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Randomized Controlled Trial
. 2021 Feb 23;143(8):790-804.
doi: 10.1161/CIRCULATIONAHA.120.047987. Epub 2020 Dec 3.

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons

Bernard R Chaitman  1 , Karen P Alexander  2 , Derek D Cyr  2 , Jeffrey S Berger  3 , Harmony R Reynolds  3 , Sripal Bangalore  3 , William E Boden  4 , Renato D Lopes  2 , Marcin Demkow  5 , Gian Piero Perna  6 , Robert K Riezebos  7 , Edward O McFalls  8 , Subhash Banerjee  9 , Akshay Bagai  10 , Gilbert Gosselin  11 , Sean M O'Brien  2 , Frank W Rockhold  2 , David D Waters  12 , Kristian A Thygesen  13 , Gregg W Stone  14 , Harvey D White  15 , David J Maron  16 , Judith S Hochman  3 ; ISCHEMIA Research Group
Affiliations
Randomized Controlled Trial

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons

Bernard R Chaitman et al. Circulation. .

Abstract

Background: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI).

Methods: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions.

Results: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001).

Conclusions: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Keywords: catheterization; drug therapy; myocardial infarction; myocardial ischemia; myocardial revascularization.

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Conflict of interest statement

Disclosure Statements

Dr. Bernard R. Chaitman reports grants from National Heart, Lung and Blood Institute during the conduct of the study, personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside the submitted work;

Dr. Karen P. Alexander reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Derek Cyr reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Jeffrey S. Berger reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Harmony Reynolds reports grants from National Heart, Lung and Blood Institute during the conduct of the study; non-financial support from Abbott Vascular, non-financial support from Siemens, non-financial support from BioTelemetry, outside the submitted work;

Dr. Sripal Bangalore repots grants from National Heart, Lung, and Blood Institute during the conduct of the study; grants and personal fees from Abbott Vascular, personal fees from Biotronik, personal fees from Pfizer, personal fees from Amgen, personal fees from Reata, outside the submitted work;.

Dr. William E. Boden reports grants from National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Abbvie, grants from Amarin, grants from Amgen, personal fees from Amgen, personal fees from Cleveland Clinic Clinical Coordinating Center, personal fees from Janssen, outside the submitted work

Dr. Lopes reports grants from National Heart, Lung and Blood Institute, during the conduct of the study; other from Bayer, other from Boehringer Ingleheim, grants and other from Bristol-Myers Squibb, other from Daiichi Sankyo, grants and other from Glaxo Smith Kline, grants and other from Medtronic, other from Merck, grants and other from Pfizer, other from Portola, grants and other from Sanofi, outside the submitted work;.

Dr. Marcin Demkow reports grants from National Heart, Lung and Blood Institute during the conduct of the study and receives proctoring honoraria from ABBOTT, EDWARDS, BOSTON and MEDTRONIC

Dr. Gian Piero Perna reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Robert K. Riezebos reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Edward O. McFalls reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Subhash Banerjee reports grants from National Heart, Lung and Blood Institute during the conduct of the study; reports consulting honoraria from Medtronic, Astra Zeneca, Livmor Inc.; Institutional research grants: Boston Scientific Corp., Chiesi

Dr. Akshay Bagai reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Gilbert Gosselin reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Sean M. O’Brien reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Frank W. Rockhold reports grants from National Heart, Lung and Blood Institute, during the conduct of the study; grants and personal fees from Janssen, personal fees from Merck HeathCare KGaA, personal fees from Merck Research Labs, personal fees from Novo Nordisk, personal fees from KLSMC, personal fees from Aldeyra, personal fees from Rhythm , personal fees from Phathom, grants and personal fees from AstraZeneca, personal fees from Complexa, grants and personal fees from Eidos, other from Athira, other from Spencer Healthcare, outside the submitted work;

Dr. David D. Waters reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Kristian A. Thygesen reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Gregg W. Stone reports grants and personal fees from National Heart, Lung, and Blood Institute , during the conduct of the study; personal fees from Terumo, personal fees from Amaranth, personal fees from Shockwave, personal fees and other from Valfix, personal fees from TherOx, personal fees from Reva, personal fees from Vascular Dynamics, personal fees from Robocath, personal fees from HeartFlow, personal fees from Gore, personal fees from Ablative Solutions, personal fees from Matrizyme, personal fees from Miracor, personal fees from Neovasc, personal fees from V-wave, personal fees from Abiomed, personal fees from Claret, personal fees from Sirtex, personal fees and other from Ancora, personal fees and other from Qool Therapeutics, other from Cagent, other from Applied Therapeutics, other from Biostar family of funds, other from MedFocus family of funds, personal fees and other from SpectraWave, personal fees from MAIA Pharmaceuticals, personal fees and other from Orchestra Biomed, other from Aria, personal fees from Vectorious, other from Cardiac Success, outside the submitted work; .

Dr Harvey D. White reports grants from National Heart, Lung and Blood Institute during the conduct of the study; reports receiving grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) from Sanofi-Aventis and Regeneron Pharmaceuticals, for the ACCELERATE study (A Study of Evacetrapib in High-Risk Vascular Disease) from Eli Lilly, for the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With EpaNova in High CV Risk Patients With Hypertriglyceridemia) from Omthera Pharmaceuticals, , for the HEART-FID study (Randomized Placebo-Controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency) from American Regent; for the CAMELLIA-TIMI study (A Study to Evaluate the Effect of Long-term Treatment With BELVIQ [Lorcaserin HC] on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors) from Eisai Inc, for the dal-GenE study (Effect of Dalcetrapib vs Placebo on CV Risk in a Genetically Defined Population With a Recent ACS) from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type2 Diabetes Post Worsening Heart Failure) from Sanofi-Aventis Australia Pty Ltd, and for the CLEAR Outcomes Study (Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid [ETC-1002] or Placebo) from Esperion Therapeutics Inc. He was on the Advisory Board for Genentech, Inc. and received lecture fees from AstraZeneca.

Dr. David J. Maron reports grants from National Heart, Lung and Blood Institute during the conduct of the study

Dr. Judith S. Hochman is Study Chair for the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial for which, in addition to support by a National Heart, Lung, and Blood Institute grant, devices and medications were provided by Abbott Vascular, Medtronic, Inc, St Jude Medical Inc, Volcano Corporation, Arbor Pharmaceuticals LLC, AstraZeneca, Merck Sharp and Dohme Corp, Omron Healthcare Inc, and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca.

Figures

Figure 1.
Figure 1.. Distribution of first MI events by type.
The difference in total MI rates between the primary and secondary MI definitions was primarily due to increased procedural MI events using the secondary MI definition. Type 4a and 5 MI’s accounted for 20.1% of all MI’s using the primary definition and 40.6% using the secondary definition.
Figure 2.
Figure 2.. Results for MI type according to treatment strategy
With the primary definition, there were slightly more first MI events in the conservative strategy whereas the opposite was true using the secondary MI definition. Dark blue shows spontaneous type 1 MI’s that were reduced in the invasive strategy regardless of which MI definition was used. The incidence of type 2 MI’s shown in light blue were similar. Procedural MI’s (orange) were more common in the invasive strategy and, as expected, occurred with greater frequency using the secondary definition (right panel). Stent related type 4b (stent thrombosis-related) and 4c MI’s (in-stent restenosis-related) shown in red were more frequent in the invasive strategy.
Figure 3.
Figure 3.. Spontaneous Type 1 MI by Strategy and by MI Definitions Management after Cath by Invasive Strategy vs Conservative Strategy.
Spontaneous type 1 MI events were significantly more frequent in the conservative strategy regardless of type of revascularization procedure performed or MI definition used. Group differences are significant at p<0.001 and individual pairwise comparisons to the CON group are significant at p <0.001 after adjustment for multiple comparisons. CON = conservative strategy; INV-PCI = invasive strategy patients that received PCI; INV-CABG = invasive strategy patients that received coronary bypass surgery; INV-None = invasive strategy patients that did not receive coronary revascularization (59.6% had non-obstructive coronary disease at catheterization).
Figure 3.
Figure 3.. Spontaneous Type 1 MI by Strategy and by MI Definitions Management after Cath by Invasive Strategy vs Conservative Strategy.
Spontaneous type 1 MI events were significantly more frequent in the conservative strategy regardless of type of revascularization procedure performed or MI definition used. Group differences are significant at p<0.001 and individual pairwise comparisons to the CON group are significant at p <0.001 after adjustment for multiple comparisons. CON = conservative strategy; INV-PCI = invasive strategy patients that received PCI; INV-CABG = invasive strategy patients that received coronary bypass surgery; INV-None = invasive strategy patients that did not receive coronary revascularization (59.6% had non-obstructive coronary disease at catheterization).
Figure 4.
Figure 4.. Outcomes according to treatment strategy and MI definition.
Unadjusted cumulative incidence plot of the 5-component primary ISCHEMIA end-point using the primary MI (left upper panel) and secondary MI (right upper panel) definitions and the composite end-point of cardiovascular death or MI using the primary (left lower panel) and secondary (right lower panel) MI definitions by randomized treatment strategy. Choice of MI definition had an important impact on the outcome results. The secondary MI definition (right panels) was associated with an increased number of early procedural MI events in the invasive as compared with the conservative strategy. The difference between treatment groups attenuated over time using the secondary definition (right panel) primarily due to the increased number of spontaneous type 1 MI events in the conservative strategy. Cardiovascular death rates were low and not statistically different between treatment groups.
Figure 4.
Figure 4.. Outcomes according to treatment strategy and MI definition.
Unadjusted cumulative incidence plot of the 5-component primary ISCHEMIA end-point using the primary MI (left upper panel) and secondary MI (right upper panel) definitions and the composite end-point of cardiovascular death or MI using the primary (left lower panel) and secondary (right lower panel) MI definitions by randomized treatment strategy. Choice of MI definition had an important impact on the outcome results. The secondary MI definition (right panels) was associated with an increased number of early procedural MI events in the invasive as compared with the conservative strategy. The difference between treatment groups attenuated over time using the secondary definition (right panel) primarily due to the increased number of spontaneous type 1 MI events in the conservative strategy. Cardiovascular death rates were low and not statistically different between treatment groups.
Figure 4.
Figure 4.. Outcomes according to treatment strategy and MI definition.
Unadjusted cumulative incidence plot of the 5-component primary ISCHEMIA end-point using the primary MI (left upper panel) and secondary MI (right upper panel) definitions and the composite end-point of cardiovascular death or MI using the primary (left lower panel) and secondary (right lower panel) MI definitions by randomized treatment strategy. Choice of MI definition had an important impact on the outcome results. The secondary MI definition (right panels) was associated with an increased number of early procedural MI events in the invasive as compared with the conservative strategy. The difference between treatment groups attenuated over time using the secondary definition (right panel) primarily due to the increased number of spontaneous type 1 MI events in the conservative strategy. Cardiovascular death rates were low and not statistically different between treatment groups.
Figure 4.
Figure 4.. Outcomes according to treatment strategy and MI definition.
Unadjusted cumulative incidence plot of the 5-component primary ISCHEMIA end-point using the primary MI (left upper panel) and secondary MI (right upper panel) definitions and the composite end-point of cardiovascular death or MI using the primary (left lower panel) and secondary (right lower panel) MI definitions by randomized treatment strategy. Choice of MI definition had an important impact on the outcome results. The secondary MI definition (right panels) was associated with an increased number of early procedural MI events in the invasive as compared with the conservative strategy. The difference between treatment groups attenuated over time using the secondary definition (right panel) primarily due to the increased number of spontaneous type 1 MI events in the conservative strategy. Cardiovascular death rates were low and not statistically different between treatment groups.
Figure 5.
Figure 5.. Adjusted risks of MI on subsequent all-cause and cardiovascular death according to MI definition.
The multivariate adjusted relative risk of all-cause death and cardiovascular death for the primary (upper panel) and secondary (lower panel) MI definitions are shown in this forest plot for procedural MI, procedural type 4a or 5 MI with ancillary evidence of myocardial ischemia, procedural MI in the invasive strategy only (Procedural MI [INV Only]), types 4b/c stent related MI’s, and type 1 MI.’s Total number of MI events and subsequent deaths are shown in the second column. In patients assigned to the invasive strategy, the adjusted hazard ratio for cardiovascular death was 2.77 times greater in patients who had a procedural MI and no non-procedural MI with the primary MI definition compared to patients who had no MI during follow-up (p=0.052). The adjusted risk of subsequent all-cause death and cardiovascular death was increased for patients that had a type 1 MI and no procedural MI compared with patients that had no MI during follow-up with the primary and secondary MI definitions (p<0.001), respectively. The adjusted risk for cardiovascular death was greater for patients that sustained a type 4b/c (stent-related) MI (p<0.001).
Figure 5.
Figure 5.. Adjusted risks of MI on subsequent all-cause and cardiovascular death according to MI definition.
The multivariate adjusted relative risk of all-cause death and cardiovascular death for the primary (upper panel) and secondary (lower panel) MI definitions are shown in this forest plot for procedural MI, procedural type 4a or 5 MI with ancillary evidence of myocardial ischemia, procedural MI in the invasive strategy only (Procedural MI [INV Only]), types 4b/c stent related MI’s, and type 1 MI.’s Total number of MI events and subsequent deaths are shown in the second column. In patients assigned to the invasive strategy, the adjusted hazard ratio for cardiovascular death was 2.77 times greater in patients who had a procedural MI and no non-procedural MI with the primary MI definition compared to patients who had no MI during follow-up (p=0.052). The adjusted risk of subsequent all-cause death and cardiovascular death was increased for patients that had a type 1 MI and no procedural MI compared with patients that had no MI during follow-up with the primary and secondary MI definitions (p<0.001), respectively. The adjusted risk for cardiovascular death was greater for patients that sustained a type 4b/c (stent-related) MI (p<0.001).
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