Cancer Mortality in Trials of Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis

Abstract

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.

Keywords: cancer; comorbidities; heart failure; mortality.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flow diagram of the systematic search and selection process. CV indicates cardiovascular; HF, heart failure; HFpEF, heart failure with preserved left ventricular ejection fraction; HFrEF, heart failure with reduced left ventricular ejection fraction; and RCTs, randomized controlled trials.

Figure 2

Cancer and CV mortality in HFrEF RCTs with cancer mortality data available. AF‐CHF indicates atrial fibrillation and congestive heart failure; CABG, coronary artery bypass graft; CHARM‐Added, candesartan in heart failure assessment of reduction in mortality and morbidity‐added; CHARM‐Alternative, candesartan in heart failure assessment of reduction in mortality and morbidity‐alternative; CONSENSUS, cooperative north scandinavian enalapril survival study; CORONA, controlled rosuvastatin multinational trial in heart failure; CV, cardiovascular; DEFINITE, defibrillators in non‐ischemic cardiomyopathy treatment evaluation; ECHO‐CRT, echocardiography guided cardiac resynchronization therapy; GESICA, grupo de estudio de la sobrevida en la insuficiencia cardiaca en Argentina; GISSI‐HF, gruppo Italiano per lo studio della sopravvivenza nell’insufficienza cardiaca heart failure; HFrEF, heart failure with reduced left ventricular ejection fraction; MADIT‐CRT, multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy; PARADIGM‐HF, prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial; RCTs, randomized controlled trials; REVERSE, resynchronization reverses remodeling in systolic left ventricular dysfunction; STICH, surgical treatment for ischemic heart failure; and V‐HeFT II, vasodilator‐heart failure trial II.

Figure 3

Pooled OR for cancer, CV, and total mortality in HFrEF RCTs with published information about cancer mortality. AF‐CHF indicates atrial fibrillation and congestive heart failure; CABG, coronary artery bypass graft; CHARM‐Added, candesartan in heart failure assessment of reduction in mortality and morbidity‐added; CHARM‐Alternative, candesartan in heart failure assessment of reduction in mortality and morbidity‐alternative; CONSENSUS, cooperative north scandinavian enalapril survival study; CORONA, controlled rosuvastatin multinational trial in heart failure; CRT(‐D), cardiac resynchronization therapy (and ICD); CV, cardiovascular; DEFINITE, defibrillators in non‐ischemic cardiomyopathy treatment evaluation; ECHO‐CRT, echocardiography guided cardiac resynchronization therapy; GESICA, grupo de estudio de la sobrevida en la insuficiencia cardiaca en Argentina; GISSI‐HF, gruppo Italiano per lo studio della sopravvivenza nell’insufficienza cardiaca heart failure; HFrEF, heart failure with reduced left ventricular ejection fraction; MADIT‐CRT, multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy; PARADIGM‐HF, prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial; RCTs, randomized controlled trials; REVERSE, resynchronization reverses remodeling in systolic left ventricular dysfunction; STICH, surgical treatment for ischemic heart failure; and V‐HeFT II, vasodilator‐heart failure trial II.

Figure 4

Potential reasons for exclusion of patients with malignancy from HFrEF RCTs. Note the overlap of criteria between trials for which cancer mortality was or was not reported. Cancer not considered means that cancer was not a direct or indirect cause of exclusion.