Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in the ISCHEMIA trial

Abstract Introduction Patients with chronic coronary syndromes (CCS) manifested by myocardial ischemia may present with typical angina or with no anginal symptoms. It is unclear whether symptom status affects prognosis in these patients. Purpose To assess whether the risk of all-cause mortality and other cardiovascular (CV) outcomes varied according to the presence or absence of angina in patients with CCS and moderate to severe myocardial ischemia in the ISCHEMIA trial. Methods The ISCHEMIA data set was obtained from the National Heart, Lung, and Blood Institute under a data use agreement. Subjects were divided into quartiles by baseline Seattle Angina Questionnaire Angina Frequency (SAQ AF) score. Quartile (Q)1 included patients with SAQ AF scores from 1-70 whereas all patients in Q4 had SAQ AF scores of 100, indicating no angina at baseline. Categorical variables were compared using the chi-squared or Fisher’s exact test. Continuous variables were compared using the student T-test or Wilcoxon rank sum test. The cumulative incidence rate of outcomes up to five years was estimated with the Kaplan-Meier method and the rate curves were compared using the log-rank test. Multivariable Cox regression models were used to estimate hazard ratios (HRs) with potential confounders from baseline characteristics, clinical history, and angiographic characteristics included. All tests were two-sided and P<0.05 was considered statistically significant. Results Of the 5,179 patients with CCS and at least moderate ischemia on stress testing, 1,434 were in Q1 and 1,635 were in Q4. Compared to Q1, patients in Q4 were older (66.4 (9.0) vs. 62.8 (9.6); P<0.001), more often male (82% vs. 73%; P<0.001), more often diabetic (43% vs. 38%; P=0.006) and less often current smokers (12% vs. 15%; P=0.001). The estimated glomerular filtration rate was lower in Q4 (82(22) vs. 86 (38); P=0.002). Fewer patients in Q4 had NYHA class II heart failure (37% vs. 62%) and more had Class I symptoms (63% vs. 38%) (P<0.001). Q4 patients had a lower ejection fraction (59% vs. 60%; P=0.002), a lower Duke jeopardy score (4.9(3.5) vs. 5.5 (3.3); P<0.001), less often had severe ischemia (47% vs. 56%), and more often had moderate ischemia (40% vs. 32 %) (P<0.001). The cumulative 5-year event rates for Q4 vs. Q1 were: all-cause death, 10.6% and 6.4% (P=0.002); CV death/MI, 16.3% vs. 13.7% (P=0.97); CV death, 7% vs. 3.7% (P=0.009); MI, 11.4% vs. 11.4% (P=0.2). On multivariable Cox regression, angina quartile (Q4 vs. Q1) was not independently associated with all-cause death (HR 1.34, 95% CI: 0.76-2.31; P=0.33), CV death/MI (HR 0.77, 95% CI: 0.52-1.14; P=0.19), CV death (HR 1.10, 95% CI: 0.50-2.43; P=0.82), or MI (HR 0.70; 95% CI: 0.45-1.08; P=0.11). Conclusion In the ISCHEMIA trial, patients with CCS and moderate to severe myocardial ischemia are at elevated risk for all-cause mortality and other major CV outcomes. This risk is not modified by the presence or absence of angina.