No Reduction in Mortality with Initial Invasive Strategy for Patients with Stable CAD

Mr. Jones is a 64-year-old former smoker with a history of hypertension and coronary artery disease (CAD) that is managed with rosuvastatin, aspirin, and carvedilol. At a follow-up visit in the clinic, he reports stable angina that occurs when briskly walking up a 4 percent grade hill during his daily 2-mile walk. Otherwise, he has no dyspnea or angina when walking on flat surfaces. A stress test with myocardial perfusion imaging reveals moderately severe ischemia. He asks about more aggressive treatment for his heart disease and whether heart stents will help him live longer.

Stable angina results from inadequate blood supply to the myocardium, which is provoked by exertion and resolves with rest. Because the oxygen demand of myocardium is directly related to heart rate and systolic blood pressure, physical activity can increase myocardial oxygen demand. If coronary artery perfusion is reduced, due to the presence of coronary artery stenosis, the increased myocardial oxygen demand cannot be met and causes myocardial ischemia. Angina is the resulting symptom.

Results from previous trials suggest that the strategy of revascularization, as compared with medical management, does not improve survival. However, these trialsexcluded patients with high-risk anatomical features and included patients with low levels of ischemia who might be less likely to benefit from an invasive strategy.

In the recently published ISCHEMIA trial, patients with stable CAD and evidence of moderate or severe reversible ischemia (on stress imaging) or severe ischemia (on exercise tests without imaging) were randomized to an invasive strategy (medical therapy plus angiography and revascularization, if appropriate) or medical therapy alone (with angiography only when initial medical therapy failed). This trial excluded patients with acute coronary syndrome (ACS) within the previous 2 months, patients who underwent coronary-artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) within the previous 12 months, patients with unprotected left main stenosis of at least 50%, left ventricular ejection fraction <35%, heart failure with severe limitation of physical activity (New York Heart Association class III or IV), renal dysfunction with a glomerular filtration rate <30 mL per minute per 1.73 m² of body-surface area, and those with a level of angina severity considered unacceptable by the patient despite maximal medical therapy.

The primary outcome was a composite of cardiovascular death, myocardial infarction, or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure. At a median of 3.2 years of follow-up, the initial invasive strategy did not improve survival, as compared with initial medical therapy. The cumulative event rates at 5 years were 16.4% and 18.2% in the invasive and medical-therapy groups, respectively (event-rate difference, -1.8 percentage points; 95% CI, −4.7 to 1.0)

Regarding the case described above, you discuss with Mr. Jones that angiography and revascularization are not likely to reduce mortality and that he should continue medical therapy. You encourage him to continue lifestyle changes, including moderate-intensity aerobic activity for at least 30-60 minutes at least 5 days per week and adhering to a healthy diet to modify risk factors for CAD.

See the NEJM Quick Take Video and the following NEJM Journal Watch summary for more details of the ISCHEMIA trial.

Allan S. Brett, MD reviewing Maron DJ et al. N Engl J Med 2020 Apr 9 Spertus JA et al. N Engl J Med 2020 Apr 9 Bangalore S et al. N Engl J Med 2020 Mar 30

Whether coronary revascularization — added to optimal medical therapy — improves outcomes among patients with stable coronary artery disease (CAD) has not been examined in recent randomized trials. Now, the ISCHEMIA trial addresses this issue.

The trial included nearly 5200 patients who had stable CAD and stress testing that showed moderate-to-severe reversible ischemia (on imaging) or severe ischemia (on exercise testing without imaging). Most patients had undergone coronary computed tomography to rule out left main stenosis (patients with left main stenosis were excluded). Patients were randomized to an invasive strategy (medical therapy plus coronary angiography, followed by stenting or bypass surgery, if feasible) or to medical therapy alone. In the invasive-strategy group, 79% of patients underwent revascularization. In the conservative-strategy group, 21% of patients eventually underwent revascularization during follow-up. Median follow-up was 3.2 years.

The primary composite outcome included death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina or heart failure. Initially, this outcome was more frequent in the invasive-strategy group than in the conservative-strategy group (5.3% vs. 3.4% at 6 months), owing to procedure-related myocardial infarctions. After roughly 2 years, the event curves crossed, and at 5 years, the estimated incidence of the primary outcome was slightly (but not significantly) higher in the conservative-strategy group (18.2% and 16.4%). Overall mortality was identical in the two groups. However, among patients who had frequent angina at baseline (65% of participants), the invasive strategy was associated with less angina during follow-up, compared with the conservative strategy.

The investigators performed a similar randomized trial (ISCHEMIA-CKD) in nearly 800 patients with advanced kidney disease (glomerular filtration rate, <30 mL/minute/1.73 m²), who were excluded from the ISCHEMIA trial; half the patients were on dialysis. During median follow-up of 2.2 years, no differences were seen between the invasive-strategy and conservative-strategy groups in incidences of death, myocardial infarction, or anginal symptoms.

Comment: For patients with stable CAD who are similar to participants in these trials, an invasive strategy is unlikely to prevent myocardial infarction or death during several years of follow-up. In general, revascularization in such patients should be reserved for those with unacceptable angina.

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James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.