ISCHEMIA Trial – Review

ISCHEMIA Trial – Review

International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial was funded by National Heart, Lung, and Blood Institute and others. 5179 patients with moderate or severe ischemia was randomized to an initial invasive strategy or an initial conservative strategy. Initial invasive strategy was angiography and revascularization when feasible. Initial conservative therapy was of medical treatment alone and angiography if medical therapy failed [1].

Primary composite outcome included death from cardiovascular causes, myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest. 318 primary outcome events in the invasive strategy group and 352 primary outcome events in the conservative strategy group occurred over a median follow up period of 3.2 years. Cumulative event rates at 6 months were 5.3% and 3.4% in the two groups. At 5 years, the cumulative event rates were 16.4% in the invasive group and 18.2% in the conservative group. 145 deaths occurred in the invasive strategy group and 144 deaths in the conservative strategy group. Authors concluded that among patients with stable coronary artery disease and moderate or severe ischemia, there was no evidence that early invasive strategy reduced the risk of ischemic cardiovascular events or all cause mortality over the study period.

Enrollment in the study was after clinically indicated stress testing showed moderate or severe reversible ischemia on imaging test or severe ischemia on exercise testing without imaging. Computed tomographic angiography was done in most patients to exclude left main coronary artery disease and nonobstructive coronary disease. More procedure related infarctions and lesser nonprocedural infarctions on follow up were noted in the invasive strategy group.

Though ISCHEMIA trial showed equivalence of invasive and noninvasive strategies, the findings do not apply to patients with acute coronary syndromes, significant left main coronary artery disease, low ejection fraction, class III/IV heart failure or those who are very symptomatic despite optimal medical therapy.

Angina related health status of the ISCHEMIA trial patients was reported in another paper [2]. Seattle Angina Questionnaire was used to assess angina related symptoms, function and quality of life. Assessments were done at randomization, 1.5 months, 3 months, 6 months and thereafter every 6 months. 35% of patients did not have angina in the previous month at baseline assessment. Patients assigned to invasive strategy had greater improvement in angina-related health status. As expected, differences were minimal among asymptomatic patients and large among those with angina at baseline.

Another related study was the ISCHEMIA-CKD trial which randomized 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing [3]. Usually patients with advanced kidney disease are excluded from clinical trials assessing revascularization in patients with stable coronary artery disease. A composite of death or nonfatal myocardial infarction was the primary outcome measured. 123 patients in the invasive strategy group and 129 patients in the conservative strategy group had a primary outcome event at a median follow up of 2.2 years. Higher incidence of stroke and higher incidence of death or initiation of dialysis was noted in the invasive strategy group. Authors concluded that early invasive strategy did not reduce death or nonfatal myocardial infarction among patients with stable coronary artery disease, advanced chronic kidney disease and moderate or severe ischemia.

Similar negative results were documented earlier by Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial at both initial 4.6 years median follow up and an extended follow-up period up to 15 years for early invasive strategy in chronic coronary syndrome [4,5].


  1. Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407.
  2. Spertus JA, Jones PG, Maron DJ, O’Brien SM, Reynolds HR, Rosenberg Y, Stone GW, Harrell FE Jr, Boden WE, Weintraub WS, Baloch K, Mavromatis K, Diaz A, Gosselin G, Newman JD, Mavromichalis S, Alexander KP, Cohen DJ, Bangalore S, Hochman JS, Mark DB; ISCHEMIA Research Group. Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1408-1419.
  3. Bangalore S, Maron DJ, O’Brien SM, Fleg JL, Kretov EI, Briguori C, Kaul U, Reynolds HR, Mazurek T, Sidhu MS, Berger JS, Mathew RO, Bockeria O, Broderick S, Pracon R, Herzog CA, Huang Z, Stone GW, Boden WE, Newman JD, Ali ZA, Mark DB, Spertus JA, Alexander KP, Chaitman BR, Chertow GM, Hochman JS; ISCHEMIA-CKD Research Group. Management of Coronary Disease in Patients with Advanced Kidney Disease. N Engl J Med. 2020 Apr 23;382(17):1608-1618.
  4. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16.
  5. Sedlis SP, Hartigan PM, Teo KK, Maron DJ, Spertus JA, Mancini GB, Kostuk W, Chaitman BR, Berman D, Lorin JD, Dada M, Weintraub WS, Boden WE; COURAGE Trial Investigators. Effect of PCI on Long-Term Survival in Patients with Stable Ischemic Heart Disease. N Engl J Med. 2015 Nov 12;373(20):1937-46.