Introduction

Quadruple therapy including a renin–angiotensin system inhibitor (RASi)/angiotensin receptor–neprilysin inhibitor (ARNi), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium–glucose co-transporter 2 inhibitor (SGLT2i) is recommended for all patients with heart failure (HF) with reduced ejection fraction (HFrEF).1 The combined use of all four foundational therapies has been estimated to reduce hospitalizations for HF (HHF) or cardiovascular mortality by up to 64%.2 Real-world uptake of these therapies relies not only on physician prescriptions but also on patients actually taking the prescribed drugs (adherence) and continuing them over the longer term (persistence).3 Therefore, these factors inevitably affect how benefits of guideline-directed medical therapy (GDMT) achieved in trials are translated into real-world HFrEF populations.4 Although previous studies have highlighted limited implementation (physician prescriptions) of HF therapies,5–8 there is a lack of data on patient adherence and persistence to HF treatments, particularly in the era of quadruple foundational therapy.

The therapeutic toolkit for HFrEF has expanded in recent years, which might impact treatment uptake both in terms of implementation and patient adherence. Specific new therapies might facilitate uptake by improving clinical status and tolerability. For example, in the PARADIGM-HF and EMPEROR-Reduced trials, respectively, ARNi and SGLT2i were linked to less discontinuation of MRA.9,10 On the other hand, the increasing pill-burden and polypharmacy has been linked to lower patient adherence in the cardiovascular field.11

Therefore, in a large and contemporary HFrEF population, we performed a comprehensive assessment of the uptake of quadruple HFrEF pharmacotherapy, ranging from (i) physician prescriptions; (ii) patient adherence; and (iii) patient persistence, as well as associated patient characteristics and outcomes.