Benefits of comprehensive disease-modifying pharmacological therapies in patients with HFrEF
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
Introduction and methods
Randomized controlled trials (RCTs) have shown that three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor–neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality due to heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy [1-3]. Treatment with MRAs and SGLT2 inhibitors showed clinical superiority when tested against placebo in addition to standard care inclusive of renin-angiotensin-system inhibitors and beta blockers [1,2]. Treatment with ARNI was superior in improving clinical outcomes when directly tested against an ACE inhibitor . Despite the benefits, real-world data have shown that MRAs, ARNIs and SGLT2 inhibitors are infrequently prescribed, even among HFrEF patients who are clinically eligible without known contraindication or intolerance [4-8].
This cross-trial analysis used overall trial-level estimates from pivotal RCTs that assessed the efficacy and safety of MRA (EMPHASIS-HF, n=27377) , ARNI (PARADIGM-HF, n=10,521) , and a SGLT2 inhibitor (DAPA-HF, n=4744)  to estimate treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, beta blocker, MRA and SGLT2 inhibitor) vs. conventional therapy (ACE inhibitor or ARB and beta blocker) in patients with chronic HFrEF.
The primary composite endpoint was CV death or first hospital admission for HF. Other endpoints were the individual components of the composite outcome and all-cause mortality. Furthermore, event-free survival (survival free from the primary composite endpoint) and overall survival were estimated.
- The HR for the imputed treatment effects of comprehensive disease-modifying therapy vs. conventional therapy on the primary composite endpoint was 0.38 (95%CI 0.30–0.47).
- The HRs of individual endpoints were 0.50 (95%CI 0.37-0.67) for CV death, 0.32 (95%CI 0.24-0.43) for first hospital admission for HF, and 0.53 (95%CI 0.40-0.70) for all-cause mortality.
- The estimated event-free survival was 14.7 years (95%CI 12.6-17.1) with comprehensive disease-modifying pharmacological therapy and 6.4 years (95%CI 4.8-8.0) with conventional therapy at age 55 years. The estimated overall survival was 17.7 years (95%CI 14.9-20.5) and 11.4 years (95%CI 9.2-13.5), respectively.
- At age 65 years, the estimated event-free survival was 13.0 years (95%CI 11.5-14.6) with comprehensive therapy and 6.7 years (95%CI 5.8-7.5) with conventional therapy. The estimated overall survival at age 65 years was 15.0 years (95%CI 13.1-16.8) and 10.6 years (95%CI 9.4-11.8), respectively.
- Difference in event-free survival between comprehensive disease-modifying therapy vs conventional therapy ranged from 2.7 additional years (95%CI 2.2-3.3) for an 80-year-old, to 8.3 additional years (95%CI 6.2-10.7) for a 55-year old. Difference in overall survival between comprehensive disease-modifying therapy vs conventional therapy was 1.4 additional years (95%CI 0.8-1.9) for an 80-year old, and 6.3 additional years (95%CI 3.4-9.1) for a 55-year-old.
- If therapy with ACE inhibitor or ARB and beta blocker and MRA was used as comparator, further optimization of the treatment regimen by switching to ARNI and adding a SGLT2 inhibitor resulted in an estimated HR of 0.64 (95%CI 0.52-0.78). Comprehensive disease-modifying pharmacological therapy was estimated to result in 1.2-4.1 additional years of event-free survival and 0.8-3.1 additional years of overall survival, compared with treatment with ACE inhibitor or ARB and beta blocker and MRA.
This cross-trial analysis used data from EMPHASIS-HF, PARADIGM-HF and DAPA-HF to estimate the aggregate benefits of comprehensive disease-modifying pharmacological therapy (ARNI, beta blocker, MRA and SGLT2 inhibitor) vs. conventional therapy (ACE inhibitor or ARB and beta blocker) in patients with chronic HFrEF. Comprehensive disease-modifying pharmacological therapy was estimated to reduce the hazard of the primary composite endpoint of CV death or hospital admission for HF, compared with conventional therapy. This also resulted in estimated benefit in event-free and overall survival among HFrEF patients aged 55 to 80 years. The largest survival gain was found in patients aged 55 years.