Cancer mortality in trials of heart failure with reduced ejection fraction. A systematic review and meta-analysis

BACKGROUND: The burden of cancer in heart failure with reduced ejection fraction is apparently growing. Randomized controlled trials (RCTs) may help understanding this observation, since they span decades of heart failure treatment. METHODS AND RESULTS: We assessed cancer, cardiovascular, and total mortality in phase 3 heart failure RCTs involving ≥90% individuals with left ventricular ejection fraction <45%, who were not acutely decompensated and did not represent specific patient subsets. The pooled odds ratios (ORs) of each type of death for the control and treatment arms were calculated using a random-effects model. Temporal trends and the impact of patient and RCT characteristics on mortality outcomes were evaluated by meta-regression analysis. Cancer mortality was reported for 15 (25%) of 61 RCTs, including 33 709 subjects, and accounted for 6% to 14% of all deaths and 17% to 67% of noncardiovascular deaths. Cancer mortality rate was 0.58 (95% CI, 0.46–0.71) per 100 patient-years without temporal trend (P=0.35). Cardiovascular (P=0.001) and total (P=0.001) mortality rates instead decreased over time. Moreover, cancer mortality was not influenced by treatment (OR, 1.08; 95% CI, 0.92–1.28), unlike cardiovascular (OR, 0.88; 95% CI, 0.79–0.98) and all-cause (OR, 0.91; 95% CI, 0.84–0.99) mortality. Meta-regression did not reveal significant sources of heterogeneity. Possible reasons for excluding patients with malignancy overlapped among RCTs with and without published cancer mortality, and malignancy was an exclusion criterion only for 4 (8.7%) of the RCTs not reporting cancer mortality. CONCLUSIONS: Cancer is a major, yet overlooked cause of noncardiovascular death in heart failure with reduced ejection fraction, which has become more prominent with cardiovascular mortality decline.