Results

Patient characteristics

Of 35 215 patients with HFrEF enrolled in SwedeHF between 2016 and 2023, the median age was 74 (IQR 64–80) years, 28% were female, 57% were enrolled in 2016–20 (triple therapy era), and 43% in 2021–23 (quadruple therapy era). Approximately 42% had history of a HHF within the previous year, 38% had New York Heart Association (NYHA) class III/IV, the median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2010 (IQR 813–4744) pg/mL, and 5% had an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2.

Several patient characteristics differed according to number of prescribed GDMT components (Table 1). Those with more than one GDMT component were slightly younger [median (IQR) age 77 (69–85), 75 (66–82), 73 (64–79), and 72 (62–78) years with mono, double, triple, and quadruple therapy, respectively), had lower NYHA class and NT-proBNP levels, but also lower EF and Charlson Comorbidity Index, and were more often referred for follow-up in specialty care or in HF nurse clinic. Those without any GDMT at baseline represented a small (∼1%) and apparently distinct sub-group, being younger [median (IQR) age 73 (61–80) years] than those with mono or double therapy, with longer HF duration, more likely a recent HHF, higher NYHA classes, and higher NT-proBNP levels.

Implementation of guideline-directed medical therapy over time

Between 2016 and 2023, the proportion of patients prescribed HFrEF pharmacotherapy increased for all GDMT components. The use of SGLT2i and quadruple therapy increased rapidly after their introduction for HFrEF in 2021. As of 2023, approximately 93% used a beta-blocker, 95% RASi/ARNi, 40% ARNi, 73% MRA, 83% SGLT2i, 60% quadruple therapy, and 29% quadruple therapy with ARNi (Figure 1).

Figure 1: Implementation of guideline-directed medical therapy over time. ARNi, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; GDMT, guideline-directed medical therapy; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose co-transporter 2 inhibitor; Quad, quadruple

For beta-blockers, RASi/ARNi, and MRA, a minority of patients were prescribed at least 100% of guideline-recommended target dose. The proportion of patients receiving at least 100% of target doses increased over time for RASi/ARNi and MRA, but not for beta-blockers, and in 2023 reached 23% for beta-blockers, 36% for RASi/ARNi, 10% for MRA, and 82% for SGLT2i; in 2023, approximately 5.7% of patients were prescribed target doses for all four pillars of quadruple GDMT and 4.4% of all four pillars of quadruple GDMT including ARNi (Table 2).

 | 2016 | 2017 | 2018 | 2019 | 2020 | 2021 | 2022 | 2023
Beta-blocker | 24.5% | 25.7% | 26.8% | 26.7% | 26.6% | 25.4% | 25.6% | 23.0%
RASi/ARNi | 27.9% | 32.9% | 33.7% | 36.3% | 38.5% | 37.5% | 37.5% | 36.3%
MRA | 4.1% | 6.4% | 7.4% | 8.0% | 8.2% | 8.5% | 8.8% | 9.8%
SGLT2i |  |  |  |  |  | 25.3% | 67.2% | 82.2%
Quadruple therapy |  |  |  |  | 2.1% | 4.2% | 5.7%
Quadruple therapy with ARNi |  |  |  |  | 1.7% | 3.2% | 4.4%

Implementation of guideline-directed medical therapy across subgroups in the quadruple therapy era

In the period 2021–23, beta-blockers were slightly more used in females (95%) than males (92%), but females were less commonly prescribed with ARNi (32% vs 43%), SGLT2i (58% vs 63%), and quadruple therapy (42% vs 45%) (Figure 2). Guideline-directed medical therapy components, as well as quadruple therapy, were less commonly prescribed with increasing age, increasing Charlson Comorbidity Index, decreasing eGFR (except greater use of SGLT2i in the eGFR range 30–59 mL/min/1.73 m2), and in patients without vs with previous HHF in the past 3 months (except for ARNi).

Figure 2: Implementation of guideline-directed medical therapy across subgroups in the period 2021–23 (quadruple therapy era). ARNi, angiotensin receptor–neprilysin inhibitor; CI, Comorbidity Index; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; GDMT, guideline-directed medical therapy; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose co-transporter 2 inhibitor; Quad, quadruple

Patient adherence and persistence

Overall high patient adherence was observed for all GDMT components (Figure 3). The proportion of patients with good adherence (≥80% PDC) was 95% for beta-blockers, 95% for RASi/ARNi, 90% for MRA, 94% for SGLT2i, and 85% for quadruple therapy.

Figure 3: Proportion of patients with good adherence (proportion of days covered ≥80%) and 1-year persistence to heart failure with reduced ejection fraction guideline-directed medical therapy. ARNi, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose co-transporter 2 inhibitor; PDC, proportion of days covered; Quad, quadruple

The proportion of patients persisting to prescribed therapy at 0.5, 1, 1.5, and 2 years, respectively, was 92%, 90%, 89%, and 88% for beta-blockers; 92%, 89%, 87%, and 87% for RASi/ARNi; 82%, 77%, 75%, and 72% for MRA; and 90%, 86%, 85%, and 85% for SGLT2i. Approximately 67% persisted on quadruple therapy at 1 year. Regarding RASi and ARNi, ARNi displayed the best adherence and 1-year persistence (93% and 88%) followed by angiotensin receptor blockers (82% and 66%) and with angiotensin-converting enzyme inhibitors last (79% and 60%). Patients with vs without a HHF at the time of SwedeHF registration or in the past 3 months were overall similarly likely to have good adherence and 1-year persistence (see Supplementary data online, Table S5).

Patient characteristics associated with adherence and persistence

Male sex was independently associated with lower adherence to beta-blockers and RASi/ARNi, and older age with better adherence to RASi/ARNi and SGLT2i. Among socioeconomic variables, living alone was associated with lower adherence to beta-blockers and RASi/ARNi and higher income with better adherence to all GDMT components. Several parameters and comorbidities potentially linked with tolerability issues were observed as independent predictors of lower adherence, including low blood pressure (RASi/ARNi), low heart rate (beta-blockers), lower eGFR (RASi/ARNi, MRA, and SGLT2i), and hyperkalaemia (MRA). Variables linked with poor health habits were associated with worse adherence, e.g. alcohol abuse (beta-blockers, RASi/ARNi, and MRA) and smoking (beta-blockers and MRA). A greater number of co-prescribed medications were associated with better adherence to beta-blockers and RASi/ARNi.

Predictors of 1-year persistence were overall directionally consistent with those of patient adherence. A full list of all independent predictors of patient adherence and 1-year persistence are detailed in Supplementary data online, Tables S6 and S7.

Explorative associations between prescriptions, patient adherence, persistence, and outcomes

Over a median follow-up of 2.3 years (interquartile range: 0.9–3.0) years, the incidence rate of experiencing a HHF/cardiovascular death was 16 (95% CI 16–16) per 100 patient-years [14 (95% CI 12–13) for HHF and 7 (95% CI 6–7) for cardiovascular deaths). As compared with having no prescribed GDMT at index, an increasing number of prescribed GDMTs were associated with progressively lower risk for HHF/cardiovascular death in crude and adjusted analyses, e.g. monotherapy [crude hazard ratio (HR) 0.81 (95% CI 0.55–1.19); adjusted HR 0.64 (0.42–0.95)], dual therapy [crude HR 0.64 (0.45–0.91); adjusted HR 0.61 (0.42–0.89)], triple therapy [crude HR 0.56 (0.40–0.79); adjusted HR 0.58 (0.40–0.83)], and quadruple therapy [crude HR 0.48 (0.34–0.68); adjusted HR 0.54 (0.37–0.78)] (Figure 4).

Figure 4: Associations between (A) implementation of, (B) good patient adherence (proportion of days covered ≥80%) to, and (C) 1-year patient persistence to failure with reduced ejection fraction guideline-directed medical therapy and hospitalization for heart failure/cardiovascular death. ARNi, angiotensin receptor–neprilysin inhibitor; BB, beta-blocker; CI, confidence interval; GDMT, guideline-directed medical therapy; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; PDC, proportion of days covered; RASi, renin–angiotensin system inhibitor; SGLT2i, sodium–glucose co-transporter 2 inhibitor

In crude and adjusted analyses, having good adherence during the first year post-index was associated with lower risk for HHF/cardiovascular death for beta-blockers [crude HR 0.70 (0.62–0.79); adjusted HR 0.77 (0.68–0.86)], RASi/ARNi [crude HR 0.54 (0.48–0.60); adjusted HR 0.74 (0.67–0.83)], MRA [crude HR 0.61 (0.55–0.67); adjusted HR 0.80 (0.72–0.89)], and SGLT2i [crude HR 0.52 (0.37–0.74); adjusted HR 0.62 (0.43–0.89)].

In crude and adjusted analyses, persisting use of therapy at 1 year post-index was associated with lower risk for HHF/cardiovascular death for beta-blockers [crude HR 0.81 (0.74–0.89); adjusted HR 0.79 (0.71–0.87)], RASi/ARNi [crude HR 0.65 (0.60–0.71); adjusted HR 0.82 (0.75–0.89)], and MRA [crude HR 0.67 (0.61–0.73); adjusted HR 0.84 (0.77–0.91)], but not significantly for SGLT2i [crude HR 0.76 (0.53–1.09); adjusted HR 0.88 (0.61–1.28)].

Sensitivity analyses

The adjusted association between number of prescribed GDMT components and HHF/cardiovascular death was consistent with the main analysis when restricted to those enrolled 2021–23 (see Supplementary data online, Table S8). The proportions of patients with good adherence (≥80% PDC) and 1-year persistence, respectively, assessed separately among de novo users (beta-blockers: 95% and 89%; RASi/ARNI: 95% and 89%, MRA: 90% and 75%, SGLT2i: 94% and 85%) were consistent with those observed in the main analysis including also prevalent users. When defining good adherence as ≥88% PDC, the proportion of patients with good adherence was slightly lower than in the main analysis (beta-blockers: 92%; RASi/ARNI: 92%, MRA: 87%, SGLT2i: 92%, quadruple therapy: 80%).