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.