CRD summary

This review concluded that results suggested vernakalant intravenous, propafenone intravenous and flecainide appeared to be effective in achieving rapid cardioversion in patients with short duration atrial fibrillation compared to other agents. Given the limitations of the review, and limited data available for some of the the interventions, the reliability of the conclusions is uncertain.

Authors' objectives

To evaluate the efficacy of pharmacologic therapies in eliciting cardioversion within two hours and eight to 24 hours in patients with recent-onset, short duration atrial fibrillation.

Searching

MEDLINE, EMBASE, Current Contents and The Cochrane Library were searched to May 2010; search terms were reported. Studies published in languages other than English were excluded. Unpublished studies were included.

Study selection

Randomised controlled trials (RCTs) that assessed the efficacy and safety of interventions used to achieve cardioversion in patients with atrial fibrillation were eligible for inclusion. Studies in patients with permanent atrial fibrillation were excluded. At least one arm of RCTs had to involve an intervention aimed at achieving timely cardioversion. Four atrial fibrillation categories were eligible for inclusion: short-duration (48 hours or less; included first occurrences and recurrent paroxysmal episodes); intermediate duration (three to seven days); persistent atrial fibrillation (at least seven days); and post-operative atrial fibrillation. However, the authors stated that due to the volume of literature and small sample sizes for intermediate, persistent and post-operative atrial fibrillation, only studies that evaluated cardioversion in patients with short-duration atrial fibrillation were assessed.

Studies were published between 1985 and 2010 and most were conducted in Europe. In the studies that reported cardioversion within two hours, the mean age ranged 51 to 69 years, 57% were male and 43% of patients had hypertension. In studies that reported cardioversion within eight to 24 hours, mean age ranged from 53 to 73 years, 56% were male and 34% of the patients had hypertension. The most commonly used rhythm control agents were flecainide, amiodarone and propafenone; doses and mode of administration varied across studies.

Two reviewers independently selected studies for the review.

Assessment of study quality

Study quality was assessed using the Centre for Reviews and Dissemination (CRD) criteria. This included an assessment of the adequacy of sequence generation and allocation concealment, similarity at baseline of prognostic variables, blinding, imbalances in attrition, selective reporting bias and the use of an intention-to-treat analysis.

The authors did not state how many reviewers performed the study selection.

Data extraction

Data were extracted the rate of cardioversion at zero to two hours and/or eight to 24 hours post-treatment.

The authors did not state how many reviewers extracted data.

Methods of synthesis

Pooled relative rates of cardioversion were calculated using a random-effects mixed treatment comparison; 50,000 iterations were used as a run-in phase. Medians and interquartile ranges (IQR), or mean and ranges, were presented for times to conversion. Odds ratios (OR) and 95% credible intervals (CrI) were calculated for pairwise comparisons.

Results of the review

Ninety-three studies met the inclusion criteria; of these, 30 included patients with short duration atrial fibrillation that reported outcomes within 24 hours and were included in the analysis. The authors stated that all of the included RCTs were qualitatively and satisfactorily evaluated across the NICE CRD criteria.

Achieving cardioversion in zero to two hours (22 studies; 2,433 participants): 33% of atrial fibrillation patients successfully cardioverted within two hours. The weighted median time to conversion was 2.6 hours (IQR 0.6 to 4.8), and mean time was 3.8 hours (range 0.2 to 11 hours). Pooled cardioversion rates were 68% for oral flecainide, 64% for intravenous flecainide, 63% for intravenous procainamide, 52% for intravenous vernakalant, 51% for intravenous propafenone, 15% for amiodarone and 11% for placebo. Pair-wise comparisons against placebo gave odds ratio of 9.63 for intravenous flecainide (95% CrI 2.38 to 36.26), 11.43 for oral flecainide (95% CrI 1.29 to 99.12), 6.93 for intravenous propafenone (95% CrI 3.36 to 13.96) and 33.26 for intravenous vernakalant (95% CrI 12.14 to 100.8). The rates obtained with intravenous vernakalant were statistically significantly greater than those obtained with oral or intravenous amiodarone, intravenous procainamide, and oral or intravenous propafenone, however, the rates of conversion were particularly low in the placebo group of the vernakalant studies.

Achieving cardioversion in eight to 24 hours (18 studies; 1,893 patients): 63% of atrial fibrillation patients successfully cardioverted within eight to 24 hours. The weighted median time to conversion was four hours (IQR three to seven), and mean time was was six hours (range 0.4 to 27 hours). Pooled cardioversion rates were 87% for oral amiodarone, 82% for intravenous propafenone, 81% for oral flecainide, 79% for oral propafenone and 61.2% for both intravenous amiodarone and sotalol. Pair-wise comparisons against placebo gave odds ratio of 13.94 for oral amiodarone (95% CrI 1.82 to 117.6), 6.53 for oral flecainide (95% CrI 1.24 to 39.58), 4.42 for intravenous propafenone (95% CrI 1.55 to 12.69), 2.84 for oral propafenone (95% CrI 1.42 to 5.43); all of which showed a statistically significant improvemenet rate in conversion over placebo. Intravenous amiodarone, diltiazem, flecainide or sotalol did not show significant benefit over placebo.

Adverse events were variably reported across the studies; results were provided in the paper.

Authors' conclusions

In pairwise comparisons of active treatment arms to one another, results suggest vernakalant intravenous, propafenone intravenous and flecainide appeared to be effective in achieving rapid cardioversion in patients with short duration atrial fibrillation compared to other agents.

CRD commentary

The review addressed a clear question supported by reproducible inclusion criteria. Relevant sources were searched for published studies; only studies published in English were included, so language bias could not be ruled out. Study selection was conducted in duplicate; it was unclear whether similar methods to reduce error and bias during data extraction and the quality assessment were employed. Study quality was assessed using appropriate criteria, but the results were presented only as a brief summary statement.

Appropriate methods of synthesis were used. Although the conclusions were based on the pairwise comparisons, they would have been similar if based on the results of the mixed treatment comparison (although vernakalant would be third in the list of effectiveness, not first). There was no investigation into the impact of the apparent clinical heterogeneity across studies. The authors acknowledged a range of limitations of the review and included studies, including that the cardioversion endpoint was relatively 'soft', and methodology used to capture it in each study may have varied; this may impact on the reliability of the results and the generalisability to clinical practice.

Given the limitations of the review, and the limited data available for some of the interventions, the reliability of the conclusions is uncertain.

Implications of the review for practice and research

Practice: The authors stated that application of the review findings to clinical practice needs to account for the variable comorbidity profiles of patients, important determinants in the selection of appropriate therapy for individual patients.

Research: The authors stated that further research comparing treatments through direct head-to-head comparisons may be warranted to confirm the findings of the review and further inform clinical practice.

Funding

Merck and Company, Inc provided funding to United BioSource, Inc where the authors were employed.

Bibliographic details

Bash LD, Buono JL, Davies GM, Martin A, Fahrbach K, Phatak H, Avetisyan R, Mwamburi M. Systematic review and meta-analysis of the efficacy of cardioversion by vernakalant and comparators in patients with atrial fibrillation. Cardiovascular Drugs and Therapy 2012; 26(2): 167-179. [PubMed: 22418856]

Original Paper URL

http://www.springerlink.com/content/26u06859r2171u06/

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Anisoles /therapeutic use; Anti-Arrhythmia Agents /therapeutic use; Atrial Fibrillation /drug therapy; Bayes Theorem; Electric Countershock /methods; Female; Flecainide /therapeutic use; Humans; Male; Middle Aged; Propafenone /therapeutic use; Pyrrolidines /therapeutic use; Randomized Controlled Trials as Topic; Treatment Outcome

AccessionNumber

12012033417

Database entry date

29/11/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.