Impact of higher comorbidity burden on guideline-directed medical therapy in patients with heart failure with reduced ejection fraction

Background Heart failure (HF) frequently coexists with multiple comorbidities, which increasingly contribute to disease complexity and influence clinical management. Although guideline-directed medical therapy (GDMT) improves outcomes in HF with reduced ejection fraction (HFrEF), multimorbidity may hinder its implementation in real-world practice. Purpose This prespecified subanalysis of the TITRATE-HF registry investigated the impact of higher comorbidity burden on GDMT use and titration, as well as its association with clinical outcomes. Methods TITRATE-HF is a prospective Dutch HF registry evaluating the implementation of the European Society of Cardiology HF guidelines across 48 Dutch hospitals, with patient enrolment between June 2022 and February 2024 and ongoing follow-up. Data were collected at baseline, 6 months, and 12 months, including GDMT use and clinical outcomes. Comorbidity burden was defined by the presence of obesity, hypertension, cerebrovascular accident, atrial rhythm disorder, diabetes mellitus, renal insufficiency, chronic obstructive pulmonary disease, and obstructive sleep apnoea syndrome. For each patient, the number of comorbidities was summed and categorized into six groups (0, 1, 2, 3, 4, and ≥5 comorbidities), to evaluate associations with GDMT use and clinical outcomes. Results For this analysis, 3,367 patients with HFrEF (left ventricular ejection fraction ≤40%) were included. In the overall cohort, 9.8% of patients had 0 comorbidities, 23.2% had 1, 26.8% had 2, 21.0% had 3, 12.4% had 4, and 6.8% had ≥5 comorbidities. When examining prescription patterns of GDMT, use of quadruple therapy decreased with higher comorbidity burden (65.8% to 55.4%, p = 0.027) (Figure 1). Additionally, prescription rates of mineralocorticoid receptor antagonists decreased with higher comorbidity burden, whereas prescription rates of renin-angiotensin system inhibitors, beta-blockers, and sodium-glucose cotransporter 2 inhibitors did not differ significantly (Figure 1). In univariable analysis, each additional comorbidity was associated with lower odds of quadruple therapy (OR 0.92, 95% CI 0.87-0.97, p = 0.001); however, this association was no longer significant after multivariable adjustment (adjusted OR 1.01, 95% CI 0.95-1.08, p = 0.71). Regarding clinical outcomes, each additional comorbidity was associated with a higher risk of the composite endpoints of all-cause mortality (ACM) and HF hospitalisations, ACM and cardiac hospitalisations, and ACM and all-cause hospitalisations (Figure 2). Conclusion In HFrEF, patients with a higher comorbidity burden less often used quadruple therapy and had a worse prognosis.Fig. 1.GDMT prescription ratesFig. 2.aHRs per additional comorbidity