Elsevier

The Lancet

Volume 396, Issue 10244, 11–17 July 2020, Pages 121-128
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(20)30748-0Get rights and content

Summary

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 β 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, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β 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 β 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, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.

Funding

None.

Introduction

Patients with heart failure with reduced ejection fraction (HFrEF) have substantially shorter life expectancies than the general population of a similar age.1, 2 Over the past three decades, stepwise advancements have been made in pharmacotherapy for patients with HFrEF. Although most patients are treated with renin–angiotensin-system inhibitors and β blockers,3, 4, 5 three drug classes have also been shown to reduce mortality due to HFrEF beyond these previously established core elements. Trials have shown clinical superiority of mineralocorticoid receptor antagonists (MRAs)6, 7 and sodium/glucose cotransporter 2 (SGLT2) inhibitors8 when each was tested against a placebo control in addition to standard care inclusive of renin–angiotensin-system inhibitors and β blockers (as tolerated). Additionally, the angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril–valsartan, has been shown to be superior when directly tested against an angiotensin-converting enzyme (ACE) inhibitor in improving clinical outcomes.9 Real-world data have highlighted that doctors infrequently prescribe these recent additions to the therapeutic armamentarium, even among patients deemed clinically eligible without apparent contraindication or documented intolerance. For instance, despite class I guideline recommendations, use of MRAs (range 33·7–35·7%) and ARNIs (13·6–19·8%) in eligible patients remains suboptimal. With the recent regulatory approval of dapagliflozin by the US Food and Drug Administration for the treatment of HFrEF, a substantial number of patients are anticipated to be eligible for potential use.3, 4, 5, 10, 11 These gaps in evidence-based medical therapies have been implicated in relatively stagnant mortality trajectories of patients living with HFrEF.12

Research in context

Evidence before this study

Patients with heart failure with reduced ejection fraction (HFrEF) have substantially shorter life expectancies than the general population of a similar age. Multiple therapies are now known to individually extend survival of patients with chronic HFrEF. Although most patients are treated with renin–angiotensin-system inhibitors and β blockers, three drug classes (angiotensin receptor–neprilysin inhibitors [ARNIs], mineralocorticoid receptor antagonists [MRAs], and SGLT2 inhibitors) have additionally been shown to reduce mortality in these patients beyond the effects of the previously established core therapeutic elements. Real-world data have highlighted incomplete use of these more recent additions to the therapeutic armamentarium.

Added value of this study

Although recently introduced therapies have each individually been tested in randomised controlled trials, our study estimates their aggregate benefits when used in a combination multidrug regimen. We used data from three contemporary randomised clinical trials of patients with chronic HFrEF, each with a median follow-up of less than 3 years. Our actuarial analysis projects long-term benefits of these therapies if used over a lifetime. We estimated that comprehensive disease-modifying pharmacological therapy (consisting of an ARNI, β blocker, MRA, and SGLT2 inhibitor) reduces the hazard of cardiovascular death or hospital admission for heart failure significantly (hazard ratio 0·38 [95% CI 0·30–0·47]) compared with conventional therapy (consisting of an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB] and β blocker). Depending on the age of therapeutic optimisation, treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 1·4 to 6·3 additional years of survival and 2·7 to 8·3 additional years free from cardiovascular death or hospital admission for heart failure compared with treatment with ACE inhibitor or ARB and β blocker alone.

Implications of all the available evidence

Compared with the conventional neurohormonal medical therapies commonly used in clinical practice, our data support the central role of comprehensive disease-modifying pharmacological therapy to halt or delay clinical progression and extend survival of patients with HFrEF. Given incomplete uptake of well established and novel therapies, innovative and disruptive implementation strategies are urgently needed to facilitate use of combination multidrug regimens in appropriately selected patients with HFrEF. The survival benefits estimated with comprehensive disease-modifying pharmacological therapy might be important in shared therapeutic decision making and future health system valuation.

Communication of the estimated treatment benefits of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitors) on clinical outcomes, especially if used over a lifetime, might facilitate decision making by patients, clinicians, health systems, and payers (ie, governmental and non-governmental entities that support the cost of health care). First, we estimated relative treatment effects of comprehensive disease-modifying pharmacological therapy versus conventional therapy (ACE inhibitor or angiotensin receptor blocker [ARB] plus β blocker) in patients with chronic HFrEF by making indirect comparisons of pivotal randomised clinical trials.6, 8, 9 Using validated actuarial methods and assuming consistent treatment effects over time, we then projected absolute survival gains with comprehensive disease-modifying pharmacological therapy if applied long term, compared with conventional therapies.

Section snippets

Study design

In this cross-trial analysis, we estimated the effect of comprehensive disease-modifying pharmacological therapy against previously established conventional therapy (ACE inhibitor or ARB plus β blocker) using overall trial-level estimates from pivotal randomised clinical trials that assessed the efficacy and safety of MRA,6 ARNI,9 and SGLT2 inhibitors.8 All participants provided written consent and the study protocol of each pivotal trial was approved by the institutional review board at each

Results

For the primary analysis, we analysed trial-level estimates from EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744; table). A schematic of the indirect comparisons across the three trials for each of the key cardiovascular endpoints is shown in the appendix. The HR for the imputed treatment effect of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus limited conventional therapy (ACE inhibitor or ARB and β blocker) on the

Discussion

A central goal of heart failure therapeutics is to safely prevent morbidities and prolong morbidity-free survival. In HFrEF, multiple therapeutic advances have offered promise in delaying clinical progression and extending disease-free survival. Combination therapy with an ARNI, β blocker, and MRA is the current guideline-recommended therapeutic standard for patients with HFrEF. In light of robust and favourable clinical trial data, the addition of SGLT2 inhibitors in a comprehensive regimen is

Data sharing

All trial funders are committed to sharing access to patient-level data and supporting clinical documents from eligible studies. The trial data availability is according to the separate criteria and processes for Pfizer, Novartis, and AstraZeneca.

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