| 1. |
- Pundi, Krishna, et al.
(author)
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Dronedarone Versus Sotalol in Antiarrhythmic Drug-Naive Veterans With Atrial Fibrillation
- 2023
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In: Circulation: Arrhythmia and Electrophysiology. - 1941-3149. ; 16:8, s. 456-467
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Journal article (peer-reviewed)abstract
- BACKGROUND: Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system. METHODS: Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes. RESULTS: The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA2DS2-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant. CONCLUSIONS: Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.
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| 2. |
- Singh, Jagmeet P., et al.
(author)
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Dronedarone versus sotalol in patients with atrial fibrillation : A systematic literature review and network meta-analysis
- 2023
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In: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 46:6, s. 589-597
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Research review (peer-reviewed)abstract
- BackgroundThere are limited comparative data on safety and efficacy within commonly used Vaughan-Williams (VW) class III antiarrhythmic drugs (AADs) for maintenance of sinus rhythm in adults with atrial fibrillation (AF). HypothesisWe hypothesized that dronedarone and sotalol, two commonly prescribed VW class III AADs with class II properties, have different safety and efficacy effects in patients with nonpermanent AF. MethodsA systematic literature review was conducted searching MEDLINE (R), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to June 15, 2021 (NCT05279833). Clinical trials and observational studies that evaluated safety and efficacy of dronedarone or sotalol in adults with AF were included. Bayesian random-effects network meta-analysis (NMA) was used to quantify comparative safety and efficacy. Where feasible, we performed sensitivity analyses by including only randomized controlled trials (RCTs). ResultsOf 3581 records identified through database searches, 37 unique studies (23 RCTs, 13 observational studies, and 1 nonrandomized trial) were included in the NMA. Dronedarone was associated with a statistically significantly lower risk of all-cause death versus sotalol (hazard ratio [HR] = 0.38 [95% credible interval, CrI: 0.19, 0.74]). The association was numerically similar in the sensitivity analysis (HR = 0.46 [95% CrI: 0.21, 1.02]). AF recurrence and cardiovascular death results were not significantly different between dronedarone and sotalol in all-studies and sensitivity analyses. ConclusionThe NMA findings indicate that, across all clinical trials and observational studies included, dronedarone compared with sotalol was associated with a lower risk of all-cause death, but with no difference in AF recurrence.
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| 3. |
- Singh, Jagmeet P., et al.
(author)
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Phased target trial design and meta-analysis in a head-to-head treatment comparison
- 2023
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In: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 32:Suppl. 1, s. 444-444
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Journal article (other academic/artistic)abstract
- Background: For conditions with rare clinical outcomes, real-world treatment comparisons are challenging to design and prone to confounding.Objectives: To present a robust methodologic approach for rigorous and transparent assessment of rare outcomes using real-world data.Methods: We emulated a target trial using an active comparator, new-user design to compare dronedarone to sotalol for rhythm control in atrial fibrillation (AF) as both are recommended for similar patient phenotypes. Using one protocol, a pre-specified stepwise approach was implemented across 4 datasets (Optum CDM; IBM MarketScan; Veterans Affairs Electronic Health Records; Swedish National Patient Register). Meta-analysis was used to ensure sufficient capture of specific, rare primary outcomes (cardiovascular (CV) hospitalization and ventricular proarrhythmia) and to evaluate consistency of findings across patient populations. Steps 1–3 focused on cohort selection, propensity score matching (PSM), baseline equipoise and residual confounding assessment via negative control outcome analyses. In steps 4–6, outcomes in the individual cohorts were analyzed using an as-treated approach and Cox proportional hazards models. Step 7 included a heterogeneity assessment, meta-analysis using fixed effects models, and hypothesis testing using a hierarchical approach. In step 8, sensitivity analyses, including E-values and Inverse Probability of Censoring Weighting, were conducted to verify the robustness of findings.Results: In step 1, 35,467 sotalol and 27,955 dronedarone patients with AF who were antiarrhythmic drug-naive were identified across databases. In steps 2–3, 23,275 dronedarone patients were PS-matched to 23,275 sotalol patients. Baseline covariates were well-balanced and little-to-no residual confounding was observed via the negative control analyses. Individual HRs were estimated in steps 4–6, and, when no significant heterogeneity between databases was observed, hazard ratios (HRs) were pooled across datasets in step 7. For example, for CV hospitalization, dronedarone was superior to sotalol with no heterogeneity (HR: 0.91; 95% CI: 0.85, 0.97; Cochran Q p-value: 0.32). Eleven sensitivity analyses were conducted in step 8 and confirmed that findings were generally robust.Conclusions: An active comparator, new-user design using the target trial approach coupled with meta-analysis generated consistent findings across databases and countries using one protocol. Similar methods, including a pre-specified stepwise approach, negative control outcome, and tests for robustness should be considered for real-world studies where specific, rare outcomes need to be examined in a rigorous and transparent way.
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