Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. (Cardiovascular Medicine).

Objective: To conduct a meta-analysis of randomised controlled trials to estimate the effectiveness of antiarrhythmic drugs at promoting sinus rhythm in patients with atrial fibrillation.

Design: Articles were identified by using a comprehensive search of English language papers indexed in Medline from 1966 to August 2001. For the outcomes of sinus rhythm and death, a random effects model was used to model repeated assessments within a study at different time points.

Setting: Emergency departments and ambulatory clinics.

Patients: Patients with atrial fibrillation.

Interventions: Antiarrhythmic agents grouped according to their Vaughan-Williams class.

Main outcome measures: Sinus rhythm and mortality.

Results: 91 articles met a priori criteria far inclusion in the analysis. Median duration of follow up was one day (range 0.04-1096, mean (SD) 46 (136) days). The median proportion of patients in sinus rhythm at follow up was 55% (range 0-100%) and 32% (range 0-90%) receiving active treatment and placebo, respectively. Median survival was 99% (range 55-100%] and 99% (range 55-100%). Compared with placebo, the following drug classes were associated with increased sinus rhythm at follow up: IA (treatment difference 21.5%, 95% confidence interval (CI) 16.3% to 26.8%); IC (treatment difference 33.1%, 95% CI 23.3% to 42.9%); and III (treatment difference 17.4%, 95% CI. 11.5% to 23.3%). Class IC drugs were associated with increased sinus rhythm at follow up compared with class IV drugs (treatment difference 43.2%, 95% CI 11.5% to 75.0%). There was no significant difference in mortality between any drug classes.

Conclusions: Class IA, IC, and III drugs are associated with increased sinus rhythm at follow up compared with placebo. It is unclear whether any antiarrhythmic drug class is associated with increased or decreased mortality.

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Atrial fibrillation is the most common cardiac arrhythmia' and can be associated with disabling complications. (1,2) Atleast 5% of admissions for cardiovascular disease are for management of atrial fibrillation. (1)

Patients in atrial fibrillation can receive treatment to decrease embolic complications, to promote sinus rhythm, or to control ventricular rate. Each of these treatments is associated with particular risks and benefits. Although the effectiveness of anticoagulant treatment in atrial fibrillation is well established, use of electrical cardioversion or antiarrhythmic drugs may offer additional benefits. Compared with patients with atrial fibrillation, patients in whom sinus rhythm is restored have fewer strokes, (2) greater cardiac output, (3) and reversal of cardiomyopathy. (3-5) However, attempts to maintain sinus rhythm may be associated with increased mortality. (6) Furthermore, as many as 75% of patients relapse into chronic atrial fibrillation within 12 months of restoration of sinus rhythm. (7) Any reduction in the mortality or morbidity caused by stroke that is attained by use of antiarrhythmic drugs may be offset by adverse drug effects or relapse to atrial fibrillation.

Antiarrhythmic treatment to restore and maintain sinus rhythm after atrial fibrillation has been evaluated in many small trials. These trials evaluated several drugs, each of which has unique mechanisms of action and side effects. A large trial underway is evaluating the effectiveness of antiarrhythmic drugs in patients with atrial fibrillation. In the AFFIRM study (atrial fibrillation follow-up investigation of rhythm management), the choice of antiarrhythmic drug was at the discretion of the physician. (8) Therefore, the results of this study are unlikely to determine whether a specific antiarrhythmic drug has long term effectiveness in atrial fibrillation. Despite ongoing and previous trials, there is major interphysician variability in prescribing behaviours related to antiarrhythmic treatment in patients with atrial fibrillation. (9)

Meta-analysis is a method of pooling the results of individual trials statistically to provide an overall estimate of the effectiveness of a treatment. The combination of several studies can yield additional power to detect significant differences between treatments. Therefore, the purpose of this meta-analysis was to estimate the effectiveness of various classes of antiarrhythmic drugs in patients with atrial fibrillation. Using a protocol that was developed a priori, we conducted a meta-analysis based on conventional techniques. (10,11) The protocol consisted of selection criteria for the primary studies, definitions of the primary end points, and an analysis plan.

METHODS

Identification of trials

Our aim was to identify all randomised controlled trials for which results were available by August 2001. A randomised controlled trial was defined as a research study in which patients were assigned prospectively to a treatment group by random allocation. Studies were identified by using a comprehensive search of English language articles indexed in Medline for the keywords "atrial fibrillation" and "antiarrhythmic agents". Potentially relevant randomised trials were identified by combining these keywords with the Cochrane Collaboration's search strategy. (12) Only references published in the English language were considered. The bibliographies of published studies were reviewed to identify additional references. The authors of the primary studies were not contacted to identify additional studies. All published primary studies, but not unpublished studies or abstracts, were considered for inclusion in the analysis.

Classification of antiarrhythmic agents

All antiarrhythmic agents were grouped according to their mechanism of action by using the Vaughan-Williams classification system. Accordingly, drugs that were studied were classified as class I, which block sodium channels; class II, which block [beta] receptors (for example, practolol); class III, which prolong repolarisation (for example, amiodarone, dofetilide, ibutilide, sotalol, and lidofiazine); class IV, which block calcium channels (for example, clonidine, diltiazem, magnesium, and verapamil); and other agents (for example, digoxin). Class I agents were subclassified as IA, which depress action potential upstroke, slow conduction, and prolong repolarisation (for example, cibenzoline, disopyramide, procainamide, and quinidine); and class IC, which depress upstroke depolarisation, slow conduction, and have a slight effect on repolarisation (for example, flecainide, pilsicainide, and propafenone.)

Inclusion and exclusion criteria

A priori exclusion criteria were studies that did not use a randomised study design; enrolled patients with induced atrial fibrillation; evaluated treatments other than antiarrhythmic agents; evaluated use of antiarrhythmic agents for prophylaxis of atrial fibrillation alone; followed up patients for < 60 minutes after drug administration; or lacked data on the proportion of patients in sinus rhythm at study follow up.

Study quality

The quality of each primary study was evaluated by using a validated assessment tool. (13) This is a three item scale that measures the methodological quality of clinical studies. Individual items are randomisation, blinding, and withdrawal and dropout. Allocation concealment was also included (with two additional bonus points). (14) Therefore, the maximum number of points per study was seven. Numbers were abstracted twice by two independent reviewers, and checked for accuracy after data entry.

Outcomes and data abstraction

The following variables were extracted from each study, if available: type and dose of intervention and control drugs; type and dose of concomitant drugs; number, age, and sex of patients randomly allocated; duration of follow up; number of patients who dropped out; number of patients who withdrew; number of patients in sinus rhythm at each follow up; and number of patients deceased. For the purpose of this analysis, patients were considered to have dropped out of the study if they were lost to follow up. Patients were considered to have withdrawn if they stopped taking the study drug.

All studies were independently reviewed for eligibility, data abstraction, and study quality (by MG, FM, GN, BS, and AT). Differences were resolved by discussion until consensus was achieved. Data were abstracted twice and checked for accuracy after data entry.

Primary analyses

Data were analysed by using the SAS mixed procedure. (15) Primary analyses compared the effect of each class of antiarrhythmic agent on the two outcome measures: the proportion of patients in sinus rhythm at the time of study follow up, and mortality.

For each outcome measure, a repeated measures random effects model was used to model the repeated assessments within a study at different time points. (16) In the model, the outcome measure at each time point was weighted by the inverse variance of the outcome measure estimate. The model included treatment, assessment time, and a trial factor to force treatment comparison within the trial. Standard residual diagnostics were used to check for model goodness of fit. Least square means and their 95% confidence intervals (CI) for treatment difference were derived from the fitted models at …