Long-Term Survival After Initial Invasive or Conservative Management of Stable Coronary Disease in ISCHEMIA-EXTEND

Importance: It is unknown whether routine invasive management of chronic coronary disease improves long-term survival when added to guideline-directed medical therapy. Objective: To compare the effects of initial invasive and conservative strategies on long-term mortality in patients with chronic coronary disease. Design, Setting, and Participants: In this long-term follow-up study of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), an international trial of patients with chronic coronary disease, moderate or severe ischemia, left ventricular ejection fraction of 35% or more, and no left main coronary artery disease, unacceptable angina, or recent acute coronary syndrome, participants were randomized at 320 sites in 37 countries beginning August 2012 and followed up through December 2025. Data were analyzed using the intention-to-treat principle. Intervention: ISCHEMIA randomized patients to an initial invasive strategy of guideline-directed medical therapy plus coronary angiography and revascularization (when feasible) or an initial conservative strategy with guideline-directed medical therapy alone, with invasive management for failure of medical therapy. Main Outcomes and Measures: All-cause, cardiovascular, and noncardiovascular mortality were analyzed using cumulative incidence estimates, Cox and Fine-Gray models, bayesian analysis, and restricted mean survival time. Results: Among 5179 participants, median age was 64 (IQR, 58-70) years; 23% were female, 42% had diabetes, and median ejection fraction was 60% (IQR, 55%-65%). During 9-year median follow-up (range, 1 day to 13.4 years), 1071 deaths occurred (782 during extended follow-up): 672 cardiovascular, 359 noncardiovascular, and 40 unclassified. All-cause 11-year mortality was not significantly different between groups (25.8% invasive vs 26.9% conservative; estimated difference, -1.0 percentage point [95% CI, -4.2 to 2.1 percentage points]; adjusted hazard ratio [AHR], 0.97 [95% CI, 0.86-1.09]). By bayesian analysis, the posterior probability of more than 1 percentage-point survival benefit to invasive vs conservative was low (18%). Cardiovascular mortality at 11 years was 15.8% in the invasive group vs 17.1% in the conservative group (estimated difference, -1.4 percentage points [95% CI, -4.0 to 1.3 percentage points]; AHR, 0.88 [95% CI, 0.75-1.02]). Noncardiovascular mortality at 11 years was 9.1% in the invasive group vs 8.1% in the conservative group (estimated difference, 1.0 percentage point [95% CI, -0.9 to 2.9 percentage points]; AHR, 1.18 [95% CI, 0.96-1.45]). Eleven-year restricted mean survival was not significantly different (estimated difference, 14 days [95% CI, -41 to 70 days]). Conclusions and Relevance: In this study, long-term all-cause mortality in patients with high-risk chronic coronary disease was not significantly different after routine invasive vs initial conservative management. Trial Registration: ClinicalTrials.gov Identifier: NCT04894877.

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Journal
JAMA
Published
2026-11-07
DOI
https://doi.org/10.1001/jama.2026.20375
Primary Topic
Coronary Interventions and Diagnostics
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article
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article

Long-Term Survival After Initial Invasive or Conservative Management of Stable Coronary Disease in ISCHEMIA-EXTEND

Andrea B. Troxel, Philippe Gabríel Steg, João Vicente Vitola, Adam Witkowski et al.
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JAMA
Coronary Interventions and Diagnostics
article

Long-Term Survival After Initial Invasive or Conservative Management of Stable Coronary Disease in ISCHEMIA-EXTEND

Andrea B. Troxel, Philippe Gabríel Steg, João Vicente Vitola, Adam Witkowski, Paul Christian Schulze, Călin Pop, John A. Spertus, Marianna Andrade, Herwig Walter Schuchlenz, Yves Rosenberg, Raffi Bekeredjian, András Vértes, Daniel B. Mark, Hanna Szwed, Ann Banfield, Santhosh Satheesh, Lorenzo Monti, Alvaro Rabelo Alves, Abraham Oomman, Jorik R. Timmer, Paul J. Galiwango, Harmony R. Reynolds, Svetlana R. Apostolovic, Ranjan Kachru, Gregg W. Stone, Shaun G. Goodman, Andrea Montara, Yifan Xu, Eapen Punnoose, Goran R. Stankovic, Albert Varga, David Joel Maron, Jonathan D. Newman, Mandeep S. Sidhu, Paulo Caramori, Upendra Kaul, Roxy Senior, Sripal Bangalore, Whady Armindo Hueb, Georg Nickenig, Aleksandras Laucevičius, Rebecca Anthopolos, Harvey Douglas White, Radosław Pracoń, William E. Boden, Carlo Briguori, Géza Fontos, Amar Uxa, Sasko A. Kedev, Kurt Huber, Marcin Demkow, Marie Hauguel‐Moreau, John Francis Beltrame, Bogdan Popescu, Jacob Allen Udell, Béla Péter Merkely, Rogério Tumelero, Paola E. P. Smanio, Judith S. Hochman, Aldo Pietro Maggioni, Graham S. Hillis, Jeffrey S. Berger, Jose Luis Lopez-Sendon, Sean M. O’Brien, Atul Mathur, Pallav Garg, Robert A. Harrington, Cholenahally Nanjappa Manjunath, James Cha, Walter Enrique Mogrovejo Ramos, Johann Christopher, Milind Avdhoot Gadkari, Renato D. Lopes, Michel Slama, Pascal Goube, Ariel Díaz, Alexandre de Quadros, Sudhir R. Naik, Adnan Hameed, Stephanie Boumakis, Kevin Bainey, Gurpreet Singh Wander, Andrew Howarth, Estevao Figueiredo, Michelle Chang, Paolo Calabro, Nuno Ferreira, Rúben Ramos, Benjamin Chow, Fausto Pinto, Jorge Escobedo, Expedito Ribeiro da Silva, José Marin-Neto, Shintaro Nakano, Purvez Grant, Ralph Stewart, Luis Guzmán, Claudio Mesquita, Carisi Polanczyk, Jarozlaw Drozdz
article en

Abstract

Importance: It is unknown whether routine invasive management of chronic coronary disease improves long-term survival when added to guideline-directed medical therapy. Objective: To compare the effects of initial invasive and conservative strategies on long-term mortality in patients with chronic coronary disease. Design, Setting, and Participants: In this long-term follow-up study of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), an international trial of patients with chronic coronary disease, moderate or severe ischemia, left ventricular ejection fraction of 35% or more, and no left main coronary artery disease, unacceptable angina, or recent acute coronary syndrome, participants were randomized at 320 sites in 37 countries beginning August 2012 and followed up through December 2025. Data were analyzed using the intention-to-treat principle. Intervention: ISCHEMIA randomized patients to an initial invasive strategy of guideline-directed medical therapy plus coronary angiography and revascularization (when feasible) or an initial conservative strategy with guideline-directed medical therapy alone, with invasive management for failure of medical therapy. Main Outcomes and Measures: All-cause, cardiovascular, and noncardiovascular mortality were analyzed using cumulative incidence estimates, Cox and Fine-Gray models, bayesian analysis, and restricted mean survival time. Results: Among 5179 participants, median age was 64 (IQR, 58-70) years; 23% were female, 42% had diabetes, and median ejection fraction was 60% (IQR, 55%-65%). During 9-year median follow-up (range, 1 day to 13.4 years), 1071 deaths occurred (782 during extended follow-up): 672 cardiovascular, 359 noncardiovascular, and 40 unclassified. All-cause 11-year mortality was not significantly different between groups (25.8% invasive vs 26.9% conservative; estimated difference, -1.0 percentage point [95% CI, -4.2 to 2.1 percentage points]; adjusted hazard ratio [AHR], 0.97 [95% CI, 0.86-1.09]). By bayesian analysis, the posterior probability of more than 1 percentage-point survival benefit to invasive vs conservative was low (18%). Cardiovascular mortality at 11 years was 15.8% in the invasive group vs 17.1% in the conservative group (estimated difference, -1.4 percentage points [95% CI, -4.0 to 1.3 percentage points]; AHR, 0.88 [95% CI, 0.75-1.02]). Noncardiovascular mortality at 11 years was 9.1% in the invasive group vs 8.1% in the conservative group (estimated difference, 1.0 percentage point [95% CI, -0.9 to 2.9 percentage points]; AHR, 1.18 [95% CI, 0.96-1.45]). Eleven-year restricted mean survival was not significantly different (estimated difference, 14 days [95% CI, -41 to 70 days]). Conclusions and Relevance: In this study, long-term all-cause mortality in patients with high-risk chronic coronary disease was not significantly different after routine invasive vs initial conservative management. Trial Registration: ClinicalTrials.gov Identifier: NCT04894877.

JAMA
St. Michael's Hospital (CA), National Institutes of Health (US), University Health Network (CA), University of Auckland (NZ), University of Alberta (CA), Duke University (US), University of Toronto (CA), Université Paris Cité (FR), Hospital Universitario La Paz (ES), Northwick Park Hospital (GB), NYU Langone Health (US), VA New England Healthcare System (US), Associazione Nazionale Medici Cardiologi Ospedalieri (IT), Royal Brompton Hospital (GB), Assistance Publique – Hôpitaux de Paris (FR), Hospital La Paz Institute for Health Research (ES), National Heart, Lung, and Blood Institute (US), Canadian VIGOUR Centre (CA), Institute of Cardiology (PL), Stanford Medicine (US), Saint Luke's Hospital (US), Hôpital Bichat-Claude-Bernard (FR), Weill Cornell Medicine (US), Health New Zealand (NZ), Albany Medical College (US), HCF Fondazione ANMCO per il Tuo cuore ETS (IT), Duke Clinical Research Institute (US), New York University (US), University of Missouri–Kansas City (US), Albany Medical Center Hospital (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
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Coronary Interventions and Diagnostics
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