Initial Invasive or Conservative Strategy for Stable Coronary Disease

Abstract

Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.

Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.

Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).

Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find 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 over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Figure 1.. Enrollment, Randomization, and Follow-up.

Unprotected left main coronary artery (LMCA) disease was defined as 50% or greater LMCA stenosis without a bypass graft to the left coronary artery. To maximize information about baseline coronary anatomy, available coronary computed tomographic angiographic (CCTA) images obtained less than 1 year before enrollment in 130 patients were subsequently collected for CCTA core laboratory review. The percentage of projected follow-up completed was calculated with the number of patient-years of observed follow-up as the numerator and the number of patient-years of expected follow-up as the denominator. The percentages of patients who underwent angiography and revascularization differ from the cumulative incidence function rates, which account for censoring. The percentage of patients who underwent angiography includes a small number of patients in the invasive-strategy group who underwent angiography before randomization and did not undergo repeat angiography after randomization and before bypass surgery. A total of 15% of the patients in the conservative-strategy group underwent revascularization before a primary outcome event occurred. CAD denotes coronary artery disease, eGFR estimated glomerular filtration rate, and IQR interquartile range.

Figure 2.. Time-to-Event Curves for the Primary Composite Outcome and Other Outcomes.

Panel A shows the cumulative incidence of the primary composite outcome of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest in the conservative-strategy group and the invasive-strategy group. Panel B shows the cumulative incidence of death from cardiovascular causes or myocardial infarction. Panel C shows the cumulative incidence of death from any cause, and Panel D shows the cumulative incidence of myocardial infarction. In each panel, the inset shows the same data on an enlarged y axis.

Figure 3.. Analyses of Heterogeneity of Treatment Effect for the Primary Outcome.

Only the first event per patient was counted in these analyses. Ischemia severity was based on core-laboratory interpretation. A total of 1266 patients did not undergo core-laboratory-interpreted computed tomographic (CT) angiography for the trial and did not have an available previous CT angiogram within 1 year before the trial for core-laboratory interpretation, and 923 patients had a CT angiography core-laboratory interpretation in which the number of diseased vessels could not be evaluated. When trial images could be interpreted for this variable, the number of diseased vessels on CT angiography was based on a 50% stenosis threshold. Data on CAD severity based on 50% stenosis exclude 4 patients with no diseased vessels. Stenosis of the proximal left anterior descending (LAD) coronary artery was reported when the proximal LAD segment could be evaluated on CT angiography. Patients were considered to have high attainment of guideline-based medical therapy at baseline if they met all the following criteria: low-density lipoprotein cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) and receipt of any statin, systolic blood pressure of less than 140 mm Hg, receipt of aspirin or other antiplatelet or anticoagulant agent, and no smoking. Patients who were determined by the core laboratory to have moderate ischemia on a nonimaging exercise-stress test did not meet ischemia eligibility, yet some such patients underwent randomization. This explains the discrepancy between the “no” category under ischemia eligibility (13.8%) and the “none or mild” category for the “degree of baseline ischemia” subgroup (11.9%).