Mortality and ventricular arrhythmias in patients on d,l-sotalol for rhythm control of atrial fibrillation: A nationwide cohort study Hanna Lenhoff, MD,* Hans J€arnbert-Petersson, PhD,† Borje Darpo, MD, PhD,‡ Per Tornvall, MD, PhD,* Mats Frick, MD, PhD* From the *Department of Clinical Science and Education, Division of Cardiology, Karolinska Institutet, South Hospital, Stockholm, Sweden, † Department of Clinical Science and Education, Karolinska Institutet, South Hospital, Stockholm, Sweden, and ‡ Clario, Philadelphia, Pennsylvania. BACKGROUND Use of d,l-sotalol for rhythm control in patients with atrial fibrillation (AF) has raised safety concerns. Previous ran- domized studies are few and not designed for mortality outcome. OBJECTIVE The purpose of this study was to compare the inci- dences of mortality and ventricular arrhythmias in AF patients treated with d,l-sotalol for rhythm control vs matched control pa- tients treated with cardioselective beta-blockers. METHODS This population-based cohort study included AF patients from the Swedish National Patient Registry (2006–2017) who un- derwent rhythm control after a second cardioversion. Incidence rates (IRs) and adjusted hazard ratios (aHRs) for mortality and a composite endpoint of cardiac arrest/death and ventricular arrhyth- mias were calculated for the overall cohort and a 1:1 propensity score matched cohort of d,l-sotalol vs beta-blocker treatment. RESULTS Among patient treated with d,l-sotalol (n 5 4987) and beta-blocker (n 5 27,078) (mean follow-up 458 days), all-cause mortality was lower in patients treated with d,l-sotalol: IR 1.21; 95% confidence interval 0.95–1.52 vs 2.42 (2.26–2.60) deaths per 100 patient-years; aHR 0.66 (0.52–0.83). The difference in mor- tality persisted in the propensity score matched comparison (n 5 4953 in each group): aHR 0.63 (0.48–0.86). No differences were observed in the composite outcome: IR in propensity cohorts 2.13 (1.78–2.52) vs 2.07 (1.73–2.53) events per 100 years; aHR 1.01 (0.78–1.29). CONCLUSION There was no excess mortality with d,l-sotalol compared with cardioselective beta-blockers in patients undergoing rhythm control treatment for AF after a second cardioversion. Our results indicate that the risk associated with d,l-sotalol treatment for AF can be mitigated by careful patient selection and strict adher- ence to follow-up protocols. KEYWORDS Atrial fibrillation; Antiarrhythmic drug; Sotalol; Cardio- version; Adverse effect; Mortality (Heart Rhythm 2023;20:1473–1480) © 2023 Heart Rhythm Society. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity and mortality, as well as increased health care expenditures.1 The treatment strategy for symptomatic AF and AF associ- ated with heart failure is maintenance of sinus rhythm (SR).2 Until recently, no study has shown that an early rhythm control strategy is associated with a lower risk of adverse cardiovascular outcomes.3,4 Despite progress with pulmonary vein ablation, 25%–30% of patients experience recurrence of AF.5,6 Furthermore, ablation-related serious adverse events have been reported, with an incidence as high as 7%.7,8 Therefore, treatment with antiarrhythmic drugs (AADs) for rhythm control remains the main option in many patients. d,l-Sotalol is one of the recommended AADs for mainte- nance of SR.9,10 d,l-Sotalol, hereafter termed “sotalol,” is a Vaughan Williams class III AAD with potent IKr-blocking properties, and patients taking sotalol are at increased risk of ventricular arrhythmias. Sotalol is also indicated for the treatment of symptomatic ventricular arrhythmias in patients with an implantable cardioverter-defibrillator. A meta- analysis of studies of patients with AF has shown increased mortality associated with treatment with several AADs, including sotalol.11 However, the included studies on sotalol were small, had short follow-up, and were not designed for mortality as an outcome. To reduce the risk of ventricular ar- rhythmias, sotalol should be restricted to patients with struc- turally normal hearts.2,12 This knowledge has led to changes in guidelines. As a result, more stringent use of sotalol has been recommended.9,13–15 However, the true incidence of Address reprint requests and correspondence: Dr Hanna Lenhoff, VO Kardiologi, S€odersjukhuset, Sjukhusbacken 10, 11883 Stockholm, Sweden. E-mail address:
[email protected]. 1547-5271/© 2023 Heart Rhythm Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.hrthm.2023.08.019
adverse events with sotalol therapy for AF in a guideline- selected population is unknown. In the absence of large randomized studies of patients mir- roring daily practice, real-world data obtained from Swedish patient registries could fill the knowledge gap regarding the safety of sotalol in AF. Therefore, the present study was per- formed to examine the incidences and risks of mortality and ventricular arrhythmias in patients with rhythm control of AF, and to test our hypothesis that there is no excess mortality in patients treated with sotalol. Methods The study was designed as a population-based cohort study using data from 3 nationwide Swedish health registers. The National Patient Register (NPR), which includes both hospi- talized and specialized outpatient clinic patients, was linked to the Drug Prescription Register and the Cause of Death Register. The National Board of Health and Welfare (www. socialstyrelsen.se) managed the data, linking the registers together using civic identification numbers given to all per- manent residents in Sweden. The original study population comprised all patients diag- nosed with AF (International Classification of Diseases, Tenth Revision [ICD-10] I48) between January 1, 2006, and December 31, 2017, for a total of 548,120 patients (Figure 1). To identify patients with a rhythm control strat- egy, only adult patients who had undergone cardioversion (CV) were included (DF010, DF026, and DF027). In Swe- den, most patients are offered 1 attempt at CV treated with cardioselective beta-blockers. Sotalol initiation and follow- up typically is performed by cardiologists in an outpatient setting, in the absence of risk factors. To establish a cohort in which a rhythm control strategy was intended, an addi- tional inclusion criterion required that patients should previ- ously have undergone 1 CV, that is, they were included at the date of their second CV (n 5 38,454). The only exclusion criteria were a previous diagnosis of ventricular arrhythmia, resuscitation, or insertion of an implantable cardioverter- defibrillator. Background characteristics, sex assigned at birth, and comorbidities were collected from NPR, as pri- mary or secondary diagnosis, with information from 1997 and later (Supplemental Table A.1). The study was conduct- ed in accordance with the principles of the Declaration of Helsinki and was approved by the Regional Ethical Review Board in Stockholm, Sweden (EPN 2017/2555-31). Treatment and exposure definition Pharmacotherapy at baseline was collected from Anatomical Therapeutic Chemical (ATC) codes of prescribed drugs up to 12 months ahead of inclusion (Table A.2). Metoprolol and bi- soprolol, the most common cardioselective beta-blockers used in Sweden, were chosen as control treatment. Patients were defined as treated when a dispensation was confirmed 4 months before the date of inclusion, that is, date of the sec- ond CV. In Sweden, drug prescriptions cannot be made for more than 120 days at a time, and patients were considered “on treatment” if they had regular dispensations, at least every 150 days to allow for some gap in dispensations. After the last dispensation, a 120-day treatment period was ac- counted for, unless the patient was censored due to death or prescription of another AAD (flecainide, disopyramide, dro- nedarone, or amiodarone). Patients on sotalol were not al- lowed to cross over to the beta-blocker group, and vice versa. Outcomes The primary outcome was all-cause mortality. The secondary outcomes were a composite of arrhythmic events, defined as any diagnosis of cardiac arrest/death or ventricular arrhythmias, as well as the individual arrhythmic components of cardiac ar- rest including sudden cardiac death and survival after cardiopul- monary resuscitation, or a diagnosis of ventricular arrhythmias. Statistical analysis To compare baseline characteristics (Table 1), an unpaired t test was used for means and the c2 test for proportions. Follow-up time was defined from the second CV, with first inclusion January 1, 2006, and last inclusion December 31, 2017, until mortality, discontinuity, or end of study October 10, 2018, whichever occurred first. Discontinuity was defined as when the patient was dispensed any other AAD (disopyramide, dronedarone, flecainide, amiodarone) or any beta-blocker to avoid crossovers, or as 120 days after last drug dispensation. All patients underwent follow-up for a minimum of 10 months and a maximum of 13 years (Supplemental Figure A.1). To study the occurrence of all-cause mortality and second- ary endpoints in each group, incidence rates (IRs) were calcu- lated.16 IR represents the number of events per accumulated time of exposure, that is, the sum of each patient’s individual follow-up time. To test the difference in survival times between the treat- ment groups, 2 methods were used. First, Kaplan-Meier (KM) analysis and log-rank test were used. Second, Cox regression analysis was performed to evaluate the impact of baseline characteristics on the endpoints. The Cox regression model included adjustment for treatment (sotalol vs beta- blocker, using beta-blockers as the reference), as well as diag- nosis at baseline, drugs used within 12 months before the index, sex, and age (Table 1, and Supplemental Tables A.1 and A.2). Hazard ratios (HRs), both crude and adjusted hazard ratio (aHR; model 2), for mortality and secondary outcomes were presented along with corresponding 95% confidence in- tervals (CIs). The assumption of proportional hazards was tested using a log-minus-log plot and by examining the corre- lation of scaled Schoenfeld residuals with time. Because patients treated with sotalol and beta-blocker differed in background characteristics, we also used propen- sity score matching with logistic regression to control poten- tially confounding variables, including diagnosis of comorbidities, drug treatments, gender, and age (Table 1, and Tables A.1 and A.2). We created a propensity score matched cohort of patients included at second CV using 1474 Heart Rhythm, Vol 20, No 11, November 2023
beta-blockers in the unadjusted comparison. Among patients treated with sotalol (n 5 4987), 75 (1.5%) met the primary outcome, and among patients treated with beta-blocker (n 5 27078), 816 (3.0%) met the primary outcome. The IR of all-cause mortality in patients on sotalol and on beta- blockers was 1.21 (0.95–1.52) vs 2.42 (2.26–2.60) deaths per 100 years, respectively, resulting in HR of 0.50 (0.39– 0.63) (Figure 2A). The factors with the strongest association with mortality in the crude analysis were advanced age and renal failure (Supplemental Table A.4). In the adjusted anal- ysis, all-cause mortality remained lower in patients treated with sotalol [aHR 0.66 (0.52–0.83)] (Table 2). In the propensity score matched cohorts (n 5 4953 in respective group), all-cause mortality was lower in patients treated with sotalol compared to the matched control group on beta-blockers, with 73 (1.5%) vs 126 (2.5%) deaths, respectively. In the matched groups, the IR for mortality was 1.19 (0.93–1.49) deaths per 100 years in patients treated with sotalol vs 2.01 (1.67–2.39) deaths per 100 years in pa- tients treated with beta-blocker, with a crude HR for mortality of 0.59 (0.44–0.79) (Figure 2B). Ischemic heart disease was the most common underlying cause of death, and cardiovas- cular causes constituted 2 % of total deaths. Stroke and intra- cranial bleedings were causal in 8% of the deaths, whereas malignancies were the second most common cause of death (28%) (Supplemental Table A.5). Compared in adjusted analysis, aHR for all-cause mortality was 0.63 (0.47–0.85) in favor of patients on sotalol. In subgroup analysis, HR for all-cause mortality was lower in patients treated with sotalol in most clinically relevant subgroups (Figure 3). There was a significant interaction between treatment and age, with only elderly (aged .65 years) patients treated with sotalol having lower mortality. Secondary outcomes There was no difference in the composite arrhythmic outcome in the total cohort: IR 2.16 (1.81–2.56) in patients treated with sotalol vs 2.10 (1.95–2.26) events per 100 years in patients treated with beta-blocker, and aHR of 1.10 (0.91– 1.33) (Table 2, and Supplemental Tables A.6 and A.7). The propensity matched cohorts showed similar results: IR 2.13 (1.78–2.52) vs 2.07 (1.73–2.53) for the composite arrhythmic outcome, and aHR of 1.01 (0.78–1.29). Ventricular arrhyth- mias occurred with similar frequency in the 2 propensity score matched groups: IR 1.38 (1.10–1.71) in patients treated with sotalol and 1.26 (1.00–1.57) events per 100 years in pa- tients treated with beta-blocker, and aHR of 1.05 (0.76–1.43). Discussion Sotalol is widely used as an AAD for the treatment of AF worldwide.3,15,18 A serious and potentially life-threatening adverse effect of sotalol is pronounced QTc prolongation, which may trigger torsades de pointes (TdP), a specific form of polymorphic ventricular arrhythmia. A previous meta-analysis showed that sotalol increases mortality in AF Table 1 Background characteristics Total cohort Propensity matched cohort d,l-Sotalol Beta-blocker P value* d,l-Sotalol Beta-blocker (n 5 4987) (n 5 27,078) (n 5 4953) (n 5 4953) P value* Age (y) 67.50 6 9.83 67.47 6 10.42 .87 67.46 6 9.82 67.68 6 9.48 .25 Women 1553 (31.1) 8791 (32.5) .068 1537 (31.0) 1542 (31.1) .91 CHADS-VASc score 2.38 6 1.94 2.50 6 2.07 .001 2.37 6 1.94 2.37 6 1.91 .41 Ischemic stroke, TIA 411 (8.2) 2378 (8.8) .22 406 (8.2) 374 (7.6) .23 Ischemic heart disease 993 (19.9) 5672 (20.9) .099 983 (19.8) 879 (17.7) .007 CHF 692 (13.9) 5947 (22.0) .001 677 (13.7) 702 (14.2) .47 Hypertension 2729 (54.7) 15706 (58.0) .001 2713 (54.8) 2742 (55.4) .56 Diabetes mellitus 533 (10.7) 3349 (12.4) .001 533 (10.7) 505 (10.1) .38 OSAS 286 (5.7) 1863 (6.9) .003 283 (5.7) 325 (6.6) .043 Chronic kidney disease 63 (1.3) 871 (3.2) .001 61 (1.2) 100 (2.0) .002 COPD 135 (2.7) 1295 (4.8) .001 131 (2.6) 197 (4.0) .001 Pacemaker 158 (3.2) 1011 (3.7) .055 156 (3.1) 136 (2.7) .26 Thyroid disease 334 (6.7) 2068 (7.6) .021 329 (6.6) 332 (6.7) .90 Malignancy 644 (12.9) 4210 (15.5) .001 635 (12.4) 592 (12.0) .19 ACE inhibitor/ARB 2570 (51.5) 15755 (58.2) .001 2547 (51.4) 2755 (55.6) .001 Digoxin 878 (17.6) 4746 (17.5) .89 868 (17.5) 846 (17.1) .58 Diuretic 1309 (26.2) 9401 (34.7) .01 1294 (26.1) 1572 (31.7) .001 Statins 1805 (36.2) 9674 (35.7) .53 1795 (36.2) 1622 (32.7) .001 NOAC or warfarin 3928 (78.8) 22736 (84.0) .001 3905 (78.8) 4202 (85.6) .001 Antidiabetic drug 435 (8.7) 2757 (10.2) .002 432 (8.7) 423 (8.5) .75 Aspirin or platelet inhibitor 1915 (38.4) 7946 (29.3) .001 1902 (38.4) 1405 (28.4) .001 Values are given as mean 6 SD or n (%) unless otherwise indicated. ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin receptor blocker; CHF 5 congestive heart failure; COPD 5 chronic obstructive pulmonary disease; NOAC 5 novel oral anticoagulants; OSAS 5 obstructive sleep apnea; TIA 5 transient ischemic attack. *All P values derived from Student t test or c2 test. Drugs dispensed within 12 months before index. 1476 Heart Rhythm, Vol 20, No 11, November 2023
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