Phenotypes and therapy in heart failure and cardiovascular disease

Background Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction. However, both human and animal studies have shown that they also exert beneficial effects on endothelial function, inflammation and hemodynamics. In epidemiological studies their use has been associated with lower risk of incident cardiovascular (CV) disease and of death/heart failure hospitalisation (HFH) after a myocardial infarction.

Unmet needs in heart failure (HF) vary according to ejection fraction (EF) subgroups. Patients with HF and reduced EF (HFrEF) have access to life- prolonging therapies, but the implementation of these treatments remains suboptimal. In contrast, patients with HF and preserved EF (HFpEF) have limited therapeutic options, largely due to the heterogeneity of this condition, the multitude of competing risk factors, and limited pathophysiological understanding. Whether an additional HF phenotype characterized by a supranormal EF could help improve prognosis in HFpEF remains unclear.

Aims The aim of study I was to assess the prognosis of men with stable coronary artery disease (CAD) treated with PDE5i vs alprostadil. The overarching aim of the subsequent three studies was to improve the understanding of certain aspects of drug implementation in HFrEF and of prognosis in HFpEF. Specifically, these studies aimed to:

• In HFpEF: Investigate the frequency distribution of EF, identify patient characteristics associated with EF >60%, and evaluate prognosis across varying EF values (study II) .
• In HFrEF: Determine the probability of mineralocorticoid receptor antagonist (MRA) discontinuation and its predictors during the first year of treatment among new users, as well as the probability of MRA reinitiation in the subsequent year (study III)
• In HFrEF: Examine first-year adherence to and discontinuation of sodium- glucose cotransporter 2 inhibitors (SGLT2i), along with predictors of these outcomes among new users, and evaluate the probability of SGLT2i reinitiation in the following year (study IV)

Materials All studies were register-based. For study I, the cohort was selected by linking data from the National Patient Register (NPR) and the National Prescribed Drug Register. For study II, the cohort was derived from the Swedish HF Registry (SwedeHF). For studies III and IV, the cohorts were selected by linking data from SwedeHF and the National Prescribed Drug Register. Linkage with Statistics Sweden was used to retrieve socioeconomic variables in all studies. The NPR was also used to obtain information on comorbidities (for all studies) and on hospitalizations (for studies I and II). Finally, the Cause of Death Register was utilized in all studies.

Study I: Among 18,542 Swedish men with stable CAD 16,548 were subsequently treated with PDE5i and 1,994 with alprostadil, between 2006-2013. PDE5i users had fewer comorbidities, required less comedications, and had higher level of education. Treatment with PD5i was independently associated with lower risk of all-cause and CV death, revascularisation, myocardial infarction and HFH. The lower risk of death was dose dependent and stronger in younger men.

Study II: Among 5,576 patients with HFpEF enrolled in SwedeHF between 2017- 2021 and with EF measured continuously, 21% had EF>60%. An EF>60% was associated with more severe symptoms, female sex, hypertrophic cardiomyopathy, hypertension and valvular disease. The risk of all-cause and non- CV death and all-cause hospitalisation was higher with EF>55% in crude but not in adjusted analyses.

Study III: Among 11,474 patients with HFrEF enrolled in SwedeHF between 2006- 2021 and initiated on MRA 71% remained on therapy at one year. Advanced kidney disease, hyperkalaemia, lack of follow-up in specialty care, more severe heart failure, comorbidities, and markers of sociodemographic frailty were associated with discontinuation. Among those who discontinued, 46% reinitiated treatment the following year.

Study IV: Among 6,216 patients with HFrEF, enrolled in SwedeHF, who were initiated on SGLT2i therapy between 2019-2022 first-year adherence was 84% and only 16% discontinued therapy at one year. Chronic kidney disease, hypertension, diabetes mellitus, ischemic heart disease, lower income and non- use of anticoagulants were associated with non-adherence and discontinuation. Among discontinuers, 42% reinitiated treatment the following year.

Conclusions The studies in this thesis suggest that:

1) In men with stable CAD treatment with PDE5i vs alprostadil is independently associated with better prognosis, but confirming any causal relationship requires a randomized controlled trial.
2) Patients with higher EF in HFpEF may be underrepresented in SwedeHF, have a specific phenotype and tend to have a higher crude risk of death and hospitalization for non-CV causes.

3) One-third of new MRA users with HFrEF discontinue treatment within the first year, although nearly half of them restart therapy in the following year.
4) Treatment persistence and adherence among new SGLT2i users with HFrEF in SwedeHF is generally very high.

List of scientific papers

I. Daniel P. Andersson; Laura Landucci; Ylva Trolle Lagerros; Alessandra Grotta; Rino Bellocco; Mikael Lehtihet; Martin J. Holzmann. Association of Phosphodiesterase-5 Inhibitors Versus Alprostadil with Survival in Men with Coronary Artery Disease. J Am Coll Cardiol, 2021 Mar 30;77(12):1535-1550. https://doi.org/10.1016/j.jacc.2021.01.045

II. Laura Landucci; Ulrika Ljung Faxén; Lina Benson; Giuseppe MC Rosano; Ulf Dahlström; Lars H. Lund; Gianluigi Savarese. Characterizing heart failure across the spectrum of the preserved ejection fraction: does heart failure with supranormal ejection fraction exist? Data from the Swedish Heart Failure Registry. J Am Heart Assoc, 2025 Mar 13. https://doi.org/10.1161/JAHA.124.037502

III. Laura Landucci; Ulrika Ljung Faxén; Lina Benson; Ulf Dahlström; Juan J. Carrero; Gianluigi Savarese; Lars H. Lund. Discontinuation and reinitiation of mineralocorticoid receptor antagonists in patients with heart failure and reduced ejection fraction. Eur J Heart Fail, 2024 Nov 26. https://doi.org/10.1002/ejhf.3523

IV. Laura Landucci; Ulrika Ljung Faxén; Lina Benson; Gianluigi Savarese; Lars Lund. Adherence, discontinuation and reinitiation of Sodium- Glucose cotransporter 2 Inhibitors in patients with heart failure and reduced ejection fraction. [Manuscript]