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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 16th 2010
Chicago, IL – AHA Scientific Sessions
Background
Myocardial Infarction (MI) is a key endpoint in RCTs evaluating new therapies
However heterogeneity in MI definition may affect comparisons across RCTs as well as meta-analyses
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;36:959-69.
Hence, we explored the extent to which they are applied in contemporary, large, cardiovascular RCTs
Methods – Search Criteria
We performed a systematic review of CV RCTs with > 500 patients where MI was part of the primary endpoint initiated after the 2000 ESC/ACC MI redefinition
publication
Search terms included: Acute Coronary Syndrome Myocardial Infarction Coronary Artery Disease Percutaneous Coronary Intervention Coronary Artery By-pass Grafting
Metrics of Guideline Recommendations Adherence
Adherence to 2000 ESC/ACC consensus document was captured using 3 of its key recommendations Use of troponin to define endpoint MI Separate reporting of spontaneous and procedural MI Enzymatic infarct size reporting (i.e., AUC or peak
biomarker value)
We evaluated: % RCTs referencing the 2000 ESC/ACC consensus
document & % of RCTs referencing any consensus document
endorsed by the ACC, AHA, or ESC
Flowchart for Study Screening Process
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
2,729 RCTs screened 134 (5%) met inclusion criteria
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: 1-15.6 months)
9 additional RCTs had design paper published but not primary results (from which MI def’n can be assessed)
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
(n=7 RCTs)
3 Comp
(n=28 RCTs)
4 Comp
(n=11 RCTs)
>4 Comp
(n=8 RCTs)
Pro
po
rtio
n o
f M
I eve
nts
wit
hin
th
e p
rim
ary
EP
Index Event At Enrollment into RCTs
STE-ACS (n=18 RCTs)
NSTE-ACS (n=34 RCTs)
Stable CAD (n=32 RCTs)
Other Cond (n=11 RCTs)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Referencing of Consensus Documents in RCTs
55 RCTs with primary results + 9 Only Design = 64 RCTs evaluable. Overall, 31.2% of RCTs (20/64) sourced a consensus document
ESC/ACC 2000 (n=5)Universal MI 2007 (n=5)Other Cons Doc (from AHA,ESC,AHA) (n=10)None (n=44)
Use of Troponin to Define Endpoint MI
12 RCTs (18.7%) had no MI definition published 52 residual RCTs evaluable for troponin use
38.5% (20/52) used Troponin to define MI [66.7% (12/18) among those that referenced a consensus document] Only 1 used troponin for procedural MI 2 used troponin only if CK-MB not available No RCT specified the 99th percentile as the MI
decision limit
Separate Reporting and Infarct Size
Only 1/55 RCT (1.8%) reported separately spontaneous and procedural MI in the primary results
NO RCTs reported infarct size, either by area under the curve of biomarker release or peak values
Conclusions
MI contributes substantially to primary outcome measures in contemporary large RCTs
However, there is surprisingly little implementation
of ESC/ACC recommendations for MI definition and reporting
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
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% Group 2: ACS RCTs
A coronary revascularization could be performed as part of the index enrolling ACS but not required
Median Revascularization rate 62.8% 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
(N=31 RCTs)
ACS RCTs
(N=13 RCTs)
Other RCTs
(n=11 RCTs)
Pro
po
rtio
n o
f M
I eve
nts
wit
hin
th
e p
rim
ary
EP
Supplementary Slide 2
Use of Troponin to Define MI According to Revascularization Group
Interventional RCTs
ACS RCTs Other RCTs0
5
10
15
20
25
30
35
NO Tn
YES Tn
Adjust. MI Rate in RCTs by Revascularization Groups
Interventional RCTs
(N=31 RCTs)
ACS RCTs
(N=13 RCTs)
Other RCTs
(n=11 RCTs)
MI
%*
N o
f co
mp
on
ents
Supplementary Slide 3