Implementation of ESC/ACC Definition of Myocardial Infarction in Contemporary, Large RCTs: A Systematic Review Sergio Leonardi, L. Kristin Newby, E. Magnus Ohman, Paul W. Armstrong. November 16 th 2010 November 16 th 2010 Chicago, IL – AHA Scientific Sessions

Disclosures Information None of the authors have relevant financial disclosures

Background n Myocardial Infarction (MI) is a key endpoint in RCTs evaluating new therapies n However heterogeneity in MI definition may affect comparisons across RCTs as well as meta-analyses n The 2000 ESC/ACC MI definition 1 consensus recommendations were aimed at resolving this 1: Antman E, Bassand J-P, Klein W, et al. 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;36: n Hence, we explored the extent to which they are applied in contemporary, large, cardiovascular RCTs

Methods – Search Criteria n We performed a systematic review of CV RCTs with l > 500 patients l where MI was part of the primary endpoint l initiated after the 2000 ESC/ACC MI redefinition publication n Search terms included: l Acute Coronary Syndrome l Myocardial Infarction l Coronary Artery Disease l Percutaneous Coronary Intervention l Coronary Artery By-pass Grafting

Metrics of Guideline Recommendations Adherence Metrics of Guideline Recommendations Adherence n Adherence to 2000 ESC/ACC consensus document was captured using 3 of its key recommendations l Use of troponin to define endpoint MI l Separate reporting of spontaneous and procedural MI l Enzymatic infarct size reporting (i.e., AUC or peak biomarker value) n We evaluated: l % RCTs referencing the 2000 ESC/ACC consensus document & l % of RCTs referencing any consensus document endorsed by the ACC, AHA, or ESC

Flowchart for Study Screening Process Final RCTs Medline ClinicalTrials. gov 985 Studies identified: 114 RCTs included 1744 Abstracts identified: 20 Additional RCTs included = 134 RCTs Time Period Explored : Sep 1, 2000 to May 5, 2010 Exclusion if any of the following: 1. ≤ 500 pts enrolled 2. MI not part of the primary EP 3. Started before Sep 2000 Time Period Explored : Sep 1, 2000 to May 5, 2010 Exclusion if any of the following: 1. ≤ 500 pts enrolled 2. MI not part of the primary EP 3. Started before Sep 2000

Summary of RCTs Evaluated n 2,729 studies screened  134 RCTs (5%) met inclusion criteria n Of these 55 (41%) RCTs had primary results including 297,467 pts, 13,526 end-point MIs and a median FU of 9 months (IQR: months) n 9 additional RCTs had design paper published but not primary results (from which MI def’n can be assessed) n MIs contributed a median 40.3% (IQR: 22.9, 61.2) of events in the primary composites, a % that decreased with increasing number of components

Relationship Between Proportion MI Events Within Primary Endpoint and Number of Components 2 Comp 2 Comp (n=7 RCTs) 3 Comp 3 Comp (n=28 RCTs) 4 Comp 4 Comp (n=11 RCTs) >4 Comp >4 Comp (n=8 RCTs) Proportion of MI events within the primary EP

Index Event At Enrollment into RCTs

Heterogeneity of MI Definition Across the 10 Largest RCTs Studied Acronym Spontaneous MIPCI-related MICABG-related MI Pref. Biom.Thres.Pref Biom. Thres. Definition 1. ONTARGET N.AN.A. 2. ExTRACT N.A1CKMB3 >5*ULN+Qw OR >10*ULN 3. OASIS 5 CKMB2 3 >5*ULN OR Qw 4. PLATO CKMB/cTn1CKMB3 >5*ULN+Qw OR >10*ULN 5. CHARISMA N.A. 6. ACUITY CKMB/cTn1CKMB3 >5*ULN+Qw OR >10*ULN 7. TRITON CKMB/cTn1CKMB3 or 5 >10*ULN OR Qw 8. OASIS 6 CKMB2 3 >5*ULN OR Qw 9. ADVANCE N.A. 10. BEAUTIFUL N.A. N.A.: Not Available (MI Definition NOT Published), Qw: Q waves, cTn: cardiac troponin; ULN: Upper Limit of Normal

Referencing of Consensus Documents in RCTs n 55 RCTs with primary results + 9 Only Design = 64 RCTs evaluable. Overall, 31.2% of RCTs (20/64) sourced a consensus document

Use of Troponin to Define Endpoint MI n 12 RCTs (18.7%) had no MI definition published  52 residual RCTs evaluable for troponin use n 38.5% (20/52) used Troponin to define MI [ 66.7% (12/18) among those that referenced a consensus document] l Only 1 used troponin for procedural MI l 2 used troponin only if CK-MB not available l No RCT specified the 99 th percentile as the MI decision limit

Separate Reporting and Infarct Size n Only 1/55 RCT (1.8%) reported separately spontaneous and procedural MI in the primary results n NO RCTs reported infarct size, either by area under the curve of biomarker release or peak values

Conclusions n MI contributes substantially to primary outcome measures in contemporary large RCTs n However, there is little implementation of ESC/ACC recommendations for MI definition and reporting n Appropriate strategies for uniform implementation of the MI endpoint in cardiovascular RCTs appear urgently required

Contribution of MI to Primary Endpoint in RCTs by Revascularization Groups n Group 1: Interventional RCTs All patients underwent a coronary revascularization (PCI/CABG) either as part of the randomized intervention or as inclusion criterion  Rate of coronary revascularization ≈ 100% n Group 2: ACS RCTs A coronary revascularization could be performed as part of the index enrolling ACS but not required A coronary revascularization could be performed as part of the index enrolling ACS but not required  Median Revascularization rate 62.8% n Group 3: Other RCTs Broad group of RCTs were a coronary revascularization was possible, but not expected  Median Revascularization rate 3.8 % Supplementary Slide 1

MI Events in RCTs by Revascularization Groups Interventional RCTs Interventional RCTs (N=31 RCTs) ACS RCTs ACS RCTs (N=13 RCTs) Other RCTs Other RCTs (n=11 RCTs) Proportion of MI events within the primary EP Supplementary Slide 2

Use of Troponin to Define MI According to Revascularization Group Supplementary Slide 3

Adjust. MI Rate in RCTs by Revascularization Groups Interventional RCTs Interventional RCTs (N=31 RCTs) ACS RCTs ACS RCTs (N=13 RCTs) Other RCTs Other RCTs (n=11 RCTs) MI %* N of components Supplementary Slide 4