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Randomized Controlled Trial

Impact of Complete Revascularization in the ISCHEMIA Trial

Gregg W Stone et al. J Am Coll Cardiol. .

Abstract

Background: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported.

Objectives: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management.

Methods: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management.

Results: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR.

Conclusions: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Keywords: complete revascularization; coronary artery disease; ischemia; prognosis; revascularization.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by National Institutes of Health grants U01HL105907, U01HL105462, U01HL105561, U01HL105565, T32 HL079896. This project was also supported in part by Clinical Translational Science Award No. 11UL1 TR001445 from the National Center for Advancing Translational Sciences and by grants from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Devices or medications were provided by Abbott Vascular (previously St Jude Medical, Inc), Medtronic, Inc, Phillips (previously Volcano Corporation), and Omron Healthcare, Inc; and medications were provided by Amgen Inc, Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Espero Pharmaceuticals, Merck Sharp & Dohme Corp, and Sunovion Pharmaceuticals. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, and Abbott; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his daughter is an employee at IQVIA; and his employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Ali has received institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems Inc, Medtronic Inc, National Institute of Health, Opsens Medical, Philips, and Teleflex; has received consulting fees from AstraZeneca, Philips, and Shockwave; and has equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr Genereux has received consulting, advisory, and speaker fees from Abbott Vascular, Abiomed, Edwards Lifesciences, Medtronic, and BioTrace Medical; has served as a consultant for Boston Scientific, CARANX Medica, Cardiovascular System Inc (PI Eclipse Trial), GE Healthcare, iRythm Technologies, Opsens, Siemens, Teleflex, and 4C Medical (PI Feasibility study); has equity in and served as a consultant for Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; has served as a consultant for and received speaker fees from Shockwave; and has served as a proctor for, received an institutional research grant from, and served as PI for the EARLY-TAVR and PROGRESS trials for Edwards Lifesciences. Dr Bangalore has received grants from the National Heart, Lung, and Blood Institute; has received grants and personal fees from Abbott Vascular; and has received personal fees from Biotronik, Pfizer, Amgen, and Reata. Dr Mavromatis has received grants from the National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute (CV Inflammation Reduction Trial and GMCSF in PAD-3 Trial), CSL Behring, St Jude Medical, Medtronic, DalCor Pharmaceuticals, AstraZeneca, Novartis, and Regeneron; and is a Member of the American College of Cardiology and Society of Cardiovascular Angiography and Interventions. Dr Dwivedi has received grants from the National Heart, Lung, and Blood Institute. Dr Chen has received grants from the National Heart, Lung, and Blood Institute. Dr Chaitman has received grants from the National Heart, Lung, and Blood Institute; and has received personal fees from Merck, Novo Nordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi-Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside the submitted work. Dr Berman has received royalties for nuclear cardiology software from Cedars-Sinai Medical Center. Dr Boden has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grants from Abbvie, Amarin, and Amgen; and has received personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen. Dr White has received grant support paid to the institution and fees for serving on Steering Committees from Sanofi, Regeneron Pharmaceuticals, Eli Lilly, Omthera Pharmaceuticals, American Regent, Eisai Inc, DalCor Pharma UK, Inc, CSL Behring, NHI, Sanofi Australia Pty Ltd, Esperion Therapeutics, Inc, and the National Institutes of Health; and has served on the Advisory Board for Genentech, Inc (an affiliate of F. Hoffmann-La Roche Ltd, ‘Roche’; Lytics Post-PCI Advisory Board at European Society of Cardiology). Dr Fremes has received NPI CIHR funding for the ROMA and STICH3C studies. Dr Reynolds has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received nonfinancial support from Abbott Vascular, Siemens, and BioTelemetry. Dr Spertus has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; has received grants from American College of Cardiology; has received personal fees from Blue Cross Blue Shield of Kansas City; and has a patent Copyright to Seattle Angina Questionnaire, with royalties paid and Equity in Health Outcomes Sciences. Dr Hochman is PI for the ISCHEMIA trial for which, in addition to support by the National Heart, Lung, and Blood Institute grant, devices and medications were provided by Medtronic, Inc, Abbott Vascular, Inc (formerly St Jude Medical, Inc), Royal Philips NV (formerly Volcano Corporation), Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Merck Sharp & Dohme Corp, Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc, Espero BioPharma, and Amgen Inc; and has received financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Maron has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. Derivation of the patient cohorts.
For OBJECTIVE 1 (right dashed-box), among INV-assigned patients, the impact of achieving ACR and FCR vs. ICR were assessed in 1801 and 1742 patients respectively. For OBJECTIVE 2 (left dashed-box), IPW with CR as a time-dependent variable was used to estimate the hypothetical ideal treatment effect had 2296 INV-assigned patients without prior CABG in whom the completeness of revascularization could be assessed by the angiographic core laboratory received CR at the time of randomization, compared with CON management in 2498 patients without prior CABG. ACR, anatomic complete revascularization. CABG, coronary artery bypass grafting. CON, conservative treatment strategy. CR, complete revascularization. FCR, functional complete revascularization. ICR, incomplete revascularization. INV, invasive treatment strategy. IPW, inverse probability weighting.
Figure 2.
Figure 2.. Mode and completeness of revascularization in revascularized INV patients.
Left: The type of first revascularization procedure performed in 1824 patients assigned to an INV management strategy in whom revascularization was completed within 6 months after randomization. Right: Rates of ACR (top) and FCR (bottom) achieved in all patients and by revascularization modality. PCI was performed in approximately three-quarters of patients. In these unadjusted analyses, CR was achieved more frequency with PCI than CABG. PCI, percutaneous coronary intervention. Other abbreviations as in Figure 1.
Figure 3.
Figure 3.. Relationship between complete revascularization and outcomes with invasive management.
Five-year time-to-first event rates are shown for CV death or MI (left graphs), CV death (middle graphs), and MI (right graphs) in 1824 INV-assigned patients according to the achievement of ACR (top) and FCR (bottom). CR was associated with reduced rates of both CV death and MI (more so after ACR than FCR), although the relative reduction was attenuated after adjustment for differences in baseline clinical and angiographic characteristics. CI, confidence interval. CV, cardiovascular. HR, hazard ratio. MI, myocardial infarction. Other abbreviations as in Figure 1.
Figure 4.
Figure 4.. Mode and completeness of revascularization in all INV patients.
Left: The type of first revascularization procedure performed or treatment with medical therapy alone in 2296 patients within 6 months after randomization to an INV management strategy. Right: Rates of ACR (top) and FCR (bottom) achieved in all patients and by treatment modality. In these unadjusted analyses, CR was achieved more frequency with PCI than CABG. Abbreviations as in Figures 1 and 2.
Figure 5.
Figure 5.. Outcomes after complete and incomplete revascularization compared with conservative management.
Five-year IPW-adjusted time-to-first event rates are shown for CV death or MI (left graphs), CV death (middle graphs), and MI (right graphs) according to the achievement of ACR (top figures) and FCR (bottom figures) in 2296 patients assigned to invasive management compared with 2498 patients assigned to conservative management (excluding patients with prior CABG from both groups). CR (especially ACR) was associated with reduced rates of both CV death and MI compared with both ICR and CON management. The outcomes in INV patients with ICR were roughly comparable to or slightly better than those in the CON group. Abbreviations as in Figures 1 and 3.
Central Illustration.
Central Illustration.. Impact of complete revascularization in the ISCHEMIA trial.
Objective 1 (left half of figure) assessed the frequency and impact of CR among patients assigned to INV management. Objective 2 (right half of figure) assessed the impact that achieving CR in all patients assigned to INV would have had compared with CON management. In the right graph, INV-ACR and INV-FCR vs. CON represent the IPW-modeled differences in rates. INV vs. CON for the ISCHEMIA trial represents the unadjusted differences in rates from the overall ISCHEMIA trial intention-to-treat cohort. See text for details. BMI, body mass index. CTO, chronic total occlusion. LM, left main. PLAD, proximal left anterior descending artery. Other abbreviations as in Figures 1-3.
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Comment in

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