Clinician Article

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.

  • Vaduganathan M
  • Claggett BL
  • Jhund PS
  • Cunningham JW
  • Pedro Ferreira J
  • Zannad F, et al.
Lancet. 2020 Jul 11;396(10244):121-128. doi: 10.1016/S0140-6736(20)30748-0. Epub 2020 May 21. (Original)
PMID: 32446323
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  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 6/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and ß blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.

METHODS: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, ß blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and ß blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and ß blocker).

FINDINGS: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.

INTERPRETATION: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, ß blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.


Clinical Comments


We do not know the value, beyond marketing, of statistical gymnastics of this sort. All clinical trials include only a select population. Combining trials together will not make this selection go away but will amplify the uncertainty. It is also odd and noteworthy that devices such as CRT are not included in this analysis, which substantially limits its value. It is sad, but not totally surprising, that Lancet published this paper that is too close to marketing to merit publication in such a high-ranking journal.


This is an important article for shared therapeutic decision-making. I am constantly expanding application of MRAs, ARNIs and SGLT2 inhibitors in my patients with HFrEF. So far, however, I was focused mainly on obtaining good patient adherence with one or two drugs from these classes added to conventional therapy. This article provides an impressive estimate of the lifelong benefits of mortality and event-free survival achieved by the use of comprehensive disease-modifying therapy by including combined multidrug treatment with drugs from all these classes in HFrEF patients. For that reason, these data will likely be a practice-changing stimulus for me. Besides patient compliance, having in mind heterogenous etiology of HFrEF and the modest duration of follow-up in the RCT included in the analysis, my only concern is the assumption that observed treatment benefits will persist throughout life. That will hopefully be confirmed in future clinical practice.

General Internal Medicine-Primary Care(US)

It`s interesting to see confirmation of the beneficial role of SGLT2 inhibitors in the management of patients with HFpEF.

Internal Medicine

I think composites of 3-4 novel drugs might not be realistic. Which combination of 2-3 drugs are the most beneficial in association with cost-effectiveness should be evaluated.

Internal Medicine

This is an important analysis of modern therapy for CHF. The authors, however, may have overlooked possible confounding of how all these therapies actually function together and their potential interactions. Thus, there still should be RCTs of various combination treatments in patients with CHF to ensure we are optimally informed about the relative benefits and risks of combination therapy, especially when we are considering 5-6 agents in combination.

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