Consistency of HFrEF treatment effect in underrepresented groups in randomized clinical trials

Figures

• 

  Fig. 1. Cumulative treatment effect of Class-I recommended HF guideline-directed medical therapy classes on all-cause mortality. Estimates obtained from Tromp et al.12. ACEi Angiotensin-converting enzyme inhibitor, ARNI Angiotensin receptor-neprilysin inhibitor, BB Betablocker, MRA Mineralocorticoid receptor antagonist, SGLT2i Sodium glucose cotransporter-2 inhibitor. Change in relative risk of all-cause mortality with 95% confidence interval: ARNI + BB + MRA + SGLT2i: RRR = 0.61 (0.51–0.69). ARNI + BB + MRA: RRR = 0.56 (0.46–0.63). ACEI + BB + MRA: RRR = 0.48 (0.39–0.56). ACEI + BB: RRR = 0.31 (0.23–0.39). ACEI: RRR = 0.11 (0.04–0.18).

• 

  Fig. 2. Mean age and demographics of participants in pivotal HF randomized clinical trials. A-HeFT African-American Heart Failure Trial, CIBIS-II Cardiac Insufficiency Bisoprolol Study II, CHARM-Alternative Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (Alternative), CONSENSUS Cooperative North Scandinavian Enalapril Survival Study, COPERNICUS Carvedilol Prospective Randomized Cumulative Survival, DAPA-HF dapagliflozin and prevention of adverse outcomes in Heart Failure, DIG Digitalis Investigation Group, ELITE II Evaluation of Losartan In The Elderly II, EMPEROR-REDUCED Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction, EMPHASIS-HF Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, GALACTIC-HF Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure, MERIT-HF Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure, PARADIGM-HF Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure, RALES Randomized Aldactone Evaluation Study, SHIFT Systolic Heart failure…

• 

  Fig. 3. Consistency of heart failure treatment effect in underrepresented subgroups. HF Heart failure, GDMT Guideline directed medical therapy, MRA Mineralocorticoid receptor antagonist, RASi Renin-angiotensin system inhibitor, RCT Randomized clinical trial, SGLT2i Sodium glucose cotransporter-2 inhibitor. This figure illustrates the representativeness (low in red, moderate in orange, and high in green) of various subgroups in randomized clinical trials for Class I recommended heart failure therapies, as well as the robustness of evidence regarding the consistency of treatment effects. While current literature does not show significant heterogeneity in the treatment effects of Class I recommended therapies, this absence of heterogeneity may either indicate a true lack of variation or a lack of statistical power to detect it. The number of crosses in the figure reflects the robustness (low +, moderate ++, and high + + +) of the data supporting the absence of heterogeneity, with one cross indicating limited available data and three crosses representing strong, reliable data confirming the absence of heterogeneity.