Efficacy and safety of once-daily carvedilol in patients with atrial fibrillation: A randomized, double-blind, placebo-controlled trial

Heart rate (HR) control is a mainstay of atrial fibrillation (AF) management. Guidelines recommend first-line β-blockers for HR control in paroxysmal, persistent, or permanent AF.1January C.T. Wann S. Alpert J.S. et al.2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.J Am Coll Cardiol. 2014; 64: e1-e76Crossref PubMed Scopus (3017) Google Scholar Carvedilol, a non-selective β-blocker, has a documented HR-lowering effect; in a dose-escalation study of Japanese patients with chronic AF (AF Carvedilol study), each dose of carvedilol (5, 10 or 20 mg, once daily) significantly reduced HR from baseline (HR ≥80 bpm) during 6 weeks of treatment.2Inoue H. Atarashi H. Okumura K. et al.Heart rate control by carvedilol in Japanese patients with chronic atrial fibrillation: The AF Carvedilol study.J Cardiol. 2017; 69: 293-301Abstract Full Text Full Text PDF PubMed Google Scholar Although off-label carvedilol indications include AF,3Singh S. Carvedilol. 2022; Accessed February 23, 2024. https://www.statpearls.com/ArticleLibrary/viewarticle/102Google Scholar there are currently no phase 3 clinical trial data to support carvedilol use for HR control in patients with AF. We report results from a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of patients with persistent or permanent AF treated with once-daily carvedilol (Dilatrend® SR Capsule, Chong Kun Dang Pharmaceutical, Seoul, Republic of Korea) 8, 16 or 32 mg for 6 weeks (NCT03950843). Eligible patients who received carvedilol during the 6-week treatment period entered a 4-week open-label extension. Overall, 154 subjects were enrolled (safety analysis set [SAS]). Subjects in the full analysis set received carvedilol (n = 93) or placebo (n = 42): mean (SD) age 66.4 (9.6) years, mostly male (72.6%), with a mean (SD) resting HR of 98.3 (14.7) bpm, and CHA2DS2-VASc score of 2.43 (1.64), and the majority (80.7%) had a modified European Heart Rhythm Association (EHRA) score of 2a. Most subjects had persistent AF (77.0%) and the mean (SD) AF duration was 60.7 (73.8) months. There were no significant between group differences in baseline characteristics. Change in 24-hour mean HR from baseline to week 6 (primary endpoint) was reduced significantly by carvedilol vs. placebo (P < 0.0001; Figure 1A); changes were maintained in the 4-week extension period. Post-hoc subgroup analysis showed that changes in 24-hour mean HR from baseline to week 6 with carvedilol were dose-dependent: respective mean (SD) changes for carvedilol 8 mg (n = 14), 16 mg (n = 26), and 32 mg (n = 53) were −5.07 (5.97), −9.69 (6.34), and −7.58 (8.00) (P = 0.0072, P < 0.0001, and P < 0.0001, respectively). More subjects achieved HR <80 bpm at week 6 (secondary endpoint) in carvedilol vs. placebo groups (30.1% vs. 14.3%; P = 0.0499), with a risk difference of 15.82 (95% confidence interval: 1.72–29.93). Carvedilol was associated with significant improvement in modified EHRA scores from baseline to week 6 (P < 0.0001; secondary endpoint). Mean hourly HR at baseline was similar between the two groups (Figure 1B, upper panel) but, at week 6, carvedilol produced significant changes from baseline in mean HR at each hourly time point. In contrast, no significant changes from baseline in hourly mean HR were found in the placebo group. At week 6, modest but significant decreases in mean hourly HR were generally observed with carvedilol compared to placebo during the daytime, but there were fewer significant between-group differences at nighttime (exploratory endpoints; Figure 1B, lower panel). In the SAS, 60 treatment-emergent adverse events (TEAEs) were reported in 43 subjects (27.9%) during the 6-week trial: 43 AEs in 31 subjects (29.8%) in the carvedilol group, and 17 in 12 subjects (24.0%) in the placebo group. Most TEAEs were mild (41 cases) or moderate (18 cases) in severity. The most common TEAEs were dizziness in 9 subjects (5.8%) and dyspnea in 7 subjects (4.6%). This is the first pivotal phase 3 clinical trial to show the efficacy of once-daily carvedilol for HR control in patients with AF. Compared with placebo, carvedilol significantly decreased 24-hour mean HR from baseline to week 6 and this effect was maintained during the 4-week extension period. Changes were dose-dependent with higher carvedilol doses (16 and 32 mg) effecting larger changes than the 8 mg dose. Similar results were reported in the AF Carvedilol Japanese trial of patients with persistent or permanent AF, which demonstrated that once-daily carvedilol significantly reduced HR from baseline during 6 weeks of treatment.2Inoue H. Atarashi H. Okumura K. et al.Heart rate control by carvedilol in Japanese patients with chronic atrial fibrillation: The AF Carvedilol study.J Cardiol. 2017; 69: 293-301Abstract Full Text Full Text PDF PubMed Google Scholar In conclusion, carvedilol for 6 weeks was effective in reducing HR in patients with AF and maintained efficacy during the extension period. Carvedilol was well tolerated and the safety profile was consistent with previous reports.