Shveta S Raju

Rate- and Rhythm-Control Therapies in Patients With Atrial Fibrillation: A Systematic Review

Atrial fibrillation (AF) is a major public health problem in the United States. More than 2.3 million Americans are estimated to have AF (1). The known association between AF and substantial mortality, morbidity, and health care costs compounds the effect of this condition. Not only is the risk for death in patients with AF twice that of patients without it, but AF can result in myocardial ischemia and infarction, exacerbate heart failure (HF), and cause tachycardia-induced cardiomyopathy if the ventricular rate is not well-controlled (25). The most dreaded complication of AF is thromboembolism, especially stroke (6). In some patients, AF or therapies to manage this condition can severely depreciate quality of life (710). Furthermore, the management of AF and its complications is responsible for nearly

Rate- and Rhythm-Control Therapies in Patients With Atrial Fibrillation

16 billion in additional costs to the U.S. health care system per year (11). Despite the substantial public health effect of AF, uncertainties around its management remain. In particular, the comparative safety and effectiveness of different rate- and rhythm-control therapies for patients with AF are unclear. We conducted this systematic review to evaluate the comparative safety and effectiveness of rate- versus rhythm-control strategies; medications used for ventricular rate control; strict versus more lenient rate-control strategies; nonpharmacologic rate-control therapies versus medications; electrical cardioversion and antiarrhythmic medications for restoration of sinus rhythm; and catheter ablation, surgical ablation, and antiarrhythmic medications for maintenance of sinus rhythm. Methods We developed and followed a standard protocol for our review. Full details of our methods, search strategies, results, and conclusions are presented in a comparative effectiveness review commissioned by the Agency for Healthcare Research and Quality (AHRQ) and are available at www.effectivehealthcare.ahrq.gov (12). Data Sources and Searches We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for studies published between 1 January 2000 and 12 November 2013. Data before 2000 have been summarized in an AHRQ report on the management of new-onset AF published in 2001 (1315). Study Selection We identified randomized, controlled trials (RCTs) published in English that were comparative assessments of pharmacologic or nonpharmacologic rate- or rhythm-control therapies aimed at treating adults with AF. Observational studies were also allowed for comparisons of strict versus lenient rate control or cardiac resynchronization therapy versus other rhythm-control therapies. The following outcomes were considered: restoration of sinus rhythm (conversion), maintenance of sinus rhythm, recurrence of AF at 12 months, development of cardiomyopathy, death (all-cause and cardiac), myocardial infarction, cardiovascular hospitalizations, HF symptoms, control of AF symptoms, quality of life, functional status, stroke and other embolic events, bleeding events, and adverse effects of therapy. Data Extraction and Quality Assessment One investigator abstracted and another confirmed data related to study setting and design, patient characteristics, details of treatment, comparators, and relevant outcomes. The quality of individual studies was evaluated using the approach described in AHRQs Methods Guide for Effectiveness and Comparative Effectiveness Reviews (16). Investigators also assessed factors that limited applicability of the evidence. Data Synthesis and Analysis For each treatment comparison and outcome of interest, we determined the feasibility of completing a quantitative synthesis (meta-analysis) based on the volume of relevant literature, conceptual homogeneity of the studies (both in terms of study population and outcomes), and completeness of the reporting of results. We considered meta-analysis for outcomes that at least 3 studies reported. For our evaluation of rate- versus rhythm-control strategies, we grouped all rate-control strategies together and all rhythm-control strategies together, regardless of the specific medication or procedure. We grouped pharmacologic interventions by class, considering rate-controlling calcium-channel blockers and all -blockers each to be similar enough to be grouped together. We categorized procedures into electrical cardioversion, atrioventricular node (AVN) ablation, AF ablation by pulmonary vein isolation (PVI) (by open surgical, minimally invasive, or transcatheter procedures), and different types of surgical maze procedures and explored comparisons among these categories. In addition, for the comparisons focusing on medications versus procedures, we also explored grouping all medications together and comparing them with all procedures. When a meta-analysis was appropriate, we used a random-effects model to synthesize the available evidence quantitatively using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We used a standardized approach to rank the overall strength of evidence (SOE) for each outcome (16). Role of the Funding Source Primary funding was provided by AHRQ. Neither the technical experts nor AHRQ representatives had a role in the literature search, data analysis, interpretation of the data, or decision to submit the manuscript for publication. Results We screened 10495 abstracts, evaluated 570 full-text articles, and included 200 articles representing 162 studies involving 28836 patients (Figure 1). Tables 1 to 6 of the Supplement provide details about these studies and their populations for each topic described here. Table 7 of the Supplement lists identified and potential limitations of the studies. The full AHRQ report highlights additional findings (12). Figure 1. Summary of evidence search and selection. AAD = antiarrhythmic drug; CRT = cardiac resynchronization therapy; RCT = randomized, controlled trial. * Some studies were relevant to more than 1 topic. Supplement. Tables Rate- Versus Rhythm-Control Strategies We included 16 RCTs in this analysis: 13 compared pharmacologic rhythm-control versus rate-control strategies (1729) and 3 compared a rhythm-control strategy with PVI versus a rate-control strategy that involved AVN ablation and implantation of a pacemaker in 1 study (30) and rate-controlling medications in the other 2 (31, 32). Ten RCTs (17, 18, 2022, 2428) provided information on outcomes of interest and were combined quantitatively (Figure 2). Of these, 5 included only patients with persistent AF (2022, 25, 28), 1 included only patients with paroxysmal AF (17), and 4 included patients with paroxysmal or persistent AF (18, 24, 26, 27). Two studies (17, 22) compared a single-chamber pacemaker plus AVN ablation versus a dual-chamber pacemaker plus AVN ablation plus an antiarrhythmic medication; all others compared largely unspecified rate-control with rhythm-control strategies. Figure 2. Meta-analysis forest plots. AAD = antiarrhythmic drug; PVI = pulmonary vein isolation. A. All-cause mortality for rate- vs. rhythm-control strategies. B. Cardiovascular mortality for rate- vs. rhythm-control strategies. C. Stroke for rate- vs. rhythm-control strategies. D. Restoration of sinus rhythm for monophasic vs. biphasic waveforms. E. Maintenance of sinus rhythm for PVI vs. AAD therapy. Figure 2. Continued. Data from the included studies showed moderate SOE that pharmacologic rate- and rhythm-control strategies are of comparable efficacy with regard to their effect on all-cause mortality (odds ratio [OR], 1.34 [95% CI, 0.89 to 2.02]; Q= 21.71; P= 0.003) (Figure 2, A) (18, 2022, 24, 2628), cardiac mortality (OR, 0.96 [CI, 0.77 to 1.20]; Q= 3.55; P= 0.47) (Figure 2, B) (18, 21, 22, 24, 25), and stroke (OR, 0.99 [CI, 0.76 to 1.30]; Q= 7.02; P= 0.43) (Figure 2, C) (17, 18, 2022, 24, 27, 28). Although the meta-analysis for all-cause mortality showed a potential benefit, it did not reach statistical significance and 6 of the 8 studies (6069 patients [95%]) had ORs that crossed 1, resulting in a final moderate SOE. For cardiac mortality (Figure 2, B), point estimates were inconsistent and CIs were wide for 2 of the 5 studies (18, 21), but there was no evidence of heterogeneity; therefore, our SOE rating was not affected. For the outcome of stroke, there was no evidence of heterogeneity, but the findings were mostly driven by 1 large, good-quality RCT (4060 patients), which was inconsistent with several of the smaller studies, reducing our confidence in the finding and in the SOE. These studies largely included older patients with mild AF symptoms. Three RCTs compared pharmacologic rate-control strategies with rhythm-control strategies using antiarrhythmic medications (17, 18, 22). These RCTs showed fewer cardiovascular hospitalizations with the rhythm-control strategies (17, 18, 22). Although data from 5 RCTs suggest that there is no difference between pharmacologic rate- and rhythm-control strategies in their effect on HF symptoms (17, 22, 24, 26, 46) (Table 1), a prespecified substudy of the Atrial Fibrillation and Congestive Heart Failure study showed that a higher proportion of time spent in sinus rhythm was associated with a greater improvement in New York Heart Association class (29). Table 1. Summary of SOE and Effect Estimates for Rate- Versus Rhythm-Control Strategies Three studies compared a rhythm-control strategy involving catheter ablation with a rate-control strategy involving rate-controlling medications (32) or AVN ablation combined with implantation of a pacemaker (30) or rate-controlling medications (31). One study showed that catheter ablation was better than pharmacologic rate control at improving symptoms, neurohormonal status, and objective physiologic exercise capacity (32). Another study showed that PVI isolation was superior to AVN ablation and pacemaker implantation in improving quality of life, 6-minute walk distance, and ejection fraction (30). Another study showed that PVI resulted in long-term restoration o