4-drug combo poised to become new standard for HFrEF treatment

In the treatment of patients with heart failure with reduced ejection fraction (HFrEF), a comprehensive disease-modifying strategy combining four drugs—namely angiotensin receptor–neprilysin inhibitor (ARNI), β blocker, mineralocorticoid receptor antagonist (MRA), and sodium/glucose cotransporter 2 (SGLT2) inhibitor—yields incremental benefits that contribute to stopping or delaying clinical progression and extending survival, as shown in a study.

“A central goal of heart failure therapeutics is to safely prevent morbidities and prolong morbidity-free survival. In HFrEF … combination therapy with an ARNI, β blocker, and MRA is the current guideline-recommended therapeutic standard,” according to the investigators.

“In light of robust and favourable clinical trial data, the addition of SGLT2 inhibitors in a comprehensive regimen is poised to be adopted in clinical practice guidelines. Indeed, dapagliflozin is now approved for use by the US Food and Drug Administration in the treatment of patients with HFrEF,” they added.

In the current study, the investigators estimated the effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) vs conventional therapy (ACE inhibitor or ARB and β blocker) in chronic HFrEF. They used data from three pivotal clinical trials (EMPHASIS-HF, n=2,737; PARADIGM-HF, n=8,399; DAPA-HF, n=4,744), each with a median follow-up of <3 years.

Comprehensive disease-modifying therapy proved more beneficial than the conventional approach in terms of the primary endpoint of a composite of cardiovascular death or first hospital admission for heart failure (hazard ratio [HR], 0.38, 95 percent confidence interval [CI], 0.30–0.47). [Lancet 2020;396:121-128]

Results were consistent when the endpoints were assessed individually, with the comprehensive strategy conferring greater protection against cardiovascular death (HR, 0.50, 95 percent CI, 0.37–0.67), hospital admission for heart failure (HR, 0.32, 95 percent CI, 0.24–0.43), and all-cause mortality (HR, 0.53, 95 percent CI, 0.40–0.70).

With lifetime use and assuming consistent benefits, the investigators noted that treatment with the ARNI/β blocker/MRA/SGLT2 inhibitor combination should increase event-free survival by 2.7 years for an 80-year-old and by 8.3 years for a 55-year-old, as well as absolute survival by 1.4 and 6.3 years, respectively, relative to conventional therapy.

They pointed out that even patients who are already treated with ACE inhibitor or ARB, β blocker, and MRA combination may significantly benefit from further optimization by switching to an ARNI and adding an SGLT2 inhibitor.

“Younger patients with HFrEF, who would be anticipated to have longer projected survival and treatment duration, stand to benefit the most from survival gains related to comprehensive disease-modifying pharmacological therapy. Yet, for all age groups analysed, meaningful gains in life-years were projected,” according to the investigators.

“The survival benefits estimated with comprehensive disease-modifying pharmacological therapy might be important in shared therapeutic decision making and future health system valuation,” they said.

What is now needed are aggressive implementation strategies to facilitate use of combination multidrug regimens in appropriately selected patients with HFrEF, in view of incomplete uptake of well-established and novel therapies, they added.

The investigators acknowledged several study limitations. These include the lack of data that inform other practical aspects that might influence decision making around its implementation—specifically the potential for nonadherence, either due to incremental out-of-pocket expenditures and therapeutic complexity, as well as safety issues related to comprehensive therapy.