Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity

Abstract

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy.

Methods: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory-interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest).

Results: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61-1.30]; severe ischemia HR, 0.83 [95% CI, 0.57-1.21]; P=0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86-1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98-1.91]; P=0.04 for trend, P=NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06-6.98]) and MI (HR, 3.78 [95% CI, 1.63-8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%-12.4%]), but 4-year all-cause mortality was similar.

Conclusions: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01471522.

Keywords: coronary artery bypass; coronary artery disease; ischemia; myocardial revascularization; percutaneous coronary intervention.

Figure 1.. Association between Ischemia Severity and Outcomes

See Table 1 for details of ischemia severity categories. Covariates for adjustment included: age, sex, region (North America and Europe, Asia, Other), diabetes, hypertension, current smoking, prior MI, heart failure or New York Heart Association Class II, prior revascularization, angina frequency (Seattle Angina Questionnaire angina frequency subscale score ≤60, 61–90, 91–100), new or increasing angina, eGFR, ejection fraction and body-mass index.

Figure 2.. Association between CAD Severity and Outcomes

V denotes vessel. Covariates for adjustment included: ischemia severity, age, sex, region (North America and Europe, Asia, Other), diabetes, hypertension, current smoking, prior MI, heart failure or New York Heart Association Class II, prior revascularization, angina frequency (Seattle Angina Questionnaire angina frequency subscale score ≤60, 61–90, 91–100), new or increasing angina, eGFR, ejection fraction and body-mass index.

Figure 3.. Ischemia Severity and Outcomes by Treatment Group

Shading indicates the half-width of confidence bands for the difference between treatment groups. CON = conservative strategy, INV = invasive strategy.

Figure 4.. Anatomic Severity of Coronary Artery Disease and All-Cause Mortality by Treatment Group

Shading indicates the half-width of confidence bands for the difference between treatment groups. CON = conservative strategy, INV = invasive strategy, V=vessel.

Figure 5.. Anatomic Severity of Coronary Artery Disease and Myocardial Infarction by Treatment Group

Shading indicates the half-width of confidence bands for the difference between treatment groups. CON = conservative strategy, INV = invasive strategy, V=vessel. The trial primary endpoint was a composite of CV death, MI, hospitalization for heart failure, hospitalization for unstable angina, and resuscitated cardiac arrest.