Abstract

Myocardial infarction (MI) is a key endpoint in randomized controlled trials (RCTs), but heterogeneous definitions limit comparisons across RCTs or meta-analyses. The 2000 European Society of Cardiology/American College of Cardiology MI redefinition and the 2007 universal MI definition consensus documents made recommendations to address this issue. In cardiovascular randomized trials, we evaluated the impact of implementation of three key recommendations from these reports—troponin use to define MI; separate reporting of spontaneous and procedure-related MI; and infarct size reporting. We searched ClinicalTrials.gov and MEDLINE databases for cardiovascular RCTs with more than 500 patients in which enrolment began between September 2000 and July 2012 and that listed MI in the primary endpoint. We searched English-language publications with primary results or design papers. Of 3222 studies screened, 96 (3.0%) met our criteria. We extracted enrolment start date, number of patients and MI events, follow-up duration, and coronary revascularization rate. Data extraction quality was assessed by duplicated extractions. Of 96 RCTs, 80 had a primary results publication, comprising 608 091 patients and 43 621 endpoint MIs. Myocardial infarction represented 45.3% (95% confidence interval, 40.2–50.4) of events in the primary composite endpoint. Troponin defined MI in 57% (53/93) of trials with an MI definition available. Of these RCTs, three used troponin only if creatine kinase-MB was unavailable, six used troponin to define peri-procedural MI, seven specified the 99th percentile as the MI decision limit, and three reported spontaneous and procedure-related MI separately. None reported biomarker-based infarct size, but five reported MI as multiples of the assay upper limit of normal. Although MI is a major component of cardiovascular RCT primary endpoints, standardized MI reporting and implementation of consensus document recommendations for MI definition are limited. Developing appropriate strategies for uniform implementation is required.

Introduction

Myocardial infarction (MI) is a widely accepted non-fatal cardiovascular endpoint employed to assess efficacy and/or safety of new treatments in clinical trials. However, failure to use a standard MI definition has emerged as a major challenge. In September 2000, recognizing the superior sensitivity and prognostic utility of troponin compared with creatine kinase (CK)-MB, an expert consensus document from the European Society of Cardiology (ESC) and American College of Cardiology (ACC) provided guidance to the scientific and clinical communities on redefining MI and proposed troponin as the diagnostic ‘gold standard’.1 To improve consistency across randomized controlled trials (RCTs), this document specified that MI endpoints in RCTs be classified as spontaneous vs. related to coronary revascularization procedures and that the quantity of myonecrosis be determined. A 2007 and, most recently, a 2012 update reasserted troponin as the preferred biomarker for myonecrosis and also recommended that clinicians and investigators categorize MI type according to a five-category classification scheme, including whether the MI was spontaneous or revascularization-related.2,3 Prior to the release of the 2012 Universal Definition of MI document, we undertook the current study to evaluate the extent to which the 2000 and 2007 consensus recommendations had been implemented in contemporary cardiovascular RCTs.

Methods

We performed a systematic review of cardiovascular RCTs with more than 500 patients in which MI was part of the primary endpoint. The 500-patient threshold was selected to identify RCTs with enough MI endpoints to adequately assess all recommended components of MI reporting and that would be most likely to affect clinical practice. For the same reason, we limited our search to published trials. Our systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.4

Search strategy

We separately searched two databases: ClinicalTrials.gov, the official source of the US National Institutes of Health (NIH) for clinical trial registration, and the National Library of Medicine's MEDLINE database. Although RCTs could be registered on ClinicalTrials.gov for the entire period explored (1 September 2000 through 4 July 2012), the NIH mandated registration of all RCTs only after 27 September 2007.5 Because some trials that started before September 2007 may not have been captured, we used MEDLINE to complement the ClinicalTrials.gov search. Finally, we reviewed online materials using the Google search engine. We restricted our search to RCTs in cardiovascular disease, but did not restrict the type of intervention to which patients were randomized. From this pool of RCTs, those with an enrolment start date before September 2000 were excluded from further analysis. Figure 1 outlines the results of our database searches, culminating in a final set of 96 RCTs for our study; 80 had primary results published and 16 had only a design paper. Additional details of our search methodology are explained in Supplementary material online, Appendix 1.

Figure 1

Systematic review and selection of clinical trials.

Figure 1

Systematic review and selection of clinical trials.

Data abstraction

We abstracted study name; enrolment start date; publication year; numbers of patients, MI events, and components in the primary endpoint composite; reference within the publication to the 2000 ESC/ACC consensus document and the 2007 Universal Definition of MI; use of a clinical events classification committee; follow-up duration; and text of the endpoint MI definition used. Accuracy of the MI definition abstracted from the design paper and/or primary manuscript was assessed by contacting trial investigators and obtaining the endpoint MI definition for their respective trials. To ensure the quality of the data extraction process, a 30% random sample of included RCTs was re-reviewed, and the data were collected in a second abstraction sheet. In addition, a random 30% of records from each database was re-reviewed after initial screening was finalized as a quality check on RCT selection. No errors in data abstraction were identified by these quality control measures.

Metrics of guideline recommendations adherence

We determined the proportion of RCTs in which the ESC/ACC 2000 document and the 2007 Universal Definition of MI were referenced by manually reviewing the reference list of the design paper, primary results manuscript, or both. We also determined the proportion of RCTs referencing other consensus documents endorsed by the ESC, ACC, or American Heart Association (AHA). Then, we examined each trial for the use of the following key recommendations in the 2000 ESC/ACC consensus document for MI redefinition and in the 2007 Universal Definition of MI: Finally, for the subgroup of trials that started after the publication of the 2007 Universal Definition of MI, we also assessed adherence to the five-type classification scheme proposed.

  • Recommendation 1: Use of troponin for MI diagnosis and MI decision limit provided. We evaluated this recommendation in RCTs for which the MI definition (including biomarkers employed) used in the trial was published. In five trials, the biomarker employed was unavailable in the design paper or primary manuscript but was obtained by contacting the investigators.6–10 We also explored adherence to this recommendation according to coronary revascularization group and tertiles of duration of time between the publication of the ESC/ACC 2000 MI redefinition document and the start of enrolment. To explore the level of adherence to Recommendation 1 as a function of coronary revascularization rate, we created three RCT categories:

    • Interventional RCTs: RCTs in which percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) was required by protocol either as part of the randomized intervention or as an inclusion criterion. Only protocol violators did not undergo coronary revascularization, and the rate of revascularization was assumed to be near 100%.

    • Acute coronary syndrome (ACS) RCTs: RCTs in which a coronary revascularization could be performed as part of treatment for the index ACS event but was not required.

    • Other RCTs: RCTs in which coronary revascularization was possible but not expected (e.g. secondary prevention trials enrolling patients with risk factors but no prior MI or patients with chronic stable coronary artery disease).

    • Recommendation 2: Separate reporting of spontaneous MI and procedure-related (PCI or CABG) MI.

    • Recommendation 3: Report of infarct size using area under the troponin or CK-MB curve or peak biomarker values (ESC/ACC 2000 recommendation) or as a multiple of the upper limit of normal (ULN) of the applied cardiac biomarker (2007 Universal Definition of MI recommendation).

Survey

To assess underpinnings of gaps in implementing consensus document recommendations, we surveyed principal investigators of all 96 RCTs via an online questionnaire. Because some investigators (n = 17) led more than 1 RCT, 66 individual investigators were surveyed. The full text of question and answer options is provided in Supplementary material online, Appendix 2. To encourage full participation, we sent e-mail reminders and scheduled telephone calls or in-person visits as needed. Responses were received from 61 of 66 investigators (92.4%), corresponding to responses for 91 of 96 RCTs. Every investigator who responded answered all survey questions completely.

Statistical analysis

The contribution of MI to the primary composite endpoint was examined using a random effects meta-analysis to estimate the mean proportion. This approach assigns weights to trials accounting for both (i) sampling error due to finite sample size within trials and (ii) random variability due to heterogeneous populations among trials. Results are presented using mean point estimates [95% confidence intervals (CIs)] of the proportion. This proportion was also evaluated considering RCTs by coronary revascularization group and groupings of follow-up duration (timing of endpoint assessment). The same method was used to identify the revascularization proportion in ACS RCTs and Other RCTs. To address the primary hypotheses, for each recommendation, the level of adherence was calculated as the proportion of RCTs fulfilling that recommendation. In addition, for Recommendation 1, we also explored adherence by coronary revascularization group and by time from the publication of the 2000 consensus document to the start of enrolment. In a sensitivity analysis, we examined the use of the three consensus document recommendations in RCTs with more than 100 but 500 or less patients (Supplementary material online, Appendix 3).

Results

Table 1 shows RCTs with a primary results publication available. Of these 80 RCTs, all but 4 (5%)26,27,30,78 reported the use of a clinical events classification committee blinded to treatment assignment. These MI definitions are detailed in Supplementary material online, Table S1A–C, and grouping of trials by coronary revascularization rate is provided in Supplementary material online, Table S2. The rate of coronary revascularization was 50.6% (95% CI 40.0–61.1) in ACS RCTs and 4.4% (95% CI 2.1–9.0) in Other RCTs. One published trial reported MI event rates only graphically.26

Table 1

Characteristics of 80 cardiovascular published randomized clinical trials ordered by the start date of enrolment

Study name Start date PubYear Patients MI, n MI, % Follow-up duration 
REPLACE 111 November 2000 2004 1056 50 75.8 48 h 
PROVE IT TIMI 2212 November 2000 2004 4162 292 28.8 2 yearsa 
MATCH13 December 2000 2004 7599 121 9.8 18 months 
ESTEEM14 January 2001 2003 1883 83 32.7 6 months 
ISAR SWEET15 January 2001 2004 701 32 54.2 1 year 
SIRIUS16 February 2001 2003 1058 32 20.5 9 months 
PROactive6 May 2001 2005 5238 223 20.5 34.5 monthsa 
ADVANCE17 June 2001 2007 11 140 91 5.1 4.3 yearsa 
ICTUS18 July 2001 2005 1200 149 56.7 1 year 
SYNERGY19 August 2001 2004 10 027 1207 85.1 30 days 
FIRE20 October 2001 2003 651 124 88.6 30 days 
REPLACE 221 October 2001 2003 6010 392 68.3 30 days 
OnTARGET22 November 2001 2008 25 620 1291 30.6 56 monthsb 
PRIMO CABG23 January 2002 2004 3099 252 85.4 30 days 
JIKEI HEART24 January 2002 2007 3081 36 14.9 3.1 yearsb 
CHOIR25 March 2002 2006 1432 38 17.1 16 monthsb 
ALMICAD26 April 2002 2007 1233 NAc NAc 24 months 
Lee et al.27 April 2002 2005 689 13 81.3 30 days 
RACS28 April 2002 2007 1004 20 64.5 180 days 
ExTRACT TIMI 2529 October 2002 2006 20 479 767 34.2 30 days 
HEART 2D30 October 2002 2009 1115 136 35.5 32 monthsa 
CHARISMA31 October 2002 2006 15 603 301 27.2 28 monthsb 
Nussmeier et al.32 January 2003 2005 1671 2.0 40 days 
CLARITY TIMI 2833 February 2003 2005 3491 108 16.9 Index H 
ARTS II34 February 2003 2007 607 38 44.2 30 days, 1 year 
PASSION35 March 2003 2006 619 11 16.7 1 year 
OASIS 536 March 2003 2006 20 078 527 45.7 9 days 
Windecker et al.37 April 2003 2005 1012 32 37.2 9 months 
ARISE38 June 2003 2008 6144 243 22.9 24 monthsa 
ACTIVE W39 June 2003 2006 6706 59 14.8 1.28 yearsb 
PROXIMAL40 July 2003 2007 594 12.3 30 days 
ACUITY41 August 2003 2006 13 819 704 45.6 30 days 
OASIS 642 August 2003 2006 12 092 317 25.1 30 days 
EASY43 October 2003 2006 1005 107 51.2 30 days 
TYPHOON44 October 2003 2006 2019 11.7 1 year 
PRIMO CABG II45 July 2004 2011 4254 549 82.7 30 days 
SORT OUT II46 August 2004 2008 2098 98 43.4 18 months 
MULTI STRATEGY47 October 2004 2008 744 15 48.4 30 days 
MERLIN TIMI 3648 October 2004 2007 6560 477 32.9 30 days 
TRITON TIMI 3849 November 2004 2007 13 608 1095 76.9 15 months 
EARLY ACS50 November 2004 2009 9492 690 76.0 96 h 
BEAUTIFUL51 December 2004 2008 10 917 425 25.4 19 monthsb 
DOORS52 January 2005 2012 900 62 66.0 30 days 
SYNTAX53 March 2005 2009 1800 71 26.9 1 year 
HORIZONS-AMI54 March 2005 2008 3602 65 16.9 30 days 
PRECOMBAT55 March 2005 2011 600 13.3 1 year 
I CARE56 April 2005 2008 1434 24 49.0 18 monthsd 
COSTAR II57 May 2005 2008 1700 50 33.3 8 months 
ISAR LEFT MAIN58 July 2005 2009 607 29 32.6 1 year 
AIM HIGH10 September 2005 2011 3414 172 30.9 3 yearsa 
ISAR REACT 359 November 2005 2008 4570 238 61.2 30 days 
CRESCENDO60 December 2005 2010 18 695 282 38.2 13.8a 
CHAMPION-PCI61 April 2006 2009 8877 534 94.3 48 h 
CURRENT62 June 2006 2010 25 086 514 47.6 30 days 
RIVAL63 June 2006 2011 7021 125 46.8 30 days 
ISAR REACT 464 July 2006 2011 1721 117 61.9 30 days 
SPIRIT IV65 August 2006 2010 3687 82 45.1 1 year 
CH. PLATFORM66 September 2006 2009 5022 368 93.2 48 h 
PLATO67 October 2006 2009 18 093 1097 58.4 12 months 
MEND CABG II68 November 2006 2008 3023 243 89.0 30 days 
LEADERS69 November 2006 2008 1707 88 52.4 9 months 
ZEST70 November 2006 2010 2645 164 56.9 1 year 
CORONARY71 November 2006 2012 4752 328 68.6 30 days 
PRODIGY72 December 2006 2012 2013 80 40.4 24 months 
COMPARE73 February 2007 2010 1800 43 71.7 1 year 
REAL LATE74 July 2007 2010 2701 17 53.1 2 years 
ECLAT STEMI75 July 2007 2012 786 74 77.9 30 days 
ISAR TEST 476 September 2007 2009 2603 99 27.6 1 year 
TRA 2°P TIMI 5077 September 2007 2012 26 449 1237 56.1 30 monthsb 
MI FREEE78 November 2007 2011 5855 423 40.1 13.1 months 
ISAR CABG79 November 2007 2011 610 30 27.3 1 year 
TRACER80 December 2007 2011 12 944 1319 61.8 502 daysb 
ISAR TEST 581 February 2008 2011 3002 77 19.7 1 year 
RESOLUTE AC82 May 2008 2010 2292 93 50.0 1 year 
AIDA STEMI83 July 2008 2012 2065 34 25.0 90 days 
ISAR REACT 3A84 August 2008 2010 2505 209 92.5 30 days 
ATLAS ACS85 November 2008 2012 15 526 613 61.2 13 months 
PLATINUM86 January 2009 2011 1530 21 28.8 1 year 
APPRAISE 287 March 2009 2011 7392 376 65.7 241 days 
Litt et al.88 July 2009 2012 1370 15 100.0 30 days 
Study name Start date PubYear Patients MI, n MI, % Follow-up duration 
REPLACE 111 November 2000 2004 1056 50 75.8 48 h 
PROVE IT TIMI 2212 November 2000 2004 4162 292 28.8 2 yearsa 
MATCH13 December 2000 2004 7599 121 9.8 18 months 
ESTEEM14 January 2001 2003 1883 83 32.7 6 months 
ISAR SWEET15 January 2001 2004 701 32 54.2 1 year 
SIRIUS16 February 2001 2003 1058 32 20.5 9 months 
PROactive6 May 2001 2005 5238 223 20.5 34.5 monthsa 
ADVANCE17 June 2001 2007 11 140 91 5.1 4.3 yearsa 
ICTUS18 July 2001 2005 1200 149 56.7 1 year 
SYNERGY19 August 2001 2004 10 027 1207 85.1 30 days 
FIRE20 October 2001 2003 651 124 88.6 30 days 
REPLACE 221 October 2001 2003 6010 392 68.3 30 days 
OnTARGET22 November 2001 2008 25 620 1291 30.6 56 monthsb 
PRIMO CABG23 January 2002 2004 3099 252 85.4 30 days 
JIKEI HEART24 January 2002 2007 3081 36 14.9 3.1 yearsb 
CHOIR25 March 2002 2006 1432 38 17.1 16 monthsb 
ALMICAD26 April 2002 2007 1233 NAc NAc 24 months 
Lee et al.27 April 2002 2005 689 13 81.3 30 days 
RACS28 April 2002 2007 1004 20 64.5 180 days 
ExTRACT TIMI 2529 October 2002 2006 20 479 767 34.2 30 days 
HEART 2D30 October 2002 2009 1115 136 35.5 32 monthsa 
CHARISMA31 October 2002 2006 15 603 301 27.2 28 monthsb 
Nussmeier et al.32 January 2003 2005 1671 2.0 40 days 
CLARITY TIMI 2833 February 2003 2005 3491 108 16.9 Index H 
ARTS II34 February 2003 2007 607 38 44.2 30 days, 1 year 
PASSION35 March 2003 2006 619 11 16.7 1 year 
OASIS 536 March 2003 2006 20 078 527 45.7 9 days 
Windecker et al.37 April 2003 2005 1012 32 37.2 9 months 
ARISE38 June 2003 2008 6144 243 22.9 24 monthsa 
ACTIVE W39 June 2003 2006 6706 59 14.8 1.28 yearsb 
PROXIMAL40 July 2003 2007 594 12.3 30 days 
ACUITY41 August 2003 2006 13 819 704 45.6 30 days 
OASIS 642 August 2003 2006 12 092 317 25.1 30 days 
EASY43 October 2003 2006 1005 107 51.2 30 days 
TYPHOON44 October 2003 2006 2019 11.7 1 year 
PRIMO CABG II45 July 2004 2011 4254 549 82.7 30 days 
SORT OUT II46 August 2004 2008 2098 98 43.4 18 months 
MULTI STRATEGY47 October 2004 2008 744 15 48.4 30 days 
MERLIN TIMI 3648 October 2004 2007 6560 477 32.9 30 days 
TRITON TIMI 3849 November 2004 2007 13 608 1095 76.9 15 months 
EARLY ACS50 November 2004 2009 9492 690 76.0 96 h 
BEAUTIFUL51 December 2004 2008 10 917 425 25.4 19 monthsb 
DOORS52 January 2005 2012 900 62 66.0 30 days 
SYNTAX53 March 2005 2009 1800 71 26.9 1 year 
HORIZONS-AMI54 March 2005 2008 3602 65 16.9 30 days 
PRECOMBAT55 March 2005 2011 600 13.3 1 year 
I CARE56 April 2005 2008 1434 24 49.0 18 monthsd 
COSTAR II57 May 2005 2008 1700 50 33.3 8 months 
ISAR LEFT MAIN58 July 2005 2009 607 29 32.6 1 year 
AIM HIGH10 September 2005 2011 3414 172 30.9 3 yearsa 
ISAR REACT 359 November 2005 2008 4570 238 61.2 30 days 
CRESCENDO60 December 2005 2010 18 695 282 38.2 13.8a 
CHAMPION-PCI61 April 2006 2009 8877 534 94.3 48 h 
CURRENT62 June 2006 2010 25 086 514 47.6 30 days 
RIVAL63 June 2006 2011 7021 125 46.8 30 days 
ISAR REACT 464 July 2006 2011 1721 117 61.9 30 days 
SPIRIT IV65 August 2006 2010 3687 82 45.1 1 year 
CH. PLATFORM66 September 2006 2009 5022 368 93.2 48 h 
PLATO67 October 2006 2009 18 093 1097 58.4 12 months 
MEND CABG II68 November 2006 2008 3023 243 89.0 30 days 
LEADERS69 November 2006 2008 1707 88 52.4 9 months 
ZEST70 November 2006 2010 2645 164 56.9 1 year 
CORONARY71 November 2006 2012 4752 328 68.6 30 days 
PRODIGY72 December 2006 2012 2013 80 40.4 24 months 
COMPARE73 February 2007 2010 1800 43 71.7 1 year 
REAL LATE74 July 2007 2010 2701 17 53.1 2 years 
ECLAT STEMI75 July 2007 2012 786 74 77.9 30 days 
ISAR TEST 476 September 2007 2009 2603 99 27.6 1 year 
TRA 2°P TIMI 5077 September 2007 2012 26 449 1237 56.1 30 monthsb 
MI FREEE78 November 2007 2011 5855 423 40.1 13.1 months 
ISAR CABG79 November 2007 2011 610 30 27.3 1 year 
TRACER80 December 2007 2011 12 944 1319 61.8 502 daysb 
ISAR TEST 581 February 2008 2011 3002 77 19.7 1 year 
RESOLUTE AC82 May 2008 2010 2292 93 50.0 1 year 
AIDA STEMI83 July 2008 2012 2065 34 25.0 90 days 
ISAR REACT 3A84 August 2008 2010 2505 209 92.5 30 days 
ATLAS ACS85 November 2008 2012 15 526 613 61.2 13 months 
PLATINUM86 January 2009 2011 1530 21 28.8 1 year 
APPRAISE 287 March 2009 2011 7392 376 65.7 241 days 
Litt et al.88 July 2009 2012 1370 15 100.0 30 days 

PubYear is the year of publication; MI, n is the absolute number of myocardial infarction within the primary endpoint; MI, % is the proportion of myocardial infarction endpoint events within the primary composite.

aMean follow-up duration.

bMedian follow-up duration.

cThe ALMICAD trial did report the actual number of MI events.

dThe I CARE trial was terminated early at 18 months for efficacy.

Contribution of myocardial infarction to the primary endpoint

Using 79 RCTs with primary results provided as MI counts, we estimated that MI contributed 45.3% (95% CI 40.2–50.4) of events in the primary composite outcomes of large cardiovascular RCTs. The proportion that MI contributed to the primary composite endpoint decreased with increasing number of endpoint components (Supplementary material online, Figure S1) and was highest among Interventional RCTs and trials with a follow-up duration of ≤1 month (Table 2).

Table 2

Myocardial infarction contribution to the primary endpoint by revascularization group and by follow-up duration

Category Group n MI % (95% CI) 
Revascularization rate Interventional 46 53.2 (45.7–60.5) 
ACS 16 46.8 (37.1–56.8) 
Other 17 24.3 (18.1–31.8) 
Follow-up duration ≤1 month 31 64.3 (55.5–72.1) 
Between 1 month and 1 year 25 35.6 (29.0–42.9) 
>1 year 23 32.2 (24.8–40.6) 
Category Group n MI % (95% CI) 
Revascularization rate Interventional 46 53.2 (45.7–60.5) 
ACS 16 46.8 (37.1–56.8) 
Other 17 24.3 (18.1–31.8) 
Follow-up duration ≤1 month 31 64.3 (55.5–72.1) 
Between 1 month and 1 year 25 35.6 (29.0–42.9) 
>1 year 23 32.2 (24.8–40.6) 

Proportion of MIs in the primary composite endpoint was calculated using random effects estimates with 95% CIs.

CI, confidence interval; MI, myocardial infarction.

Proportion of RCTs referencing published myocardial infarction definition documents

Among 96 RCTs with a primary results and/or design paper, 7 (7.3%) referenced the ESC/ACC 2000 document for endpoint MI definition and 18 (18.8%) referenced the Universal Definition of MI 2007 publication. In addition, 34 (35.4%) cited another consensus document (27 referenced the Academic Research Consortium definition89,90; 7 referenced the ACC Key Standards document,91 both of which referred to the ESC/ACC 2000 document). Fourteen (14.6%) RCTs published no MI definition.16,17,22,24,31,39,46,51,58,74,92–95 After contacting investigators, we received and examined 93 of 96 endpoint MI definitions (96.9%). Table 3 presents an overview of key features of these definitions in the 10 largest RCTs, which accounted for 199 448 patients (32.8% of all patients in RCTs we evaluated). In these trials, both the threshold for spontaneous MI (1× or 2× ULN) and the biomarker used (CK-MB or troponin) varied. Definitions of re-infarction in RCTs that enrolled patients with acute MI also varied (Supplementary material online, Appendix 4 and Table S3).

Table 3

Key features of the myocardial infarction definition in the 10 largest randomized clinical trials

Trial Spontaneous MI
 
PCI-related MI
 
CABG-related MI
 
Preferred biomarker Fold elevation above ULN Preferred biomarker Fold elevation above ULN Preferred biomarker Fold elevation above ULN 
TRA 2°P TIMI 5077a cTn CK-MB CK-MB/cTn 
ONTARGET22b NA NA NA NA NA NA 
CURRENT62 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
ExTRACT TIMI 2529 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
OASIS 536 CK-MB CK-MB CK-MB 5 or Qw 
CRESCENDO60 CK-MB/cTn/CK 2/1/2 CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
PLATO67 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
CHARISMA31c CK-MB/cTn 2/1 – – – – 
ATLAS85d CK-MB/cTn CK-MB CK-MB 5 (w/ com) or 10 (w/o com) 
ACUITY96 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
Trial Spontaneous MI
 
PCI-related MI
 
CABG-related MI
 
Preferred biomarker Fold elevation above ULN Preferred biomarker Fold elevation above ULN Preferred biomarker Fold elevation above ULN 
TRA 2°P TIMI 5077a cTn CK-MB CK-MB/cTn 
ONTARGET22b NA NA NA NA NA NA 
CURRENT62 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
ExTRACT TIMI 2529 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
OASIS 536 CK-MB CK-MB CK-MB 5 or Qw 
CRESCENDO60 CK-MB/cTn/CK 2/1/2 CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
PLATO67 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 
CHARISMA31c CK-MB/cTn 2/1 – – – – 
ATLAS85d CK-MB/cTn CK-MB CK-MB 5 (w/ com) or 10 (w/o com) 
ACUITY96 CK-MB/cTn CK-MB CK-MB 5 (w/ Qw) or 10 (w/o Qw) 

aTRA 2°P TIMI 50 definition of CABG-related MI required additional complications beyond biomarker criterion (new Q-waves or new left-bundle branch block; angiographically documented graft or native coronary artery occlusion; or imaging evidence of new loss or viable myocardium).

bNo MI definition published for ONTARGET.

cThe CHARISMA trial did not use a separate MI definition for procedure-related MI.

dATLAS definition of CABG-related MI required additional complications beyond biomarker criterion (new Q-waves or new left-bundle branch block; angiographically documented graft or native coronary artery occlusion; or imaging evidence of new loss or viable myocardium) for CK-MB elevation between 5× and 10× the ULN.

CABG, coronary artery bypass grafting; CK-MB, creatine-kinase-MB; com, additional complications; cTn, cardiac troponin; MI, myocardial infarction; NA, not available; PCI, percutaneous coronary intervention; Qw, Q-waves; ULN, upper limit of normal; w/, with; w/o, without.

Recommendation 1: use of troponin for myocardial infarction diagnosis and myocardial infarction decision limit provided

Among 93 RCTs with an MI definition provided, troponin was used to define the MI endpoint in 53 (57%). This proportion was 66.7% (n = 34) among 51 RCTs that referenced any consensus document for MI definition. Three of 93 RCTs used troponin to define endpoint MI only if CK-MB was unavailable,36,62,88 6 used troponin to define procedural MI, and 7 specified the 99th percentile as the MI decision limit. All other RCTs (n = 40) used CK-MB or total CK to define endpoint MI. The use of troponin to define endpoint MI by revascularization group and by time between ESC/ACC 2000 publication and the start of RCTs enrolment is shown in Figure 2A and B, respectively. Among trial types, adherence to Recommendation 1 was lowest among Interventional RCTs, and by time from publication to enrolment start, the highest use of troponin occurred among RCTs that began >74 months after the publication of the ESC/ACC 2000 document.

Figure 2

(A) Troponin use for endpoint myocardial infarction definition by coronary revascularization group. (B) Troponin use for endpoint myocardial infarction definition by time from the publication of 2000 ESC/ACC MI document to the start of trial enrolment.

Figure 2

(A) Troponin use for endpoint myocardial infarction definition by coronary revascularization group. (B) Troponin use for endpoint myocardial infarction definition by time from the publication of 2000 ESC/ACC MI document to the start of trial enrolment.

Recommendation 2: separate reporting of spontaneous myocardial infarction and myocardial infarction related to surgical or percutaneous coronary revascularization procedures

Three trials (3.7%) reported spontaneous and procedural MI separately.18,77,80 The ICTUS trial, which adhered to the 2000 ESC/ACC MI redefinition, compared an early invasive strategy with a selective invasive strategy in patients with non-ST-segment elevation MI.18 Overall, 149 MIs occurred; 32.9% were spontaneous and 67.1% were procedure-related. The TRACER80 and TRA 2°P TIMI 5077 trials reported MI using the five-type classification scheme proposed by the 2007 Universal Definition of MI.

Recommendation 3: report of comparison of size of myocardial infarction between treatment and control groups in addition to the presence/absence of myocardial infarction

No trials reported a comparison of infarct size between treatment and control groups, using area under the biomarker curve. Five trials compared MI rates between treatment and control groups, using size thresholds (e.g. 3×–5× ULN, 5×–10× ULN, or >10× ULN), but did not provide actual peak levels.11,20,21,40,68

Similar results for the use of the three recommendations explored were observed in sensitivity analyses of RCTs with more than 100 but 500 or less patients (Supplementary material online, Table S4).

2007 Universal Definition of Myocardial Infarction adherence

Of the 96 trials included, 25 (26.0%) started enrolment after the publication of the 2007 Universal Definition of MI. Of these, 11 (44.0%) referenced this definition in the design or primary results paper. Troponin defined endpoint MI in 19 (76.0%). Nine (36.0%) used the five-type classification scheme to define endpoint MI, but seven of these nine adapted this classification, typically for PCI-related (type 4a) MI definition, by using CK-MB instead of troponin.

Survey results

A survey was administered to the investigators between April 2011 and July 2012. Of 61 unique investigators responding to the survey, 54 (88.5%) responded that the use of a standard MI definition in RCTs was important, but 40 of those 54 (74.1%) also indicated that the ESC/ACC/AHA/WHF (World Heart Federation) task force definition created challenges related to assay variability and definition of re-MI and PCI-related MI. Overall, 54 investigators (88.5%) said troponin should be used to define MI in RCTs, but 18 added that they would not use high-sensitivity troponin assays. Of these 54, 38 (70.4%) specified their preference for troponin to define spontaneous but not procedural MI. The most common reasons for not favouring troponin in the procedural setting were as follows: (i) the recommended diagnostic threshold for troponin was too low (n = 23, 60.5%); (ii) a belief that there was a lack of clinical relevance of asymptomatic troponin elevations after procedures (n = 10, 26.3%); and (iii) these elevations are a marker of atherosclerosis burden but have no independent relationship with mortality (n = 10, 26.3%).

For each of the 96 trials in our analysis, we asked the principal investigator to specify whether a standardized MI definition was used; we obtained responses for 91 trials. A standard MI definition was reported in 49 trials (53.8%); 22 reported using the universal MI definition.

Discussion

In this large and broad cross-section of contemporary RCTs in cardiovascular disease, we estimated that MI contributes an average of 45.3% of events in primary endpoint composites. Despite the frequency and importance of MI as an endpoint component in RCTs that establish the evidence for the use of therapies in cardiovascular practice, MI definition was heterogeneous and implementation of recent consensus recommendations for defining MI was low. Overall, only 57.0% of RCTs used troponin to define endpoint MI, whereas 43.0% of trials used the less-specific CK-MB or total CK. This trend was especially evident among RCTs studying revascularization, of which only six trials specified troponin to define procedure-related MI. One in seven trials failed to publish any criteria for MI definition. Although the use of troponin was more frequent among RCTs in which enrolment started >74 months after the publication of the 2000 ESC/ACC consensus MI definition document, overall these findings suggest a lack of standardized implementation of one of the most important endpoint definitions in cardiovascular RCTs.

Use of troponin to define endpoint myocardial infarction

Owing to nearly absolute myocardial specificity, the use of troponins I and T was emphasized in the ESC/ACC 2000 redefinition of MI consensus statement1 and reinforced in the 2007 Universal Definition of MI document.2 Thus, it is noteworthy that slightly more than half of cardiovascular RCTs we examined used troponin to define endpoint MI. Even among RCTs that referenced a consensus document, only 66.7% used troponin to define endpoint MI and only 7 specified the recommended 99th percentile as the MI decision limit. These findings are in sharp contrast to the rapid uptake of troponins to define MI in clinical practice.97

Because failure to implement a standard approach to define MI in RCTs impairs systematic comparison of results across trials, our findings underscore the need to (i) increase awareness of consensus documents; (ii) overcome impediments to implementation of consensus recommendations in RCTs; and (iii) develop uniform standards for determining and reporting endpoint MI in RCTs and defining the role of troponin.

Spontaneous and procedural myocardial infarction reporting and infarct size

Remarkably, only three of 80 RCTs separately reported spontaneous and procedural MI, whereas five reported MI rates between treatment arms, using threshold biomarker size, and no RCT provided actual peak biomarker levels. Although there is general agreement that procedure-related myocardial necrosis has some prognostic implication, it remains controversial as to how best to weigh its impact relative to spontaneous MI.96 Indeed, separate reporting was a key consideration driving the five-group classification in the 2007 and 2012 MI definition documents.2,3 Finally, it may be useful to compare the effect of treatments using a more sensitive, continuous measure of myonecrosis, such as the peak biomarker value, in addition to the presence/absence of MI. Without consistently defining and reporting MI, it will remain challenging to compare studied populations and reported results across trials.

Understanding gaps in the implementation of consensus document recommendations

Implementation of consensus recommendations for MI definition and reporting is likely time-dependent. The use of troponin to define endpoint MI was higher in RCTs that began >74 months after ESC/ACC MI 2000 redefinition, compared with earlier trials. This may reflect increased acceptance over time of troponin as the preferred biomarker to define MI. It may also reflect that establishing endpoint definitions in the design phase of clinical trials often precedes the start of enrolment. However, even at 34–74 months (about 3–6 years after the 2000 redefinition document was published), only 48.5% of trials used troponin to define endpoint MI: this suggests it was unlikely the only factor in our findings.

Troponin was used least often to define MI in Interventional RCTs. Although the association of CK-MB elevation (mainly defined as >3× ULN) with death after coronary revascularization has been demonstrated, whether this relationship exists for troponin and at what level of elevation above the 99th percentile is less certain.98–100 This has prompted debate about the use of troponin to define procedure-related MI.101 Our investigator survey revealed a reluctance to use troponin to define procedure-related MI; only 16 of 61 investigators favoured troponin to define procedure-related MI. The most common reason cited (60.5%) was the low recommended diagnostic threshold (i.e. 3× ULN for PCI-related MI). It is reassuring that the most recent version of the Universal Definition of MI has addressed this concern by raising the recommended threshold for peri-PCI MI from 3× ULN to 5× ULN, although the task force recognizes that these thresholds are arbitrary.3

About one-fourth of respondents were concerned about clinical relevance, including that asymptomatic troponin elevation post-procedure is not clinically important or that it is a marker of atherosclerosis burden but has no independent relationship with mortality. Concerns have also been raised that interpreting peri-procedural troponin elevations is challenging and may be less relevant among patients with pre-procedural elevation.102,103 Increasingly sensitive troponin assays will add more complexity to this debate by increasing the proportion of patients with elevated baseline troponin levels. However, a recent analysis of pooled data from more than 10 000 clinical trial patients with non-ST-segment elevation ACS that assessed troponin trends before and at the time of PCI found that (i) in using pre-procedural troponin trends to identify patients with stable or falling troponin levels, 57% of patients could be assessed for peri-PCI MI, and (ii) if troponin levels were stable or falling before PCI, then a new troponin re-elevation post-PCI was associated with worse outcomes, even after accounting for pre-procedural troponin levels.104 The importance of assessing cardiac marker trends before PCI in adjudicating peri-PCI MI was also emphasized by the recent 2012 Universal Definition of MI.2,3 Thus, enhanced use of a standard MI definition that incorporates troponin will likely be most successful by iteratively addressing investigator concerns. Only reassessment of the degree of implementation of the 2012 Universal Definition of MI in several years will confirm whether the changes (which are consistent with our survey findings of reasons for failure of significant implementation to date) were successful in increasing standardized MI definition in clinical trials. We believe our survey not only has provided important insights into investigator concerns about implementing standard MI definitions in clinical trials, but it can also serve as the framework for the future reassessments of implementation.

Concern about the relevance of peri-procedural troponin elevations and MI definition thresholds does not entirely explain the low implementation of the Universal Definition of MI. Even ACS RCTs and Other RCTs incompletely incorporated ESC/ACC consensus recommendations for troponin use to define MI, particularly at the 99th percentile. This may reflect ongoing concerns about precision of some assays at the 99th percentile. Even if assays are very precise at the 99th percentile, it is also unknown whether smaller MIs that may be detected and that generally are associated with lower risk for adverse outcomes would affect the ability to detect overall treatment differences in RCTs. New generation troponin assays with even higher sensitivity will likely add more uncertainty, as recently acknowledged by the Third Universal Definition of MI.3 It is noteworthy that more than one-quarter of investigators surveyed favoured troponin to define MI, but not the use of high-sensitivity assays due to potential ‘noise’ or non-clinically relevant MI event detection. Although these concerns could lead to troponin use at a cutoff above the 99th percentile, they would not solely explain overall low rates of incorporation of troponin testing into MI endpoint definitions. To this point, 11.5% of investigators felt troponin should not be used at all to define MI in RCTs.

Future directions

The low use of consensus document recommendations we observed identifies a pressing need to implement standard definition and reporting of MI endpoints in cardiovascular RCTs. We believe that the reporting criteria developed by the ACC/AHA/ESC/WHF Writing Group for Redefinition of Myocardial Infarction should be required as part of the standardized CONSORT (Consolidated Standards of Reporting Trials) reporting system for clinical trials now adopted by major medical journals.105 Using this type of standardized reporting system, such as that recently developed for bleeding,106 would make it easier for both clinicians and clinical trialists to understand findings of RCTs. Moreover, we suggest that the redefinition of MI writing group consider modifications that address concerns and perspectives among investigators that were identified in our survey. Other specific efforts and measures that may facilitate uniform definition and reporting include the following: (i) requirements from regulatory authorities for standard MI definition in RCTs in which MI is a key component of the primary endpoint, including appropriate distinction of MI types; and (ii) requirements by journal editors that actual data for necrosis markers used to determine MI endpoints in RCTs be submitted as a supplementary file with each primary results manuscript so that they are publically available. This would provide an important opportunity for investigators, regulators, and critics to examine varying definitions of MI (e.g. varying troponin thresholds for MI) and how they affect trial results.

To successfully implement standard definition and reporting of MI in RCTs, logistical issues, including pros and cons of local laboratory vs. core laboratory troponin measurement, must be addressed. In particular, if local measurements are used, how best to incorporate and account for the wide variety and lack of standardization of available troponin assays and their varying performance characteristics must be resolved.

Limitations and strengths

We acknowledge some limitations of our systematic review but also would point to its strengths. Whereas one author (S.L.) screened and abstracted all the data, we implemented rigorous quality checks to ensure complete and consistent data abstraction. Also, the inclusion/exclusion criteria and parameters assessed were stringent, reducing the likelihood of bias that could substantially alter the results. These contentions are supported by our sensitivity analysis that examined smaller RCTs, revealing similar findings. Furthermore, we limited our search to primary results and/or design papers. RCTs may report the incidence of spontaneous and procedural MI in a secondary publication.107 However, because the consensus recommendations were designed for use in primary MI endpoint determination, we felt that a stringent approach to addressing their implementation for primary results presentation was important. More importantly, reporting results according to these key recommendations in secondary publications, which are more difficult to identify and often occur well after the primary results are published, creates unnecessary obstacles to understanding the primary results. Finally, the quality of data management and monitoring, which is usually not publicly or readily available, was not analysed in our systematic review.

Conclusions

Although MI contributes significantly to primary outcome measures in contemporary RCTs, low implementation of the 2000 ESC/ACC MI redefinition and 2007 Universal Definition of MI consensus recommendations was evident. This was particularly true regarding the use of troponin to define MI. Given the importance of MI as a metric in clinical practice, clinical trials, and epidemiological studies, it is necessary to better understand this failure and to create appropriate strategies for uniform implementation of recommendations. Our survey, from a broad cross-section of contemporary RCTs, underscores the need for further investigation to establish the most appropriate and clinically meaningful definition of peri-procedural MI.

Supplementary material

Supplementary material is available at European Heart Journal online.

Funding

This work was supported by the investigators and by the National Institutes of Health (T32HL079896 to P.J.S.). No other commercial, foundation, philanthropic, or government funding sources were used.

Conflict of interest: S.L. and P.J.S. report no conflicts of interest with the submitted work. P.W.A.: Consultancy—F. Hoffmann-LaRoche Ltd., Axio/Orexigen, Eli Lilly & Co. Merck & Co., Inc. in conjunction with DCRI. Grant/grant pending—Boehringer Ingelheim, F. Hoffman-LaRoche Ltd. & Sanofi-Aventis Canada, Inc.; Sanofi-Aventis Canada Inc.; Scios, Inc., Ortho Biotech, Johnson & Johnson, Jansen Ortho in conjunction with DCRI; GlaxoSmithKline; Amylin Pharmaceuticals, Inc. in conjunction with DCRI; Merck & Co., Inc. in conjunction with DCRI. Payment for development of educational presentations—AstraZeneca and Eli Lilly & Co. L.K.N.: Board membership—Society of Chest Pain Centers. Consultancy—Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly & Co., Genentech, Johnson & Johnson, Novartis. Grants/grants pending—Amylin, AstraZeneca, Bristol-Myers Squibb, diaDexus, GlaxoSmith Kline, Merck & Co., Inc. MURDOCK Study, NHLBI, Regado Biosciences, Roche. Payment for lectures including service on speakers bureaus—Johnson & Johnson, American Diabetes Association. Travel/accommodations/meeting expenses unrelated to activities listed—AHA, Society of Chest Pain Centers. E.M.O.: Consultancy—AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences Inc., Janssen Pharmaceuticals Inc., LipoScience, Merck & Co., Inc. Pozen, Roche, Sanofi-Aventis, The Medicines Company, WebMD. Grants/grants pending—Daiichi Sankyo, Daiichi Sankyo, Maquet.

Acknowledgements

The authors wish to thank Morgan deBlecourt for editorial assistance in the preparation of the manuscript for submission. Finally, the authors are grateful to the investigators who participated in the survey for their important feedback and contributions.

References

1
Alpert
JS
Thygesen
K
Antman
E
Bassand
JP
Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction: The Joint European Society of Cardiology/American College of Cardiology Committee
J Am Coll Cardiol
 , 
2000
, vol. 
36
 (pg. 
959
-
969
)
2
Thygesen
K
Alpert
JS
White
HD
Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction
Universal definition of myocardial infarction
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
2173
-
2195
)
3
Thygesen
K
Alpert
JS
Jaffe
AS
Simoons
ML
Chaitman
BR
White
HD
the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction
Third universal definition of myocardial infarction
Eur Heart J
 , 
2012
, vol. 
33
 (pg. 
2551
-
2567
)
4
Liberati
A
Altman
DG
Tetzlaff
J
Mulrow
C
Gøtzsche
PC
Ioannidis
JP
Clarke
M
Devereaux
PJ
Kleijnen
J
Moher
D
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration
Ann Intern Med
 , 
2009
, vol. 
151
 (pg. 
W65
-
W94
)
5
 
Guidance on New Law (Public Law 110-85) enacted to expand the scope of ClinicalTrials.gov: registration http://prsinfo.clinicaltrials.gov/fdaaa.html Accessed 4 May 2010
6
Dormandy
JA
Charbonnel
B
Eckland
DJ
Erdmann
E
Massi-Benedetti
M
Moules
IK
Skene
AM
Tan
MH
Lefèbvre
PJ
Murray
GD
Standl
E
Wilcox
RG
Wilhelmsen
L
Betteridge
J
Birkeland
K
Golay
A
Heine
RJ
Korányi
L
Laakso
M
Mokán
M
Norkus
A
Pirags
V
Podar
T
Scheen
A
Scherbaum
W
Schernthaner
G
Schmitz
O
Skrha
J
Smith
U
Taton
J
PROactive Investigators
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
Lancet
 , 
2005
, vol. 
366
 (pg. 
1279
-
1289
)
7
Choudhry
NK
Brennan
T
Toscano
M
Pettell
C
Glynn
RJ
Rubino
M
Schneeweiss
S
Brookhart
AM
Fernandes
J
Mathew
S
Christiansen
B
Antman
EM
Avorn
J
Shrank
WH
Rationale and design of the Post-MI FREEE trial: a randomized evaluation of first-dollar drug coverage for post-myocardial infarction secondary preventive therapies
Am Heart J
 , 
2008
, vol. 
156
 (pg. 
31
-
36
)
8
Pfisterer
M
Bertel
O
Bonetti
PO
Brunner-La Rocca
HP
Eberli
FR
Erne
P
Galatius
S
Hornig
B
Kiowski
W
Pachinger
O
Pedrazzini
G
Rickli
H
De Servi
S
Kaiser
C
BASKET-PROVE Investigators
Drug-eluting or bare-metal stents for large coronary vessel stenting? The BASKET-PROVE (PROspective Validation Examination) trial: study protocol and design
Am Heart J
 , 
2008
, vol. 
155
 (pg. 
609
-
614
)
9
Antman
EM
Morrow
DA
McCabe
CH
Jiang
F
White
HD
Fox
KA
Sharma
D
Chew
P
Braunwald
E
ExTRACT-TIMI 25 Investigators
Enoxaparin versus unfractionated heparin as antithrombin therapy in patients receiving fibrinolysis for ST-elevation myocardial infarction. Design and rationale for the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25)
Am Heart J
 , 
2005
, vol. 
149
 (pg. 
217
-
226
)
10
Boden
WE
Probstfield
JL
Anderson
T
Chaitman
BR
Desvignes-Nickens
P
Koprowicz
K
McBride
R
Teo
K
Weintraub
W
AIM-HIGH Investigators
Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy
N Engl J Med
 , 
2011
, vol. 
365
 (pg. 
2255
-
2267
)
11
Lincoff
AM
Bittl
JA
Kleiman
NS
Sarembock
IJ
Jackman
JD
Mehta
S
Tannenbaum
MA
Niederman
AL
Bachinsky
WB
Tift-Mann
J
III
Parker
HG
Kereiakes
DJ
Harrington
RA
Feit
F
Maierson
ES
Chew
DP
Topol
EJ
REPLACE-1 Investigators
Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial)
Am J Cardiol
 , 
2004
, vol. 
93
 (pg. 
1092
-
1096
)
12
Cannon
CP
Braunwald
E
McCabe
CH
Rader
DJ
Rouleau
JL
Belder
R
Joyal
SV
Hill
KA
Pfeffer
MA
Skene
AM
Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators
Intensive versus moderate lipid lowering with statins after acute coronary syndromes
N Engl J Med
 , 
2004
, vol. 
350
 (pg. 
1495
-
1504
)
13
Diener
HC
Bogousslavsky
J
Brass
LM
Cimminiello
C
Csiba
L
Kaste
M
Leys
D
Matias-Guiu
J
Rupprecht
HJ
MATCH investigators
Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial
Lancet
 , 
2004
, vol. 
364
 (pg. 
331
-
337
)
14
Wallentin
L
Wilcox
RG
Weaver
WD
Emanuelsson
H
Goodvin
A
Nyström
P
Bylock
A
ESTEEM Investigators
Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial
Lancet
 , 
2003
, vol. 
362
 (pg. 
789
-
797
)
15
Mehilli
J
Kastrati
A
Schühlen
H
Dibra
A
Dotzer
F
von Beckerath
N
Bollwein
H
Pache
J
Dirschinger
J
Berger
PP
Schömig
A
Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators
Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel
Circulation
 , 
2004
, vol. 
110
 (pg. 
3627
-
3635
)
16
Moses
JW
Leon
MB
Popma
JJ
Fitzgerald
PJ
Holmes
DR
O'Shaughnessy
C
Caputo
RP
Kereiakes
DJ
Williams
DO
Teirstein
PS
Jaeger
JL
Kuntz
RE
SIRIUS Investigators
Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery
N Engl J Med
 , 
2003
, vol. 
349
 (pg. 
1315
-
1323
)
17
Patel
A
MacMahon
S
Chalmers
J
Neal
B
Woodward
M
Billot
L
Harrap
S
Poulter
N
Marre
M
Cooper
M
Glasziou
P
Grobbee
DE
Hamet
P
Heller
S
Liu
LS
Mancia
G
Mogensen
CE
Pan
CY
Rodgers
A
Williams
B
ADVANCE Collaborative Group
Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial
Lancet
 , 
2007
, vol. 
370
 (pg. 
829
-
840
)
18
de Winter
RJ
Windhausen
F
Cornel
JH
Dunselman
PH
Janus
CL
Bendermacher
PE
Michels
HR
Sanders
GT
Tijssen
JG
Verheugt
FW
Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators
Early invasive versus selectively invasive management for acute coronary syndromes
N Engl J Med
 , 
2005
, vol. 
353
 (pg. 
1095
-
1104
)
19
Ferguson
JJ
Califf
RM
Antman
EM
Cohen
M
Grines
CL
Goodman
S
Kereiakes
DJ
Langer
A
Mahaffey
KW
Nessel
CC
Armstrong
PW
Avezum
A
Aylward
P
Becker
RC
Biasucci
L
Borzak
S
Col
J
Frey
MJ
Fry
E
Gulba
DC
Guneri
S
Gurfinkel
E
Harrington
R
Hochman
JS
Kleiman
NS
Leon
MB
Lopez-Sendon
JL
Pepine
CJ
Ruzyllo
W
Steinhubl
SR
Teirstein
PS
Toro-Figueroa
L
White
H
SYNERGY Trial Investigators
Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial
JAMA
 , 
2004
, vol. 
292
 (pg. 
45
-
54
)
20
Stone
GW
Rogers
C
Hermiller
J
Feldman
R
Hall
P
Haber
R
Masud
A
Cambier
P
Caputo
RP
Turco
M
Kovach
R
Brodie
B
Herrmann
HC
Kuntz
RE
Popma
JJ
Ramee
S
Cox
DA
FilterWire EX Randomized Evaluation Investigators
Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration system during percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts
Circulation
 , 
2003
, vol. 
108
 (pg. 
548
-
553
)
21
Lincoff
AM
Bittl
JA
Harrington
RA
Feit
F
Kleiman
NS
Jackman
JD
Sarembock
IJ
Cohen
DJ
Spriggs
D
Ebrahimi
R
Keren
G
Carr
J
Cohen
EA
Betriu
A
Desmet
W
Kereiakes
DJ
Rutsch
W
Wilcox
RG
de Feyter
PJ
Vahanian
A
Topol
EJ
REPLACE-2 Investigators
Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial
JAMA
 , 
2003
, vol. 
289
 (pg. 
853
-
863
)
22
Yusuf
S
Teo
KK
Pogue
J
Dyal
L
Copland
I
Schumacher
H
Dagenais
G
Sleight
P
Anderson
C
The ONTARGET Investigators
Telmisartan, ramipril, or both in patients at high risk for vascular events
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
1547
-
1559
)
23
Verrier
ED
Shernan
SK
Taylor
KM
Van de Werf
F
Newman
MF
Chen
JC
Carrier
M
Haverich
A
Malloy
KJ
Adams
PX
Todaro
TG
Mojcik
CF
Rollins
SA
Levy
JH
PRIMO-CABG Investigators
Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial
JAMA
 , 
2004
, vol. 
291
 (pg. 
2319
-
2327
)
24
Mochizuki
S
Dahlöf
B
Shimizu
M
Ikewaki
K
Yoshikawa
M
Taniguchi
I
Ohta
M
Yamada
T
Ogawa
K
Kanae
K
Kawai
M
Seki
S
Okazaki
F
Taniguchi
M
Yoshida
S
Tajima
N
Jikei Heart Study Group
Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study
Lancet
 , 
2007
, vol. 
369
 (pg. 
1431
-
1439
)
25
Singh
AK
Szczech
L
Tang
KL
Barnhart
H
Sapp
S
Wolfson
M
Reddan
D
CHOIR Investigators
Correction of anemia with epoetin alfa in chronic kidney disease
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2085
-
2098
)
26
Khanal
S
Obeidat
O
Hudson
MP
Al-Mallah
M
Bloome
M
Lu
M
Greenbaum
AB
Kugelmass
AD
Weaver
WD
Active Lipid Management In Coronary Artery Disease (ALMICAD) Study
Am J Med
 , 
2007
, vol. 
120
 (pg. 
734.e11
-
e17
)
27
Lee
SW
Park
SW
Hong
MK
Lee
CW
Kim
YH
Park
JH
Kang
SJ
Han
KH
Kim
JJ
Park
SJ
Comparison of cilostazol and clopidogrel after successful coronary stenting
Am J Cardiol
 , 
2005
, vol. 
95
 (pg. 
859
-
862
)
28
Bernardi
V
Szarfer
J
Summay
G
Mendiz
O
Sarmiento
R
Alemparte
MR
Gabay
J
Berger
PB
Long-term versus short-term clopidogrel therapy in patients undergoing coronary stenting (from the Randomized Argentine Clopidogrel Stent [RACS] trial)
Am J Cardiol
 , 
2007
, vol. 
99
 (pg. 
349
-
352
)
29
Antman
EM
Morrow
DA
McCabe
CH
Murphy
SA
Ruda
M
Sadowski
Z
Budaj
A
López-Sendón
JL
Guneri
S
Jiang
F
White
HD
Fox
KA
Braunwald
E
ExTRACT-TIMI 25 Investigators
Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1477
-
1488
)
30
Raz
I
Wilson
PW
Strojek
K
Kowalska
I
Bozikov
V
Gitt
AK
Jermendy
G
Campaigne
BN
Kerr
L
Milicevic
Z
Jacober
SJ
Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial
Diabetes Care
 , 
2009
, vol. 
32
 (pg. 
381
-
386
)
31
Bhatt
DL
Fox
KAA
Hacke
W
Berger
PB
Black
HR
Boden
WE
Cacoub
P
Cohen
EA
Creager
MA
Easton
JD
Flather
MD
Haffner
SM
Hamm
CW
Hankey
GJ
Johnston
SC
Mak
KH
Mas
JL
Montalescot
G
Pearson
TA
Steg
PG
Steinhubl
SR
Weber
MA
Brennan
DM
Fabry-Ribaudo
L
Booth
J
Topol
EJ
CHARISMA Investigators
Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1706
-
1717
)
32
Nussmeier
NA
Whelton
AA
Brown
MT
Langford
RM
Hoeft
A
Parlow
JL
Boyce
SW
Verburg
KM
Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery
N Engl J Med
 , 
2005
, vol. 
352
 (pg. 
1081
-
1091
)
33
Sabatine
MS
Cannon
CP
Gibson
CM
López-Sendón
JL
Montalescot
G
Theroux
P
Claeys
MJ
Cools
F
Hill
KA
Skene
AM
McCabe
CH
Braunwald
E
CLARITY-TIMI 28 Investigators
Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation
N Engl J Med
 , 
2005
, vol. 
352
 (pg. 
1179
-
1189
)
34
Tsuchida
K
Colombo
A
Lefèvre
T
Oldroyd
KG
Guetta
V
Guagliumi
G
von Scheidt
W
Ruzyllo
W
Hamm
CW
Bressers
M
Stoll
HP
Wittebols
K
Donohoe
DJ
Serruys
PW
The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II)
Eur Heart J
 , 
2007
, vol. 
28
 (pg. 
433
-
442
)
35
Laarman
GJ
Suttorp
MJ
Dirksen
MT
van Heerebeek
L
Kiemeneij
F
Slagboom
T
van der Wieken
LR
Tijssen
JG
Rensing
BJ
Patterson
M
Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
1105
-
1113
)
36
Yusuf
S
Mehta
SR
Chrolavicius
S
Afzal
R
Pogue
J
Granger
CB
Budaj
A
Peters
RJ
Bassand
JP
Wallentin
L
Joyner
C
Fox
KA
The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators
Comparison of fondaparinux and enoxaparin in acute coronary syndromes
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
1464
-
1476
)
37
Windecker
S
Remondino
A
Eberli
FR
Jüni
P
Räber
L
Wenaweser
P
Togni
M
Billinger
M
Tüller
D
Seiler
C
Roffi
M
Corti
R
Sütsch
G
Maier
W
Lüscher
T
Hess
OM
Egger
M
Meier
B
Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization
N Engl J Med
 , 
2005
, vol. 
353
 (pg. 
653
-
662
)
38
Tardif
JC
McMurray
JJ
Klug
E
Small
R
Schumi
J
Choi
J
Cooper
J
Scott
R
Lewis
EF
L'Allier
PL
Pfeffer
MA
Aggressive Reduction of Inflammation Stops Events (ARISE) Trial Investigators
Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial
Lancet
 , 
2008
, vol. 
371
 (pg. 
1761
-
1768
)
39
Connolly
S
Pogue
J
Hart
R
Pfeffer
M
Hohnloser
S
Chrolavicius
S
Pfeffer
M
Hohnloser
S
Yusuf
S
ACTIVE Writing Group of the ACTIVE Investigators
Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial
Lancet
 , 
2006
, vol. 
367
 (pg. 
1903
-
1912
)
40
Mauri
L
Cox
D
Hermiller
J
Massaro
J
Wahr
J
Tay
SW
Jonas
M
Popma
JJ
Pavliska
J
Wahr
D
Rogers
C
The PROXIMAL trial: proximal protection during saphenous vein graft intervention using the Proxis Embolic Protection System: a randomized, prospective, multicenter clinical trial
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
1442
-
1449
)
41
Stone
GW
McLaurin
BT
Cox
DA
Bertrand
ME
Lincoff
AM
Moses
JW
White
HD
Pocock
SJ
Ware
JH
Feit
F
Colombo
A
Aylward
PE
Cequier
AR
Darius
H
Desmet
W
Ebrahimi
R
Hamon
M
Rasmussen
LH
Rupprecht
HJ
Hoekstra
J
Mehran
R
Ohman
EM
ACUITY Investigators
Bivalirudin for patients with acute coronary syndromes
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2203
-
2216
)
42
Yusuf
S
Mehta
SR
Chrolavicius
S
Afzal
R
Pogue
J
Granger
CB
Budaj
A
Peters
RJ
Bassand
JP
Wallentin
L
Joyner
C
Fox
KA
OASIS-6 Trial Group
Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial
JAMA
 , 
2006
, vol. 
295
 (pg. 
1519
-
1530
)
43
Bertrand
OF
De Larochellière
R
Rodés-Cabau
J
Proulx
G
Gleeton
O
Nguyen
CM
Déry
JP
Barbeau
G
Noël
B
Larose
E
Poirier
P
Roy
L
Early Discharge After Transradial Stenting of Coronary Arteries Study Investigators
A randomized study comparing same-day home discharge and abciximab bolus only to overnight hospitalization and abciximab bolus and infusion after transradial coronary stent implantation
Circulation
 , 
2006
, vol. 
114
 (pg. 
2636
-
2643
)
44
Spaulding
C
Henry
P
Teiger
E
Beatt
K
Bramucci
E
Carrié
D
Slama
MS
Merkely
B
Erglis
A
Margheri
M
Varenne
O
Cebrian
A
Stoll
HP
Snead
DB
Bode
C
TYPHOON Investigators
Sirolimus-eluting versus uncoated stents in acute myocardial infarction
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
1093
-
1104
)
45
Smith
PK
Shernan
SK
Chen
JC
Carrier
M
Verrier
ED
Adams
PX
Todaro
TG
Muhlbaier
LH
Levy
JH
PRIMO-CABG II Investigators
Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials
J Thorac Cardiovasc Surg
 , 
2011
, vol. 
142
 (pg. 
89
-
98
)
46
Galloe
AM
Thuesen
L
Kelbaek
H
Thayssen
P
Rasmussen
K
Hansen
PR
Bligaard
N
Saunamäki
K
Junker
A
Aarøe
J
Abildgaard
U
Ravkilde
J
Engstrøm
T
Jensen
JS
Andersen
HR
Bøtker
HE
Galatius
S
Kristensen
SD
Madsen
JK
Krusell
LR
Abildstrøm
SZ
Stephansen
GB
Lassen
JF
SORT OUT II Investigators
Comparison of paclitaxel- and sirolimus-eluting stents in everyday clinical practice: The SORT OUT II randomized trial
JAMA
 , 
2008
, vol. 
299
 (pg. 
409
-
416
)
47
Valgimigli
M
Campo
G
Percoco
G
Bolognese
L
Vassanelli
C
Colangelo
S
de Cesare
N
Rodriguez
AE
Ferrario
M
Moreno
R
Piva
T
Sheiban
I
Pasquetto
G
Prati
F
Nazzaro
MS
Parrinello
G
Ferrari
R
Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study (MULTISTRATEGY) Investigators
Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: the MULTISTRATEGY randomized trial
JAMA
 , 
2008
, vol. 
299
 (pg. 
1788
-
1799
)
48
Morrow
DA
Scirica
BM
Karwatowska-Prokopczuk
E
Murphy
SA
Budaj
A
Varshavsky
S
Wolff
AA
Skene
A
McCabe
CH
Braunwald
E
MERLIN-TIMI 36 Trial Investigators
Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: The MERLIN-TIMI 36 randomized trial
JAMA
 , 
2007
, vol. 
297
 (pg. 
1775
-
1783
)
49
Wiviott
SD
Braunwald
E
McCabe
CH
Montalescot
G
Ruzyllo
W
Gottlieb
S
Neumann
FJ
Ardissino
D
De Servi
S
Murphy
SA
Riesmeyer
J
Weerakkody
G
Gibson
CM
Antman
EM
TRITON-TIMI 38 Investigators
Prasugrel versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
 , 
2007
, vol. 
357
 (pg. 
2001
-
2015
)
50
Giugliano
RP
White
JA
Bode
C
Armstrong
PW
Montalescot
G
Lewis
BS
van 't Hof
A
Berdan
LG
Lee
KL
Strony
JT
Hildemann
S
Veltri
E
Van de Werf
F
Braunwald
E
Harrington
RA
Califf
RM
Newby
LK
EARLY ACS Investigators
Early versus delayed, provisional eptifibatide in acute coronary syndromes
N Engl J Med
 , 
2009
, vol. 
360
 (pg. 
2176
-
2190
)
51
Fox
K
Ford
I
Steg
PG
Tendera
M
Ferrari
R
BEAUTIFUL Investigators
Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial
Lancet
 , 
2008
, vol. 
372
 (pg. 
807
-
816
)
52
Houlind
K
Kjeldsen
BJ
Madsen
SN
Rasmussen
BS
Holme
SJ
Nielsen
PH
Mortensen
PE
for the DOORS Study Group
On-pump versus off-pump coronary artery bypass surgery in elderly patients: results from the Danish on-pump versus off-pump randomization study
Circulation
 , 
2012
, vol. 
125
 (pg. 
2431
-
2439
)
53
Serruys
PW
Morice
M-C
Kappetein
AP
Colombo
A
Holmes
DR
Mack
MJ
Ståhle
E
Feldman
TE
van den Brand
M
Bass
EJ
Van Dyck
N
Leadley
K
Dawkins
KD
Mohr
FW
SYNTAX Investigators
Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease
N Engl J Med
 , 
2009
, vol. 
360
 (pg. 
961
-
972
)
54
Stone
GW
Witzenbichler
B
Guagliumi
G
Peruga
JZ
Brodie
BR
Dudek
D
Kornowski
R
Hartmann
F
Gersh
BJ
Pocock
SJ
Dangas
G
Wong
SC
Kirtane
AJ
Parise
H
Mehran
R
HORIZONS-AMI Trial Investigators
Bivalirudin during primary PCI in acute myocardial infarction
N Engl J Med
 , 
2008
, vol. 
358
 (pg. 
2218
-
2230
)
55
Park
SJ
Kim
YH
Park
DW
Yun
SC
Ahn
JM
Song
HG
Lee
JY
Kim
WJ
Kang
SJ
Lee
SW
Lee
CW
Park
SW
Chung
CH
Lee
JW
Lim
DS
Rha
SW
Lee
SG
Gwon
HC
Kim
HS
Chae
IH
Jang
Y
Jeong
MH
Tahk
SJ
Seung
KB
Randomized trial of stents versus bypass surgery for left main coronary artery disease
N Engl J Med
 , 
2011
, vol. 
364
 (pg. 
1718
-
1727
)
56
Milman
U
Blum
S
Shapira
C
Aronson
D
Miller-Lotan
R
Anbinder
Y
Alshiek
J
Bennett
L
Kostenko
M
Landau
M
Keidar
S
Levy
Y
Khemlin
A
Radan
A
Levy
AP
Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
341
-
347
)
57
Krucoff
MW
Kereiakes
DJ
Petersen
JL
Mehran
R
Hasselblad
V
Lansky
AJ
Fitzgerald
PJ
Garg
J
Turco
MA
Simonton
CA
III
Verheye
S
Dubois
CL
Gammon
R
Batchelor
WB
O'Shaughnessy
CD
Hermiller
JB
Jr
Schofer
J
Buchbinder
M
Wijns
W
COSTAR II Investigators Group
A novel bioresorbable polymer paclitaxel-eluting stent for the treatment of single and multivessel coronary disease: primary results of the COSTAR (Cobalt Chromium Stent With Antiproliferative for Restenosis) II study
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
1543
-
1552
)
58
Mehilli
J
Kastrati
A
Byrne
RA
Bruskina
O
Iijima
R
Schulz
S
Pache
J
Seyfarth
M
Massberg
S
Laugwitz
KL
Dirschinger
J
Schömig
A
LEFT-MAIN Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions Study Investigators. Paclitaxel-versus sirolimus-eluting stents for unprotected left main coronary artery disease
J Am Coll Cardiol
 , 
2009
, vol. 
53
 (pg. 
1760
-
1768
)
59
Kastrati
A
Neumann
FJ
Mehilli
J
Byrne
RA
Iijima
R
Büttner
HJ
Khattab
AA
Schulz
S
Blankenship
JC
Pache
J
Minners
J
Seyfarth
M
Graf
I
Skelding
KA
Dirschinger
J
Richardt
G
Berger
PB
Schömig
A
ISAR-REACT 3 Trial Investigators
Bivalirudin versus unfractionated heparin during percutaneous coronary intervention
N Engl J Med
 , 
2008
, vol. 
359
 (pg. 
688
-
696
)
60
Topol
EJ
Bousser
MG
Fox
KA
Creager
MA
Despres
JP
Easton
JD
Hamm
CW
Montalescot
G
Steg
PG
Pearson
TA
Cohen
E
Gaudin
C
Job
B
Murphy
JH
Bhatt
DL
CRESCENDO Investigators
Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial
Lancet
 , 
2010
, vol. 
376
 (pg. 
517
-
523
)
61
Harrington
RA
Stone
GW
McNulty
S
White
HD
Lincoff
AM
Gibson
CM
Pollack
CV
Jr
Montalescot
G
Mahaffey
KW
Kleiman
NS
Goodman
SG
Amine
M
Angiolillo
DJ
Becker
RC
Chew
DP
French
WJ
Leisch
F
Parikh
KH
Skerjanec
S
Bhatt
DL
Platelet inhibition with cangrelor in patients undergoing PCI
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
2318
-
2329
)
62
Mehta
SR
Bassand
JP
Chrolavicius
S
Diaz
R
Eikelboom
JW
Fox
KA
Granger
CB
Jolly
S
Joyner
CD
Rupprecht
HJ
Widimsky
P
Afzal
R
Pogue
J
Yusuf
S
CURRENT-OASIS 7 Investigators
Dose comparisons of clopidogrel and aspirin in acute coronary syndromes
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
930
-
942
)
63
Jolly
SS
Yusuf
S
Cairns
J
Niemelä
K
Xavier
D
Widimsky
P
Budaj
A
Niemelä
M
Valentin
V
Lewis
BS
Avezum
A
Steg
PG
Rao
SV
Gao
P
Afzal
R
Joyner
CD
Chrolavicius
S
Mehta
SR
RIVAL Trial Group
Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial
Lancet
 , 
2011
, vol. 
377
 (pg. 
1409
-
1420
)
64
Kastrati
A
Neumann
FJ
Schulz
S
Massberg
S
Byrne
RA
Ferenc
M
Laugwitz
KL
Pache
J
Ott
I
Hausleiter
J
Seyfarth
M
Gick
M
Antoniucci
D
Schömig
A
Berger
PB
Mehilli
J
ISAR-REACT 4 Trial Investigators
Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction
N Engl J Med
 , 
2011
, vol. 
365
 (pg. 
1980
-
1989
)
65
Stone
GW
Rizvi
A
Newman
W
Mastali
K
Wang
JC
Caputo
R
Doostzadeh
J
Cao
S
Simonton
CA
Sudhir
K
Lansky
AJ
Cutlip
DE
Kereiakes
DJ
SPIRIT IV Investigators
Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease
N Engl J Med
 , 
2010
, vol. 
362
 (pg. 
1663
-
1674
)
66
Bhatt
DL
Lincoff
AM
Gibson
CM
Stone
GW
McNulty
S
Montalescot
G
Kleiman
NS
Goodman
SG
White
HD
Mahaffey
KW
Pollack
CV
Jr
Manoukian
SV
Widimsky
P
Chew
DP
Cura
F
Manukov
I
Tousek
F
Jafar
MZ
Arneja
J
Skerjanec
S
Harrington
RA
CHAMPION PLATFORM Investigators
Intravenous platelet blockade with cangrelor during PCI
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
2330
-
2341
)
67
Wallentin
L
Becker
RC
Budaj
A
Cannon
CP
Emanuelsson
H
Held
C
Horrow
J
Husted
S
James
S
Katus
H
Mahaffey
KW
Scirica
BM
Skene
A
Steg
PG
Storey
RF
Harrington
RA
Freij
A
Thorsén
M
PLATO Investigators
Ticagrelor versus clopidogrel in patients with acute coronary syndromes
N Engl J Med
 , 
2009
, vol. 
361
 (pg. 
1045
-
1057
)
68
Alexander
JH
Emery
RW
Jr
Carrier
M
Ellis
SJ
Mehta
RH
Hasselblad
V
Menasche
P
Khalil
A
Cote
R
Bennett-Guerrero
E
Mack
MJ
Schuler
G
Harrington
RA
Tardif
JC
MEND-CABG II Investigators
Efficacy and safety of pyridoxal 5′-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial
JAMA
 , 
2008
, vol. 
299
 (pg. 
1777
-
1787
)
69
Windecker
S
Serruys
PW
Wandel
S
Buszman
P
Trznadel
S
Linke
A
Lenk
K
Ischinger
T
Klauss
V
Eberli
F
Corti
R
Wijns
W
Morice
MC
di Mario
C
Davies
S
van Geuns
RJ
Eerdmans
P
van Es
GA
Meier
B
Jüni
P
Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial
Lancet
 , 
2008
, vol. 
372
 (pg. 
1163
-
1173
)
70
Park
DW
Kim
YH
Yun
SC
Kang
SJ
Lee
SW
Lee
CW
Park
SW
Seong
IW
Lee
JH
Tahk
SJ
Jeong
MH
Jang
Y
Cheong
SS
Yang
JY
Lim
DS
Seung
KB
Chae
JK
Hur
SH
Lee
SG
Yoon
J
Lee
NH
Choi
YJ
Kim
HS
Kim
KS
Kim
HS
Hong
TJ
Park
HS
Park
SJ
Comparison of zotarolimus-eluting stents with sirolimus- and paclitaxel-eluting stents for coronary revascularization: the ZEST (comparison of the efficacy and safety of zotarolimus-eluting stent with sirolimus-eluting and paclitaxel-eluting stent for coronary lesions) randomized trial
J Am Coll Cardiol
 , 
2010
, vol. 
56
 (pg. 
1187
-
1195
)
71
Lamy
A
Devereaux
PJ
Prabhakaran
D
Taggart
DP
Hu
S
Paolasso
E
Straka
Z
Piegas
LS
Akar
AR
Jain
AR
Noiseux
N
Padmanabhan
C
Bahamondes
JC
Novick
RJ
Vaijyanath
P
Reddy
S
Tao
L
Olavegogeascoechea
PA
Airan
B
Sulling
TA
Whitlock
RP
Ou
Y
Ng
J
Chrolavicius
S
Yusuf
S
CORONARY Investigators
Off-pump or on-pump coronary-artery bypass grafting at 30 days
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
1489
-
1497
)
72
Valgimigli
M
Campo
G
Monti
M
Vranckx
P
Percoco
G
Tumscitz
C
Castriota
F
Colombo
F
Tebaldi
M
Fucà
G
Kubbajeh
M
Cangiano
E
Minarelli
M
Scalone
A
Cavazza
C
Frangione
A
Borghesi
M
Marchesini
J
Parrinello
G
Ferrari
R
Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators
Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial
Circulation
 , 
2012
, vol. 
125
 (pg. 
2015
-
2026
)
73
Kedhi
E
Joesoef
KS
McFadden
E
Wassing
J
van Mieghem
C
Goedhart
D
Smits
PC
Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial
Lancet
 , 
2010
, vol. 
375
 (pg. 
201
-
209
)
74
Park
SJ
Park
DW
Kim
YH
Kang
SJ
Lee
SW
Lee
CW
Han
KH
Park
SW
Yun
SC
Lee
SG
Rha
SW
Seong
IW
Jeong
MH
Hur
SH
Lee
NH
Yoon
J
Yang
JY
Lee
BK
Choi
YJ
Chung
WS
Lim
DS
Cheong
SS
Kim
KS
Chae
JK
Nah
DY
Jeon
DS
Seung
KB
Jang
JS
Park
HS
Lee
K
Duration of dual antiplatelet therapy after implantation of drug-eluting stents
N Engl J Med
 , 
2010
, vol. 
362
 (pg. 
1374
-
1382
)
75
Kim
JS
Park
SM
Kim
BK
Ko
YG
Choi
D
Hong
MK
Seong
IW
Kim
BO
Gwon
HC
Hong
BK
Tahk
SJ
Park
SW
Kim
CJ
Jeong
MH
Yoon
J
Jang
Y
ECLAT-STEMI Trial Investigators
Efficacy of clotinab in acute myocardial infarction trial-ST elevation myocardial infarction (ECLAT-STEMI)
Circ J
 , 
2012
, vol. 
76
 (pg. 
405
-
413
)
76
Byrne
RA
Kastrati
A
Kufner
S
Massberg
S
Birkmeier
KA
Laugwitz
KL
Schulz
S
Pache
J
Fusaro
M
Seyfarth
M
Schömig
A
Mehilli
J
Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Investigators
Randomized, non-inferiority trial of three limus agent-eluting stents with different polymer coatings: the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) Trial
Eur Heart J
 , 
2009
, vol. 
30
 (pg. 
2441
-
2449
)
77
Morrow
DA
Braunwald
E
Bonaca
MP
Ameriso
SF
Dalby
AJ
Fish
MP
Fox
KA
Lipka
LJ
Liu
X
Nicolau
JC
Ophuis
AJ
Paolasso
E
Scirica
BM
Spinar
J
Theroux
P
Wiviott
SD
Strony
J
Murphy
SA
TRA 2P–TIMI 50 Steering Committee and Investigators
Vorapaxar in the secondary prevention of atherothrombotic events
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
1404
-
1413
)
78
Choudhry
NK
Avorn
J
Glynn
RJ
Antman
EM
Schneeweiss
S
Toscano
M
Reisman
L
Fernandes
J
Spettell
C
Lee
JL
Levin
R
Brennan
T
Shrank
WH
Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial
Full coverage for preventive medications after myocardial infarction
N Engl J Med
 , 
2011
, vol. 
365
 (pg. 
2088
-
2097
)
79
Mehilli
J
Pache
J
Abdel-Wahab
M
Schulz
S
Byrne
RA
Tiroch
K
Hausleiter
J
Seyfarth
M
Ott
I
Ibrahim
T
Fusaro
M
Laugwitz
KL
Massberg
S
Neumann
FJ
Richardt
G
Schömig
A
Kastrati
A
Is Drug-Eluting-Stenting Associated with Improved Results in Coronary Artery Bypass Grafts? (ISAR-CABG) Investigators
Drug-eluting versus bare-metal stents in saphenous vein graft lesions (ISAR-CABG): a randomised controlled superiority trial
Lancet
 , 
2011
, vol. 
378
 (pg. 
1071
-
1078
)
80
Tricoci
P
Huang
Z
Held
C
Moliterno
DJ
Armstrong
PW
Van de Werf
F
White
HD
Aylward
PE
Wallentin
L
Chen
E
Lokhnygina
Y
Pei
J
Leonardi
S
Rorick
TL
Kilian
AM
Jennings
LH
Ambrosio
G
Bode
C
Cequier
A
Cornel
JH
Diaz
R
Erkan
A
Huber
K
Hudson
MP
Jiang
L
Jukema
JW
Lewis
BS
Lincoff
AM
Montalescot
G
Nicolau
JC
Ogawa
H
Pfisterer
M
Prieto
JC
Ruzyllo
W
Sinnaeve
PR
Storey
RF
Valgimigli
M
Whellan
DJ
Widimsky
P
Strony
J
Harrington
RA
Mahaffey
KW
TRACER Investigators
Thrombin-receptor antagonist vorapaxar in acute coronary syndromes
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
20
-
33
)
81
Massberg
S
Byrne
RA
Kastrati
A
Schulz
S
Pache
J
Hausleiter
J
Ibrahim
T
Fusaro
M
Ott
I
Schömig
A
Laugwitz
KL
Mehilli
J
Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting Versus Zotarolimus- Eluting Stents (ISAR-TEST 5) Investigators
Polymer-free sirolimus- and probucol-eluting versus new generation zotarolimus-eluting stents in coronary artery disease: the Intracoronary Stenting and Angiographic Results: Test Efficacy of Sirolimus- and Probucol-Eluting versus Zotarolimus-eluting Stents (ISAR-TEST 5) trial
Circulation
 , 
2011
, vol. 
124
 (pg. 
624
-
632
)
82
Serruys
PW
Silber
S
Garg
S
van Geuns
RJ
Richardt
G
Buszman
PE
Kelbaek
H
van Boven
AJ
Hofma
SH
Linke
A
Klauss
V
Wijns
W
Macaya
C
Garot
P
DiMario
C
Manoharan
G
Kornowski
R
Ischinger
T
Bartorelli
A
Ronden
J
Bressers
M
Gobbens
P
Negoita
M
van Leeuwen
F
Windecker
S
Comparison of zotarolimus-eluting and everolimus-eluting coronary stents
N Engl J Med
 , 
2010
, vol. 
363
 (pg. 
136
-
146
)
83
Thiele
H
Wöhrle
J
Hambrecht
R
Rittger
H
Birkemeyer
R
Lauer
B
Neuhaus
P
Brosteanu
O
Sick
P
Wiemer
M
Kerber
S
Kleinertz
K
Eitel
I
Desch
S
Schuler
G
Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial
Lancet
 , 
2012
, vol. 
379
 (pg. 
923
-
931
)
84
Schulz
S
Mehilli
J
Neumann
FJ
Schuster
T
Massberg
S
Valina
C
Seyfarth
M
Pache
J
Laugwitz
KL
Büttner
HJ
Ndrepepa
G
Schömig
A
Kastrati
A
Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3A Trial Investigators
ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
2482
-
2491
)
85
Mega
JL
Braunwald
E
Wiviott
SD
Bassand
JP
Bhatt
DL
Bode
C
Burton
P
Cohen
M
Cook-Bruns
N
Fox
KA
Goto
S
Murphy
SA
Plotnikov
AN
Schneider
D
Sun
X
Verheugt
FW
Gibson
CM
ATLAS ACS 2–TIMI 51 Investigators
Rivaroxaban in patients with a recent acute coronary syndrome
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
9
-
19
)
86
Stone
GW
Teirstein
PS
Meredith
IT
Farah
B
Dubois
CL
Feldman
RL
Dens
J
Hagiwara
N
Allocco
DJ
Dawkins
KD
PLATINUM Trial Investigators
A prospective, randomized evaluation of a novel everolimus-eluting coronary stent: the PLATINUM (a Prospective, Randomized, Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System [PROMUS Element] for the Treatment of Up to Two de Novo Coronary Artery Lesions) trial
J Am Coll Cardiol
 , 
2011
, vol. 
57
 (pg. 
1700
-
1708
)
87
Alexander
JH
Lopes
RD
James
S
Kilaru
R
He
Y
Mohan
P
Bhatt
DL
Goodman
S
Verheugt
FW
Flather
M
Huber
K
Liaw
D
Husted
SE
Lopez-Sendon
J
De Caterina
R
Jansky
P
Darius
H
Vinereanu
D
Cornel
JH
Cools
F
Atar
D
Leiva-Pons
JL
Keltai
M
Ogawa
H
Pais
P
Parkhomenko
A
Ruzyllo
W
Diaz
R
White
H
Ruda
M
Geraldes
M
Lawrence
J
Harrington
RA
Wallentin
L
APPRAISE-2 Investigators
Apixaban with antiplatelet therapy after acute coronary syndrome
N Engl J Med
 , 
2011
, vol. 
365
 (pg. 
699
-
708
)
88
Litt
HI
Gatsonis
C
Snyder
B
Singh
H
Miller
CD
Entrikin
DW
Leaming
JM
Gavin
LJ
Pacella
CB
Hollander
JE
CT angiography for safe discharge of patients with possible acute coronary syndromes
N Engl J Med
 , 
2012
, vol. 
366
 (pg. 
1393
-
1403
)
89
Cutlip
DE
Windecker
S
Mehran
R
Boam
A
Cohen
DJ
van Es
GA
Steg
PG
Morel
MA
Mauri
L
Vranckx
P
McFadden
E
Lansky
A
Hamon
M
Krucoff
MW
Serruys
PW
Academic Research Consortium: clinical end points in coronary stent trials: a case for standardized definitions
Circulation
 , 
2007
, vol. 
115
 (pg. 
2344
-
2351
)
90
Mauri
L
Hsieh
WH
Massaro
JM
Ho
KK
D'Agostino
R
Cutlip
DE
Stent thrombosis in randomized clinical trials of drug-eluting stents
N Engl J Med
 , 
2007
, vol. 
356
 (pg. 
1020
-
1029
)
91
Cannon
CP
Battler
A
Brindis
RG
Cox
JL
Ellis
SG
Every
NR
Flaherty
JT
Harrington
RA
Krumholz
HM
Simoons
ML
Van De Werf
FJ
Weintraub
WS
Mitchell
KR
Morrisson
SL
Brindis
RG
Anderson
HV
Cannom
DS
Chitwood
WR
Cigarroa
JE
Collins-Nakai
RL
Ellis
SG
Gibbons
RJ
Grover
FL
Heidenreich
PA
Khandheria
BK
Knoebel
SB
Krumholz
HL
Malenka
DJ
Mark
DB
Mckay
CR
Passamani
ER
Radford
MJ
Riner
RN
Schwartz
JB
Shaw
RE
Shemin
RJ
Van Fossen
DB
Verrier
ED
Watkins
MW
Phoubandith
DR
Furnelli
T
American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee)
J Am Coll Cardiol
 , 
2001
, vol. 
38
 (pg. 
2114
-
2130
)
92
Pettersen
AA
Seljeflot
I
Abdelnoor
M
Arnesen
H
Unstable angina, stroke, myocardial infarction and death in aspirin non-responders. A prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design
Scand Cardiovasc J
 , 
2004
, vol. 
38
 (pg. 
353
-
356
)
93
Cannon
CP
Giugliano
RP
Blazing
MA
Harrington
RA
Peterson
JL
Sisk
CM
Strony
J
Musliner
TA
McCabe
CH
Veltri
E
Braunwald
E
Califf
RM
IMPROVE-IT Investigators
Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes
Am Heart J
 , 
2008
, vol. 
156
 (pg. 
826
-
832
)
94
Ridker
PM
Thuren
T
Zalewski
A
Libby
P
Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Am Heart J
 , 
2011
, vol. 
162
 (pg. 
597
-
605
)
95
Lamas
GA
Goertz
C
Boineau
R
Mark
DB
Rozema
T
Nahin
RL
Drisko
JA
Lee
KL
Design of the Trial to Assess Chelation Therapy (TACT)
Am Heart J
 , 
2012
, vol. 
163
 (pg. 
7
-
12
)
96
Prasad
A
Gersh
BJ
Bertrand
ME
Lincoff
AM
Moses
JW
Ohman
EM
White
HD
Pocock
SJ
McLaurin
BT
Cox
DA
Lansky
AJ
Mehran
R
Stone
GW
Prognostic significance of periprocedural versus spontaneously occurring myocardial infarction after percutaneous coronary intervention in patients with acute coronary syndromes: an analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
477
-
486
)
97
Pulkki
K
Suvisaari
J
Collinson
P
Ravkilde
J
Stavljenic-Rukavina
A
Hammerer-Lercher
A
Baum
H
van Dieijen-Visser
MP
Laitinen
P
A pilot survey of the use and implementation of cardiac markers in acute coronary syndrome and heart failure across Europe. The CARdiac MArker Guideline Uptake in Europe (CARMAGUE) study
Clin Chem Lab Med
 , 
2009
, vol. 
47
 (pg. 
227
-
234
)
98
Bhatt
DL
Topol
EJ
Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes
Circulation
 , 
2005
, vol. 
112
 (pg. 
906
-
922
)
99
Kini
AS
Lee
P
Marmur
JD
Agarwal
A
Duffy
ME
Kim
MC
Sharma
SK
Correlation of postpercutaneous coronary intervention creatine kinase-MB and troponin I elevation in predicting mid-term mortality
Am J Cardiol
 , 
2004
, vol. 
93
 (pg. 
18
-
23
)
100
Cavallini
C
Savonitto
S
Violini
R
Arraiz
G
Plebani
M
Olivari
Z
Rubartelli
P
Battaglia
S
Niccoli
L
Steffenino
G
Ardissino
D
Italian ‘Atherosclerosis, Thorombosis, and Vascular Biology’ and ‘Society for Invasive Cardiology-GISE’ Investigators
Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study
Eur Heart J
 , 
2005
, vol. 
26
 (pg. 
1494
-
1498
)
101
Vranckx
P
Cutlip
DE
Mehran
R
Kint
PP
Silber
S
Windecker
S
Serruys
PW
Myocardial infarction adjudication in contemporary all-comer stent trials: balancing sensitivity and specificity. Addendum to the historical MI definitions used in stent studies
EuroIntervention
 , 
2010
, vol. 
5
 (pg. 
871
-
874
)
102
Cantor
WJ
Newby
LK
Christenson
RH
Tuttle
RH
Hasselblad
V
Armstrong
PW
Moliterno
DJ
Califf
RM
Topol
EJ
Ohman
EM
SYMPHONY and 2nd SYMPHONY Cardiac Markers Substudy Investigators
Prognostic significance of elevated troponin I after percutaneous coronary intervention
J Am Coll Cardiol
 , 
2002
, vol. 
39
 (pg. 
1738
-
1744
)
103
Prasad
A
Rihal
CS
Lennon
RJ
Singh
M
Jaffe
AS
Holmes
DR
Jr
Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T levels in 5487 patients
Circ Cardiovasc Interv
 , 
2008
, vol. 
1
 (pg. 
10
-
19
)
104
Tricoci
P
Leonardi
S
White
JA
Tinga
B
Giugliano
RP
White
HD
Armstrong
PW
Kleiman
NS
Sulimov
V
Tanguay
JF
Lewis
BS
James
SK
Gibson
CM
Braunwald
E
Van de Werf
F
Califf
RM
Mahaffey
KW
Newby
LK
Re-elevation of troponin following percutaneous coronary intervention significantly predicts 1-year mortality in patients with high-risk non–ST-segment elevation acute coronary syndromes
Circulation
 , 
2011
, vol. 
124
 pg. 
A9150
 
105
Moher
D
Schulz
KF
Altman
D
CONSORT Group (Consolidated Standards of Reporting Trials)
The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials
JAMA
 , 
2001
, vol. 
285
 (pg. 
1987
-
1991
)
106
Mehran
R
Rao
SV
Bhatt
DL
Gibson
CM
Caixeta
A
Eikelboom
J
Kaul
S
Wiviott
SD
Menon
V
Nikolsky
E
Serebruany
V
Valgimigli
M
Vranckx
P
Taggart
D
Sabik
JF
Cutlip
DE
Krucoff
MW
Ohman
EM
Steg
PG
White
H
Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium
Circulation
 , 
2011
, vol. 
123
 (pg. 
2736
-
2747
)
107
Morrow
DA
Wiviott
SD
White
HD
Nicolau
JC
Bramucci
E
Murphy
SA
Bonaca
MP
Ruff
CT
Scirica
BM
McCabe
CH
Antman
EM
Braunwald
E
Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction
Circulation
 , 
2009
, vol. 
119
 (pg. 
2758
-
2764
)

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