Beta-blocker dose titration, functional capacity, and all-cause mortality in patients with heart failure and reduced ejection fraction

Background Physical activity is recommended as part of comprehensive heart failure (HF) management alongside pharmacotherapy to improve outcomes. Treatment with beta-blockers (BB) reduces mortality and improves HF symptoms but may also impair exercise capacity due to BB-induced chronotropic incompetence. Purpose To explore the association between change in BB dose during GDMT titration, physical activity, and mortality in patients with chronic HF with reduced left ventricular ejection fraction (LVEF). Methods We analysed all HF patients with an LVEF ≤40% registered in the Norwegian Heart Failure Registry from 2013–2025 who had self-reported physical activity and 6-minute walking test (6MWT) data available at the first and last visit during guideline-directed medical therapy (GDMT) titration follow-up. Patients were stratified according to change in BB dose during follow-up, and associations with changes in physical activity and 6MWT were analysed using linear and logistic regression. Cox regression was used to determine associations with all-cause mortality. All models were adjusted for age, sex, body mass index, smoking status, HF aetiology, LVEF, blood pressure, heart rate, NYHA functional class, comorbidities, NT-proBNP, eGFR, and haemoglobin, and use of ACEi/ARBs/ARNIs, MRA, and SGLT2i. Results In total, 16,441 patients (mean age 68.4±11.8 years; 24.6% females) were included. After a median (IQR) up-titration period of 143 (81–239) days, 40% had escalated BB therapy, 48% had no change, and 12% had reduced the BB dose. In adjusted analyses, BB dose reduction was associated with a small increase in absolute 6MWT distance (6.32 meters [95% CI 1.58 – 11.07]) but with a 25% higher likelihood of decreasing light physical activity (RRR 1.25 [1.02–1.53]). BB dose escalation was associated with a decrease in absolute 6MWT distance (-6.53 meters [-9.67 – -3.38)) but with a 23% higher likelihood of increasing light physical activity (RRR 1.23 [1.07–1.42]) and 13% higher likelihood of increasing vigorous physical activity (RRR 1.13 [1.02–1.25]). Changes in BB dose during the titration visits were not associated with all-cause mortality during one year of follow-up after the last titration visit. Increased 6WMT and vigorous physical activity during follow-up were associated with reduced all-cause mortality risk (HR 0.53 [0.42–0.67] and HR 0.45 [0.35–0.60], respectively), whereas increased light physical activity was not associated with all-cause mortality. Conclusion During GDMT titration in HFrEF, BB dose adjustments were associated with small, divergent changes in 6MWT distance and self-reported physical activity, but not with one-year all-cause mortality. Improvements in 6MWT distance and increases in vigorous physical activity were associated with lower 1-year mortality. This underscores the complexity of optimizing BB therapy in HFrEF and supports an individualized approach to BB dosing.