Benefits of comprehensive disease-modifying pharmacological therapies in patients with HFrEF
This cross-trial analysis estimated that comprehensive disease-modifying pharmacological therapy in HFrEF patients reduces the hazard of CV death or hospital admission, compared with conventional therapy.
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 trialsLiterature - Vaduganathan M, Claggett BL, Jhund PS et al., - The Lancet. 2020. doi: 10.1016/S0140-6736(20)30748-0.
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 [3]. 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) [1], ARNI (PARADIGM-HF, n=10,521) [2], and a SGLT2 inhibitor (DAPA-HF, n=4744) [3] 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.
Main results
- 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.
Conclusion
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.
References
1. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364: 11–21.
2. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17.
3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995–2008.
4. Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry. J Am Coll Cardiol 2018; 72: 351–66.
5. Komajda M, Schöpe J, Wagenpfeil S, et al. Physicians’ guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail 2019; 21: 921–29.
6. Brunner-La Rocca HP, Linssen GC, Smeele FJ, et al. Contemporary drug treatment of chronic heart failure with reduced ejection fraction: the CHECK-HF registry. JACC Hear Fail 2019; 7: 13–21.
7. Vaduganathan M, Fonarow GC, Greene SJ, et al. Contemporary treatment patterns and clinical outcomes of comorbid diabetes mellitus and HFrEF: the CHAMP-HF registry. JACC Heart Fail 2020; published online May 6. DOI:10.1016/j.jchf.2019.12.015.
8. Greene SJ, Fonarow GC, DeVore AD, et al. Longitudinal titration of medical therapy for heart failure with reduced ejection fraction: CHAMP-HF registry. J Am Coll Cardiol 2019; 73: 2365–83.