Real-world utilisation of angiotensin-neprilysin inhibitors in older adults with heart failure

Over the last decade, treatment for heart failure with reduced ejection fraction (HFrEF) has advanced, with the incremental addition of novel evidencebased medical therapies. The landmark PARADIGMHF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) study showed that the angiotensin receptorneprilysin inhibitor (ARNI) sacubitril/valsartan was superior to enalapril in reducing risk of death and HF hospitalisations. This has paved the way for rapid incorporation of ARNI into the treatment guidelines for HFrEF, with additional indications on the horizon. We are now in an era of quadruple therapy that incorporates an optimal combination of betablockers, ACE inhibitors (ACEi)/ angiotensin receptor blockers (ARB)/ ARNI, mineralocorticoid receptor antagonists (MRA) and sodium/glucose cotransporter-2 inhibitors (SGLT2i) for chronic HFrEF. In this issue of Heart, Dr Desai and colleagues evaluate the realworld utilisation of ARNI in HFrEF patients age ≥65 years using the Medicare database (2014– 2017). Case ascertainment of HF was based on International Classification of Diseases (ICD) codes, with further stratification dependent on a validated claimsbased algorithm and/or ARNI initiation to limit the reference group to those with HFrEF. While there may be some degree of misclassification, the recently expanded US Food and Drug Administration indication for ARNI based on post hoc analysis of PARAGONHF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with preserved EF) would suggest that those with HFpEF at the lower end of the ‘normal’ EF spectrum may derive similar benefit to those with HFrEF. Hence, ARNI is now indicated in patients with chronic HF regardless of EF. In the current manuscript, separate subcohorts were created from the HFrEF population with an ‘initiator’ group (newly starting ARNI or ACEi/ARB who were previously naïve to these medications) and a ‘switcher’ group (switching from baseline ACEi to either ARNI or ARB). As noted by the authors, these populations may differ in that de novo initiators likely have a more recent diagnosis of HFrEF, whereas switchers likely represent longerstanding disease. The estimated treatment benefit (time to worsening HF or allcause mortality) was stronger in the switcher cohort (HR 0.79 for ACEi to ARNI vs ARB) than the initiator cohort and persisted when the endpoints were assessed individually. The comparison of only switchers in the latter group avoids depletion of susceptible patients and reduces potential confounding by treatment history or by potential for newly diagnosed versus more chronic HF. While clinical trials provide foundational knowledge, the necessity to balance inclusion and exclusion criteria to minimise study dropout or competing risk may limit external validity and thus may not be reflective of realworld outcomes. The current study seeks to address this knowledge gap by confirming the efficacy of ARNI in a broader cohort with a higher prevalence of older patients (76 years vs 64 years), higher proportion of women (33% vs 21%) and higher proportion of black individuals (11% vs 5%) as compared with the PARADIGMHF study (table 1). Furthermore, 12%–14% of those exposed to ARNI in the current study had chronic kidney disease. The pharmacokinetics of ARNI are known to be impacted by both renal and hepatic impairment, as well as older age, so these are important distinctions. In essence, this study confirms the PARADIGMHF results and supports the benefit of ARNI over ACEi/ARB in a broader population of patients with HFrEF.