Study Summary

In the multinational ISCHEMIA trial1, investigators compared the efficacy of invasive and conservative approaches to the treatment of patients with stable ischemic heart disease (SIHD). Potential trial participants who had moderate-to-severe ischemia on stress testing (>10% LV ischemia on nuclear, ≥3 segments with moderate or severe hypokinesis on stress echocardiography) were screened with a blinded CT coronary angiogram. Patients with significant left main stenosis, acute coronary syndromes within two months, or absence of obstructive epicardial coronary artery disease (defined as >50% stenosis in a major epicardial vessel) were excluded. Other notable exclusion criteria included LVEF < 35%, NYHA class III–IV heart failure, unacceptable angina burden despite medical therapy, PCI or CABG within 1 year, and eGF) <30 ml/min. Eligible patients were then randomly assigned 1:1 to a routine invasive strategy (n = 2,588) involving coronary angiography and coronary revascularization with PCI or CABG, or to a conservative strategy (n = 2,591) of optimal medical therapy with angiography reserved for therapeutic failure. Patients with advanced chronic kidney disease (CKD) undergoing dialysis and with moderate-to-severe ischemia were considered for inclusion in the ISCHEMIA-CKD substudy. Follow-up (median 3.3 years in both arms) was complete in 99.4% and 99.7% in the invasive and conservative arms, respectively.

In the invasive group, at 4-years follow up, 96% of patients had undergone cardiac catheterization and 80% revascularization (74% with PCI, 26% with CABG). In the conservative group, at 4-years follow up 28% had undergone cardiac catheterization, and 23% revascularization. The primary outcome of cardiovascular death, myocardial infarction (MI), resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure at 3.3 years occurred in 13.3% of the invasive group compared with 15.5% of the medical therapy group (P = 0.34). Of the secondary outcomes, only the HRs for periprocedural MI (invasive vs conservative HR 2.98, 95% CI 1.87–4.74, P <0.01) and spontaneous MI (invasive vs conservative HR 0.67, 95% CI 0.53–0.83, P <0.01) reached statistical significance. Quality of life assessments were completed for 4,617 of study participants and were included in a separate analysis.2 A statistically significant improvement in symptoms of angina was seen in the invasive group compared with the conservative group, with treatment effect dependent upon severity of baseline angina. For patients with weekly angina at baseline, 15% in the conservative arm were likely to be angina-free at 3 months follow-up versus 45% in the invasive arm (NNT=3).

In the ISCHEMIA-CKD substudy3, 777 patients were randomly assigned to invasive or conservative strategies. In the invasive arm, coronary angiography and revascularization were performed with renal protective strategies. The adjusted HR for the primary endpoint of death or MI (median follow-up 2.3 years and 2.5 years in the invasive and conservative arms, respectively) was 1.01 (P = 0.95).

Commentary

Study Strengths: ISCHEMIA was a large, multicenter, randomized clinical trial, and the largest ever to assess the relative efficacy of conservative and invasive strategies for patients with SIHD. The study population was reflective of high-risk patients, with 87% classified as having moderate or severe ischemia. The trial was adequately powered to detect an 18.5% relative reduction in the primary endpoint, and an impressive 88% of patients responded to the quality of life questionnaire.

Study Limitations: Patients with acute coronary syndrome within 2 months, highly symptomatic patients, those with left main stenosis, and LVEF <35% were excluded. As such, the results cannot be applied to these subsets of patients. Baseline characteristics indicate that >50% of participants reported no, or only Class I, angina4 rendering these results generalizable to patients with minimal symptoms. As the trial was not blinded and did not have a placebo or sham procedure arm, a significant placebo effect may exist. In addition, crossovers from conservative to invasive therapy have attenuated between-group differences in the intention-to-treat analysis reported thus far.

Next Steps/Clinical Perspective: The ISCHEMIA trial demonstrated that, in patients with SIHD with at least moderate ischemia, routine invasive therapy was not associated with a reduction in major adverse events compared with optimal medical therapy. Patients in the invasive arm had higher rates of periprocedural MI, but lower rates of spontaneous MI and less severe symptoms than patients in the medical arm. Further data on the completeness of revascularization will be essential in analyzing the differences between the therapies. Given the crossing of event curves, longer-term follow-up will be essential to determine if there is a lasting difference between treatments.

References

1. +
Presented by Judith  S. Hochman at the American Heart Association Annual Scientific Sessions (AHA 2019); Philadelphia, PA, USA; November 16, 2019.
2. +
Presented by John  A. Spertus at the American Heart Association Annual Scientific Sessions (AHA 2019); Philadelphia, PA, USA; November 16, 2019.
3. +
Presented by Sripal  Bangalore at the American Heart Association Annual Scientific Sessions (AHA 2019); Philadelphia, PA, USA; November 16, 2019.
4. +
Hochman,  J. S. et al. Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial. JAMA Cardiol. 4: 273–86 (2019).