Heart failure is a disease state that requires a significant number of medications. Guideline-based standards of care now include numerous medications. How did we get there? I outline my top 5 heart failure clinical trials of all time. Feel free to leave a comment if you have a different top 5 or if you feel we missed something important!
Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients with Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)
Going back to 2000, we have the MERIT-HF trial, the first of the top 5 heart failure clinical trials of all time. In this randomized, double-blinded, placebo-controlled clinical trial, 3,991 patients with congestive heart failure (CHF) were assigned to receive metoprolol CR/XL 25 mg daily (NYHA Class II), or 12.5 mg daily (NYHA class III or IV), titrated up to a target dose of 200 mg daily, or a matching placebo. The primary outcomes were to assess the effects of beta-blocker controlled-release/extended-release therapy on mortality, hospitalizations, symptoms, and quality of life in patients with CHF. The inclusion criteria were patients with CHF, NYHA Class II to IV, and ejection fraction of 40% or less, and were stable on the optimal standard of therapy (i.e., combinations of diuretics and an ACE inhibitor). The incidence of the defined endpoints was lower in the intervention group versus matching placebo. The risk reduction for total mortality or all-cause hospitalizations was 19%. Additionally, NYHA functional class improved in the metoprolol CR/XL group versus placebo.
A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure
This study enrolled 5,010 patients with CHF to assess the long-term effects of the addition of valsartan to standard therapy for heart failure. To be included in this randomized, double-blinded, placebo-controlled study, patients had to have heart failure NYHA Class II-IV, be clinically stable, and have an ejection fraction of less than 40%. Patients were assigned valsartan 160 mg twice daily or a matching placebo. Primary outcomes were mortality and the combined endpoint of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of IV inotropic or vasodilator therapy for at least four hours. There was a 13.2% lower incidence of the combined endpoint with valsartan than placebo. Overall mortality was similar between groups, but fewer hospitalizations for heart failure and improved NYHA symptoms and ejection fraction in the valsartan group.
Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure
In this randomized controlled clinical study, patients (N = 8,442) were assigned to receive an angiotensin receptor-neprilysin inhibitor LCZ696 (sacubitril-valsartan) 200 mg twice daily or enalapril 10 mg twice daily, in addition to standard therapy. Enrolled patients must have an NYHA Class II-IV and an ejection fraction less than 40%. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. The trial was stopped early due to finding a statistically significant benefit with sacubitril-valsartan. For the primary endpoint, a composite of death in the sacubitril-valsartan group was 21.8% compared to 26.5% in the enalapril group. Sacubitril-valsartan also lowered the hospitalization risk for heart failure and symptoms of heart failure.
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
DAPA-HF makes the list of top 5 heart failure clinical trials. It represents an onslaught of more recent data for our heart failure patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2) were found to reduce the risk of a first hospitalization for heart failure in patients with type 2 diabetes. This randomized controlled clinical trial aimed to assess if the same benefit would be seen in patients with heart failure and a reduced ejection fraction, regardless of type 2 diabetes diagnosis. 4,744 patients with heart failure NYHA Class II-IV and ejection fraction of 40% or less were enrolled to receive dapagliflozin 10 mg daily or a matched placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure or cardiovascular death. In the treatment group, the primary outcome occurred in 16.3% of patients, versus 21.2% in the placebo group. The effects of dapagliflozin on the primary outcome was consistent in patients with and without diabetes.
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
In this randomized, double-blinded, placebo-controlled clinical trial, 3,730 patients with heart failure were assigned to either receive empagliflozin 10 mg daily or a matched placebo, in addition to recommended therapy. Included patients had NYHA Class II-IV and an ejection fraction of 40% or less. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. A primary outcome event occurred in 19.4% of patients in the empagliflozin group and 24.7% in the placebo group. The effects of empagliflozin on the primary outcome was consistent in patients with and without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group. Additionally, investigators observed a slowed decline in eGFR in the treatment group versus placebo, with patients experiencing a lower risk of serious renal outcomes. However, uncomplicated urinary tract infections were higher in the empagliflozin group.
This article was written by Sarah Zahirudin, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCGP, BCPS
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(Reference: Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of Controlled-Release Metoprolol on Total Mortality, Hospitalizations, and Well-being in Patients with Heart Failure: The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA. 2000;283(10):1295- 1302). Available at https://jamanetwork.com/journals/jama/fullarticle/192477).
(Reference: Cohn J, Tognoni G, Valsartan Heart Failure Trial Investigators. A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure. N Engl J Med. 2001;345(23):1667-1675. Available at https://www.nejm.org/doi/full/10.1056/NEJMoa010713).
(Reference: McMurray J, Packer M, Desai A, et al., for the PARADIGM-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11);993-1004. Available at https://www.nejm.org/doi/full/10.1056/NEJMoa1409077).
(Reference: McMurray J, Solomon S, Inzucchi S, et al., for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381:1995-2008. Available at https://www.nejm.org/doi/full/10.1056/NEJMoa1911303).
(Reference: Packer M, Anker S, Butler J, et al., for the EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383:1413-1424. Available at https://www.nejm.org/doi/full/10.1056/NEJMoa2022190).
Amazing Sara , you’ve concluded all top 5 HF trial with the intervention of Dapa/empa , metoprolol CR , angiotensin neprolysin inhibitor , all in small interesting article .
That’s how clinical pharmacist works .