Causes of cardiovascular and noncardiovascular death in the ISCHEMIA trial

Abstract

Background: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial demonstrated no overall difference in the composite primary endpoint and the secondary endpoints of cardiovascular (CV) death/myocardial infarction or all-cause mortality between an initial invasive or conservative strategy among participants with chronic coronary disease and moderate or severe myocardial ischemia. Detailed cause-specific death analyses have not been reported.

Methods: We compared overall and cause-specific death rates by treatment group using Cox models with adjustment for pre-specified baseline covariates. Cause of death was adjudicated by an independent Clinical Events Committee as CV, non-CV, and undetermined. We evaluated the association of risk factors and treatment strategy with cause of death.

Results: Four-year cumulative incidence rates for CV death were similar between invasive and conservative strategies (2.6% vs 3.0%; hazard ratio [HR] 0.98; 95% CI [0.70-1.38]), but non-CV death rates were higher in the invasive strategy (3.3% vs 2.1%; HR 1.45 [1.00-2.09]). Overall, 13% of deaths were attributed to undetermined causes (38/289). Fewer undetermined deaths (0.6% vs 1.3%; HR 0.48 [0.24-0.95]) and more malignancy deaths (2.0% vs 0.8%; HR 2.11 [1.23-3.60]) occurred in the invasive strategy than in the conservative strategy.

Conclusions: In International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, all-cause and CV death rates were similar between treatment strategies. The observation of fewer undetermined deaths and more malignancy deaths in the invasive strategy remains unexplained. These findings should be interpreted with caution in the context of prior studies and the overall trial results.

Figure 1:

Time to event curves for the outcome of death from any cause. The shaded region of the plot displays the half width of the confidence interval for the difference between treatment groups. Overlap of the lines and shading indicates that the 95% CI for the difference includes zero. Figure 1A: Cumulative incidence of death from any cause in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1B: Cumulative incidence of cardiovascular death in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1C: Cumulative incidence of non-cardiovascular death in the conservative strategy group and invasive strategy group. Figure 1D: Cumulative incidence of undetermined death in the conservative strategy group and invasive strategy group.

Figure 1:

Time to event curves for the outcome of death from any cause. The shaded region of the plot displays the half width of the confidence interval for the difference between treatment groups. Overlap of the lines and shading indicates that the 95% CI for the difference includes zero. Figure 1A: Cumulative incidence of death from any cause in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1B: Cumulative incidence of cardiovascular death in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1C: Cumulative incidence of non-cardiovascular death in the conservative strategy group and invasive strategy group. Figure 1D: Cumulative incidence of undetermined death in the conservative strategy group and invasive strategy group.

Figure 1:

Time to event curves for the outcome of death from any cause. The shaded region of the plot displays the half width of the confidence interval for the difference between treatment groups. Overlap of the lines and shading indicates that the 95% CI for the difference includes zero. Figure 1A: Cumulative incidence of death from any cause in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1B: Cumulative incidence of cardiovascular death in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1C: Cumulative incidence of non-cardiovascular death in the conservative strategy group and invasive strategy group. Figure 1D: Cumulative incidence of undetermined death in the conservative strategy group and invasive strategy group.

Figure 1:

Time to event curves for the outcome of death from any cause. The shaded region of the plot displays the half width of the confidence interval for the difference between treatment groups. Overlap of the lines and shading indicates that the 95% CI for the difference includes zero. Figure 1A: Cumulative incidence of death from any cause in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1B: Cumulative incidence of cardiovascular death in the conservative strategy group and invasive strategy group. From N Engl J Med, Maron DJ, et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease, 382:1395–1407. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission. Figure 1C: Cumulative incidence of non-cardiovascular death in the conservative strategy group and invasive strategy group. Figure 1D: Cumulative incidence of undetermined death in the conservative strategy group and invasive strategy group.

Figure 2:

The interaction with death type is used to assess whether a covariate’s association with death differed by cause of death.

Figure 3:

Time to event curves for the cumulative incidence plot of new malignancy during the study period for the conservative strategy arm and invasive strategy arm. The gray shaded region of the plot displays the half width of the confidence interval for the difference between treatment groups. Overlap of the lines and shading indicates that the 95% CI for the difference includes zero.