SUPPLEMENTAL MATERIAL. eFigure 1. Proportion (random effects estimates with 95% confidence intervals) of myocardial infarction in the primary endpoint ...
SUPPLEMENTAL MATERIAL eFigure 1. Proportion (random effects estimates with 95% confidence intervals) of myocardial infarction in the primary endpoint composite according to the number of components in the primary composite eTable 1A. Criteria used to define myocardial infarction across the trial studied: Interventional Randomized Controlled Trials eTable 1B. Criteria used to define myocardial infarction across the trial studied: Acute Coronary Syndrome Randomized Controlled Trials eTable 1C. Criteria used to define myocardial infarction across the trial studied: Other Randomized Controlled Trials eTable 2. Revascularization group (Interventional, Acute Coronary Syndrome, Others) and rate of coronary revascularization among 80 trials with primary results publications available eTable 3. Definition of re-infarction in acute myocardial infarction trials eTable 4. Assessment of the 3 key recommendations on myocardial infarction definition and reporting in the sensitivity analysis of trials with >100 but ≤500 patients eAppendix 1. Search Methodology eAppendix 2. Principal Investigator Survey eAppendix 3. Sensitivity Analysis eAppendix 4. Definition of Re-infarction in Acute Myocardial Infarction Trials
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eFigure 1. Proportion (random effects estimates with 95% confidence intervals) of myocardial infarction in the primary endpoint composite according to the number of components in the primary composite.
Abbreviations: MI, myocardial infarction; EP, endpoint; RCT, randomized controlled trial; Comp., components.
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eTable 1A. Criteria used to define myocardial infarction across the trial studied: Interventional Randomized Controlled Trials Trial REPLACE 1 ISAR SWEET SIRIUS
Biomarker CK-MB (or CK) >3 CK-MB >3 CK >2 and CK-MB >1
Symptoms Not required Not required >20 min
ECG New Qw New Qw New Qw
FIRE REPLACE 2 Spontaneous PCI or CABG PRIMO CABG
CK-MB >3
Not required
Not required
CK-MB (or CK) >2 CK-MB (or CK) >3 CK-MB >100 ng/mL or CK-MB >70 ng/ML
Not required Not required Not required
New Qw New Qw New Qw
Lee SW et al
CK-MB >3
≥30 min
New changes
CK-MB (or CK) >2 CK-MB (or CK) >3 CK-MB (or CK) >5 CK-MB >25 ng/mL 3.7 ng/mL
Not required Not required Not required >20 min
New Qw New Qw Not required New Qw
ECG and BIO Either ECG or BIO
Peak CK-MB/peak total CK >10% or CKMB >3 Peak CK-MB/peak total CK >10% or CKMB >5
Not required
New Qw
ECG and BIO
Not required
New Qw
ECG and BIO
CK >2 and CK-MB >1 CK >5 CK-MB >3
Not required Not required Not required
New Qw New Qw New Qw
Either ECG or BIO
CK-MB >1; if no ECG: CK >2 and CK-MB or cTn >1 CK-MB or TnI >3 CK-MB (or CK) >1.5 (3
Recurrent SYM Not required
CK-MB or CK >2
>20 min
New Qw or ST deviation
Either Qw or 1) 2 3) >7 d BIO >1 and either SYM or BIO
CK-MB >3 CK-MB >5
Not required Not required
Not required Not required
RACS Spontaneous PCI CABG Nussmeier NA et al
ARTS II PCI
CABG
PASSION Non-CABG CABG PROXIMAL
Windecker S et al
EASY TYPHOON SORT OUT II Spontaneous PCI MULTI STRATEGY Spontaneous
PCI CABG
Comments Either BIO or ECG Either BIO or ECG BIO and either SYM or ECG
Either BIO or ECG Either BIO or ECG CK-MB >100 or CKMB >70 and Qw 4 d Either ECG or BIO and SYM
2 of 4 (including new WMA)
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eTable 1A. Criteria used to define myocardial infarction across the trial studied: Interventional Randomized Controlled Trials Trial TRITON Spontaneous
Biomarker
Symptoms
ECG
Comments
CK-MB or cTn >1
>20 min
ST deviation >1mm or new Qw
CK-MB >3 in 2 s or CK-MB >5 in 1 s CK-MB >10 CK-MB >5 or peak CK-MB/peak total CK >10%
Not required
New Qw
BIO and either SYM or ECG. In patients not stable/falling: ST (re)-elevation or hemodynamic compromise Either BIO or ECG
Not required Not required
New Qw New Qw
Either BIO or ECG >7 d randomization: either criterion. ULN (or previous nadir) CK-MB x 3 (cTn x 3 allowed only in patients with normal baseline BIO)
≥30 min
SYM and either BIO or ECG Definition according to baseline status
CK-MB x 10 (or CKMB x 5 + ECG) CK >2 and CK-MB >1 CK-MB (or CK) >2 CK-MB (or CK) >2
Not required
New ECG changes New ECG changes (required only in patients with rising BIO) New Qw
Not required Not required Not required
New Qw New Qw New Qw
Either BIO or ECG Either BIO or ECG Either BIO or ECG
CK-MB >2
Typical SYM
New Qw
CK-MB (or CK) >3 + 50% increase than pre-PCI CK-MB (or CK) >10 CK >2 and CK-MB >1
Not required
New Qw
BIO and either SYM or ECG Either BIO or ECG
Not required Not required
New Qw New Qw
Either BIO or ECG Either BIO or ECG
CK-MB >2
Typical SYM
New Qw
CK-MB (or CK) >3 + 50% increase than pre-PCI CK-MB (or CK) >10 CK-MB >100 ng/mL or CK-MB >70 ng/mL or CK-MB >25 ng/mL
Not required
New Qw
BIO and either SYM or ECG Either BIO or ECG
Not required Not required
New Qw New Qw
Not required
New Qw
COMPARE
CK >2 and CK-MB or cTn >1 CK-MB or cTn >1
Ischemic SYM
New changes
REAL LATE
CK-MB >3
≥30 min
New changes
PCI CABG SYNTAX
HORIZONS AMI Spontaneous PCI
CABG COSTAR II ISAR LEFT MAIN ISAR REACT 3/3A CHAMPION PCI Spontaneous PCI
CABG SPIRIT IV CH. PLATFORM Spontaneous PCI
CABG MEND CABG II
LEADERS
≥30 min required in patients with abnormal BIO levels
Either BIO or ECG CK-MB >100; or CK-MB >70 and Qw 25 >4 d Either BIO or ECG BIO and either SYM, ECG, or pathological evidence Either ECG or BIO and SYM
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eTable 1A. Criteria used to define myocardial infarction across the trial studied: Interventional Randomized Controlled Trials Trial PHOENIX Spontaneous
Biomarker
Symptoms
ECG
Comments
cTn > 1
Ischemic SYM
PCI
CK-MB >3
Ischemic SYM
New changes New changes
CABG
CK-MB >5
Not required
New Qw
BIO and SYM and/or ECG BIO only in baseline normal. SYM, ECG, and /or angiographic complications required in baseline abnormal BIO and either ECG, new WMA, new graft or native coronary occlusion
CK-MB >1
Ischemic SYM
BIO and SYM and/or ECG
CK-MB >3 CK-MB >5
Not required Not required
CK-MB/cTn >1 if normal or >50% from prior value if abnormal BIO
>30 min
New changes Not required New changes ST elevation
New Qw New changes
BIO w/ or w/o ECG BIO and SYM, ECG, new WMA, or pathological evidence. For PCIrelated MI BIO >3. BIO and SYM and/or ECG
ACCOAST Spontaneous PCI CABG AIDA STEMI
CORONARY Operative Non-operative
CKMB >5 Rise and fall of BIO >1
Ischemic SYM
cTn/CK-MB >1
Ischemic SYM
New changes
Spontaneous
cTn/CK-MB >1
Ischemic SYM
PCI
Ischemic SYM
ENIGMA II
CK-MB (re)-elevation >3 cTn >1
New changes New Qw
Ischemic SYM
New Qw
ISAR CABG Spontaneous PCI
cTn/CK-MB >1 CK-MB >3
Not required Ischemic SYM >30 min
Not required New Qw
CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
DAPT
BIO and ECG 24 h BIO + SYM
ECLAT STEMI
CABG
BIO and SYM and/or ECG 24 h BIO +ECG BIO and SYM, ECG, new WMA, or pathological evidence
If stable/falling BIO at baseline: BIO >3 or BIO >1 + ECG. If rising BIO at baseline: SYM + BIO.
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eTable 1A. Criteria used to define myocardial infarction across the trial studied: Interventional Randomized Controlled Trials Trial PLATINUM Spontaneous
Biomarker
Symptoms
ECG
Comments
cTn >2
Not required
BIO and ECG, or new WMA. If new Qw, only CKMB/cTn >1
Peri-PCI PRECOMBAT
CK/cTn >3 CK-MB >5
Not required Ischemic SYM
New ST-T wave changes or new LBBB Not required New Qw or new LBBB
PRODIGY
CK-MB >3
Ischemic SYM
New changes
RESOLUTE AC
CK-MB >3
Ischemic SYM
New Qw
CK-MB (or CK) or cTn >2
>20 min
New Qw or ST deviation
CK-MB (or CK) >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required Not required
New Qw New Qw
CK-MB >1 CK-MB (or CK) >3
Not required >30 min
Not required New changes
CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
RIVAL Spontaneous
PCI CABG ISAR TEST 4 and 5 Spontaneous PCI
CABG
Within 7 d of index MI: ECG + BIO. After 7 d of index MI: BIO >1 and SYM or ECG. Within 48 h: only BIO. After 48 h: (nonprocedural) CKMB/cTn >1 or new Qw with SYM or ECG . SYM or ECG only if BIO N.A. Different definition according to presence of MI at baseline and timing of endpoint relative to qualifying MI
Either BIO or ECG. SYM only in nonstable/falling patients
Abbreviations: BIO, biomarker(s); CABG, coronary artery bypass grafting; CK, creatine kinase; CK-MB, creatine kinase-MB; cTn: cardiac troponin; ECG, electrocardiogram; LBBB, left bundle branch block; N.A., not available; PCI, percutaneous coronary intervention; Qw, Q waves; SYM, symptom(s); TnI: troponin I, ULN, upper limit of normal; WMA, wall motion abnormalities.
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eTable 1B. Criteria used to define myocardial infarction across the trial studied: Acute Coronary Syndrome Randomized Controlled Trials Trial PLATO Spontaneous
PCI CABG CLARITY Spontaneous
PCI CABG ICTUS Spontaneous PCI ExTRACT Spontaneous
PCI CABG SYNERGY Spontaneous
PCI CABG PROVE IT Spontaneous PCI CABG ESTEEM Spontaneous PCI CABG
Biomarker
Symptoms
ECG
Comments
CK-MB or cTn >1
Recurrent SYM
ECG changes; ST elevation
BIO and either SYM or ECG. ST elevation required 3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
Not required
New Qw
CK-MB or cTn >1
>20 min
ST deviation >1 mm or new Qw
CK-MB (or CK) >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
Not required
New Qw
CK-MB >1 Not required
Not required Not required
New Qw New Qw
BIO >1
Chest pain
ECG changes
CK-MB (or CK) >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
Not required
New Qw
CK-MB (or CK) >2
>20 min
New Qw or new ST elevation
CK-MB (or CK) >3 CK-MB (or CK) >5
Not required
New Qw
Not required
New Qw
CK-MB >1 (or CK >2) CK-MB (or CK) >3 CK-MB (or CK) >5
Not required
New Qw or LBBB New Qw or LBBB New Qw or LBBB
CK-MB >2 CK-MB >3 CK-MB >5
Ischemic SYM Not required Not required
Not required Not required
BIO and either SYM or ECG. In patients not stable/falling: ST (re)-elevation or hemodynamic compromise
Different definition according to BIO + at baseline and timing of endpoint
BIO or new Qw; ST elevation or BIO required 2
>20 min
New Qw or ST deviation
Different definition according to presence of MI at baseline and timing of endpoint
CK-MB (or CK) >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
Not required
New Qw
CK-MB (or CK) or cTn >2
>20 min
New Qw or ST deviation
CK-MB (or CK) >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
Not required
New Qw
CK-MB/cTn (or CK) >2
>20 min
New Qw or new ST elevation
CK-MB (or CK) >3 CK-MB (or CK) >5
Not required
New Qw
Not required
New Qw
CK-MB or cTn >1
>30 min
New ECG changes
PCI
CK-MB (or CK) >3
>30 min
New Qw
CABG
Not required
New Qw
ARISE
CK-MB >10 (w/o Qw) or 5 (w/ Qw) CK-MB or cTn >1
SYM of ischemia
ECG changes
APPRAISE 2
CK-MB or cTn >1
SYM of ischemia
ECG changes
PCI CABG OASIS 6 Spontaneous
PCI CABG EARLY ACS Spontaneous
PCI CABG ACUITY Spontaneous
Different definition according to presence of MI at baseline and timing of endpoint
BIO or new Qw; ST elevation or BIO required 1
>10 min
New ST deviation or Qw
BIO and SYM, ECG, new WMA, or pathological evidence
CK-MB (or CK) >3 CK-MB >10 (w/o additional complications) or 5 (w/ additional complications)
Not required
Not required
Not required
New Qw
BIO and either ECG, new WMA, new graft or native coronary occlusion
CK-MB or cTn >1 or CK>2
Sign and SYM of ischemia >30 min
New ST elevation, new Qw
CK-MB (or CK) >3 CK-MB (or CK) >5
Not required
New Qw
Within 18 h: SYM + ECG. After 18 h: BIO and/or new Qw. BIO and/or ECG
Not required
New Qw
BIO and/or ECG
CK-MB or cTn >1
SYM of ischemia
New ST deviation or Qw
BIO and SYM, ECG, new WMA, or pathological evidence
Cardiac markers >3 Cardiac markers >5
Not required
Not required
Not required
New Qw
cTn or CK-MB >1
>20 min
New Qw or ST deviation
CK-MB/cTn >1 or CK >2
>10 min
New Qw or ischemic changes
CK-MB (or CK) >3 CK-MB (or CK) >5
New Qw New Qw
BIO and either ECG, new WMA, new graft or native coronary occlusion BIO and ECG or SYM Different definition according to presence of MI at baseline and timing of endpoint Either BIO or ECG Either BIO or ECG
Abbreviations: BIO, biomarker(s); CABG, coronary artery bypass grafting; CK, creatine kinase; CK-MB, creatine kinase-MB; cTn, cardiac troponin; ECG, electrocardiogram; LBBB, left bundle branch block; MI, myocardial infarction; PCI, percutaneous coronary intervention; Qw, Q waves; SYM, symptom(s); w/, with; w/o, without; WMA, wall motion abnormalities.
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eTable 1C. Criteria used to define myocardial infarction across the trial studied: Other Randomized Controlled Trials Trial ACTIVE W
Biomarker CK-MB or cTn >1
Symptoms Ischemic SYM
ECG New Qw or ischemic changes
BEAUTIFUL
cTn >1
Typical SYM
New Qw
OnTARGET PROactive Spontaneous PCI CABG ADVANCE
Unpublished
–
–
cTn or CK-MB Not required Not required CK-MB >2 or cTn >1 Elevated CK-MB or cTn
>30 min Not required Not required >15 min or requiring Tx >20–30 min
ECG evidence ECG evidence ECG evidence ST changes or new Qw New ST deviation or Qw
CHOIR
CK-MB or cTn >1
>15 min
ALMICAD
Postitive CK-MB or cTn CK-MB or cTn >1 or CK >2 CK >2 or cTn or CK-MB >1
>30 min
New ECG changes New Qw
>20 min or requiring Tx >20 min or requiring Tx
New Qw or Rw >Sw in V1 New Qw or dominant Rw in V1
2 of 3
CK-MB or cTn >1
>10 min
New ST deviation or Qw
BIO and SYM, ECG, new WMA, or pathological evidence
CK-MB (or CK) >3 CK-MB (or CK) >5
Not required Not required
New Qw New Qw
CK-MB or cTn >1
Ischemic SYM
New Qw or ischemia
CK-MB or CK >2 or cTn >1
Ischemic SYM
BIO and SYM and/or ECG
CK-MB >3 CK-MB >10 (w/o Qw) or 5 (w/ Qw)
Not required Not required
New ST deviation, new LBBB, or new Qw Not required New Qw
CK-MB/cTn >2
Ischemic SYM
New ST deviation or Qw
CK-MB >3 CK-MB >10 or cTn >20 (w/o Qw) or 5 (w/ Qw)
Not required
New Qw
BIO and SYM, ECG, new WMA, or pathological evidence BIO or ECG
JIKEI HEART
MATCH CHARISMA
TRA 2P Spontaneous
PCI CABG
I CARE CRESCENDO Spontaneous
PCI CABG AIM HIGH Spontaneous
PCI CABG
Comments BIO with either SYM or ECG or PCI/CABG BIO with either SYM or ECG – 2 of 3 Only ECG 2 of 3 Integrated assessment also including coronary angiography 2 of 3 2 of 3
2 of 3
BIO and either ECG, new WMA, new graft or native coronary occlusion BIO and either SYM or ECG
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eTable 1C. Criteria used to define myocardial infarction across the trial studied: Other Randomized Controlled Trials Trial HEART 2D
Biomarker CK-MB/cTn >1
Symptoms Ischemic SYM
ECG New ST deviation, new LBBB, or new Qw
Comments BIO and SYM and/or ECG
SAVOR Spontaneous
CK-MB or cTn >1
>10 min
New ST deviation or Qw
BIO and SYM, ECG, new WMA, or pathological evidence
CK-MB (or CK) >3 CK-MB (or CK) >5
Not required Not required
Not required New Qw
CK-MB or cTn >1
Ischemic SYM
New ST deviation or Qw
Cardiac markers >3 Cardiac markers >5
Not required
Not required
Not required
New Qw
Unpublished cTn/CK-MB >1
– Ischemic SYM
– ECG changes
PCI CABG
STABILITY Spontaneous
PCI CABG
TACT Litt et al
BIO and either ECG, new WMA, new graft or native coronary occlusion BIO and SYM, ECG, new WMA, or pathological evidence
BIO and either ECG, new WMA, new graft or native coronary occlusion – BIO and SYM and/or ECG
Abbreviations: BIO, biomarker(s); CABG, coronary artery bypass grafting; CK, creatine kinase; CK-MB, creatine kinase-MB; cTn, cardiac troponin; ECG,electrocardiogram; LBBB, left bundle branch block; PCI, percutaneous coronary intervention; Qw, Q wave; Rw, R wave; Sw, S wave; SYM, symptom(s); Tx, treatment; V1, lead V1; w/, with; w/o, without; WMA, wall motion abnormalities.
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eTable 2. Revascularization group (Interventional, Acute Coronary Syndrome, Others) and rate of coronary revascularization among 80 trials with primary results publications available Study Name REPLACE 1 PROVE IT MATCH ESTEEM ISAR SWEET SIRIUS PROactive ADVANCE
Group Interventional ACS Other ACS Interventional Interventional Other Other
Revascularization Rate – 68.9 N.R. 12.3 – – 3.9 a N.R
ICTUS SYNERGY FIRE REPLACE 2 OnTARGET PRIMO CABG JIKEI HEART CHOIR ALMICAD Lee SW et al RACS ExTRACT CHARISMA HEART 2D Nussmeier NA et al CLARITY ARTS II PASSION OASIS 5 Windecker S et al ARISE ACTIVE W PROXIMAL ACUITY OASIS 6 EASY TYPHOON PRIMO CABG II SORT OUT II MULTI STRATEGY MERLIN TRITON TIMI 38 EARLY ACS BEAUTIFUL DOORS SYNTAX HORIZONS AMI
ACS ACS Interventional Interventional Other Interventional Other Other Other Interventional Interventional ACS Other Other Interventional ACS Interventional Interventional ACS Interventional ACS Other Interventional ACS ACS Interventional Interventional Interventional Interventional Interventional ACS Interventional ACS Other Interventional Interventional Interventional
66.8 65.3 – – 15.1 – N.R. N.R. b N.R. – – 25.8 a N.R. N.R. – 62.8 – – 43.6 – 7.8 N.R. – 67.5 – – – – – – 39.5 – 71.5 N.R. – – –
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eTable 2. Revascularization group (Interventional, Acute Coronary Syndrome, Others) and rate of coronary revascularization among 80 trials with primary results publications available Study Name PRECOMBAT I CARE COSTAR II ISAR LEFT MAIN AIM HIGH ISAR REACT 3 CRESCENDO CHAMPION PCI CURRENT RIVAL ISAR REACT 4 SPIRIT IV CH. PLATFORM PLATO MEND CABG II LEADERS ZEST CORONARY PRODIGY COMPARE REAL LATE ECLAT STEMI ISAR TEST 4 TRA 2°P MI FREEE ISAR CABG TRACER ISAR TEST 5 RESOLUTE AC AIDA STEMI ISAR REACT 3A ATLAS ACS PLATINUM APPRAISE 2 Litt et al
Group Interventional Other Interventional Interventional Other Interventional Other Interventional ACS Interventional Interventional Interventional Interventional ACS Interventional Interventional Interventional Interventional Interventional Interventional Interventional Interventional Interventional Other Other Interventional ACS Interventional Interventional Interventional Interventional ACS Interventional ACS Other
Revascularization Rate – 2.0 – – c 4.8 – N.R. – 68.8 – – – – 74.5 – – – – – – – – – 2.5 10.1 – 57.8 – – – – N.R. – N.R. 2.0
a
Reported in a composite. Graphically reported but no actual N. c Coronary or cerebrovascular revascularization. Note: For interventional trials in which revascularization was required by protocol, revascularization rate is assumed to be 100%. Abbreviations: ACS, acute coronary syndrome; N.R., not reported. b
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eTable 3. Definition of re-infarction in acute myocardial infarction trials Trial
Qualifying MI Type
Primary Criterion to Define reInfarction
Time Windows
CM Considered in the Earliest Time Window
OASIS 6
STEMI
Time
24 h – 7 d
No
TYPHOON
STEMI
Time
48 h
Yes
MULTI STRATEGY
STEMI
Time
24 h – 7 d
No
ECLAT STEMI
STEMI
Time
24 h
Yes
STREAM
STEMI
Time
18 h
No
AIDA STEMI
STEMI
Time
24 h
No
ICTUS
NSTEMI
Time
48 h
Yes
SYNERGY
NSTEMI
Time
16 h
No
OASIS 5
NSTEMI
Time
24 h – 7 d
No
EARLY ACS
NSTEMI
Time
16 h
No
PRECOMBAT
NSTEMI
Time
7d
Yes
PROVE IT TIMI 22
STEMI or NSTEMI
Time
18 h
No
PRIMO CABG
STEMI or NSTEMI
Time
4 d – 30 d
Yes
PRIMO CABG II
STEMI or NSTEMI
Time
4 d – 30 d
Yes
IMPROVE IT
STEMI or NSTEMI
Time
72 h
Yes
RIVAL
STEMI or NSTEMI
Time
24 h – 7 d
No
CURRENT/OASIS7
STEMI or NSTEMI
Time
24 h – 7 d
No
PLATO
STEMI or NSTEMI
Time
18 h
No
PASSION
STEMI
Cardiac markers
/
/
HORIZONS AMI
STEMI
Cardiac markers
/
/
ACUITY
NSTEMI
Cardiac markers
/
/
MERLIN
NSTEMI
Cardiac markers
/
/
CH. PLATFORM
NSTEMI
Cardiac markers
/
/
TRACER
NSTEMI
Cardiac markers
/
/
TRITON
STEMI or NSTEMI
Cardiac markers
/
/
PHOENIX
STEMI or NSTEMI
Cardiac markers
/
/
ESTEEM
STEMI or NSTEMI
Cardiac markers
/
/
CHAMPION PCI
STEMI or NSTEMI
Cardiac markers
/
/
PRODIGY
STEMI or NSTEMI
Cardiac markers
/
/
ISAR TEST 4
STEMI or NSTEMI
Cardiac markers
/
/
ISAR TEST 5
STEMI or NSTEMI
Cardiac markers
/
/
RESOLUTE AC
STEMI or NSTEMI
Cardiac markers
/
/
ATLAS ACS TIMI 51
STEMI or NSTEMI
Cardiac markers
/
/
ExTRACT TIMI 25
STEMI
Both
18 h
No
CLARITY
STEMI
Both
18 h
No
Abbreviations: CM, cardiac markers; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction.
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eTable 4. Assessment of the 3 key recommendations on myocardial infarction definition and reporting in the sensitivity analysis of trials with >100 but ≤500 patients Trial
Erglis et al Díaz de la Llera LS et al ARMYDA ACS NORDIC Bifurcation MUSASHI AMI SISR CLOTILDA JOCRI CAPITAL AMI De Luca et al STRATEGY ARMYDA 2 TAXi ARMYDA ADVANCE ACE Veselka et al CLEAR PLATELETS 2 STATIN STEMI CACTUS EUCATAX BBS CEREAS DES ARMYDA RECAPTURE BCIS 1 Boudriot et al CUPID EVOLVE NORDIC BALTIC III ON OFF OPTIMA SUPRIM
PMID/NCT
17678730 17584571 17394957 17060387 16616020 a 00231257 16169315 16159843 16053952 15976799 15870414 15750189 15653032 15277322 15234398 15066943 a 00469326 a 00370045 a 00808717 19103990 a 00825279 a 00120991 21531233 19643320 NCT00910481 NCT00176397 NCT01528514 NCT01135225 NCT00914199 NCT01290952 ISRCTN80874637 NCT00888485
Tot pts enr 103 120 171 413 486 384 300 162 170 122 173 255 202 153 202 400 200 200 171 350 422 341 375 383 301 201 121 291 477 411 142 362
MI Rate
MI Count
R1
R2
R3
0.12 0.03 0.10 0.00 0.01 0.02 0.07 N.A. 0.10 0.14 0.08 0.08 0.02 0.11 0.07 0.04 0.17 0.08 0.08 0.10 0.03 0.07 0.02 0.06 0.13 0.03 0.21 0.01 0.01 0.02 0.49 0.26
12 3 17 1 3 6 21 N.A. 17 17 14 20 5 17 15 14 33 15 14 34 11 24 6 24 39 6 26 4 4 10 70 94
Y Y N Y N N Y N N N N N Y N N – Y Y N N N Y N Y Y N N Y Y N N N
N N N N N N N N N N N N N N N N N N Y N N N N N N N N N N N N N
N Y N N N N Y Y N N Y Y N Y N N N Y N N N N Y N N N N N N N Y N
a
ClinicalTrials.gov identification number (NCT). Abbreviations: MI count, the absolute number of MI endpoints; MI rate, the rate of MI (MI count / total patients enrolled); NCT, ClinicalTrials.gov identification; N, no; N.A., not available; PMID, PubMed identification number; R1, Recommendation 1 (use of troponin to define endpoint MI); R2, Recommendation 2 (separate MI reporting); R3, Recommendation 3 (infarctsize reporting); Tot pts enr, total patients enrolled; Y, yes.
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eAppendix 1 Search Methodology ClinicalTrials.gov In the ClinicalTrials.gov search, we used the following keywords for condition: "acute coronary syndrome" OR "myocardial infarction" OR "percutaneous coronary intervention" OR “coronary artery bypass grafting” OR “coronary artery disease.” “Myocardial infarction” was entered as outcome. We also included corresponding acronyms (“ACS” OR “MI” OR “PCI” OR “CABG” OR “CAD”) to ensure our search was broadly inclusive. ClinicalTrials.gov provides all available publications for each registered record. When no publication was posted, a manual MEDLINE search was performed to confirm absence of a primary results and/or design paper. We restricted the initial search to adult (18–65 years old) or senior (65+ years old) and to phase III OR phase IV studies started from September 1, 2000 to July 4, 2012. These criteria returned 456 registered RCTs. After excluding RCTs with ≤500 patients and those in which MI was not part of the primary outcome measure (n=214), there were 108 RCTs. Because outcome reporting on ClinicalTrials.gov is not subject to keyword restriction (eg, MI can be also reported as re-MI or included within grouped endpoints such as “major adverse cardiovascular clinical events” [MACCE], “major adverse clinical events” [MACE], or “cardiovascular event”), we performed an additional search using the same keywords for condition but leaving outcome blank. This additional search returned 1478 RCTs, which were manually reviewed. Eleven additional RCTs were identified, yielding a final set of 119 eligible RCTs. We excluded 43 trials with no published primary results or design paper, leaving 76 RCTs identified via ClinicalTrials.gov.
MEDLINE We activated the following limits within MEDLINE: randomized controlled trial; English language; all adult; 19+ years; core clinical journals; and publication date from 2000/09/01 to 2007/09/27. The following keywords were used as free text or medical subject heading (MeSH) terms: "acute coronary syndrome" OR "myocardial infarction" OR "percutaneous coronary intervention" OR “coronary artery bypass grafting” OR “coronary artery disease.” This search returned 1744 unique records. For each, the abstract was reviewed against our inclusion criteria. If there was no evidence for exclusion, the full text article was reviewed. This MEDLINE search identified 35 RCTs, 15 of which were duplicates (ie, also registered on ClinicalTrials.gov). Together with the 76 RCTs identified from ClinicalTrials.gov, this yielded a final set of 96 RCTs for our study; 80 had primary results published and 16 had only a design paper.
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eAppendix 2 Principal Investigator Survey Investigator-level questions (61 responses out of 66 principal investigators [PIs]) 1. In 2000 (JACC 2000;36:959–69) and 2007 (JACC 2007;50:2173–95), experts of several cardiovascular societies including the American College of Cardiology (ACC), the American Heart Association (AHA), and European Society of Cardiology (ESC), developed consensus documents on the definition of myocardial infarction (MI). These documents recommended using a standard MI definition in randomized controlled trials (RCTs). Do you think that standard MI endpoint definition should be implemented across RCTs? 1.
YES, I believe using a standard definition of MI such as recommended by the ESC/ACC/AHA/WHF task force is important and would facilitate inter-trial comparisons and meta-analysis. Response 22.9%, Response Count 14
2.
YES, I believe using a standard definition of MI is important BUT use of the definition recommended by the ESC/ACC/AHA/WHF task force creates challenges for clinical trials due to assay variability, definition of re-MI, and definition of PCI-related MI. Response 65.6%, Response Count 40
3.
NO, I believe that a standard definition of MI limits flexibility given the range of measurement techniques, sites and countries involved in RCTs and the spectrum of conditions being tested. Therefore, there should be flexibility in how MI is defined. Response 11.5%, Response Count 7
2. Troponin has been recommended as the gold-standard biomarker for defining myocardial infarction. Do you think troponin should be used to define endpoint MI in randomized clinical trials? 1.
YES, troponin should be used to define endpoint MI in randomized clinical trials. (Proceed to the next question.) Response 59%, Response Count 36
2.
YES, troponin should be used to define endpoint MI in randomized clinical trials, BUT not using highsensitivity troponin assays. These may increase the “noise” and detect non-clinically relevant MI events. (Proceed to the next question.) Response 29.5%, Response Count 18
3.
NO, I DO NOT think troponin should be used to define endpoint MI in randomized clinical trials. (Click next but do NOT answer the next question. Your survey is ended.) Response 11.5%, Response Count 7
3. If you selected either YES answer (choice 1 or 2) to the previous questions, please answer this question: Do you think troponin should be implemented to define both spontaneous and procedural-related endpoint MI in randomized clinical trials or would you favor selective implementation according to the type of MI? 1.
I think troponin should be universally implemented for MI definition for both spontaneous and proceduralrelated MI endpoints. Response 29.6%, Response Count 16
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2.
I favor troponin for spontaneous (non-procedural) MI, but NOT for procedural-related (PCI/CABG) MI. (proceed to the next question on this page) Response 70.4% Response Count 38
4. If you selected option 2 for the previous question (ie, you DO NOT believe that troponin should be used to define procedural-related MI, please explain using the options below (check all that apply): a. I believe that, in patients undergoing coronary revascularizations, asymptomatic troponin elevations after the procedure are not clinically important. Response 26.3%, Response Count 10 b. Post-procedural troponin elevations are a marker of atherosclerosis burden but have no independent relationship with mortality or other adverse clinical consequences. Response 26.3%, Response Count 10 c. CK-MB has faster kinetics than troponin; thus, it is more useful to detect procedural MI in the setting of an index, enrolling MI. Response 21%, Response Count 8 d. Troponin might be used to define procedural-related MI, but the current recommended thresholds (3xULN for PCI-related MI; 5xULN for CABG-related MI) are too low. Response 60.5%, Response Count 23 e. Other. Please specify: Response 7.9%, Response Count 3 1.
Conduct of global trials that include centres with a range of resources available to them dictates a pragmatic and flexible definition. For example, CVD is now the leading cause of death in rural India, but troponin is not routinely available in healthcare facilities servicing this population.
2.
I don't believe we know the appropriate cut-off for troponin (or CK-MB) post-procedure, particularly post-CABG. It’s not just that the definition of MI needs to be associated with adverse outcomes, it also needs to be sensitive to the effect of effective therapies. We are essentially using troponin (or CK-MB) as a surrogate biomarker for mortality or other adverse clinical consequences and are faced with all the challenges of surrogate biomarkers.
3.
It is a very complex issue. We still have little evidence that long-term prognosis is influenced by troponin rise post-PCI. Most studies have not used central core-labs so it is really “garbage-in–garbageout” considering the different sensitivities of assays + differences between troponin-T (which is the most reliable and should be primarily used) and troponin-I. The main problem is that they never defined peri-procedural MI when troponins are already elevated PRIOR PCI.
Trial-level questions (91 responses out of 96 RCTs) 1. In considering the trial that you led (please refer to the trial referenced in the cover e-mail), did you use the ESC/ACC/AHA/WHF task force recommendations for MI definition or any other standard MI definition? 1. YES, I used a published standard MI definition. (If you select YES, please answer the next question on THIS PAGE.)
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Response 53.8%, Response Count 49 2. NO, I did NOT use a standard MI definition. (If you select NO, please provide in the box below the text of the definition, or a reference to the publication that contains this information, that investigators or blinded reviewers were asked to use in determining whether an endpoint MI had occurred. Then proceed to the NEXT PAGE. Response 46.2%, Response Count 42 [Space to upload MI definition.]
2. Please specify which standard definition you used: a. World Health Organization (Myocardial Infarction Community Registers. Public Health in Europe. Copenhagen, 1976) Response 10.2%, Response Count 5 b. ESC/ACC MI Redefinition (JACC 2000;36:959–69) Response 20.4%, Response Count 10 c. ACC Key Data Standard (JACC 2001;38:2114–30) Response 14.3%, Response Count 7 d. Universal MI Definition (JACC 2007;50:2173–95) Response 44.9%, Response Count 22 e. Other (please specify below) Response 10.2%, Response Count 5 1.
TIMI definition based on ESC/ACC
2.
TIMI definition based on ESC/ACC
3.
TIMI definition based on ESC/ACC
4.
TIMI definition based on ESC/ACC
5.
Cutlip 2007 ARC definition
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eAppendix 3 Sensitivity Analysis As a sensitivity analysis, we performed a revised search using our original criteria (trial enrollment start after September 2000; MI included as part of the primary endpoint; ClinicalTrials.gov and MEDLINE as databases), but changing the sample size to include RCTs with >100 patients but ≤500 patients.
Using these new criteria, we identified 32 additional RCTs with available primary results. One additional RCT (DADDY-T; PMID:20030830) had only a design paper but no MI definition was published. Nine additional RCTs failed to publish the enrollment start date and were excluded. These 32 additional trials are listed in eTable 4. The median number of MI endpoints was 14.5, and the median event rate was 7%. Twenty-six (81.2%) were included in the Interventional RCTs group, 5 (15.6%) were included in the ACS RCTs group, and 1 (3.1%) was included in the Other group.
Assessment of Recommendation 1 (R1): Use of Troponin for MI Diagnosis One trial (ACE) used “cardiac enzymes” to refer to cardiac biomarkers for MI diagnosis and was excluded. Of the remaining 31 RCTs, troponin was used to define endpoint MI in 12 RCTs (38.7%), compared with our revised systematic review in which this recommendation was followed in 57% of RCTs. Assessment of Recommendation 2 (R2): Separate Reporting of Spontaneous and Procedural MI Of the 32 RCTs with >100 but 100 but 10x ULN), but none provided actual peak biomarker levels.
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eAppendix 4 Definition of Re-infarction in Acute Myocardial Infarction Trials For trials that focused enrollment on patients with acute MI (ie, randomization within 7 days of qualifying MI onset), we further assessed endpoint MI for definition of re-infarction. Of the 93 trials with an MI definition available, 49 (52.7%) included patients with an acute MI. Of these 49 trials, 35 specified a separate definition for re-infarction. In all of these 35 trials, re-infarction was defined using either or both of 2 criteria: 1) time elapsed from qualifying MI, and 2) persistent elevation of cardiac markers at the time of assessment. Eighteen trials used the time elapsed from qualifying MI criterion only, 15 used elevated cardiac markers, and 2 used a classification of re-infarction based on a combination of both criteria. In the majority (11/18) of trials that used time as the primary criterion to define re-infarction, cardiac markers were not considered to assess re-infarction, especially in those enrolling ST-segment elevation myocardial infarction patients.
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