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Meta-Analysis of Pharmacological Treatment for HFrEF
Quick Takes
- In a network meta-analysis of 75 randomized controlled trials looking at pharmacological agents in HFrEF patients, the highest reduction in all-cause mortality was with a combination of ARNi, BBs, MRAs, and SGLT2i.
- The largest reduction in composite of cardiovascular mortality and HF hospitalization was also with this same combination.
Study Questions:
What is the aggregate benefit of pharmacological therapy for heart failure with reduced ejection fraction (HFrEF)?
Methods:
A systematic review and network meta-analysis was performed and reported according to the PRISMA statement. Databases searched included MEDLINE, EMBASE, and Cochrane Register from 1987–January 2021 for published randomized controlled trials looking at drugs for HFrEF in adults. Agents considered include digoxin, isosorbide dinitrate, and hydralazine (H-ISDN), angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), ivabradine, angiotensin receptor–neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil (cardiac-specific myosin activator). Studies where the entire population included patients with a diagnosis that would impact outcomes such as only patients with diabetes were excluded.
Results:
Overall, 75 studies enrolling 95,444 patients were included. The majority of patients had New York Heart Association class II or III. Risk for publication bias was low. The majority of studies were double-blinded, multicenter, placebo-controlled trials. Heterogeneity across studies was low. All-cause mortality was lowest for ARNi (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.66-0.85) and MRAs (HR, 0.76; 95% CI, 0.67-0.85) followed by BBs (HR, 0.78; 95% CI, 0.72-0.84), ACEi (HR, 0.89; 95% CI, 0.82-0.96), SGLT-2i (HR, 0.88; 95% CI, 0.78-0.99), and ARBs (HR, 0.95; 95% CI, 0.88-1.02). Vericiguat and omecamtiv-mecarbamil did not reduce all-cause mortality. The combination of ARNi, BBs, MRAs, and SGLT-2i was most effective in reducing all-cause mortality relative to placebo (HR, 0.39; 95% CI, 0.31-0.49) as well as composite of cardiovascular death and HF hospitalization (HR, 0.36; 95% CI, 0.29-0.46). At an age of 50 years, the combination of ARNi, BBs, MRAs, and SGLT2i led to an estimated 4.9 life-years gained and 3.3 years gained in a 70-year-old.
Conclusions:
In a comprehensive network meta-analysis of HFrEF patients, the most effective combination in reducing all-cause mortality and composite of cardiovascular death and HF hospitalization was ARNi, BBs, MRAs, and SGLT-2i. This led to an increase of 4.9 life-years for a 50-year-old and 3.3 life-years for a 70-year-old.
Perspective:
Pharmacological therapy for HFrEF has evolved with several new agents. Clinical trials with these agents have been sequential, and hence, aggregate estimates of their efficacy are lacking. Since therapy of HFrEF is centered on combination therapy that enables blockade of several different neurohormonal axes, this remains a vital question. Results from this network meta-analysis suggest that the highest all-cause mortality benefit in adult HFrEF patients was from a combination of ARNi, BBs, MRAs, and SGLT-2i. While results of this meta-analysis are not entirely surprising, easy accessibility to these medications remains a major barrier predominantly due to lack of universal coverage for these medications leading to high out-of-pocket costs and a lack of familiarity. Additional policy-level changes are necessary to ensure that there is wider acceptance and use of these medications in HFrEF patients at a nominal price for patients.
Clinical Topics: Geriatric Cardiology, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Adrenergic beta-Antagonists, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Digoxin, Geriatrics, Health Expenditures, Heart Failure, Hydralazine, Isosorbide Dinitrate, Ivabradine, Mineralocorticoid Receptor Antagonists, Neprilysin, Pharmaceutical Preparations, Receptors, Angiotensin, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume
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