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Clinical Benefit of Early Reperfusion Therapy in Patients WithST-Elevation Myocardial Infarction Usually Excluded from

Randomized Clinical Trials (Results from the MaximalIndividual Therapy in Acute Myocardial Infarction Plus

[MITRA Plus] Registry)

Oliver Koeth, MDa, Ralf Zahn, MDa, Anselm Kai Gitt, MDa,b, Timm Bauer, MDa,Claus Juenger, MDb, Jochen Senges, MDb, and Uwe Zeymer, MDa,b,*, for the Maximal Individual

Therapy in Acute Myocardial Infarction Plus (MITRA Plus) Study Group

Randomized clinical trials (RCTs) usually enroll selected patient populations that may notbe representative for patients seen in everyday practice. Therefore, concerns have beenraised regarding their external validity. For the present study we evaluated the MITRAPlus registry and included 20,175 patients with ST-elevation myocardial infarction. Wedefined RCT-ineligible patients as patients fulfilling >1 of the following criteria: age >75years, prehospital delay >12 hours, prehospital cardiopulmonary resuscitation, cardiogenicshock, impaired renal function, and previous stroke. Those patients (n � 9,369, 46.4%)were compared to patients eligible for enrollment in RCTs (n � 11,806, 53.6%). Ineligiblepatients were older (p <0.0001), more often were women (p <0.0001), and more often hadconcomitant diseases (p <0.0001). Ineligible patients less often received early reperfusiontherapy (p <0.0001), aspirin (p <0.0001), clopidogrel (p <0.0001), and statins (p <0.0001).Ineligible patients had a higher hospital mortality (20.1% vs 4.9%; p <0.0001) and a higherrate of nonfatal strokes (1.5% vs 0.4%, p <0.0001) compared to eligible patients. Earlyreperfusion therapy (thrombolysis and/or percutaneous coronary intervention [PCI]) in ineli-gible patients was associated with a significant decrease of hospital mortality (odds ratio 0.62,95% confidence interval 0.49 to 0.79), with primary PCI being more effective than thrombolytictherapy (odds ratio 0.52, 95% confidence interval 0.41 to 0.65). In conclusion, about 50% ofpatients with ST-elevation myocardial infarction seen in clinical practice are usually excludedfrom RCTs. Hospital mortality in those patients is very high. Primary PCI improves theprognosis and is therefore the preferred reperfusion strategy in these patients. © 2009 Elsevier

Inc. All rights reserved. (Am J Cardiol 2009;104:1074–1077)

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The aim of the present study was to compare patientsith ST-elevation myocardial infarction (STEMI) usually

xcluded from randomized clinical trials (RCTs; ineligibleatients) to patients eligible for enrollment but not enrolledn any clinical trial. In addition, we sought to investigateurrent use and clinical benefit of guideline-adherent acuteherapy in ineligible patients.

ethods

The Maximal Individual Therapy in Acute Myocardialnfarction Plus (MITRA Plus) registry is a German, pro-pective, multicenter, observational data pool of currentreatment of acute MI. From 1992 to 2002, 21,175 consec-tive patients were included in the MITRA Plus registry.

aDepartment of Cardiology, Herzzentrum Ludwigshafen, and bInstitutür Herzinfarktforschung Ludwigshafen an der Universität Heidelberg,udwigshafen, Germany. Manuscript received March 19, 2009; revisedanuscript received and accepted May 29, 2009.

*Corresponding author: Tel: 49-621-503-4045; fax: 49-621-503-4002.

fE-mail address: Uwe.Zeymer@t-online.de (U. Zeymer).

002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2009.05.054

he MITRA Plus registry consists of 4 consecutive subreg-stries that have been previously described: the 60 Minutes

yocardial Infarction Project (60-minute MIP),1 Maxi-al Individual Therapy in Acute Myocardial Infarction

MITRA),2 the Myocardial Infarction Registry (MIR),3 and thecute Coronary Syndromes (ACOS) registry.4 The present

nvestigation is an analysis of consecutive patients withTEMI �24 hours. Patients were recruited from 217 hos-itals in Germany, mainly community hospitals. All con-ecutive patients with STEMI were included in the MITRAlus registry. STEMI was diagnosed in the presence of thefollowing criteria: (1) persistent angina pectoris for �20inutes and ST-segment elevation �1 mm in �2 standard

eads or �2 mm in �2 contiguous precordial leads or (2)ersistent angina pectoris for �20 minutes and presence ofeft bundle branch block. STEMI was later confirmed by anncrease in cardiac enzymes to �2 times the upper limit oformal. For this study we defined ineligible patients asatients fulfilling �1 of the following criteria: age �75ears, prehospital delay �12 hours, prehospital cardiopul-onary resuscitation, cardiogenic shock, impaired renal

unction, and previous stroke. Eligible patients were defined

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1075Coronary Artery Disease/Reperfusion Therapy in STEMI

s patients not fulfilling 1 of those criteria and meeting theligibility criteria for �1 of the following contemporaryrials in patients with STEMI: Assessment of the Safety andfficacy of a New Treatment Strategy with Percutaneousoronary Intervention (ASSENT-4 PCI) trial,5 Combinedbciximab REteplase Stent Study in Acute Myocardial In-

arction (CARESS-in-AMI) trial,6 and Grupo de Analisis dea Cardiopatia Isquernica Aguda-1 (GRACIA-1) trial.7 Mor-ality, nonfatal reinfarction, and nonfatal stroke were de-ned as major adverse cardiac and cerebrovascular eventsMACCEs). The definition of MACCEs in this study doesnclude target lesion or vessel revascularizations. Data con-erning the early intrahospital period (first 48 hours) wereollected by use of a record form within the first 2 days athe intensive care unit. Clinical events after the initial periodntil hospital discharge were registered on a separate recordorm. A prospective follow-up was performed after 12 � 2onths in about 40% of patients. All data sheets were sent

o the central data processing center (Institut für Herzinfark-forschung, Ludwigshafen, Germany) for uniform monitor-ng and registration. Absolute numbers, percentages, medi-ns, and quartiles were computed to describe the patientopulation. Categorical variables were compared using chi-quare or Fisher’s exact test and calculating the odds ratioOR) and 95% confidence interval (CI). Propensity scorenalysis was used to evaluate the clinical benefit of earlyeperfusion therapy (thrombolysis and/or percutaneous cor-nary intervention [PCI]), primary PCI, and thrombolysis.or the propensity score analysis the following variables

able 1aseline characteristics

aselineharacteristics

RCT-IneligiblePatients

(n � 9,369)

RCT-EligiblePatients

(n � 11,806)

p Value

ean age (years) 75.5 61.9 �0.0001omen 3,885 (41.6%) 2,779 (23.6%) �0.0001

revious MI 1,595 (17.0%) 1,596 (13.5%) �0.0001revious PCI or

coronary arterybypass graft

108 (7.6%) 115 (8.5%) 0.38

ypertension 4,267 (45.5%) 4,783 (40.5%) �0.0001iabetes mellitus 2,522 (26.9%) 2,200 (18.6%) �0.0001ypercholesterolemia* 957 (57.7%) 1,548 (66.6%) �0.0001nterior acute MI 4,553 (51.9%) 5,270 (46.6%) �0.0001

* Low-density lipoprotein cholesterol �130 mg/dl and/or history ofypercholesterolemia and/or actual medication for hypercholesterolemia.

able 2cute adjunctive medication within 48 hours after admission

cute Adjunctiveedication

RCT-IneligiblePatients

(n � 9,369)

RCT-EligiblePatients

(n � 11,806)

p Value

spirin 8,664 (93.0%) 11,408 (97.1%) �0.0001lopidogrel 466 (32.9%) 593 (44.0%) �0.0001tatins 1,189 (48.1%) 2,033 (66.1%) �0.0001ngiotensin-convertingenzyme inhibitors

5,432 (60.1%) 7,510 (66.1%) �0.0001

blockers 5,191 (56.9%) 8,602 (74.4%) �0.0001

ere included: age, gender, previous MI, previous stroke, h

iabetes mellitus, arterial hypertension, and impaired renalunction. The C-statistic for propensity score models was.697. Patients were categorized into quintiles defined byheir probabilities (propensity scores). Balance of covari-bles across the 2 groups was achieved after adjustmentor the propensity score. Balance was tested statisticallyy linear regression for continuous variables and logisticegression for dichotomous variables. Propensity scoreuintiles were then added to the final logistic regressionodel. Balance was tested statistically by linear regres-

ion for continuous variables and logistic regression forichotomous variables. A p value �0.05 was consideredtatistically significant. All p values were results of 2-ailed tests.

esults

For the present study we evaluated the MITRA Plusegistry and included 11,806 patients with STEMI eligibleor enrollment in RCTs and 9,369 patients with STEMIsually excluded from RCTs. In total 53.5% of ineligibleatients were �75 years old, 3.3% had a previous stroke,3.1% prehospital cardiopulmonary resuscitation, 5.5% im-aired renal function, 40.7% prehospital delay �12 hours,nd in 11.0% STEMI was complicated by cardiogenichock. Baseline characteristics and acute adjunctive medi-ation of ineligible and eligible patients are listed in Tablesand 2. Baseline characteristics of the 2 groups differedarkedly. Ineligible patients less often received early reper-

usion therapy (thrombolysis and/or PCI) within 24 hoursompared to eligible patients (Figure 1). Ineligible patientsot receiving reperfusion therapy were older (p �0.0001),ore often were women (p �0.0001), and more often had

iabetes mellitus (p �0.0001), hypertension (p �0.01), and

igure 1. Rates of early reperfusion therapy in eligible (black bars) andneligible (gray bars) patients within 24 hours.

able 3n-hospital events

vents RCT-IneligiblePatients

(n � 9,369)

RCT-EligiblePatients

(n � 11,806)

p Value

ll-cause mortality 1,887 (20.1%) 582 (4.9%) �0.0001onfatal reinfarction 252 (3.4%) 345 (3.1%) 0.2onfatal stroke 109 (1.5%) 47 (0.4%) �0.0001ACCEs 2,247 (24.0%) 971 (8.2%) �0.0001

ypercholesterolemia (p �0.05) compared to ineligible pa-

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1076 The American Journal of Cardiology (www.AJConline.org)

ients receiving reperfusion therapy. Ineligible patients hadigher in-hospital mortality and a higher rate of nonfataltrokes compared to eligible patients. There was no differ-nce in reinfarction, whereas a higher combined rate ofACCEs was observed in ineligible patients (Table 3).

arly reperfusion therapy (thrombolysis and/or PCI) in in-ligible patients was associated with a significant decreasef in-hospital mortality (OR 0.62, 95% CI 0.49 to 0.79).rimary PCI compared to thrombolysis was more effectiveOR 0.52, 95% CI 0.41 to 0.65) in decreasing mortality. Thelinical event rate in patients with 1-year follow up isresented in Table 4.

iscussion

Patients with STEMI included in RCTs represent a se-ected subgroup of patients with a low adverse event rate.his subgroup may therefore not be representative of pa-

ients encountered in everyday practice. About 50% of pa-ients seen in clinical practice are usually excluded fromCTs. In the present study ineligible patients more oftenad concomitant diseases compared to eligible patients. Inddition, ineligible patients less often received early reper-usion therapy and adjunctive guideline-recommended med-cation. Ineligible patients had a 4 times higher hospitalortality compared to eligible patients. These findings are

n line with results of an analysis of the Global Registry ofcute Coronary Events (GRACE) registry. Steg et al8 di-ided consecutive patients with acute MI enrolled in theRACE registry into 3 groups: participants of RCTs, eligi-le but not enrolled patients, and ineligible patients. Withhis analysis they demonstrated that participants of RCTsad the lowest a priori risk of death, eligible but not enrolledatients had a higher risk, and ineligible patients had theighest risk. Hospital mortality showed a similar gradient3.6%, 7.1%, and 11.4%, p �0.001). Multivariable analysisdjusted for baseline risk, use and type of reperfusion ther-py, and delay from symptom onset to admission consis-ently showed a higher mortality rate for eligible but notnrolled patients than for participants of clinical trials. Theigher rate in the use of evidence-based medication andevascularization in RCT participants may result in themproved risk-adjusted outcome. However, adjustment foraseline differences can be performed only for known con-ounders, but the frequency of unknown confounders is anmportant reason to perform RCTs. However, extending thendings obtained in RCTs to the general population may be

able 4linical events between discharge and one-year follow-up

vents After Discharge RCT-IneligiblePatients

(n � 2,601)

RCT-EligiblePatients

(n � 4,221)

p Value

ortality after discharge 445 (17.2%) 227 (5.2%) �0.0001onfatal reinfarctionafter discharge

102 (5.3%) 210 (5.8%) 0.41

onfatal stroke afterdischarge

38 (3.9%) 35 (1.9%) �0.01

ACCEs after discharge 583 (22.5%) 468 (11.1%) �0.0001

roblematic. Brown et al9 categorized in a cohort study

based on the Nottingham Heart Attack Register) patientsdmitted with an acute MI as participants of a thrombolyticrial, receiving nontrial thrombolysis, or deemed ineligibleor lytic treatment. With this study they showed that patientsnrolled in thrombolytic trials were at low risk. In addition,hey demonstrated that patients deemed ineligible forhrombolysis received less surveillance, were less likely toe revascularized or receive trial-proved treatments, and hadpoor long-term outcome not entirely explained by in-

reased age or severity of infarction. We previously dem-nstrated that in clinical practice about 1/2 of patients re-eiving primary PCI would have not been included inCTs.10 Pocock and Elbourne11 reported in 2000 on theanger of clinical trials not being representative. Caused byhe preselection, high-quality RCTs often reflect personalhoices and beliefs. In this context Yan et al12 formulatedhat a clinical trial–derived risk model cannot be general-zed to real-world patients with acute coronary syndromes.espite all doubts concerning the representativeness and

xternal validity of RCTs, in the present study early reper-usion therapy in ineligible patients was associated with aignificant decrease in hospital mortality. In patients withTEMI, primary PCI seems to be the therapy of first choice.he 0.9% absolute decrease in hemorrhagic stroke and the.0% absolute decrease in total stroke are established ben-fits of primary PCI.13 In addition, primary PCI seems to beetter than thrombolytic therapy at decreasing overall short-erm mortality.14,15 In our study primary PCI was associatedith an adjusted lower hospital mortality compared to

hrombolytic therapy in patients usually excluded fromCTs. Therefore, primary PCI seems the preferred reperfu-

ion strategy in these high-risk patients and all effortshould be made to establish a network between hospitalsith and without angioplasty facilities to improve hospital

nd transportation logistics to keep the time loss from ad-ission to primary PCI as short as possible. However, if

rimary PCI cannot be performed within 3 hours, throm-olysis is still a valid option.

ppendix

The personnel and institutions who participated in theITRA Plus study are listed elsewhere.1–4

1. Rustige J, Schiele R, Burczyk U, Koch A, Gottwik M, Neuhauss KL,Tebbe U, Uebis R, Senges J. The 60 minutes Myocardial InfarctionProject. Treatment and clinical outcome of patients with acute myo-cardial infarction in Germany. Eur Heart J 1997;18:1438–1446.

2. Schuster S, Koch A, Burczyk U, Schiele R, Glunz HG, Voigtlander T,Limbourg P, Stuby K, Berg G, Gieseler U, Jakob M, Hauptmann P,Senges J. Use of coronary angiography after acute myocardial infarc-tion in Germany: a comparison of daily clinical practice with interna-tional guidelines. MITRA study. Z Kardiol 1999;88:795–801.

3. Wagner S, Schneider S, Schiele R, Fischer F, Dehn H, Grube R,Becker G, Baumgartel B, Altmann E, Senges J. Acute myocardialinfarction in Germany between 1996 and 1998: therapy and intrahos-pital course. Results of the Myocardial Infarction Registry (MIR) inGermany. Z Kardiol 1999;88:857–867.

4. Zeymer U, Gitt AK, Jünger C, Heer T, Wienbergen H, Koeth O, BauerT, Mark B, Zahn R, Gottwik M, Senges J; Acute COronary Syndromes(ACOS) registry investigators. Effect of clopidogrel on 1-year mortal-

ity in hospital survivors of acute ST-segment elevation myocardialinfarction in clinical practice. Eur Heart J 2006;27:2661–2666.

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1077Coronary Artery Disease/Reperfusion Therapy in STEMI

5. ASSENT-4 PCI Investigators. Primary versus tenecteplase-facilitatedpercutaneous coronary intervention in patients with ST-segment ele-vation acute myocardial infarction (ASSENT-4 PCI): randomised trial.Lancet 2006;367:569–578.

6. Di Mario C, Dudek D, Piscione F, Mielecki W, Savonitto S, MurenaE, Dimopoulos K, Manari A, Gaspardone A, Ochala A, Zmudka K,Bolognese L, Steg PG, Flather M; CARESS-in-AMI (Combined Ab-ciximab REteplase Stent Study in Acute Myocardial Infarction) Inves-tigators. Immediate angioplasty versus standard therapy with rescueangioplasty after thrombolysis in the Combined Abciximab REteplaseStent Study in Acute Myocardial Infarction (CARESS-in-AMI): anopen, prospective, randomised, multicentre trial. Lancet 2008;371:559–568.

7. Fernandez-Aviles F, Alonso JJ, Castro-Beiras A, Vazquez N, BlancoJ, Alonso-Briales J, Lopez-Mesa J, Fernandez-Vazquez F, Calvo I,Martinez-Elbal L, San Roman JA, Ramos B. Routine invasive strategywithin 24 hours of thrombolysis versus ischaemia-guided conservativeapproach for acute myocardial infarction with ST-segment elevation(GRACIA-1): a randomised controlled trial. Lancet 2004;364:1045–1053.

8. Steg PG, Lopez-Sendon J, Lopez de Sa E, Goodman SG, Gore JM,Anderson FA Jr, Himbert D, Allegrone J, Van de Werf F; GRACEInvestigators. External validity of clinical trials in acute myocardialinfarction. Arch Intern Med 2007;167:68–73.

9. Brown N, Melville M, Gray D, Young T, Skene AM, Wilcox RG,Hampton JR. Relevance of clinical trial results in myocardial infarc-tion to medical practice: comparison of four year outcome in partici-pants of a thrombolytic trial, patients receiving routine thrombolysis,and those deemed ineligible for thrombolysis. Heart 1999;81:598–602.

0. Zahn R, Schiele R, Seidl K, Bergmeier C, Haase KK, Glunz HG,Hauptmann KE, Voigtländer T, Gottwik M, Senges J, for the Maximal

Individual Therapy in Acute Myocardial Infarction (MITRA) Study

Group. Primary angioplasty for acute myocardial infarction in patientsnot included in randomized studies. Am J Cardiol 1999;83:1314–1319.

1. Pocock SJ, Elbourne DR. Randomized trials or observational tribula-tions? N Engl J Med 2000;342:1907–1909.

2. Yan AT, Jong P, Yan RT, Tan M, Fitchett D, Chow CM, Roe MT,Pieper KS, Langer A, Goodman SG; Canadian Acute Coronary Syn-dromes Registry Investigators. Clinical trial-derived risk model maynot generalize to real-world patients with acute coronary syndrome.Am Heart J 2004;148:1020–1027.

3. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intra-venous thrombolytic therapy for acute myocardial infarction: a quan-titative review of 23 randomised trials. Lancet 2003;361:13–20.

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

5. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasya-mani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ,Pearle DL, Sloan MA, Smith SC Jr. 2007 Focused update of theACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College ofCardiology/American Heart Association task force on practice guide-lines: developed in collaboration with the Canadian CardiovascularSociety endorsed by the American Academy of Family Physicians:2007 writing group to review new evidence and update the ACC/AHA2004 guidelines for the management of patients with ST-elevationmyocardial infarction, writing on behalf of the 2004 writing commit-

tee. Circulation 2008;117:296–329.