Lifetime Benefits of Pharmacological Therapy in HFrEF

Quick Takes

  • Using data from three trials, comprehensive therapy with ARNI, beta-blocker, MRA, and SGLT-2 inhibitor was associated with a 60% lower hazard for cardiovascular death and HF hospitalization when compared to ACE inhibitor/ARB therapy with beta-blocker.
  • Number needed to treat to prevent one cardiovascular death or HF hospitalization with comprehensive therapy was 6-8 compared to ACE inhibitor/ARB and beta-blocker.
  • Number needed to treat to prevent one all-cause mortality comprehensive therapy was 8-16 compared to ACE inhibitor/ARB and beta-blocker.

Study Questions:

What are the lifetime treatment benefits of comprehensive disease-modifying pharmacological therapy on clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF)?

Methods:

This was a cross-trial study of EMPHASIS-HF, PARADIGM-HF, and DAPA-HF. Comprehensive therapy was defined as combination of mineralocorticoid receptor antagonist (MRA), beta-blocker, angiotensin receptor-neprilysin inhibitor (ARNI), and sodium glucose cotransporter-2 (SGLT-2) inhibitor. The pharmacological effect of comprehensive therapy was tested against conventional therapy (angiotensin-converting enzyme [ACE] inhibitor or angiotensin-receptor blocker [ARB] and beta-blocker). The primary endpoint was composite of cardiovascular death or first HF hospitalization.

Results:

The hazard ratio for treatment effect of combined ARNI, beta-blocker, MRA, and SGLT-2 inhibitor treatment for composite of cardiovascular death or first HF hospitalization was 0.38 (95% confidence interval, 0.30-0.47) as compared to conventional therapy. The number needed to treat with comprehensive therapy to prevent one cardiovascular death or HF hospitalization was 4-6. With regard to mortality, absolute risk reduction with comprehensive therapy was 6-13% over 3 years with a number needed to treat of 8-16 to prevent one death. Baseline life expectancies varied by age and survival gains were calculated across ages 55-80 years. At age 55 and 65 years, survival was 6.3 years more with comprehensive therapy as compared to conventional therapy. At age 80 years, survival with comprehensive therapy was 2.7 years more.

Conclusions:

Comprehensive therapy with an ARNI, beta-blocker, MRA, and SGLT-2 inhibitor lowered risk for cardiovascular death or HF hospitalization by over 60% compared to therapy with ACE inhibitor or ARB and beta-blocker with a number needed to treat of 4-6. Number needed to treat to prevent one death was 8-16 with comprehensive therapy compared to conventional therapy.

Perspective:

Trials examining efficacy of pharmacological therapy in HFrEF have been staggered and performed over a span of several decades. In the last decade, three new agents have shown a survival benefit in this population: MRA, ARNI, and SGLT-2 inhibitors. However, their additive effect when compared to conventional therapy has not been examined. This cross-trial study provides estimates of benefit of a combination therapy with ARNI, beta-blocker, MRA, and SGLT-2 inhibitors when compared to decades old conventional therapy for HFrEF. Apart from a large reduction in cardiovascular death and HF rehospitalization, the survival benefit seen was largest in younger individuals.

Important limitations to note include limited generalizability due to use of trial data which may not apply to real-world cohorts and overestimation of benefit, as the authors assumed an additive effect of each agent. However, incidence of adverse effects and cost implications of these agents were not reported. ARNI and SGLT-2 inhibitors are currently not generic and thus, associated with significant cost burden. Hence, individual patient-level risk-benefit discussions with patients should be considered. An additional concern is medication adherence, as new HFrEF therapy will now include at the least four different medications. A polypill may pave the way for the future.

Keywords: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Geriatrics, Heart Failure, Medication Adherence, Mineralocorticoid Receptor Antagonists, Neprilysin, Peptidyl-Dipeptidase A, Secondary Prevention, Sodium-Glucose Transporter 2, Stroke Volume


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