keelan PC, Bielak LF, Ashai K, Jamjoum LS, Denktas AE, Rumberger JA, Sheedy II PF, Peyser PA, Schwartz RS. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation. 2001;104:412-417.


16. Clouse ME. How useful is computed tomography for screening for coronary artery disease? Noninvasive screening for coronary artery disease with computed tomography is useful. Circulation. 2006;113:125-146.

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17. Lamont DH, Budoff MJ, Shavelle DM, Shavelle R, Brundage BH, Hagar JM. Coronary calcium scanning adds incremental value to patients with positive stress tests. Am Heart J. 2002;143:861-867.

18. Schmermund A, Baumgart D, Sack S, Mohlenkamp S, Gronemeyer D, Seibel R, Erbel R. Assessment of coronary calcification by electron-beam computed tomography in symptomatic patients with normal, abnormal or equivocal exercise stress test. Eur Heart J. 2000;21:1674-1682.

19. Shavelle DM, Budoff MJ, Lamont DH, Shavelle RM, Kennedy JM, Brundage BH. Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease. J Am Coll Cardiol. 2000;36:32-38.

20. Pryor DB, Shaw L, McCants CB, Lee KL, Mark DB, Harrell FE, Jr., Muhlbaier LH, Califf RM. Value of the history and physical in identifying patients at increased risk for coronary artery disease. Ann Intern Med. 1993;118:81-90.

21. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Jr., Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-832.

22. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, Mark DB, McCallister BD, Mooss AN, O’Reilly MG, Winters WL, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40:1531-1540.

23. Guidelines for cardiac exercise testing. ESC Working Group on Exercise Physiology, Physiopathology and Electrocardiography. Eur Heart J. 1993;14:969-988.

24. Ascoop CAPL, van Zeijl LGPM, Pool J, Simoons ML (1994) Cardiac exercise testing-I indications, staff, equipment, conduct and procedures. Guidelines for cardiac exercise testing. Neth J Cardiol 2:1–11

25. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003;24:28-66.

26. Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, De Feyter PJ, Specchia G, Ruzyllo W. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2002;23:1809-1840.

27. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines for percutaneous coronary interventions: the task force for percutaneous coronary interventions of the European society of cardiology. Eur Heart J. 2005;26:804-847.

28. Meijler AP, Rigter H, Bernstein SJ, Scholma JK, McDonnell J, Breeman A, Kosecoff JB, Brook RH. The appropriateness of intention to treat decisions for invasive therapy in coronary artery disease in The Netherlands. Heart. 1997;77:219-224.

29. Rigter H, Meijler AP, McDonnell J, Scholma JK, Bernstein SJ. Indications for coronary revascularisation: a Dutch perspective. Heart. 1997;77:211-218.

30. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, Hart JC, Herrmann HC, Hillis LD, Hutter AM, Jr., Lytle BW, Marlow RA, Nugent WC, Orszulak TA. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 2004;110:e340-e437.

31. Smith SC, Jr., Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO, Gibbons RJ, Alpert JP, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith SC, Jr. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)--executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty). J Am Coll Cardiol. 2001;37:2215-2239.

32. Detrano RC, Anderson M, Nelson J, Wong ND, Carr JJ, Nitt-Gray M, Bild DE. Coronary calcium

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measurements: effect of CT scanner type and calcium measure on rescan reproducibility--MESA study. Radiology. 2005;236:477-484.

33. Becker CR, Jakobs TF, Aydemir S, Becker A, Knez A, Schoepf UJ, Bruening R, Haberl R, Reiser MF. Helical and single-slice conventional CT versus electron beam CT for the quantification of coronary artery calcification. AJR Am J Roentgenol. 2000;174:543-547.

34. Knez A, Becker C, Becker A, Leber A, White C, Reiser M, Steinbeck G. Determination of coronary calcium with multi-slice spiral computed tomography: a comparative study with electron-beam CT. Int J Cardiovasc Imaging. 2002;18:295-303.


36. Horiguchi J, Shen Y, Akiyama Y, Hirai N, Sasaki K, Ishifuro M, Ito K. Electron beam CT versus 16-slice spiral CT: how accurately can we measure coronary artery calcium volume? Eur Radiol. 2006;16:374-380.

37. Horiguchi J, Fukuda H, Yamamoto H, Hirai N, Alam F, Kakizawa H, Hieda M, Tachikake T, Marukawa K, Ito K. The impact of motion artifacts on the reproducibility of repeated coronary artery calcium measurements. Eur Radiol. 2007;17:81-86.

38. Mahnken AH, Muhlenbruch G, Koos R, Das M, Pohl S, Stanzel S, Gunther RW, Wildberger JE. Influence of a small field-of-view size on the detection of coronary artery calcifications with MSCT: in vitro and in vivo study. Eur Radiol. 2006;16:358-364.

39. Muhlenbruch G, Klotz E, Wildberger JE, Koos R, Das M, Niethammer M, Hohl C, Honnef D, Thomas C, Gunther RW, Mahnken AH. The accuracy of 1- and 3-mm slices in coronary calcium scoring using multi-slice CT in vitro and in vivo. Eur Radiol. 2007;17:321-329.

40. van Ooijen PM, Vliegenthart R, Witteman JC, Oudkerk M. Influence of scoring parameter settings on Agatston and volume scores for coronary calcification. Eur Radiol. 2005;15:102-110.

41. Sandstede JJ, Stoffels J, Wendel F, Ritter C, Beer M, Hahn D. Different reconstruction intervals for exclusion of coronary artery calcifications by retrospectively gated MDCT. AJR Am J Roentgenol. 2006;186:193-197.

42. Hoffmann U, Siebert U, Bull-Stewart A, Achenbach S, Ferencik M, Moselewski F, Brady TJ, Massaro JM, O’Donnell CJ. Evidence for lower variability of coronary artery calcium mineral mass measurements by multi-detector computed tomography in a community-based cohort--consequences for progression studies. Eur J Radiol. 2006;57:396-402.

43. Bax JJ, van der Wall EE. Assessment of coronary artery disease in patients with (a)symptomatic diabetes. Eur Heart J. 2006;27:631-632.

44. Janssen CH, Kuijpers D, Vliegenthart R, Overbosch J, van Dijkman PR, Zijlstra F, Oudkerk M. Coronary artery calcification score by multislice computed tomography predicts the outcome of dobutamine cardiovascular magnetic resonance imaging. Eur Radiol. 2005;15:1128-1134.

45. Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, Guerci AD, Lima JA, Rader DJ, Rubin GD, Shaw LJ, Wiegers SE. Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation. 2006;114:1761-1791.

46. Muhlenbruch G, Seyfarth T, Soo CS, Pregalathan N, Mahnken AH. Diagnostic value of 64-slice multi-detector row cardiac CTA in symptomatic patients. Eur Radiol. 2007;17:603-609.

47. Goldstein JA, Gallagher MJ, O’Neill WW, Ross MA, O’Neil BJ, Raff GL. A randomized controlled trial of multi-slice coronary computed tomography for evaluation of acute chest pain. J Am Coll Cardiol. 2007;49:863-871.

48. Dewey M, Dubel HP, Schink T, Baumann G, Hamm B. Head-to-head comparison of multislice computed tomography and exercise electrocardiography for diagnosis of coronary artery disease. Eur Heart J. 2006.

49. Dewey M, Hamm B. Cost effectiveness of coronary angiography and calcium scoring using CT and stress MRI for diagnosis of coronary artery disease. Eur Radiol. 2007;17:1301-1309.

Chapter 8

Summary, implications and future perspectives

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Summary and implications

This aim of the thesis was to evaluate some of the unresolved issues on the pathway from risk association to risk stratification with regard to C-reactive protein, urinary albumin excretion and coronary calcium. This thesis shows that C-reactive protein is associated to angiographic evidence of coronary artery disease as well as clinical outcome, accounts for a large proportion of coronary risk, may improve the prediction of coronary events and has the potential to change clinical management. With regard to urinary albumin excretion, these associations were less conclusive for angiograpic evidence of coronary artery disease, the prediction of coronary events and change in clinical management. Nevertheless, urinary albumin excretion in combination with the metabolic syndrome identifies subjects who benefit from statin treatment. With regard to coronary calcium, levels of coronary calcifications were associated with angiographic evidence of coronary artery disease. Furthermore, measurement of coronary calcium by electron beam computed tomography is an appropriate alternative for exercise testing for coronary risk stratification in subjects at increased coronary risk, and may result in a change in clinical management. Below, the chapters of this thesis are summarized. A general overview of the contribution of this thesis to the evidence in advantage or disadvantage of coronary risk stratification is given in table 1.Chapter 2 describes the incidence of coronary events and invasive cardiac procedures in PREVEND participants without previous documented coronary artery disease (n=8,139). It was shown that 3% had a first coronary event (death, myocardial infarction, percutaneous coronary intervention or coronary artery bypass surgery). Most subjects undergoing coronary angiography for an acute event underwent a revascularization procedure during 5 years of follow up. However, just one third of coronary angiographies for stable angina were followed by a revascularization procedure. The other two-third had an indication for pharmacologic treatment or needed no specific thearpy. Since coronary angiography is a procedure with a small but potential risk of complications, these results implicate that the diagnostic strategy in patients with stable angina should be reconsidered. The use of novel cardiac CT scans may play a role in this setting. All available coronary angiograms (n=216) of the PREVEND participants have been reviewed for detailed analysis. The presence of luminal narrowing, and characteristics of unstable coronary artery disease, such as thrombosis, ulcus, and plaque irregularity, were described. Thse plaque characteristics are known to be associated with a worse clinical outcome. Chapter 3 evaluates whether C-reactive protein, measured at the baseline of the PREVEND study in 1997, is associated with these characteristics of stable and unstable angiographic disease at a coronary angiogram during follow up. It was shown that levels of C-reactive protein at baseline were associated with these characteristics. This observation supports the concept that hs-CRP significantly contributes to coronary atherogenesis. An independent association between microalbuminuria and angiographic characteristics of coronary artery disease, however, could not be demonstrated.

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In line with earlier reports, elevated C-reactive protein and microalbuminuria were present in 24% and 14% of the PREVEND population without previous documented coronary artery disease, respectively. Chapter 4 shows that the association between C-reactive protein and the occurrence of a first coronary event persisted after adjustment for traditional risk factors of the Framingham risk score, although the association became weaker. A similar observation was made for urinary albumin excretion, and adjusted relative risks of 1.6 and 1.4 were found for urinary albumin excretion of 15-30 mg/24h and >30 mg/24h, in line with earlier reports. This implies that the associated risk with these risk measures is partly attributable to other risk factors. Although no effect was shown on the measures of global fit and predictive ability, addition of C-reactive protein and urinary albumin excretion to the Framingham risk score was associated with a reclassification of almost two-thirds of subjects with 10 year risk above 20% to the lower risk category. However, the observed risk in these subjects was still relatively high and therefore the clinical consequences are limited. The Framingham risk score was not optimally calibrated in the PREVEND study population. A model including individual Framingham risk factors refitted in this population yielded a better calibration and predictive ability. When urinary albumin excretion and C-reactive protein were added to this model, only C-reactive protein was selected and was associated with a small improvement in risk prediction. Addition of C-reacitve protein was associated with a correct reclassification of a small number of subjects into a lower or higher risk category. Therefore, guidelines advocating standard measurement of C-reactive protein in the assessment of coronary risk can be regarded as premature.

Table 1. Issues on the pathway from risk association to risk stratification. Contribution of the current thesis.*

The risk measure: UAE† CRP CC

-is associated with the atherosclerotic process ±[±] +[+] +[+]

-adds independent information about coronary risk +[±] +[+] +

-accounts for a large proportion of coronary risk ±[+] ±[+] +

-can be tested in routine clinical practice + + ±-equates or improves the current standard for risk prediction

?[-] ±[±] ?[+]1/±2

-improves patient outcome compared with other available ways of identifying and treating coronary risk

? ? ?

-changes clinical management ?[-] ±[±] ±[+]1/+2

-is a target for intervention -[-] ? -

Explanation of symbols: current evidence is to the advantage (+) or disadvantage (-) of the statement; is is inconclusive (±) or not available yet (?) with regard to the risk measure. *The symbols between the square brackets refer to this thesis. 1compared to exercise testing; 2compared to currently used prediction models such as the Framingham risk score. † applies to non-diabetic populations.

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It has long been known that the metabolic syndrome is more frequently present in subjects with high normal or increased levels of urinary albumin excretion (microalbuminuria). A combination of these characteristics may identify subjects at increased coronary risk. Chapter 5 evaluates the impact of pravastatin treatment on the incidence of coronary events in subjects with microalbuminuria and the metabolic syndrome in a substudy of the PREVEND Intervention Trial. The benefit of statin therapy was observed in particular in patients with the combination of microalbuminuria and the metabolic syndrome. This study therefore supports the use of statins in microalbuminuric subjects with the metabolic syndrome to reduce the incidence of coronary events. Since levels of urinary albumin excretrion were not affected by pravastatin, this study does not support the use of urinary albumin excretion as target for intervention. Asymptomatic subjects at intermediate coronary risk and low risk subjects with symptoms of coronary artery disease may need diagnostic testing for risk stratification. Both measurement of coronary calcium scores, by electron beam computed tomography, and exercise testing are well established tests for this purpose. The Chapters 6 and 7 show that of these two tests, measurement of coronary calcium scores is preferred as initial diagnostic test in these subjects. In Chapter 6, 153 asymptomatic subjects with ST-T changes on a rest ECG were selected from the population based PREVEND cohort study and underwent measurement of calcium scores by electron beam computed tomography and exercise testing. A low calcium score was associated with obstructive coronary artery disease in 1%, while a normal exercise test was associated with obstructive coronary artery disease in 7%. A high calcium score was associated with obstructive coronary artery disease in 69%, while an abnormal exercise test was associated with obstructive coronary artery disease in 39%. Chapter 7 compared the performance of coronary calcium versus the exercise test in 304 low risk patients with symptoms of coronary artery disease, with a normal ECG and troponin levels, presenting at the emergency department of the University Medical Center of Groningen. A low calcium score was associated with obstructive coronary artery disease in 0%, while a normal exercise test was associated with obstructive coronary artery disease in 6%. A high calcium score was associated with obstructive coronary artery disease in 57%, while an abnormal exercise test was associated with obstructive coronary artery disease in 30%. In none of the two study populations any hard coronary events occurred during follow up. Our results therefore implicate that measurement of CCS is an appropriate initial screening test in these populations. The low incidence of significant coronary artery disease in subjects with low calcium scores implies that measurement of coronary calcium can be used as effective filter before further diagnostic testing in patients with suspected coronary artery disease. This thesis provides evidence that in about 15-20% of subjects undergoing exercise testing, clinical management can be affected by measurement of coronary calcifications. This number is based on subjects with a positive or non-diagnostic exercise tests and low calcium score, thereby avoiding unnecessary further diagnostic testing, and subjects with a negative exercise test result and high calcium score, thereby necessitating the initiation of medical treatment,

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and often a revascularization procedure. Therefore, measurement of coronary calcium seems to be an appropriate alternative for the exercise test as intitial diagnostic test for risk stratification in these patients. However, from Chapters 6 and 7 it remains unclear which diagnostic strategy should be followed in subjects with an intermediate coronary calcium score. This should therefore be the focus of future investigations.

Future perspectives

The role of urinary albumin excretion in cardiovascular risk stratification beyond coronary risk, namely in cerebral and peripheral as well as renal vascular disease needs to be studied. In asymptomatic populations, future research should focus on prediction models including C-reactive protein, as well as measurement of coronary calcfications, and compare these to the current standard of risk prediction with regard to clinical outcome. Measurement of coronary calcifications in a clinical setting needs to be further explored. Since exercise testing is part of coronary risk assessment in general practice, the comparison of exercise testing versus measurement of coronary calcium should be extended to these populations. Futhermore, strategies for follow up diagnostic testing in subjects with intermediate calcium scores should be evaluated.

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List of abbreviations AIC Akaike’s Information CriterionACS acute coronary syndromeAUC area under the receiver operating characteristics curveCABG coronary artery bypass graft surgeryCAD coronary artery diseaseCAG coronary angiographyCHD coronary heart diseaseCC coronary calciumCCS coronary calcium scoreCRP C-reactive proteinCT computed tomographyEB(C)T electron beam (computed) tomographyECG electrocardiogramFRS Framingham risk scoreHDL high-density lipoproteinLDL low-density lipoproteinMACE major adverse cardiac eventMDCT multidetector computed tomographyMPS myocardial perfusion imaging MS metabolic syndromePCI percutaneous coronary interventionPREVEND Prevention of REnal and Vascular ENdstage DiseasePREVEND IT PREVEND Intervention TrialROC receiver operating characteristicsSTEMI ST-elevation myocardial infarctionUAE urinary albumin excretion

Nederlandse samenvatting

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Samenvatting

Kransslagadervernauwing en hartklachten

Kransslagadervernauwing is een van de belangrijkste ziekten in de westerse wereld. De kransslagaderen zijn de bloedvaten die het hart van bloed en zuurstof voorzien. Vernauwing van deze vaten kan tot zuurstoftekort in de hartspier aanleiding geven. Dit kan tot uitkoming door pijn op de borst (“angina pectoris”) en heftige benauwdheid. Vaak ontstaat dit tijdens inspanning en gaan de klachten over in rust. Echter, soms is het zuurstoftekort ernstiger en gaan de klachten niet over. In dat geval spreekt men van een hartinfarct of hartaanval. Door langdurig zuurstoftekort ontstaat beschadiging van het hart, waardoor hartfalen kan ontstaan. Soms kan iemand aan een hartinfarct overlijden. Gelukkig zijn er tegenwoordig goede mogelijkheden om dit te behandelen. Vaak zal in het ziekenhuis een catheterisatie worden verricht, waarbij via de lies- of armslagader een slangetje wordt opgevoerd naar de kransslagaderen, contrast wordt ingespoten en met behulp van röntgenstralen foto’s van de kransslagaderen worden gemaakt (“het coronairangiogram”). Als een vernauwing wordt aangetoond kan iemand behandeld worden met medicijnen of met een dotterbehandeling of een operatie waarbij een omleiding (“bypass”) wordt aangelegd.

Hoe ontstaat kransslagadervernauwing? Bloedvaten in het lichaam zijn flexibele vaten met een belangrijke taak. De binnenbekleding van bloedvaten bestaat uit een netwerk van cellen die in samenwerking met stofjes in het bloed zorgen dat het bloed niet stolt, maar blijft stromen. Daarnaast zorgen deze cellen ervoor dat voedingsstoffen en afweercellen en -stoffen op de juiste plek in het lichaam terechtkomen. Door onze leef- en eetgewoonten, en genetische aanleg, kunnen er al op jonge leeftijd (ongeveer 10-40 jaar) veranderingen ontstaan in de binnenbekleding van de bloedvaten, en ook van de kransslagaderen. Helaas beïnvloeden die veranderingen de werking van de vaatwand. Hierdoor ontstaat een lichte ontsteking van de binnenbekleding, waardoor deze cellen veranderen, vervetten, bloedstolsels of kalk kunnen gaan bevatten, het vat in groeien en uiteindelijk de bloedstroom kunnen belemmeren. Dit heet kransslagadervernauwing. Niet iedereen met kransslagadervernauwing krijgt last van pijn op de borst of een hartinfarct. Gebeurt dit wel, dan treedt dit meestal pas op in mannen ouder dan 40 jaar en vrouwen ouder dan 50 jaar.

Wie krijgt last van kransslagadervernauwing?Omdat de tijd tussen het ontstaan van de vaatveranderingen en een hartinfarct dus vaak een periode is van tientallen jaren, is het belangrijk om vroeg in te kunnen schatten wie kans loopt op het krijgen van een hartinfarct. Immers, iemand kan dan behandeld worden met medicijnen, zoals cholesterol- of bloeddrukverlagers, om te voorkomen dat een hartinfarct ontstaat. Deze risico-inschatting is helaas niet gemakkelijk. Op dit moment geven de Nederlandse richtlijnen aan om dit met behulp van risicofactoren zoals leeftijd, geslacht, roken, suikerziekte, cholesterol en hoge bloeddruk in te schatten. Het is tegenwoordig bekend dat zowel de ontstekingsstof “C-reactive protein” (een meting in het bloed) als eiwit in de urine een mogelijke rol

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spelen in het ontstaan van kransslagadervernauwing. Daarnaast kan men tegenwoordig met een CT scan de hoeveelheid kalk in de kransslagaderen meten. Het doel van dit proefschrift is om meer inzicht te krijgen in de rol van deze nieuwe risicokenmerken in het ontstaan van kransslagadervernauwing en voorspellen van hartinfarcten.

Samenvatting per hoofdstuk

Voor de hoofdstukken 2 tot en met 6 van dit proefschrift is gebruik gemaakt van de gegevens van het PREVEND onderzoek in Groningen. Aan het PREVEND onderzoek deden in totaal 8592 inwoners van de stad Groningen mee, van wie het grootste deel geen eerdere hartklachten had meegemaakt. Het PREVEND onderzoek begon in 1997 en had als doel meer inzicht te krijgen in de rol van eiwit in de urine en andere risicofactoren in het ontstaan van nier- en hart- en vaatziekten. Van de deelnemers werden urine en bloed afgenomen, een hartfilmpje (“electrocardiogram”) gemaakt en medische gegevens verzameld. In hoofdstuk 2 wordt beschreven dat van de PREVEND deelnemers (n = 8139) zonder eerdere ernstige hartklachten, 3% een eerste hartinfarct meemaakte of een dotterbehandeling of omleidingsoperatie kreeg in 5 jaar tijd. De meeste mensen die een catheterisatie ondergingen na een hartinfarct, werden vervolgens ook gedotterd of kregen een hartoperatie. Echter, bij de mensen die een catheterisatie ondergingen vanwege pijn op de borst, was slechts in een derde een dotterbehandeling of hartoperatie nodig, terwijl in tweederde een behandeling met medicijnen kon volstaan of behandeling niet nodig was. Omdat een catheterisatie een onderzoek is met enig risico, moet er onderzocht worden of andere onderzoeken met minder risico, bijvoorbeeld CT scans, hier een vervangende rol kunnen spelen. Van de PREVEND deelnemers die een catheterisatie hebben ondergaan, zijn alle films van de kransslagaderen (het “coronairangiogram”) nauwkeurig bekeken. Er is gekeken of de vaten vernauwd waren, wandafwijkingen lieten zien of een stolsel bevatten. De aanwezigheid van een vernauwing met stolsel geeft grote kans om de bloedstroom te gaan belemmeren en kan leiden tot een hartinfarct. In hoofdstuk 3 is onderzocht of het “C-reactive protein”, gemeten bij aanvang van de PREVEND studie in 1997, een grotere kans geeft op hebben van kransslagadervernauwing, vaatwandafwijking of stolsels. Dit bleek inderdaad zo te zijn, terwijl dit voor eiwit in de urine niet duidelijk was. Deze bevinding bevestigt de rol van “C-reactive protein” in het ontstaan van kransslagadervernauwingen. In hoofdstuk 4 hebben we binnen het PREVEND onderzoek onderzocht of het meten van “C-reactive protein” en eiwit in de urine zin heeft om in te schatten of iemand ernstige hartklachten zal krijgen binnen 5 jaar ( overlijden, hartinfarct, dotterbehandeling of omleidingsoperatie). We hebben eerst deze kans geschat met behulp van leeftijd, geslacht, roken, bloeddruk, suikerziekte en cholesterol, aan de hand van het veelgebruikte Framingham model. Het bleek dat dit model de kans op ernstige hartklachten in een deel van de mensen overschat, en in een ander deel

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juist onderschat. De stof “C-reactive protein” leidde tot een betere inschatting op het krijgen van een hartinfarct, terwijl de rol van eiwit in de urine beperkt was. Vervolgens hebben we een nieuw model bestudeerd, waarin leeftijd, geslacht, roken, bloeddruk, suikerziekte en cholesterol, en ook “C -reactive protein” werden opgenomen. Dit model gaf een betere inschatting van de kans op het krijgen van een hartinfarct in vergelijking met het Framingham model. Deze gegevens laten zien dat “C-reactive protein” een rol zou moeten krijgen bij het voorspellen van de kans op een hartinfarct. Eiwit in de urine komt vaker voor bij mensen met kenmerken van het metabool syndroom. Het metabool syndroom is de naam voor een combinatie van de volgende kenmerken: hoge bloeddruk, overgewicht, een verkeerd vetspectrum in het bloed en een verhoogd suikergehalte. Binnen de PREVEND Intervention Trial, hebben we onderzocht of het innemen van een cholesterol verlagend medicijn, pravastatine, een beschermend effect heeft bij mensen met eiwit in de urine en het metabool syndroom. Hoofdstuk 5 laat zien dat in de 286 mensen met eiwit in de urine en het metabool syndroom het aantal ernstige hartklachten, namelijk overlijden, hartinfarct, dotterbehandeling of omleidingsoperatie, met 60% afneemt door behandeling met pravastatine. Dit konden we niet aantonen in 578 mensen met eiwit in de urine, die weinig tot geen kenmerken hadden van het metabool syndroom. Het meten van kalk in de wand van de kransslagaderen is tegenwoordig mogelijk met CT scans. Hierbij word met behulp van röntgenstralen foto’s gereconstrueerd van de kransslagaderen zonder dat het nodig is om met een slangetje naar het hart te gaan en contrastvloeistof in te spuiten, zoals bij een catheterisatie gebeurd. Meer verkalkingen wijzen op een grotere kans op het krijgen van een hartinfarct. De afwezigheid van verkalkingen geeft aan dat er geen ernstige kransslagadervernauwing is en dat de kans op een hartinfarct heel klein is. In de hoofdstukken 6 en 7 hebben we onderzocht of het meten van verkalkingen van de kransslagaderen een goed alternatief zou kunnen zijn voor de fietstest. De fietstest is de meest gebruikte test om in te schatten of mensen een kransslagadervernauwing hebben, Met name als er een verhoogde kans bestaat op het krijgen van een hartinfarct zoals bij de aanwezigheid van veel risicofactoren (hoge bloeddruk, hoog cholesterol, afwijkingen op het electrocardiogram) of als er klachten zijn die kunnen duiden op een hartinfarct. In hoofdstuk 6 hebben 153 PREVEND deelnemers zonder eerdere hartklachten, maar met een licht afwijkend electrocardiogram, een fietstest en een meting van de verkalking van de kransslagaderen ondergaan. Het bleek dat de verkalkingen van de kransslagaderen beter aan kon geven of iemand kransslagadervernauwing heeft of niet. Bij 69% van de mensen met veel verkalking van de kransslagaderen bleek kransslagadervernauwing aanwezig te zijn, in vergelijking tot 39% van de mensen met een afwijkende fietstest. Daarnaast bleek dat in 7% van de mensen met een normale fietstest er toch kransslagadervernauwing was, in vergelijking met 1% van degenen zonder verkalking van de kransslagaderen. Hoofdstuk 7 beschrijft een vergelijkbaar onderzoek bij 304 mensen die zich met pijn op de borst hadden gemeld op de spoedopvang van het Universitair Medisch Centrum Groningen. Ook uit dit onderzoek blijkt dat de verkalking van de kransslagaderen

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Samenvatting

beter aangeeft of iemand kransslagadervernauwing heeft. Alle mensen die geen verkalking hadden, konden veilig naar huis worden gestuurd omdat binnen deze groep geen kransslagadervernauwing werd gevonden en er binnen 1 jaar tijd geen hartinfarct ontstond. In de mensen met een normale fietstest bleek echter bij 6% toch kransslagadervernauwing aanwezig te zijn. Uit de hoofdstukken 6 en 7 blijkt dat er nog onduidelijkheid bestaat over wat het beste vervolgonderzoek is voor mensen met matige verkalking van de kransslagaderen, bij geen en bij veel verkalking is het beleid duidelijk.

Aanbevelingen voor toekomstig onderzoek

Toekomstig onderzoek moet zich richten op nieuwe modellen die de kans op een toekomstig hartinfarct inschatten. Hiervoor lijkt een belangrijke plaats voor de ontstekingsstof “C-reactive protein” en de meting van de verkalking van de kransslagaderen middels een CT scan. Daarnaast moet de rol van eiwit in de urine nog verder onderzocht worden. De meting van de verkalking van de kransslagaderen moet vergeleken worden met de fietstest in grote groepen patiënten die zich melden bij de huisarts met pijn op de borst of bij een mogelijk verhoogd risico op een toekomstig hartinfarct. Daarnaast moet verder onderzoek zich richten op het vergelijken van vervolgonderzoeken bij mensen met matige verkalking van de kransslagaderen.

Dankwoord

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Dankwoord

Het dankwoord geeft de auteur de gelegenheid om degenen die bij dit proefschrift betrokken zijn geweest te bedanken. Hiervoor wil ik graag enkele met naam noemen.

Ten eerste wil ik mijn eerste promotor, professor Zijlstra, bedanken. Beste Felix, je zakelijke manier van aanpak en coachende instelling hebben de voorwaarden voor een uiterst prettige promotietijd gecreëerd. Hartelijk dank voor je nauwe betrokkenheid bij het onderzoek. Ik denk dat er weinig promovendi zijn in Nederland die hun manuscripten binnen gemiddeld 2 dagen van commentaar voorzien terug krijgen.

In de tweede plaats gaat mijn dank uit naar mijn tweede promotor, professor van Gilst. Beste Wiek, toen ik in Groningen solliciteerde ging mijn interesse uit naar de mogelijkheid om onderzoek te doen binnen het PREVEND cohort onderzoek. Je hebt me die mogelijkheid geboden, wat heeft geresulteerd in een belangrijk deel van mijn proefschrift. Dank voor je kritische blik en gezelligheid op congresdagen/avonden.

Vervolgens wil ik graag mijn derde promotor, professor Hillege, bedanken. Beste Hans, we hebben ons hoofd in de afgelopen jaren menigmaal gebroken over de methoden voor onze analyses binnen de PREVEND studie. Je was altijd bereid hier tijd voor te maken en uitleg over te geven, zelfs om 22 uur ’s avonds, wat niet zelden voorkwam. Ik heb je positieve instelling erg gewaardeerd. Van harte gelukgewenst met je benoeming tot bijzonder hoogleraar in de cardiorenale interacties.

Vervolgens wil ik graag professor van Veldhuisen en dr. van den Berg bedanken. Beste Dirk-Jan en Maarten, dank voor de mogelijkheid die ik heb gekregen om in het UMCG de opleiding tot cardioloog te volgen.

De leden van de beoordelingscommissie, professor Oudkerk, professor Tijssen en professor van der Wall, wil ik bedanken voor het kritisch beoordelen van het proef-schrift.

Voor het opzoeken en bekijken van CAGs en het catheteriseren en zo nodig dotteren van patiënten wil ik alle medewerkers van de HC bedanken, en in het bijzonder professor Zijlstra, dr. Tio en dr. Jessurun. Beste Felix, René en Gillian, dank voor het beoordelen van vele fietstesten en CAGs, en het mij bijbrengen van de basis van coronairangiografie. Dr. de Smet, wil ik graag noemen voor het opzetten van IVUS gerelateerd onderzoek. Beste Bart, het heeft niet geleid tot een hoofdstuk in dit boekje, maar hopelijk kunnen we dit in de toekomst nog eens verder uitwerken. Dr. Anthonio, beste Rutger, dank voor je hulp bij het maken van de voorkant van het proefschrift.

Voor het faciliteren van, verrichten van en assisteren tijdens fietstesten in het kader van de PREVEND fietstest EBCT studie, gaat mijn dank uit naar Johan Koster en alle laboranten van de polikliniek Cardiologie (in het bijzonder Astrid en Arne). Dank voor jullie inzet!

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Dankwoord

Mijn dank gaat tevens uit naar drs. Riksta Dikkers, dr. Tineke Willems en medewerkers van de afdeling Radiologie voor hun bijdrage in het verwerven en verwerken van de coronaire kalkmetingen.

Voor dit proefschrift heb ik gebruik mogen maken van de gegevens van de PREVEND studie, die verzameld worden op de PREVEND polikliniek in het Triade gebouw van het UMCG. Ik wil graag degenen bedanken die hier de dagelijkse leiding over hebben, namelijk professor de Jong en dr. Gansevoort. Beste Paul en Ron, dank voor de prettige samenwerking. Doktersassistentes Anna, Roelie, Martha, Annet en Annie en de studenten wil ik bedanken voor hun hulp in de fietstest EBCT studie en het bakje koffie op zijn tijd. Drie keer moeder worden in een maand tijd is iets waar je niet over raakt uitgepraat.

Mijn mede PREVEND onderzoekers Jacoline, Auke en Nynke, wil ik bedanken voor de leuke tijd op de polikliniek. Jacoline, mijn kamergenootje, alle inhoudelijke en niet-inhoudelijke kanten van promoveren zijn op onze kamer uitgebreid aan de orde geweest. Je bent een wetenschapper met goede sociale eigenschappen. Van harte gefeliciteerd met je plek voor de opleiding tot klinisch chemicus!

Drs. W. A. Dijk wil ik bedanken voor het aanleveren van data voor verschillende hoofdstukken van het proefschrift. Beste Arnold, dank voor je medewerking.

Trial Coördination Center medewerkers Rob Bieringa, Marco Assmann, Onno van der Velde en Diane Steenks, dank voor jullie bijdragen aan de dataverwerking van het PREVEND onderzoek.

Dr. Kors, beste Jan, dank voor je moeite voor het vervolledigen van de ECG codering van de PREVEND ECGs.

Zonder dr. Post was hoofdstuk 3 er niet geweest. Wendy, dank voor het uitwerken van de multilevel analyses. Het was een plezier om met je samen te werken.

Zonder de secretaresses van de 4e verdieping, de HC en KF zou het werk van een promovendus een stuk lastiger zijn. Alma, Audrey, Olga, Daniëlle, Morela, Ardy, Winie, Ria, Alexandra, Ellen, Manon, Alice, Janette, Liesje, Gerda, en in het bijzonder Magda, dank voor jullie gezelligheid en bereidheid om altijd weer een plekje te maken in overvolle agenda’s en van alles en nog wat te regelen. Zelfs een uurtje oppassen is jullie niet te gek.

Collega’s maken je dag: (ex-) Greenhousers Jessica, Tone, Daan, Wim, Michiel, Sheba, Sandra, Martin, Jasper, Kevin, Bas, Marcelle, Anne, Peter, Ruud, Tom, Pim, Erik, Patrick, Matthijs, Lieuwe, Anne-Chris, Folkert, Meint, Rik, Pieter-Jan en Willem-Peter: bedankt! Onderzoek doen, aangevuld met koffie en cola rondjes, af en toe uit eten, een wijnproefcursus en GVB, vormde een prettige overgang van studententijd naar het werken in de kliniek.

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Dankwoord

Abdou Sar, we were a good team during the GUIDE course “bring science to the market”. Perhaps we will continue working together in the future. I wish you all the best for the continuation of your thesis.

Dr. M. Castro Cabezas, beste Manuel, het begin van mijn onderzoeksbelangstelling lag op het Laboratorium Vasculaire Geneeskunde in Utrecht. Dank voor het overbrengen van je enthousiasme voor onderzoek. Ik stel het erg op prijs dat je in de oppositie wilt plaatsnemen!

Collega’s in het MCL, bedankt voor jullie meeleven met de vorderingen van het proefschrift.

Mijn paranimfen, Tone Svilaas en Michiel Rienstra, de tijd in de Greenhouse is het begin van een vriendschap geweest en ik stel het daarom bijzonder op prijs dat jullie mijn paranimfen willen zijn. Tone, we hebben lang een kamer gedeeld in de Greenhouse. Je doorzettingsvermogen, (Noorse?) nuchterheid en humor hebben indruk op me gemaakt. Ik hoop dat je bij mijn verdediging kunt zijn. Zo niet, dan heb je daar een hele goede reden voor! Michiel, je hebt altijd veel enthousiasme voor alles wat je doet. Je bent naar Utrecht vertrokken om daar verder te gaan met je opleiding. Hoewel dat natuurlijk erg ongezellig is, kom ik je gelukkig straks in Groningen weer tegen.

Mijn familie, vrienden, ouders en schoonouders: bedankt voor jullie interesse in dit proefschrift, jullie steun voor ons gezin en vooral het delen van vele gezellige en mooie momenten.

Valérie, ons bijzondere meisje, dit proefschrift is aan jou opgedragen, omdat de afronding hiervan samenviel met jouw fantastische start.

Lieve Steven, we hebben de afgelopen 2 jaar vele uren samen in de studeerkamer doorgebracht, en met resultaat: jij van harte gefeliciteerd met je MBA titel. Ik zie er naar uit om je ook weer buiten of op het water tegen te komen. Je t’aime.

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Curriculum Vitae

Christiane Anneliese Geluk was born in Rotterdam on September 29th 1977. She graduated from secondary school at the Marnix Gymnasium in Rotterdam in 1995. In the same year she started Medical School at the University of Antwerp in Belgium. She continued Medical School from 1997 onwards at the University Medical Center Utrecht in Utrecht. During her study she conducted research at the Laboratory of Vascular Medicine, department of Internal Medicine (dr. M. Castro Cabezas, prof. dr. D.W. Erkelens) of the University Medical Center Utrecht, for which she received the Dirk Durrer N.V.V.C. award for the best clinical manuscript in the Netherlands Heart Journal of 2006. Parts of her clinical rotations were performed in Indonesia, France and Curaçao. She obtained her medical degree in 2003. In the same year, she worked as resident at the Department of Cardiology of the University Medical Center Groningen for four months. In 2003 she started as research physician at the Department of Cardiology (prof. dr. F. Zijlstra, prof. dr. W.H. van Gilst, dr. J.L. Hillege) of the University Medical Center Groningen in Groningen, which resulted in the current thesis. She participated in the training program of the Graduate School for Drug Exploration (GUIDE) in Groningen. In January 2007, she started her first two years of Cardiology residency at the Department of Internal Medicine at the Medisch Centrum Leeuwarden in Leeuwarden.

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Geluk CA, Asselbergs FW, Bakker SJL, Gansevoort RT, de Jong PE, van Gilst WH, Grobbee DE, Zijlstra F, Hillege HL. The predictive value of adding urinary albumin excretion and high-sensitive C-reactive protein to Framingham Risk. Submitted.

Geluk CA, Dikkers R, Perik PJ, Tio RA, Götte MJW, Hillege HL, Vliegenthart R, Houwers JB, Willems TP, Oudkerk M, Zijlstra F. Measurement of coronary calcium scores or exercise testing as initial diagnostic tool in low-risk patients with suspected coronary artery disease. European Radiology 2007 [Epub ahead of print]

Geluk CA, Dikkers R, Kors JA, Tio RA, Slart RHJA, Vliegenthart R, Hillege HL, Willems TP, de Jong PE, van Gilst WH, Oudkerk M, Zijlstra F. Measurement of coronary calcium scores or exercise testing as initial screening tool in asymptomatic subjects with ST-T changes on the resting ECG: an evaluation study. BMC Cardiovasc Disord. 2007 Jul 13;7(1):19

Geluk CA, Tio RA, Tijssen JGP, van Dijk RB, Dijk WA, Hillege HL, de Jong PE, van Gilst WH, Zijlstra F. Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study. Neth Heart J. 2007 Apr;15(4):133-41.

Geluk CA, Post WJ, Hillege HL, Tio RA, Tijssen JGP, van Dijk RB, Dijk WA, Bakker SJL, de Jong PE, van Gilst WH, Zijlstra F. C-Reactive protein and angiographic characteristics of stable and unstable coronary artery disease – data from the prospective PREVEND cohort. Atherosclerosis, 2006 [Epub ahead of print]

Geluk CA, Zijlstra F. Gatekeeper for coronary angiography (letter). Eur Heart J. 2006 May;27(9):1127-8.

Geluk CA, Halkes CJM, de Jaegere PPTh, Plokker HWM, Castro Cabezas M. Coronary risk factors and metabolic disorders in first-degree relatives of normocholesterolaemic patients with premature atherosclerosis. Neth Heart J 2006; 14(4):125-131.

Geluk CA, Zijlstra F. Electron beam computed tomography with suspected CAD: the preferred initial diagnostic test in clinically stable patients. Neth Heart J 2006;14(1):24-25.

Geluk CA, Asselbergs FW, Hillege HL, Bakker SJL, de Jong PE, van Gilst WH, Zijlstra F. Impact of statins in subjects with the metabolic syndrome: a substudy of the PREVEND Intervention Trial. Eur Heart J 2005;26(13):1314-20.

Dorgelo J, Willems TP, Geluk CA, Janssen CHC, van Ooyen PMA, Zijlstra F, Oudkerk M. The role of multidetector computed tomography to predict the need for invasive

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treatment in patients with non ST elevation acute coronary syndrome. Eur Radiol. 2005 Apr;15(4):708-13.

Geluk CA, Halkes CJM, Jaegere PP de, Plokker HWM, Erkelens DW, Castro Cabezas M. Daytime triglyceridemia in normocholesterolemic patients with premature atherosclerosis and in their first degree relatives. Metabolism. 2004 Jan;53(1):49-53. Van den Brink MR, Geluk CA, Lindner JR, Velthuis BK, Vonken EJ, Cramer MJM. Novel ways to noninvasively detect inflammation of the myocardium: contrast-enhanced MRI and myocardial contrast echocardiography. Neth Heart J. 2003;11(4):163-168.

Geluk CA, Otterspoor LC, Boeck B de, Gevers RMM, Velthuis BK, Cramer MJM. Magnetic resonance imaging in acute myocarditis: a case report and a review of literature. Neth J Med. 2002 Jun;60(5):223-7.

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University of Groningen Coronary risk stratification Geluk ... · Bristol Meyers Squibb BV, Boehringer Ingelheim BV, Dade Behring BV, Medtronic BV, Pfizer BV, Siemens, Schering-Plough,