Role of non-cardiac comorbidities in heart failure across the ejection fraction spectrum : diagnosis, treatment and prognosis

Background. Heart failure (HF) represents a significant challenge due to its heterogeneous nature across the spectrum of ejection fraction (EF). This heterogeneity is in part characterized by a difference in distribution and prognostic role of comorbidities, both cardiac and non-cardiac, which impact patientŐs outcome and influence diagnostic and therapeutic approaches. Understanding patient profiles, where comorbidity has a key role, is crucial for optimizing HF trials and management strategies which involve also the effective management of non-cardiac comorbidities such as type 2 diabetes mellitus (T2DM), iron deficiency (ID), and chronic obstructive pulmonary disease (COPD).

Aims. The primary aim of this thesis was to examine the role of non-cardiac comorbidities in patients with HF across the EF spectrum, in terms of epidemiology, treatment and clinical trial design aspects, by using data from the Swedish Heart Failure Registry (SwedeHF). Specific aims were to investigate:

Ą Implementation of, independent predictors of, and outcomes associated with sodium-glucose contransporter-2 inhibitor (SGLT2i) use in patients with HF and T2DM (study I).

Ą Epidemiology of ID in HF; and the implementation of, independent predictors of, and outcomes associated with ID testing and ferric carboxymaltose (FCM) use in patients with ID and HF (study II).

Ą Real-world eligibility for sotagliflozin based on the SOLOIST-WHF selection criteria in patients stabilized after a HF hospitalization and with T2DM (study III).

Ą Prevalence of, independent predictors of, and outcomes associated with COPD in patients with HF (study IV).

Materials. All studies were based on data from SwedeHF, linked with additional national registries, with main statistical methods being logistic regression models for enhancing patient profiling, and Cox regression models for assessing independent associations between the exposures and the outcomes.

Study I: Use of SGLT2i in HF and T2DM. Among 6,805 HF patients with T2DM use of SGLT2i increased gradually to ~12% in 2018. Patient characteristics independently associated with SGLT2i use included younger age, a follow-up in specialty care, ischemic heart disease (IHD), preserved renal function, and absence of anemia. SGLT2i use was associated with a 30% lower risk of cardiovascular (CV) death or HF hospitalization, regardless of EF, metformin use, and renal function.

Study II: ID in HF. Of 21,496 HF patients enrolled in 2017-2018, ID testing was performed in 27%, revealing ID in 49% of tested patients. ID was associated with higher all-cause hospitalizations regardless of anemia. Only 19% of patients with ID received FCM. Independent predictors of ID testing and FCM use included anemia, higher New York Heart Association class, HF with reduced EF, and specialty care referral.

Study III: Eligibility for Sotagliflozin. Applying SOLOIST-WHF trial selection criteria to 5,453 inpatients with T2DM and stabilized after a HF hospitalization, 27.2% were eligible whether all selection criteria were applied, and 62.8% whether only those more likely to impact its implementation in clinical practice were considered. Eligible patients had more severe HF and higher event rates, particularly CV and HF events.

Study IV: COPD in HF. Among 97,904 HF patients enrolled in 2005-2021, COPD prevalence was 13%, highest in HFpEF (16%). COPD was linked with higher EF, female sex, smoking, peripheral artery disease, and lower education. COPD was independently associated with a 15% higher risk of CV death or HF hospitalization and worse outcomes regardless of EF. COPD patients had slightly lower use of guideline-directed HF treatments.

Conclusions. The studies presented in this thesis indicate that SGLT2i use in patients with HF and T2DM increased over time between 2013 and 2018, particularly among younger patients with IHD and preserved renal function, and was associated with lower morbidity and mortality (study I). ID testing was underutilized and ID was frequent and associated with worse outcome, with many diagnosed patients not receiving recommended FCM treatment, indicating suboptimal adherence to HF guidelines (study II). Of HF patients with T2DM, a small proportion was eligible for sotagliflozin if applying trial selection criteria, questioning clinical trial findings generalizability to daily clinical practice (study III). COPD was prevalent in HF, and most in HFpEF, associated with more severe HF, higher comorbidity burden, slight HF undertreatment, and worse outcomes regardless of EF (study IV).

List of scientific papers

I. Peter Moritz Becher*, Benedikt Schrage*, Giulia Ferrannini, Lina Benson, Javed Butler, Juan Jesus Carrero, Francesco Cosentino, Ulf Dahlstršm, Linda Mellbin, Giuseppe M C Rosano, Gianfranco Sinagra, Davide Stolfo, Lars H Lund, Gianluigi Savarese. Use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry. European Journal of Heart Failure. 2021, 23, 1012Đ1022.
https://doi.org/10.1002/ejhf.2131

II. Peter Moritz Becher, Benedikt Schrage, Lina Benson, Marat Fudim, Carin Corovic Cabrera, Ulf Dahlstršm, Giuseppe M C Rosano, Ewa A Jankowska, Stefan D Anker, Lars H Lund, Gianluigi Savarese. Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the Swedish Heart Failure Registry. European Journal of Heart Failure. 2021, 23, 1844-1854.
https://doi.org/10.1002/ejhf.2338

III. Peter, Moritz Becher*, Gianluigi Savarese*, Lina Benson, Ulf Dahlstršm, Patric Karlstršm, Peter G M Mol, Marco Metra, Deepak L Bhatt, Bertram Pitt, Lars H Lund. Eligibility for sotagliflozin in a real-world heart failure population-based on the SOLOIST-WHF trial enrolment criteria: data from the Swedish Heart Failure Registry. European Heart Journal - Cardiovascular Pharmacotherapy. 2023, 9, 343-352.
https://doi.org/10.1093/ehjcvp/pvad012

IV. Peter Moritz Becher, Felix Lindberg, Lina Benson, Camilla Hage, Ulf Dahlstršm, Stephan Rosenkranz, Francesco Cosentino, Giuseppe MC Rosano, Stefan Blankenberg, Paulus Kirchhof, Frieder Braunschweig, Lars H Lund, Gianluigi Savarese. Phenotyping patients with chronic obstructive pulmonary disease and heart failure: data from the Swedish Heart Failure Registry. [Submitted]