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November 19, 2019

ISCHEMIA Provides Clarity on Invasive Strategies Versus Medical Therapy to Manage Higher-Risk Patients With Stable Ischemic Heart Disease

November 16, 2019—At the American Heart Association (AHA) scientific sessions 2019, held November 16–18 in Philadelphia, Pennsylvania, Judith S. Hochman, MD, presented findings from the ISCHEMIA trial, which sought to determine the best management strategy for higher-risk patients with stable ischemic heart disease and moderate to severe ischemia on stress testing. John A. Spertus, MD, then presented the quality-of-life (QOL) findings from the ISCHEMIA trial.

In the same session at AHA 2019, Sripal Bangalore, MD, presented primary results of clinical outcomes from ISCHEMIA-CKD, which was designed to determine whether an invasive strategy reduces the risk of the primary endpoint outcomes when compared with a conservative strategy in patients with advanced chronic kidney disease (CKD) and moderate or severe ischemia on stress testing. Additionally, Dr. Spertus presented the QOL findings from the ISCHEMIA-CKD trial.

The study results with presentation slides and more information from the ISCHEMIA trials can be accessed at ischemiatrial.org. The findings from the ISCHEMIA studies will be published in major medical journals beginning in 2020, advised the investigators.

The ISCHEMIA trial examined the risk of primary outcome in patients with significant but stable coronary artery disease (CAD) who went underwent routine, invasive procedures (percutaneous coronary interventions [PCI] with stenting or coronary artery bypass grafting [CABG]) when compared with similar patients who received optimal medical therapy (OMT) only. It also compared the two treatment strategies in terms of their ability to provide symptom relief from angina and QOL improvements.

In the international trial that began in 2012, the ISCHEMIA investigators randomly assigned 5,179 patients in 37 countries to one of the two treatment strategies.

The primary endpoint in the ISCHEMIA trial is a composite of cardiovascular (CV) death, myocardial infarction (MI), resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. A major secondary endpoint is CV death or MI. Other secondary endpoints include the individual components of the primary composite endpoint, stroke, all-cause mortality, a secondary definition of MI, and composites of these different endpoints.

As presented by Dr. Hochman, the ISCHEMIA trial showed that an initial invasive strategy as compared with an initial conservative strategy did not demonstrate a reduced risk for the primary endpoint and major secondary endpoint over a median of 3.3 years. The probability of a benefit of at least a 10% relative risk reduction on all-cause mortality with an invasive strategy was low at < 10%, based on prespecified Bayesian analysis.

In the invasive strategy (n = 2,588), the first procedure was PCI in 74% of patients (successful stent placement in 93%; of these, 98% were drug-eluting stents) and 26% underwent CABG. The conservative strategy (n = 2,591) of OMT included lifestyle advice and medications (eg, aspirin, statins), with cardiac catheterization reserved only for OMT failure.

Dr. Hochman reported that the curves crossed for the five-component primary endpoint and the major secondary endpoint at approximately 2 years from randomization. Therefore, in the primary endpoint, investigators looked at the absolute difference of the invasive versus conservative strategy in terms of event occurrence, with an approximately 2% higher estimated rate with an invasive strategy at 6 months (3.0% vs 0.8%) and an approximately 2% lower estimated rate with an invasive approach at 4 years (13.3% vs 15.5%; adjusted hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.8–1.08; P = .34).

The major secondary endpoint showed the same pattern of crossing curves at approximately 2 years. There was an approximately 2% absolute difference at 6 months for an invasive strategy versus a conservative strategy (3.0% vs 0.9%) and an approximately 2% absolute difference at 4 years (11.7% vs 13.9%; adjusted HR, 0.9; 95% CI, 0.77–1.06; P = .21).

Adding stroke to the primary endpoint for the net clinical benefit, CV death was similar between groups (HR, 0.95; 95% CI, 0.82–1.10; P = .5); all-cause death was also similar (6.5% vs 6.4%; HR, 1.05; 95% CI, 0.83–1.32; P = .67).

Additionally, Dr. Hochman reported that MIs were the main driver of the primary and secondary endpoints, with the same pattern of crossing curves at 2 years (HR, 0.92; 95% CI, 0.76–1.11; P = .38). As expected, procedural MIs were higher in the invasive group, whereas spontaneous MIs were lower, with a separation of the curve from the conservative group at approximately 1 year.

There was low all-cause mortality in both groups despite high-risk clinical characteristics, high-risk ischemia, and extensive CAD. Additionally, there was no heterogeneity of treatment effect, including by type of stress test, severity of ischemia, or extent of CAD, and there were very low rates of procedure-related stroke and death, reported Dr. Hochman.

Next at AHA 2019, Dr. Spertus reported that ISCHEMIA QOL showed that patients with stable CAD and moderate to severe ischemia had significant, durable improvements in angina control and QOL with an invasive strategy if they had angina (daily/weekly or monthly). In patients without angina, an invasive strategy led to minimal symptom or QOL benefits as compared with a conservative strategy. In patients with angina, shared decision-making should occur to align treatment with patients’ goals and preferences, concluded Dr. Spertus.

The ISCHEMIA-CKD trial presented by Dr. Bangalor was composed of patients who had advanced kidney disease and an abnormal stress test showing moderate to severe ischemia of the heart.

The study sought to determine whether an invasive strategy of PCI or CABG reduced the risk of primary outcome versus a conservative OMT strategy in patients with advanced CKD and moderate or severe ischemia on stress testing. The ISCHEMIA-CKD investigators randomized 777 patients to the invasive strategy (n = 388) or the conservative strategy (n = 389). Patient characteristics included median age of 63 years, 31% were women, and 53% were on dialysis. In those patients not on dialysis, 86% had CKD stage 4 and 14% had CKD stage 5 at baseline.

The findings showed that, with low rates of procedural complications (stroke, acute kidney injury), an initial invasive strategy did not demonstrate a reduced risk of clinical outcomes as compared with an initial conservative strategy.

In the QOL study of ISCHEMIA-CKD, Dr. Spertus reported that patients with stable CAD, advanced CKD, and moderate to severe ischemia did not have a substantial improvement in angina control and QOL over time; however, given the large proportion of asymptomatic patients at baseline, the possibility of a small benefit in symptomatic patients cannot be excluded.

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