Objectives

The primary aim of the ISCHEMIA trial was to determine whether an initial invasive strategy of cardiac catheterization and optimal revascularization, if feasible, in addition to optimal medical therapy, will reduce major adverse cardiovascular events in participants with stable ischemic heart disease and moderate or severe ischemia compared with an initial conservative strategy of optimal medical therapy alone. The ISCHEMIA-CKD trial had the same aim but with participants that also had advanced kidney disease.

Background

Evidence from clinical trials of stable ischemic heart disease (SIHD) supports the use of intensive lifestyle and pharmacologic interventions to inhibit the progression of atherosclerosis and reduce the likelihood of major adverse cardiac events, including myocardial infarction (MI) and cardiovascular (CV) death. In addition to this secondary prevention, many patients also undergo routine cardiac catheterization and revascularization as part of their management. Clinical trial evidence to date, however, has failed to demonstrate that an initial invasive strategy reduces death or MI as compared with an initial conservative strategy of optimal medical therapy (OMT) in SIHD patients. Most of the pivotal randomized comparisons between medicine and coronary artery bypass graft surgery (CABG) were conducted before the use of current pharmacologic therapies, such as statins. More recent trials using contemporary medical therapy do not include large numbers of higher-risk participants to test whether an invasive approach with OMT reduces risk in patients with more advanced SIHD as compared with OMT alone. Thus, the motivating premise for the ISCHEMIA Trial was to determine whether routine cardiac catheterization and revascularization, when feasible, improves prognosis in patients with more severe ischemia who may derive the greatest clinical benefit from an invasive approach.

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. The presence of kidney disease has been associated with an increased risk of procedural complications from coronary angiography and revascularization and it remains uncertain whether a routine invasive approach when compared with a conservative strategy is beneficial in such patients. Most trials involving patients with cardiovascular disease have either excluded patients with advanced kidney disease or included too few to permit a confident estimation of treatment benefits. ISCHEMIA-CKD was conducted to test whether there is incremental benefit of an invasive strategy in patients with stable coronary disease and advanced chronic kidney disease.

Participants

Patients considered eligible for inclusion in either trial were ≥21 years of age, had SIHD, and moderate or severe ischemia on stress imaging or severe ischemia on non-imaging exercise tolerance testing. Consenting patients were enrolled and most underwent a blinded coronary computed tomography angiogram (CCTA). (CCTA was usually performed in participants with normal renal function and not performed in participants with estimated glomerular filtration (eGFR) of <60 mL/min). Participants with unprotected left main disease (≥50% stenosis) or those without obstructive CAD (<50% stenosis in all major coronary arteries) as determined by a CCTA were excluded from ISCHEMIA.

For inclusion in ISCHEMIA-CKD, participants also had advanced kidney disease defined as an eGFR <30 mL/min per 1.73 m2 of body-surface area or on dialysis, and moderate or severe ischemia on stress testing.

The ISCHEMIA study randomized a total of 5179 participants, 2588 to the invasive strategy and 2591 to the conservative strategy. ISCHEMIA-CKD randomized a total of 777 participants, 388 to the invasive strategy and 389 to the conservative strategy.

Design

ISCHEMIA and ISCHEMIA-CKD were prospective randomized multi-center trials that ran in parallel at most of the same sites. Eligible participants in both trials were randomized to either an invasive or conservative strategy. The goal of the invasive strategy was revascularization of all ischemic territories (based on results of stress test findings and/or diagnostic catheterization), incorporating fractional flow reserve (FFR) for selection of target vessels, where appropriate. The selection of percutaneous coronary intervention (PCI) vs. CABG was left to the discretion of the heart team per local standards and expertise but guided by several general principles. OMT recommendations based on guideline-directed medical therapy for secondary prevention were applied equally to both treatment groups. OMT goals included lifestyle changes, as well as medication adherence. In patients assigned to the conservative strategy, cardiac catheterization was reserved for failure of OMT.

In ISCHEMIA, selected procedural details were collected, including specific procedures performed, stents placed, and ICU days. Follow-up data collection included hospitalizations, selected outpatient care, major diagnostic tests, and medication use. Quality of Life (QoL) data was collected at baseline and during follow-up at 3, 12, 24, and 36 months after randomization.

In ISCHEMIA-CKD, participants were followed-up at 1.5, 3, 6, and 12 months following randomization during the first year and every 6 months thereafter until planned follow-up completion. During follow-up visits, participants were assessed for potential endpoint events, medication adherence, lifestyle adherence, and health related QoL.

The primary endpoint of ISCHEMIA was time from randomization until the first occurrence of any event from the primary composite of CV death, MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. The primary outcome of ISCHEMIA-CKD was a composite of death or nonfatal MI.

Conclusions

Among patients with SIHD and moderate or severe ischemia, there was no evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause.

ISCHEMIA Trial Research Group, Maron DJ, Hochman JS, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J. 2018;201:124-135. doi:10.1016/j.ahj.2018.04.011

Maron DJ, Hochman JS, Reynolds HR, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020;382(15):1395-1407. doi:10.1056/NEJMoa1915922

Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, there was no evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction.

Bangalore S, Maron DJ, Fleg JL, et al. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease (ISCHEMIA-CKD): Rationale and design. Am Heart J. 2018;205:42-52. doi:10.1016/j.ahj.2018.07.023

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