Key result
Comprehensive disease-modifying pharmacologic therapy (ARNI, beta-blocker, MRA, and SGLT2i) was estimated to reduce the hazard of cardiovascular death or HF hospitalization by 62% (HR 0.38) compared to limited conventional therapy.
Why the study?
The expected treatment benefits of combined use of ARNI, β blocker, MRA, and SGLT2 inhibitor in patients with chronic HFrEF are not known due to prior studies using different background therapies.
Does comprehensive disease-modifying pharmacologic therapy improve event-free and overall survival in patients with HFrEF compared with limited conventional therapy?
Meta-Analysis (n=15,880)
Yes
Does comprehensive disease-modifying pharmacologic therapy improve event-free and overall survival in patients with HFrEF compared with limited conventional therapy?
Hazard Ratio: 0.38 (95% CI 0.3–0.47)
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“It is a remarkable achievement that comprehensive therapy (ARNI, beta blocker, MRA, SGLT2 inhibitors) versus conventional therapy (ACE inhibitors, beta blockers) for HFrEF improves survival free from hospitalisation by 8.3 years for a 55-year-old and 2.7 years for an 80-year-old patient.”
“Compared with conventional dual therapy with a beta-blocker and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, treating a 55-year-old patient with quadruple therapy is projected to extend life by >6 years.”
“There's been some resistance to adopting comprehensive therapy for heart failure patients. What we did here was to say, 'What might the benefit be over a patient's lifetime?' And the benefit we're seeing is pretty dramatic.”
Optimization to comprehensive disease-modifying pharmacologic therapy in HFrEF may substantially delay clinical progression and extend survival by up to 6 years compared to conventional therapy.
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.
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Vaduganathan et al. (2020) conducted a meta-analysis in Heart failure with reduced ejection fraction (HFrEF) (n=15,880). Comprehensive disease-modifying pharmacologic therapy (ARNI, beta-blocker, MRA, SGLT2i) vs. Limited conventional therapy (ACEi/ARB and beta-blocker) was evaluated on Composite of cardiovascular death or first HF hospitalization (HR 0.38, 95% CI 0.30-0.47). Comprehensive disease-modifying pharmacologic therapy (ARNI, beta-blocker, MRA, and SGLT2i) was estimated to reduce the hazard of cardiovascular death or HF hospitalization by 62% (HR 0.38) compared to limited conventional therapy.
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