Sana M. Al-Khatib, MD, MHS; Nancy M. Allen LaPointe, PharmD; Ranee Chatterjee, MD, MPH; Matthew J. Crowley, MD; Matthew E. Dupre, PhD; David F. Kong, MD; Renato D. Lopes, MD, PhD; Thomas J. Povsic, MD, PhD; Shveta S. Raju, MD; Bimal Shah, MD; Andrzej S. Kosinski, PhD; Amanda J. McBroom, PhD; Gillian D. Sanders, PhD
Disclaimer: The authors of this article are responsible for its contents. Statements in the article should not be construed as endorsements by AHRQ or the U.S. Department of Health and Human Services.
Grant Support: By AHRQ (contract 290-2007-10066-I).
Disclosures: Dr. Allen LaPointe reports grants from AHRQ during the conduct of the study and grants from Pfizer outside the submitted work. Dr. Kong reports grants from AHRQ during the conduct of the study. Dr. Lopes reports personal fees from Bayer, Boehringer Ingelheim, and Pfizer; grants and personal fees from Bristol-Myers Squibb; and grants from GlaxoSmithKline outside the submitted work. Dr. Shah reports personal fees from Bristol-Myers Squibb, Cardinal, Castlight, and Janssen Pharmaceutical and grants from Amgen, Amylin/BMS, and Lilly outside the submitted work. Dr. McBroom reports other funding from AHRQ during the conduct of the study. Dr. Sanders reports grants from AHRQ during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1467.
Requests for Single Reprints: Sana M. Al-Khatib, MD, MHS, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715; e-mail, email@example.com.
Current Author Addresses: Drs. Al-Khatib, Allen LaPointe, Dupre, Kong, Lopes, Shah, Kosinski, McBroom, and Sanders: Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.
Dr. Chatterjee: Sutton Station Internal Medicine, 5832 Fayetteville Road, Suite 113, Durham, NC 27713.
Dr. Crowley: Durham Veterans Affairs Medical Center, Health Services Research & Development (152), 508 Fulton Street, Durham, NC 27705.
Dr. Povsic: Duke University Medical Center, Bell Building, Room 348, Durham, NC 27710.
Dr. Raju: Gwinnett Clinic, 475 Philip Boulevard, Suite 100, Lawrenceville, GA 30046.
Author Contributions: Conception and design: S.M. Al-Khatib, N.M. Allen LaPointe, D.F. Kong, R.D. Lopes, S.S. Raju, B. Shah, A.J. McBroom, G.D. Sanders.
Analysis and interpretation of the data: S.M. Al-Khatib, N.M. Allen LaPointe, R. Chatterjee, M.J. Crowley, D.F. Kong, R.D. Lopes, T.J. Povsic, S.S. Raju, B. Shah, A.S. Kosinski, A.J. McBroom, G.D. Sanders.
Drafting of the article: S.M. Al-Khatib, N.M. Allen LaPointe, R. Chatterjee, M.J. Crowley, A.J. McBroom, G.D. Sanders.
Critical revision of the article for important intellectual content: N.M. Allen LaPointe, R. Chatterjee, M.J. Crowley, D.F. Kong, R.D. Lopes, T.J. Povsic, B. Shah, A.J. McBroom, G.D. Sanders.
Final approval of the article: N.M. Allen LaPointe, M.J. Crowley, R.D. Lopes, T.J. Povsic, B. Shah, G.D. Sanders.
Statistical expertise: D.F. Kong, A.S. Kosinski, G.D. Sanders.
Obtaining of funding: G.D. Sanders.
Administrative, technical, or logistic support: M.E. Dupre, A.J. McBroom, G.D. Sanders.
Collection and assembly of data: S.M. Al-Khatib, N.M. Allen LaPointe, R. Chatterjee, M.J. Crowley, M.E. Dupre, R.D. Lopes, B. Shah, A.J. McBroom, G.D. Sanders.
Al-Khatib SM, Allen LaPointe NM, Chatterjee R, Crowley MJ, Dupre ME, Kong DF, et al. Rate- and Rhythm-Control Therapies in Patients With Atrial Fibrillation: A Systematic Review. Ann Intern Med. 2014;160:760-773. doi: 10.7326/M13-1467
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Published: Ann Intern Med. 2014;160(11):760-773.
The comparative effectiveness of treatments for atrial fibrillation (AF) is uncertain.
To evaluate the comparative effectiveness of rate- and rhythm-control therapies.
English-language studies in PubMed, EMBASE, and the Cochrane Database of Systematic Reviews between January 2000 and November 2013.
Two reviewers independently screened citations to identify comparative studies that assessed rate- or rhythm-control therapies in patients with AF.
Reviewers extracted data on study design, participant characteristics, interventions, outcomes, applicability, and quality.
200 articles (162 studies) involving 28 836 patients were included. When pharmacologic rate- and rhythm-control strategies were compared, strength of evidence (SOE) was moderate supporting comparable efficacy with regard to all-cause mortality (odds ratio [OR], 1.34 [95% CI, 0.89 to 2.02]), cardiac mortality (OR, 0.96 [CI, 0.77 to 1.20]), and stroke (OR, 0.99 [CI, 0.76 to 1.30]) in older patients with mild AF symptoms. Few studies compared rate-control therapies and included outcomes of interest, which limited conclusions. For the effect of rhythm-control therapies in reducing AF recurrence, SOE was high favoring pulmonary vein isolation versus antiarrhythmic medications (OR, 5.87 [CI, 3.18 to 10.85]) and the surgical maze procedure (including pulmonary vein isolation) done during other cardiac surgery versus other cardiac surgery alone (OR, 7.94 [CI, 3.63 to 17.36]).
Studies were heterogeneous in interventions, populations, settings, and outcomes.
Pharmacologic rate- and rhythm-control strategies have comparable efficacy across outcomes in primarily older patients with mild AF symptoms. Pulmonary vein isolation is better than antiarrhythmic medications at reducing recurrences of AF in younger patients with paroxysmal AF and mild structural heart disease. Future research should address uncertainties related to subgroups of interest and the effect of different therapies on long-term clinical outcomes.
Agency for Healthcare Research and Quality.
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 (2–5).
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 (7–10). Furthermore, the management of AF and its complications is responsible for nearly $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.
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).
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 (13–15).
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.
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 AHRQ's Methods Guide for Effectiveness and Comparative Effectiveness Reviews(16). Investigators also assessed factors that limited applicability of the evidence.
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 β-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).
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.
We screened 10 495 abstracts, evaluated 570 full-text articles, and included 200 articles representing 162 studies involving 28 836 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).
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.
We included 16 RCTs in this analysis: 13 compared pharmacologic rhythm-control versus rate-control strategies (17–29) 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, 20–22, 24–28) provided information on outcomes of interest and were combined quantitatively (Figure 2). Of these, 5 included only patients with persistent AF (20–22, 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.
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.
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, 20–22, 24, 26–28), 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, 20–22, 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 of sinus rhythm in only 50% of patients (compared with none in the medical treatment group) and did not improve ejection fraction compared with a rate-control strategy (31).
Sixteen RCTs (47–62) assessed the use of medications for ventricular rate control. Of these, 3 included only patients with permanent AF (59, 61, 62), 1 included only patients with paroxysmal AF (52), and 4 included only patients with persistent AF (50, 53, 54, 56). Most studies compared 2 or more of the following medications: a β-blocker, a calcium-channel blocker, digoxin, or amiodarone.
Although we found evidence that reduction of ventricular response during AF in symptomatic patients benefits patients by reducing the risk for tachycardia-induced cardiomyopathy, HF, and MI and by improving quality of life, data were inconclusive as to whether any 1 medication used for ventricular rate control is safer or more effective than the others (Table 2).
Table 2. Summary of SOE and Effect Estimates for Medications Used for Ventricular Rate Control
Few studies have evaluated the comparative safety and effectiveness of a strict versus more lenient rate-control strategy; these included 1 good-quality RCT (63) in patients with permanent AF and 2 observational studies (64, 65) that were secondary analyses of RCTs. There were no statistically significant differences in all-cause and cardiovascular mortality, HF symptoms, cardiovascular hospitalizations, bleeding events, quality of life, and control of AF symptoms between strict and lenient rate-control strategies, and evidence was limited by the small number of studies and the imprecision of their findings.
Six RCTs (22, 66–70) evaluated the comparative effectiveness of a procedural intervention versus a primarily pharmacologic intervention for rate control of AF (22, 66, 67, 70) or of 2 procedural interventions, with pharmacologic therapy used in only 1 group (68, 69).
The studies varied in the types of procedures and pharmacologic interventions evaluated. All studies included at least 1 treatment group with radiofrequency ablation or modification of the AVN or His bundle, most often in conjunction with pacemaker placement. The comparison groups included a pharmacologic intervention whose main purpose was to control ventricular heart rate and a procedure that involved a pacemaker implant and AVN ablation in some studies.
Four studies reported outcomes related to heart rate control at approximately 1 year. In the 3 studies that compared a procedural intervention with a pharmacologic intervention, the patients in the procedural intervention group had a lower heart rate at 12 months than those receiving the pharmacologic intervention (66, 67, 70). Three studies compared outcomes related to exercise capacity or duration, and none showed significant differences in these outcomes by treatment group of ventricular demand rate-responsive (VVIR) pacing plus His bundle ablation versus VVIR pacing plus a rate-controlling medication or of AVN ablation plus VVIR pacing versus a rate-controlling medication (66, 67, 69).
Three studies reported outcomes related to mortality and cardiovascular events. No significant differences were found by treatment group in a comparison of AVN ablation plus dual-chamber demand rate-responsive pacing and antiarrhythmic therapy versus AVN ablation plus VVIR pacing alone or in a comparison of AVN ablation plus VVIR pacing versus a rate-controlling medication (22, 67, 69).
Forty-four RCTs (33–36, 49, 53, 54, 56, 58, 71–105) assessed the use of antiarrhythmic medications or electrical cardioversion for restoration of sinus rhythm. Four RCTs compared single monophasic waveform with single biphasic waveform for converting AF to sinus rhythm (33–36). All studies were done in patients with persistent AF. Pooling data from these 4 RCTs showed the superiority of a single biphasic waveform over a single monophasic waveform (OR, 4.39 [CI, 2.84 to 6.78]; Q = 2.85; P = 0.42) (Figure 2, D).
Four studies explored the use of anterolateral versus anteroposterior positioning of cardioversion electrodes in patients with persistent AF (75, 82, 86, 99). There was low SOE of no difference in restoration of sinus rhythm.
Few identified studies directly compared similar antiarrhythmic medications. The most frequent comparison was between amiodarone and sotalol, which was evaluated in 4 studies (58, 79, 80, 89) involving patients with paroxysmal or persistent AF. Meta-analysis of these studies showed no statistically significant difference in restoring sinus rhythm (OR, 1.12 [CI, 0.81 to 1.56]) (Table 3).
Table 3. Summary of SOE and Effect Estimates for Electrical Cardioversion and Antiarrhythmic Medications for Rhythm Control
Ninety studies assessed the comparative safety and effectiveness of new procedural rhythm-control therapies, other nonpharmacologic rhythm-control therapies, and pharmacologic agents for the maintenance of sinus rhythm in patients with AF. We divided these studies into 2 groups by therapy type: procedural and pharmacologic.
Seventy-two RCTs (37–46, 106–167) addressed procedures for rhythm control. Nine RCTs compared transcatheter PVI with antiarrhythmic medications. Of these, 2 included only patients with paroxysmal AF (40, 42), 2 included only patients with persistent AF (39, 45), and 5 included patients with paroxysmal or persistent AF (37, 38, 41, 43, 44). Data from these trials provide high SOE that rhythm control using transcatheter PVI is superior to antiarrhythmic medications in reducing recurrent AF over 12 months of follow-up (OR, 5.87 [CI, 3.18 to 10.85]; Q = 33.82; P < 0.001) (Figure 2, E). This SOE is strongest in younger patients with little to no structural heart disease and with no or mild enlargement of the left atrium (37–45).
The Appendix Table presents data on surgical maze procedures (including PVI) at the time of other cardiac surgery. Ten studies evaluated PVI with valvular or coronary artery bypass graft versus valvular surgery or coronary artery bypass graft alone (46, 107, 111, 113, 118, 124, 136, 137, 149, 168). Five studies evaluated traditional “cut-and-sew” maze procedures versus valvular surgery or coronary artery bypass graft alone (127, 138, 142, 146, 154). Four additional studies evaluated unique comparisons (108, 133, 155, 158). Data from 8 RCTs showed high SOE that PVI at the time of other cardiac surgery is superior to cardiac surgery alone in reducing AF recurrence over at least 12 months of follow-up in patients with persistent (111, 136, 137, 149) or long-standing persistent (46, 107, 113, 118) AF.
Appendix Table. Summary of SOE and Effect Estimates for Procedural Rhythm-Control Therapies
Of the 9 RCTs that compared PVI plus complex fractionated atrial electrographic (CFAE) ablation versus PVI alone, 1 included only patients with long-standing persistent AF (119), 2 included only patients with persistent AF (115, 160), and 4 included only patients with paroxysmal AF (112, 114, 140, 153). On the basis of the results of these heterogeneous RCTs, there is low SOE that CFAE ablation done in addition to PVI does not increase maintenance of sinus rhythm at 12 months compared with PVI only.
Regarding procedures for maintenance of sinus rhythm, 4 areas were found to need more data: the effect of transcatheter PVI on final outcomes, such as all-cause mortality, stroke, HF, and ejection fraction; the efficacy and effectiveness of transcatheter PVI by type and duration of AF, presence or absence of structural heart disease, and size of the left atrium; the best ablation approach; and the effect of the surgical maze procedure and PVI done at the time of surgery on final outcomes, such as all-cause mortality and stroke, and on the safety and durability of the effectiveness of these procedures beyond 12 months (Appendix Table).
Eighteen studies (53, 54, 78–80, 104, 169–180) evaluated the comparative safety or effectiveness of pharmacologic agents with or without external electrical cardioversion for maintaining sinus rhythm in patients with AF. Five studies evaluated the use of 1 or more pharmacologic agent, with external electrical cardioversion as a primary component of the tested intervention (53, 54, 78, 104, 180); 1 compared an antiarrhythmic medication with a rate-controlling medication (sotalol vs. bisoprolol) (179); 1 primarily evaluated the effect of the addition of verapamil to either amiodarone or flecainide (174); 1 compared the effect of 2 β-blockers for maintenance of sinus rhythm after cardioversion (169); and 10 compared 2 or more antiarrhythmic medications (79, 80, 170–173, 175–178).
Amiodarone, sotalol, and propafenone were the most commonly studied antiarrhythmic medications in RCTs assessing the pharmacologic maintenance of sinus rhythm (79, 80, 169–179). Only 1 study, a substudy of the Atrial Fibrillation Follow-up Investigation of Rhythm Management study, systematically assessed differences in mortality rates between antiarrhythmic medications and found no statistically significant difference between patients receiving amiodarone versus those receiving sotalol (172). Regarding maintaining sinus rhythm and reducing recurrence of AF, amiodarone was better than sotalol and dronedarone but did not differ from propafenone in the few studies that compared the various medications (low SOE).
This review of 162 studies involving 28 836 patients has 4 main findings. First, in older patients with mild AF symptoms, a pharmacologic rate-control strategy has comparable efficacy to a pharmacologic rhythm-control strategy in terms of its effect on all-cause mortality, cardiac mortality, and stroke. Second, we found few studies comparing different rate-controlling medications and reporting on outcomes of interest. The number of clinical trials comparing different antiarrhythmic medications was also small. Third, PVI is superior to antiarrhythmic medications at reducing AF recurrence in younger patients with no substantial structural heart disease. Fourth, the surgical maze procedure done at the time of other cardiac surgery is superior to cardiac surgery alone at reducing AF recurrence. Although our review of all available data in the literature left several unanswered questions, we provide important information on the rigor of evidence that supports or does not support certain interventions and practices.
We found evidence supporting the comparable effectiveness of pharmacologic rate- and rhythm-control strategies in their effect on all-cause mortality, cardiac mortality, and stroke. As the largest analysis to date addressing this issue to our knowledge, our review provides further confirmation that pharmacologic rate-control strategies are of comparable efficacy to pharmacologic rhythm-control strategies in patients similar to those enrolled in the RCTs (namely, older patients with mild symptoms from AF). Follow-up in the included trials ranged from 4 months to 3.5 years. Although a comparative effectiveness study of population-based administrative databases from Québec, Canada, from 1999 to 2007 also found little difference in mortality rates within 4 years of treatment initiation, mortality rates decreased steadily in the rhythm-control group after 5 years (181).
Our review found a lack of definitive evidence for better rate control with β-blockers compared with verapamil or diltiazem. Amiodarone and diltiazem are similar options for rate control, and the available evidence suggests that amiodarone or verapamil is a better option for rate control than digoxin (47, 53). For patients presenting to the emergency department with AF, metoprolol or diltiazem produces similar results for rate control. However, there is a general lack of information on comparative safety of the agents overall and within specific patient subgroups. Our findings underscore the importance of conducting studies comparing the effectiveness, tolerability, and safety of different β-blockers and in different patient populations.
Although few studies have suggested that lenient rate control may be as good as strict rate control, this finding needs to be confirmed.
Studies that explored the effect of AVN ablation and pacemaker implantation versus AVN blockers on ventricular rate control showed a significantly lower heart rate in patients who had a procedure. Studies of other outcomes found no difference by treatment group or were inconsistent. There is a need for well-designed studies comparing final outcomes in patients receiving rate-controlling medications versus those having rate-controlling procedures.
We found that biphasic waveform cardioversion was superior to monophasic waveform cardioversion. Showing no significant difference in restoration of sinus rhythm with use of anterolateral versus anteroposterior positioning of cardioversion electrodes is important and clinically helpful because health care providers often debate the superiority of 1 positioning of cardioversion electrodes over another. Although data suggest that pretreatment enhances electrical cardioversion in terms of restoration and maintenance of sinus rhythm, our review does not support 1 antiarrhythmic medication as superior to others in such pretreatment. These findings call for studies comparing the effectiveness and safety of medication pretreatments in enhancing restoration of sinus rhythm.
Although additional data are needed on final outcomes, evidence is strong in support of the use of PVI versus antiarrhythmic medications for reducing recurrences of AF in younger patients with paroxysmal AF who have mild structural heart disease or mild left atrial enlargement. These studies mostly examined PVI as second-line therapy. One recent study compared PVI with antiarrhythmic medications as first-line therapy in patients with paroxysmal AF. It found no significant difference in the burden of AF over 2 years (182). More studies are needed on PVI as first-line therapy.
The effect of PVI on final outcomes, including mortality, is being assessed by the ongoing National Heart, Lung, and Blood Institute–funded Catheter Ablation Versus Antiarrhythmic Drug Therapy for AF trial. Less evidence supports the use of PVI versus antiarrhythmic medications in similar types of patients with persistent AF. Unlike previous studies, we found that CFAE ablation in addition to PVI did not increase maintenance of sinus rhythm compared with PVI only. Although it is unclear whether this finding is due to including more patients with persistent AF in our review, the influence of AF type and duration on the effectiveness of CFAE ablation should be considered. Our findings underscore the importance of conducting well-powered and well-designed RCTs to address this issue definitively, especially as it relates to appropriate patient selection for CFAE ablation.
We found that the surgical maze procedure or PVI done at the time of cardiac surgery is superior to cardiac surgery only in reducing AF recurrence over 12 months of follow-up in patients with persistent or permanent AF. However, data on final outcomes, such as all-cause mortality, are largely absent. Therefore, our findings support exploring these interventions further in regard to their effect on final outcomes and in different patient populations.
In RCTs that examined the comparative effectiveness of different antiarrhythmic medications in maintaining sinus rhythm, we found that amiodarone, sotalol, and propafenone were the most frequently studied agents. Amiodarone did not differ from propafenone in the few studies that compared these medications. Our findings highlight the importance of future research to compare different antiarrhythmic medications in specific patient populations.
Our review has limitations. By using narrow eligibility criteria, the included studies may not be representative of the full clinical spectrum of patients and settings. Although understanding racial and sex differences in the effectiveness of rhythm control versus rate control is of interest, these data do not exist. Trials of procedures typically use highly selected operators and may not apply to less experienced operators. Our review was limited to English-language publications. In this analysis, we had to rely on the description of the papers' authors about the techniques that they used and the extent of ablation. Because of the heterogeneity and inherent difficulties in monitoring patients for recurrence of AF, findings related to this outcome should be interpreted with this limitation in mind.
As the largest analysis examining pharmacologic rate versus rhythm control to our knowledge, our review provides confirmation that pharmacologic rate- and rhythm-control strategies are of comparable efficacy in older patients with mild symptoms from AF. Although more data are needed on final outcomes, robust evidence supports the use of PVI versus antiarrhythmic medications for reducing recurrences of AF in younger patients with paroxysmal AF and mild structural heart disease. Uncertainties still exist within specific subgroups of interest, among therapies within each strategic approach, and about the effect of strategies on long-term clinical outcomes. Our review highlights areas for future research needed for clinical decision making in the treatment of AF.
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