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Combining ARNIs, SGLT2 Inhibitors, and MRAs Could Benefit HFrEF Patients

New research suggests combining agents from the 3 classes could pay major dividends in terms of event-free and overall survival.

Scott Solomon, MD

With so many patients and clinicians struggling to find an effective treatment algorithm for heart failure with reduced ejection fraction (HFrEF), results of a new study examining a comprehensive therapy including multiple popular drug classes could help extend the lives of these patients.

Conducted by physicians from Brigham and Women’s Hospital, the analysis determined concomitant use of mineralocorticoid receptor antagonists (MRAs), angiotensin receptor—neprilysin inhibitors (ARNIs), and sodium/glucose cotransporter 2 (SGLT2) inhibitors could reduce risk of cardiovascular events by 50%, risk of hospital admission for heart failure for 68%, and risk of all-cause mortality by 47%.

"There's been some resistance to adopting comprehensive therapy for heart failure patients," said study investigator Scott Solomon, MD, director of noninvasive cardiology at Brigham and Women’s Hospital, in a statement. “What we did here was to say, 'What might the benefit be over a patient's lifetime?' And the benefit we're seeing is pretty dramatic."

Despite all 3 classes of therapy showing benefit for patients with HFrEF, use of 3 as a combination treatment has been met with hesitancy by many clinicians. In an effort to estimate how patients might benefit from such treatment, investigators conducted a cross-trial analysis of the EMPHASIS-HF, PARADIGM-HF, and DAPA-HF trials.

From EMPHASIS-HF, investigators identified 2737 patients older than 55 years of age and who had chronic HFrEF with New York Heart Association class II symptoms followed for a median duration of 21 months. Patients in the study were randomized to eplerenone 25—50 mg once daily or matching placebo. Study protocol required these patients to be on maximally tolerated ACE inhibitor or ARBs and a β blocker at baseline.

From PARADIGM-HF, investigators identified 8399 patients 18 years of age and older who had HFrEF classified as New York Heart Association functional class II-IV and increased natriuretic peptides with a median follow-up of 27 months. Patients in this trial were randomized to enalapril 10 mg twice daily or sacubitril—valsartan 200 mg twice daily. Study protocol required these to be treated with stable doses of ACE inhibitor or ARB plus β blocker for at least 4 weeks.

From DAPA-HF, investigators identified 4744 patients 18 years of age and older who had chronic HFrEF with New York Heart Association class II-IV symptoms and increased natriuretic peptides with median follow-up of 18 months. Patients in the study were randomized to dapagliflozin once daily or matching placebo. A subgroup of patients in DAPA-HF were treated with ARNIs at baseline and were included in a sensitivity analysis.

Using data from these clinical trials, investigators performed an actuarial analysis to estimate the lifetime benefit of taking all 3 of the aforementioned therapy classes in addition to standard treatment. Investigators’ analyses were based on the assumption relative treatment effects would be consistent over time.

The endpoint of the investigators’ primary analysis was a composite of cardiovascular death or first hospital admission for heart failure. Additional analyses assessed for all-cause mortality and both of the primary outcomes individually.

Results indicated a comprehensive disease-modifying therapy, which was defined as use of all 3 therapies simultaneously, was associated with a reduction in risk of the composite endpoint of cardiovascular death or hospitalization for heart failure (HR, 0.38; 95% CI, 0.30-0.47) versus conventional therapy. Additionally, comprehensive disease-modifying therapy was associated with lower risk of cardiovascular death alone (HR, 0.50; 95% CI, 0.37-0.67), hospital admission for heart failure alone (HR, 0.32; 0.24-0.43), and all-cause mortality (HR, 0.53; 0.40-0.70) versus conventional therapy.

Based on the results of their analyses, investigators estimated treatment with comprehensive disease-modifying therapy could result in additional years free from cardiovascular death or first hospital admission—specifically, 2.7 additional years for an 80-year-old patient to 8.3 additional years for a 55-year-old. Investigators also estimated use could result prolong survival up to 1.4 additional years for an 80-year-old patient and up to 6.3 additional years for a 55-year-old compared with conventional therapy.

Investigators caution clinicians to acknowledge the limitations of their analysis before interpreting results. Limitations included assumptions about therapy, adherence, and if benefits would continue to accrue over time. Investigators also pointed out their analysis did not assess cost or potential side effects, such as kidney toxicity, of taking these agents simultaneously.

This study, “Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials,” was published in The Lancet.