AHA 2019: ISCHEMIA shows no benefit for revascularisation in patients with stable ischaemic heart disease

Judith S Hochman

The largest trial to date to compare revascularisation with a conservative strategy in patients with stable ischaemic heart disease has found no additional benefit a median of three years after the procedure.

Data from the ISCHEMIA trial were presented at a late-breaking trial session at the American Heart Association Scientific Sessions (AHA 2019; 16–18 November, Philadelphia, USA) by Judith S Hochman (New York University School of Medicine, New York, USA). She told delegates: “Overall, an initial invasive strategy did not demonstrate a reduced risk as compared with an initial conservative strategy over a median 3.3 years for the primary endpoint—a composite of cardiovascular (CV) death, myocardial infarction (MI), and hospitalisation for unstable angina, heart failure, or resuscitated cardiac arrest—and the major secondary endpoint of CV death or MI.

The ISCHEMIA trial, supported by the US National Heart, Lung, and Blood Institute, looked at whether there is a benefit to adding cardiac catheterisation and, if feasible, revascularisation to optimal medical therapy in stable patients with at least moderate ischaemia on a stress test.

Among the exclusion criteria were New York Heart Association (NYHA) class III–IV Heart Failure, unacceptable angina despite medical therapy, ejection fraction <35%, and an estimated glomerular filtration rate (eGFR) <30 mL/min (enrolled in ISCHEMIA CKD). The median age of participants was 64 years, with 23% being women, 34% nonwhite, and 42% diabetic; 90% had a history of angina.

Of the 8,518 patients enrolled, 5,179 who had stable ischemic heart disease that was moderate or severe on stress testing were randomised to either an initial invasive treatment strategy (2,588) or to an initial conservative strategy (2,591). Patients who underwent stress testing for clinical indications at enrolling sites were screened for eligibility if the site determined that moderate or severe ischemia was present on a stress imaging test, or severe ischemia was present on a non-imaging exercise tolerance test. Blinded coronary computed tomography angiography (CCTA) performed in 73% (3,192) of randomized participants , found that 77% had multivessel coronary artery disease (CAD), and 87% had left anterior descending stenosis. In 54% of these patients, ischaemia was classified as severe, with 46% exhibiting triple vessel coronary disease. The remaining participants underwent nonimaging exercise tolerance testing.

Those in the invasive strategy group had routine cardiac catheterisation, followed by revascularisation with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible to achieve optimal revascularisation. The conservative strategy group only received cardiac catheterisation when optimal medical therapy failed. Both groups received secondary prevention that included lifestyle and pharmacological interventions.

Median follow-up for both groups was 3.3 years (>99 % of expected patient-years of follow up). The adjusted hazard ratio (HR) for the primary endpoint was 0.93 (95% confidence interval [CI] 0.8–1.08, p=0.34).

Hochman said: “The curves cross for the primary endpoint and the major secondary endpoint at approximately two years from randomisation: there is about a two in 100 higher estimated rate with the invasive strategy at six months, and about two in 100 lower estimated rate with the invasive strategy at four years.” At six months, the absolute difference in the estimated rate of reaching the primary endpoint was 1.9% (95% CI 0.8–3) in favour of the conservative strategy; at four years, it was 2.2% (95% CI -4.4–0) in favour of the invasive strategy.

For the major secondary endpoints of CV death or MI, the adjusted HR was 0.9 (95% CI 0.77–1.06, p=0.21). The findings for absolute differences were the same as that for the primary endpoint; at six months it was 1.9% (95% CI 0.9–3) in favour of the conservative strategy, and at four years it was 2.2% in favour of the invasive strategy (95% CI -4.4% to -0.1%). For net clinical benefit, which added stroke to the primary endpoint, HR was 0.95 (95% CI 0.82–11), with a similar trend for absolute differences.

All-cause mortality was 6.5% with the invasive strategy vs. 6.4% for conservative treatment, with an adjusted HR of 1.05 (95% CI 0.83–1.32, p=0.67). “The probability of at least a 10% relative risk reduction of the invasive strategy on all-cause mortality was <10%,” said Hochman, “based on the prespecified Bayesian analysis.”

The adjusted HR for MI was 0.92 (95% CI 0.76–1.11, p=0.38). The rate of procedural MIs was higher in the invasive group (adjusted HR 2.98, 95% CI 1.87–4.74, p<0.01), but the rate of spontaneous MIs was lower in these patients (adjusted HR 0.67, 95% CI 0.53–0.83, p<0.01).

The rates of procedure-related stroke and death were very low, which Hochman attributed to the fact that only high volume PCI sites with a low complication rate were selected for the trial. In addition, there was no heterogeneity of treatment effect for the primary endpoint in prespecified subgroups—such as degree of baseline ischaemia and severity of CAD—or for any characteristic, such as age, sex, race, or ethnicity.

Hochman outlined the limitations of the trial, which included that it was  not blinded, that its findings may not be generalisable to centres with higher procedural complication rates, and that the results are not applicable to groups who were excluded from enrollment. In addition, the women who were enrolled were more often excluded from randomisation than men because they had less ischaemia and more non-obstructive coronary artery disease (CAD).

Data from a substudy on primary quality of life indices in ISCHEMIA that looked at whether an invasive strategy in stable patients with at least moderate ischaemia improves patients’ health status (symptoms, function, and quality of life) were also presented at AHA 2019 by John A Spertus (Saint Luke’s Mid America Heart Institute and University of Missouri-Kansas City, Kansas, USA).

In all, 2,322 of conservative therapy patients were included in the analyses of treatment effect, and 2,295 of invasive strategy patients. The primary QoL outcome was the Seattle Angina Questionnaire (SAQ)-7, a summary score of angina frequency, quality of life, and physical limitations, with secondary QoL outcomes of the SAQ angina frequency and quality of life scores.

Missing SAQ data was a limitation of the analysis, said Spertus, although this was <10%. He also highlighted a skewed enrollment towards less symptomatic patients, and the lack of a sham group. “Nonetheless,” said Spertus, “angina-free benefits were comparable with that seen in ORBITA.”

The subanalysis concluded that patients with stable CAD and moderate to severe ischaemia who had angina had significant, durable improvements in angina control and QoL with an invasive strategy. In patients without angina, an invasive strategy led to minimal symptom or quality of life benefits, compared to a conservative strategy. Spertus recommended that for patients with angina, shared decision-making should occur to align treatment with their goals and preferences.


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