Serum Cholesterol Levels Are Underevaluatedand Undertreated

Peter G. Danias, MD, PhD, Stephen O’Mahony, MD, Martha J. Radford, MD,Lisa Korman, Pharm D, and David I. Silverman, MD

W ith the recent publication of several well-designed large-scale clinical trials document-

ing the efficacy of cholesterol lowering for bothprimary and secondary prevention of coronary ar-tery disease (CAD),1–7 the benefits of aggressivetreatment of hypercholesterolemia have now beenestablished. These data strongly support the validityof the Adult Treatment Panel (ATP)/National Edu-cation Cholesterol Program (NCEP) guidelines forthe management of hypercholesterolemia, first in-troduced in 19888 and revised in 1993.9 The 1993revision emphasizes aggressive secondary preven-tion of CAD and uses low-density lipoprotein(LDL) cholesterol levels as the fundamental guide-post for treatment. As such, the ATP II/NCEPguidelines represent a widely accepted algorithmfor current management of hypercholesterolemia.At present, however, physicians’ practices with re-gard to management of hypercholesterolemia re-main uncertain. Previous reports have suggestedthat treatment practices vary widely and that fewpatients who are candidates for drug therapy forhypercholesterolemia actually receive it.10 –16 Noprevious studies have been conducted to evaluatecurrent physicians’ compliance to practice guide-lines for management of hypercholesterolemia inpatients followed in the Veterans Administration(VA) health care system. We investigated the cur-rent patterns of management of hypercholesterol-emia in relation to the ATP II/NCEP guidelines in auniversity-affiliated VA medical center.

• • •Case identification was performed through the

VA hospital laboratory’s computerized database byselecting persons who had serum total cholesteroltesting within a 3-month period (October 1, 1994 toDecember 31, 1994). One hundred forty-seven con-secutive subjects with records available for reviewwere included in this study, and their managementin relation to hypercholesterolemia was reviewedfor the subsequent 1 year. The presence of CADwas ascertained from the medical record by docu-mented prior myocardial infarction, revasculariza-tion procedures, or previous admission for unstableangina. Similarly, risk factors for CAD were re-

trieved from the medical record regarding specificdiagnosis of hypertension, family history of CAD,smoking within the last 5 years, or diabetes melli-tus, or by administration of specific medications forthese risk factors.

The earliest total cholesterol measurement foreach individual, within the 3-month case-identifica-tion period (October 1, 1994 to December 31,1994), was defined as the “entry” value. Entry andrepeat cholesterol and lipid testing for all patientswere reviewed for a duration of 12 months follow-ing the entry value. Serum total cholesterol values,performed as an isolated test or together with lipidprofile analysis (including measurement of serumtriglyceride and high-density lipoprotein [HDL]cholesterol, with or without direct LDL cholesterolmeasurement) were also recorded. The biochemical

From the Cardiology Division, University of Connecticut Health Center,Farmington; and the Connecticut Veterans Administration Health CareSystem, Newington Campus, Newington, Connecticut. Dr. Silvermanis the recipient of a Clinical Associate Physician Award from theNational Institutes of Health General Clinical Research Center GrantMO1RR06192. Dr. Silverman’s address is: Cardiology, University ofConnecticut Health Center, Farmington, Connecticut 06030-1305.Manuscript received June 30, 1997; revised manuscript received andaccepted January 30, 1998.

FIGURE 1. Lipoprotein analysis at entry for low, intermediate,and high total cholesterol levels.

TABLE I Demographic Characteristics of the Study Population

Age (yr) 62 6 12,65 72 (49%)$65 75 (51%)

GenderMen 144

(98%)Women 3 (2%)

1 Coronary artery disease 44 (30%)Coronary risk factors

Systemic hypertension 102(69%)

Smoking 46 (31%)1 Family history 48 (33%)Diabetes mellitus 35 (24%)High-density lipoprotein ,35 mg/dl 25 (17%)

Values are expressed as mean 6 SD or number (%) as appropriate.

©1998 by Excerpta Medica, Inc. 0002-9149/98/$19.00 1353All rights reserved. PII S0002-9149(98)00167-2

determination of cholesterol levels was performedfor all subjects in the routine chemistry laboratoryof the VA hospital using a standard colorimetricenzymatic determination method.17 When direct

LDL cholesterol measurementwas not available, it was calcu-lated using the Freidewald for-mula.18

Physicians’ adherence to theATP II/NCEP II guidelines was de-termined by assessing repeat cho-lesterol and lipid testing, and pre-scribing lipid-lowering medicationsover the 12 months during whichpatient data were reviewed. Thehospital’s pharmacy computerizeddatabase was reviewed for all sub-jects to assess for cholesterol-low-ering medications (including sta-tins, resins, fibrates, and niacin)prescribed during the 12-months af-ter the entry blood test. No attemptwas made to modify physicianpractice for the duration of thestudy. All data were entered in acomputerized database and cross-checked for validity. All data en-tries were reviewed for accuracy byone of the investigators (SO). Val-ues are presented as mean6 SD.Fisher’s exact test was used forcomparison of treatment rates in

patients with and without CAD. Apairedt test was used for comparisonof initial and subsequent serum cho-lesterol values.

The study population was al-most exclusively men (Table I).Thirty percent of patients had clin-ical CAD, and 80% of patientswithout CAD had$2 coronary riskfactors. Serum cholesterol level atthe time of patient identification(entry) was 2246 33 to 47 mg/dl,and 43 patients (29%) had initialserum total cholesterol levels.240 mg/dl. Sixty-six patients(45%) had a complete lipid profilewith their initial cholesterol test.The percentage of lipid profileevaluation performed at entry wassimilar for low, intermediate, andhigh total cholesterol levels (chi-square50.6, p5 0.8, Figure 1). Ofthe 147 patients, 94 (65%) had atleast 1 additional cholesterol levelwas remeasured during the follow-ing 12 months. For this subset ofpatients, initial total cholesterollevel was 2326 51 mg/dl, HDLcholesterol was 446 23 mg/dl, andestimated LDL cholesterol was

148 6 41 mg/dl. Between the first and last avail-able testing, mean total cholesterol decreased sig-nificantly in this group to 2166 39 mg/dl (p 50.004). Neither final HDL (406 12 mg/dl) nor

FIGURE 2. Physician practice for management of hypercholesterolemia in patients withclinical CAD. Entry is defined as the case-identifying initial blood test.

FIGURE 3. Physician practice for management of hypercholesterolemia in patientswithout CAD but with >2 coronary risk factors (CRFs). Entry is defined as the case-identifying initial blood test.

1354 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 81 JUNE 1, 1998

estimated LDL (1406 36 mg/dl) were significantlychanged.

At entry only 18 subjects had LDL cholesterollevels below the ATP II/NCEP II suggested target,and none of these patients had been receiving cho-lesterol-lowering medications at that time. Nineteenother patients had previously received prescriptionsfor lipid-lowering medications; of these, 12 re-ceived evaluation of lipid profile at entry, and allpatients in this group whose LDL cholesterol levelswere measured had values higher than the recom-mended target. Within 1 year, only 6 (32%) of thosereceiving medications at study entry had LDL cho-lesterol levels below the NCEP II target values.

Management practices of hypercholesterolemiafor patients with CAD are shown in Figure 2. Sim-ilarly, practices regarding persons without CAD and$2 coronary risk factors are shown in Figure 3. Inall, of 26 patients (13 with and 13 without CAD)who met ATP II/NCEP criteria for immediate ini-tiation of drug therapy for hypercholesterolemia,only 12 (46%) received drug therapy within 1 year.Additionally, a few patients who met criteria forinitiation of nonpharmacologic treatment of hyper-cholesterolemia underwent appropriate follow-uptesting of hypercholesterolemia. Only 4 of 7 pa-tients (57%) who had repeat cholesterol testingwithin 6 months received lipid-lowering medica-tions as a result of their follow-up lipid studies; afifth patient achieved target LDL cholesterol levelswithin that time period.

In summary, medical therapy of hypercholesterol-emia was indicated based on initial and 6-month fol-low-up LDL cholesterol levels for 32 persons accord-ing to the ATP II/NCEP guidelines. Only 16 (50%),however, actually received lipid-lowering medicationswithin 1 year. Although medical therapy for hyper-cholesterolemia was more common for secondary(67%) than for primary prevention (35%), this differ-ence did not achieve significance (p5 0.16).

• • •In our series, less than one half of subjects meeting

ATP II/NCEP criteria for initiation of lipid-loweringtherapy received prescriptions for cholesterol-lower-ing medications. Furthermore, among patients beingprescribed lipid-lowering medications, only one thirdachieved acceptable LDL cholesterol reduction within1 year. Our findings agree with previously reportedrates of adherence to ATP I/NCEP guidelines in otherphysician groups, including cardiologists,13 primarycare practitioners,19 and medical trainees.20 Low ratesof treatment for hypercholesterolemia have also beenreported in multiple patient populations, includingHispanic patients with multiple risk factors,11 womenwith heart disease,12 patients with chronic CAD oracute coronary syndromes,13,14 and patients undergo-ing peripheral vascular or carotid15 and coronary ar-tery revascularization.16

These data emphasize the need to redouble effortsto improve treatment of patients with or at risk forCAD, if the dramatic decline in cardiovascular deathrates witnessed over the last 10 years is to continue.

Increased public awareness, continued education ofphysicians and other allied health professionals, bettersupport systems, and specialized clinics are strategiesthat have the potential to impact substantially on thehealth of the general population and therefore shouldbe actively pursued.

In summary, <50% of patients meeting ATP II/NCEP guidelines for treatment of hypercholesterol-emia received appropriate, comprehensive therapy.Thus, hypercholesterolemia is still underevaluatedand undertreated in a university-affiliated VA med-ical center, largely as the result of incomplete physi-cian adherence to national guidelines.

Acknowledgment: We thank David D. Waters, MD-,for his critical review of the manuscript and his help-ful comments.

1. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK,Kaitaniemi P, Koskinen P, Manninen V, Ma¨enpaa H, Malkonen M, Manttari M,Norola S, Pasternack A, Pikkarainen J, Romo M, Sjo¨blom T, Nikkila EA.Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-agedmen with dyslipidemia: safety of treatment, changes in risk factors, and incidenceof coronary heart disease.N Engl J Med1987;317:1237–1245.2. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Pri-mary Prevention Trial results, I. Reduction in the incidence of coronary heartdisease.JAMA 1984;251:351–364.3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW,McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention StudyGroup. Prevention of coronary heart disease with pravastatin in men with hyper-cholesterolemia.N Engl J Med1995;333:1301–1307.4. Scandinavian Simvastatin Survival Study Group. Randomized trial of choles-terol lowering in 4444 patients with coronary heart disease: the ScandinavianSimvastatin Survival Study (4S).Lancet1994;344:1383–1389.5. Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hart-well T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, Young B, forthe Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.Effect of lovastatin on early carotid atherosclerosis and cardiovascular events.Circulation 1994;90:1679–1687.6. Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park J-SP, McGovern ME.Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I):reduction in atherosclerosis progression and clinical events. PLAC I investiga-tion. J Am Coll Cardiol1995;26:133–139.7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effectof pravastatin on coronary events after myocardial infarction in patients withaverage cholesterol levels. Cholesterol and Recurrent Events Trial investigators.N Engl J Med1996;335:1001–1009.8. NCEP Expert Panel on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults. Report of the National Cholesterol Education ProgramExpert Panel on detection, evaluation, and treatment of high blood cholesterol inadults.Arch Intern Med1988;148:36–69.9. Expert panel on detection, evaluation, and treatment of high blood cholesterol inadults. Summary of the second report of the national cholesterol education program(NCEP) expert panel on detection, evaluation and treatment of high blood cholesterolin adults (Adult Treatment Panel II).JAMA1993;269:3015–3023.10. Giles WH, Anda RF, Jones DH, Serdula MK, Merritt RK, DeStefano F.Recent trends in the identification and treatment of high blood cholesterol byphysicians.JAMA 1993;269:1133–1138.11. Laffer CL, Elijovich F. Suboptimal outcome of management of metaboliccardiovascular risk factors in Hispanic patients with essential hypertension.Hypertension1995;26:1079–1084.12. Schrot HG, Bittner V, Vittinghoff E, Herrington DM, Hulley S, for the HERSResearch Group. Adherence to national cholesterol education program treatmentgoals in postmenopausal women with heart disease. The heart and estrogen/progestin replacement study (HERS).JAMA 1997;277:1281–1286.13. Cohen MV, Byrne MJ, Levine B, Gutowski T, Addson R. Low rate oftreatment of hypercholesterolemia by cardiologists in patients with suspected andproven coronary artery disease.Circulation 1991;83:1294–1304.14. Giugliano RP, Camargo CA, Lloyd-Jones DM, Pasternack RC, O’DonnellCJ. Differences in lipid management across the spectrum of acute coronary arterydisease (abstr).J Am Coll Cardiol1996;29(suppl A):400A.15. Aspry KE, Holcroft JW, Amsterdam EA. Physician recognition of hypercho-lesterolemia in patients undergoing peripheral and carotid artery revasculariza-tion. Am J Prev Med1995;11:336–341.16. Northridge DB, Shandall A, Rees A, Buchalter MB. Inadequate managementof hyperlipidaemia after coronary bypass surgery shown by medical audit.BrHeart J 1994;72:466–467.

BRIEF REPORTS 1355

17. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determina-tion of total serum cholesterol.Clin Chem1974;20:470–475.18. Friedewald DT, Levy RI, Fredrickson DS. Estimation of the concentration oflow-density lipoprotein cholesterol in plasma, without use of the preparativeultracentrifuge.Clin Chem1972;18:499–502.

19. Hyman DJ, Maibach EW, Flora JA, Fortmann SP. Cholesterol treatmentpractices of primary care physicians.Public Health Rep1992;107:441–448.20. Leaf DA, Neighbor WE, Schaad D, Scott CS. A comparison of self-report andchart audit in studying resident physician assessment of cardiac risk factors.J Gen Intern Med1995;10:194–198.

Exercise Echocardiography in Children With KawasakiDisease: Ventricular Long Axis Is Selectively Abnormal

Michael Y. Henein, MD, PhD, Sinka Dinarevic, MD, Christine A. O’Sullivan, BSC,Derek G. Gibson, MD, and Elliot A. Shinebourne, MD

Involvement of coronary arteries in Kawasaki dis-ease may lead to aneurysm formation, myocardial

infarction, and sudden death.1,2 The natural history ofcoronary aneurysms, which occur in up to 20% ofchildren with Kawasaki disease,3–5 is not yet known.Because coronary artery disease may progress, earlyrecognition is important. Traditionally, coronary an-giography6–8 and thallium perfusion tomography9 areperformed, but they may possibly have complicationsin children. A noninvasive technique that avoids radi-ation is needed. Our purpose was to evaluate thepossible usefulness of exercise echocardiography inchildren with Kawasaki disease concentrating in par-ticular on ventricular long-axis function, changes thathave recently been shown to offer a more sensitiveindex of impaired myocardial perfusion than dochanges in short-axis function.10

• • •Between January 1992 and May 1995, 73 children

referred to the Royal Brompton Hospital were diag-nosed as having Kawasaki disease.11 Thirty of 73children (41%) (15 boys) were found to have proximalcoronary artery abnormalities identified by 2-dimen-sional transthoracic echocardiography. Their meanage was 396 25 months at the time of diagnosis and81 6 27 months at the time of study. Exercise echo-cardiography was feasible in only 17 patients (meanage 6.66 2 years). Of the 17 patients studied, 6 hadreceived intravenous gamma globu-lin therapy at the time of acute illnessas well as aspirin; 2 others receiveddypiridamole. At follow-up 13 to108 months later, all 17 were asymp-tomatic, and the 5 with aneurysmswere still taking aspirin. Eighteennormal children (mean age 7.06 0.2years, 9 boys) were also studied ascontrols by the same physician usingthe same protocol.

Transthoracic echocardiographicimaging of the coronary arteries was

From the Departments of Pediatric and AdultCardiology, Royal Brompton Hospital, London,England. Dr. Shinebourne’s address is: RoyalBrompton Hospital, Sydney Street, LondonSW3 6NP, England. Manuscript received Oc-tober 1, 1997; revised manuscript receivedand accepted January 30, 1998.

TABLE I Long-Axis Function

Variables

Normals (n 5 18) Patients (n 5 17)

Resting Exercise Resting Exercise

Long axisTotal excursion (cm)

Left 1.27 6 0.15 1.4 6 0.2§ 1.24 6 0.3 1.3 6 0.2Septal 1.23 6 0.15 1.3 6 0.25 1.19 6 0.15 1.3 6 0.3*Right 1.9 6 0.4 2.1 6 0.4† 2.0 6 0.3 2.3 6 0.3†

Peak shortening rate (cm/s)Left 6.2 6 1.2 8.8 6 2.0§ 5.8 6 1.4 7.7 6 2.1*Septal 6.0 6 1.2 8.1 6 2.0§ 5.7 6 1.2 7.2 6 2.5Right 10.6 6 2.0 13.0 6 2.5‡ 7.3 6 2.7\ 7.8 6 2.8\

Peak lengthening rate (cm/s)Left 9.6 6 2.0 11.3 6 2.0* 9.0 6 1.6 9.0 6 2.1\

Septal 8.3 6 1.6 9.0 6 2.0* 8.2 6 1.8 9.2 6 2.2Right 11.0 6 1.5 12.0 6 2.0* 10 6 1.4 9.3 6 3.1\

* p ,0.05; †p ,0.01; ‡p ,0.05; §p ,0.001 exercise versus resting within each group (paired t test);\p ,0.001, patients resting or exercise values versus normals (Mann-Whitney test).

FIGURE 1. Apical 4-chamber view with M-mode cursor at dif-ferent sites of the atrioventricular ring. LA 5 left atrium; LV 5left ventricle; RA 5 right atrium; RV 5 right ventricle.

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