Description of the condition
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia (Wyse 2002), with an incidence of 1.31% in men and 1.15% in women in the UK (DeWilde 2006), and an estimated 2.3 million adults with AF in the US (Go 2001). AF is defined as irregular contraction of the atria resulting in a mismatch of atrial and ventricular contractions. Electrocardiogram (ECG) findings often include rapid oscillatory baseline, absence of consistent P wave (contraction of the atria) and irregular ventricular response (Stiell 2011). AF is commonly associated with valvular disease, hypertension, heart failure and age, and can be classified as paroxysmal, persistent, or permanent depending on the length of time the arrhythmia persists (Verma 2011). There are two mechanisms that are thought to cause AF. One theory suggests that AF is the manifestation of one or more re-entry circuits on the atrial surface. The second theory suggests that AF is the result of abnormal conduction throughout the atria originating from one or several rapid discharge foci (Chakravarty 2012).
Description of the intervention
Initial therapy for AF is guided by the etiology and presence of co-morbidities (heart disease, hypertension, coronary artery disease, and heart failure). The goals of therapy are to prevent cardiovascular complications of AF, such as stroke, arterial emboli, heart failure, and myocardial infarction. Furthermore, treatment should aim to improve quality of life and reduce the burden of disease (Verma 2011). In the situation of acute onset of AF, which causes hemodynamic compromise, heart failure or angina and is resistant to prompt medical management, electrical cardioversion to normal sinus rhythm (NSR) is ideal. For maintenance therapy, treatment consists firstly of anticoagulation and secondly of rate or rhythm control, both of which have their own risks and benefits (Wyse 2002). Rate control involves the use of atrioventricular (AV) nodal blocking drugs (beta-blockers, non-dihydropyridine calcium channel blockers, and digoxin) to control heart rate whilst allowing the atrial fibrillation to persist. The rationale behind rate control therapy is the logical assumption that a slower ventricular response leads to improved subjective and objective outcomes. The 2010 Canadian Cardiovascular Society (CCS) guidelines emphasized the lack of evidence for this concept, and the revised resting ventricular rate target is now set at 100 beats per minute or less (Wyse 2002). Rhythm control involves converting the heart to normal sinus rhythm with electrical cardioversion or antiarrhythmic drugs (Wyse 2002).
Currently, Canadian guidelines state that there is no survival advantage in choosing rhythm control over rate control for atrial fibrillation and that both are reasonable choices depending on the clinical situation (Verma 2011). This recommendation is based in part on the results from the Cochrane review by Lafuente-Lafuente et al, which states that a rhythm control strategy with antiarrhythmics has not shown clear benefits in clinical outcomes compared to a rate control strategy (Lafuente-Lafuente 2006). In another meta-analysis by de Denus et al (de Denus 2005), which combined five randomized trials totalling 5239 patients with persistent AF or recurrent AF, there were no significant differences in all-cause mortality or ischemic stroke. There are also a number of landmark clinical trials that support the recommendation that rate control is not inferior compared to rhythm control. The AFFIRM trial (Wyse 2002) randomized 4060 patients with AF to rhythm control strategy or rate control strategy for an average of 3.5 years. The results showed that rhythm control strategy offered no clear advantage over rate control as measured by overall mortality (rhythm vs. rate control) 26.7% vs. 25.9% (P = 0.07), torsades de pointes 0.8% vs. 0.2% (P = 0.007) and hospitalization 80.1% vs. 73% (P = 0.01). In the RACE trial (Van Gelder 2002), 522 patients with recurrent persistent AF after electrical cardioversion were randomized to rhythm control and rate control for an average of 2.3 years. Results showed that rate control was not inferior to rhythm control with decreased incidence of adverse effects (including cardiovascular mortality and morbidity, thromboembolic complications, and bleeding) 0.8% vs. 4.5% (P < 0.01). In the HOT-CAFE trial (Opolski 2004), 205 patients with persistent AF were randomized to rate control vs. rhythm control therapy. The results showed that there were no statistically significant differences in the composite endpoint of all-cause mortality, number of thromboembolic events or major bleeding.
Rhythm control can be achieved through pharmacological therapy with antiarrhythmic drugs or non-drug therapies such as electrical cardioversion or catheter ablation. Traditionally, antiarrhythmic drugs have been considered first-line therapy for the maintenance of sinus rhythm (Chakravarty 2012). However, drug therapy only has modest efficacy for the maintenance of sinus rhythm and long term usage and is associated with serious adverse effects such as life threatening arrhythmia, which limit their use and tolerability (Verma 2011). Non-drug therapy, such as catheter ablation, is an option if drug therapy is not tolerated and is associated with higher success rates for maintaining sinus rhythm and increased quality of life compared to pharmacological therapies (Verma 2011). However, non-drug therapies are not without risks. The incidence of major complications from pulmonary vein ablation is reported to be 6% (1% pericardial tamponade, 1% stroke or transient ischemic attack, 0.5% pulmonary vein occlusion and 2% to 3% atrial flutter) (Govindan 2008). Generally, catheter ablation for atrial fibrillation is reserved as an option for patients who have failed on at least one antiarrhythmic drug (Verma 2011). Based on this model of treatment, AF is believed to be triggered by rapid ectopic activity from the pulmonary veins (Chakravarty 2012). By ablating around the pulmonary veins and electrically isolating them from the rest of the atria, it is believed that the trigger can be eliminated and AF prevented (Verma 2011). Ablation may not be a complete cure for AF but can reduce the burden of disease (Verma 2011). The success rate of maintaining sinus rhythm without the use of antiarrhythmic drug therapy is 60% to 75% after a single procedure and 75% to 90% after two procedures (Finta 2004). In a randomized trial comparing catheter ablation with antiarrhythmic drug therapy, 66% of patients maintained sinus rhythm without the use of drugs after a single ablation of paroxysmal AF compared to only 16% with antiarrhythmic drug therapy alone (Wilber 2010).
Direct-current cardioversion involves administering an electrical shock synchronized with the intrinsic activity of the heart to restore NSR (Fuster 2001). A systematic review assessed the effects of electrocardioversion in patients with either atrial fibrillation or atrial flutter (Mead 2005). The review looked at trials that compared electrocardioversion in addition to usual care versus usual care only, where usual care was defined as any combination of anticoagulants, antiplatelet and rate control drugs. The review found no difference in mortality between these two treatment strategies and an improvement of three domains of quality of life (physical functioning, physical role function and vitality) in the rhythm control group. However, there was a non-statistically significant increase in frequency of strokes in the electrocardioversion group. Based on the available evidence, the reviewers do not recommend electrocardioversion as a routine measure (Mead 2005). That said, cardioversion can be a useful adjunctive therapy in patients with persistent atrial fibrillation or flutter who have failed to respond to pharmacological cardioversion (Wyse 2002).
Although the therapies available can be effective in restoring sinus rhythm, the problem is the maintenance of normal sinus rhythm in the long term. Without treatment, it is estimated that only 20% to 30% of patients converted remained in sinus rhythm at one year (Oral 1999). In light of these high rates of recurrence, another strategy is to use antiarrhythmics in combination with non-drug procedures.
Newer approaches to rhythm control are emerging, exploring a combination of pharmacological and non-pharmacological therapies known as hybrid therapy. Hybrid therapy refers to the combination of the three available treatment modalities: antiarrhythmic drug treatment, catheter ablation, and pacemaker therapy or electrical cardioversion (Govindan 2008). The attraction of using a hybrid approach is that it targets multiple etiologies responsible for AF, which could result in additive benefits compared to monotherapy. Currently, the hybrid approach is generally offered only to a select group of AF patients, such as those with paroxysmal or persistent AF refractory to drug therapy and requiring ablation, those with AF and bradycardia requiring pacemaker therapy, patients who develop antiarrhythmic induced atrial flutter that can be eradicated with ablation and patients with heart failure requiring cardioversion (Govindan 2008). One proposed mechanism for why hybrid therapy may improve outcomes is that it may prevent early recurrence of arrhythmia after ablation, which has been associated with lower long term success rates compared to patients without recurrences (Govindan 2008). Therefore, adjunctive antiarrhythmics during the unstable period after a procedure may improve long term outcomes (Govindan 2008). Another form of hybrid therapy is to give a pre-dose of antiarrhythmics prior to cardioversion, where the proposed mechanism is that the antiarrhythmic may lower the energy requirement for atrial defibrillation and increase the success of cardioversion. In a study by Oral et al, 100 patients with AF were randomly assigned to undergo transthoracic cardioversion with a step-up protocol of increasing shocks, with or without pre-treatment with 1 mg of the class III antiarrhythmic agent ibutilide (Oral 1999). The results showed that pre-treatment with ibutilide significantly improved the success of transthoracic cardioversion similar to internal cardioversion, but with the advantage of using a simpler procedure and having a lower energy requirement of approximately 30% compared to without pre-treatment (Boriani 2004).
There are a number of trials that have studied the usage of hybrid therapy to enhance the success of cardioversion. Some attempts at summarizing the evidence include narrative reviews by Govindan et al (Govindan 2008) and Boriani et al (Boriani 2004) and the systematic review by Noheria et al (Noheria 2008). Currently, in a number of guidelines such as the 2010 CCS atrial fibrillation guidelines (Stiell 2011), the practice of short term usage of antiarrhythmics before electrical cardioversion is presented as an option for certain patients. However, the evidence behind this recommendation is not well quantified and the existing reviews on the subject are mainly focused on the long term use of antiarrhythmics, whereas the interest of this review is to focus on the short term use of antiarrhythmic therapy prior to non-drug procedure and the effect on clinical outcomes.
Why it is important to do this review
Long term use of antiarrhythmic medications has been shown to be beneficial in maintaining sinus rhythm post-cardioversion. In practice, clinicians may give a short course of antiarrhythmics prior to or after a planned cardioversion or catheter ablation procedure with the rationale that this may increase the likelihood of maintaining sinus rhythm and prevent cardiovascular events. However, there is actually little evidence to support this practice. There is currently no definitive review on the topic of short term usage of antiarrhythmics prior to non-drug procedures and a review is needed to confirm the benefit of using antiarrhythmic medications in this fashion.
To determine the efficacy of short term usage of antiarrhythmic medications prior to a planned cardioversion or catheter ablation procedure in modifying clinical outcomes in AF.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials. Cluster and cross-over trials will be excluded.
Types of participants
Adult patients (> 18 years old) with ECG verified AF or atrial flutter of any type and duration for which sinus rhythm is to be restored with cardioversion or catheter ablation. We will include studies in all practice settings. AF after cardiac surgery or any condition where the life expectancy was less than six months will be excluded.
Types of interventions
Any antiarrhythmic at any dose used prior to electrical cardioversion or catheter ablation, with or without post-procedure usage of antiarrhythmics, will be compared to no treatment or only electrical cardioversion or catheter ablation, with or without post-procedure usage of antiarrhythmic therapy. Both the intervention and control groups must be similar in terms of the type of AF being treated and the severity of disease. Medications used to manage co-morbidities (e.g. hypertension, heart failure) must also be similar in both groups. For trials that contain the intervention of interest along with other co-interventions, we will extract the results from the intervention of interest, if possible, or else the trial will be excluded.
Types of outcome measures
Studies must at least have one of the primary or secondary outcomes chosen for this review. For combined outcomes, we will only include studies if the individual outcomes can be extracted.
- All-cause mortality: a more informative measure compared to cardiovascular related mortality as it also accounts for adverse effects of a non-cardiac origin.
- Rate of serious adverse events (defined as causing death, life threatening, require hospitalization, prolong hospitalization, cause persistent or significant disability, cause congenital defects or require intervention to prevent permanent damage).
- Mortality due to cardiovascular causes.
- Cardiovascular event (stroke, MI, systemic embolism, peripheral embolism).
- Time to recurrence of arrhythmia.
- Withdrawal due to adverse events.
- Pro-arrhythmia (the new appearance of a sustained ventricular tachyarrhythmia, change from a non-sustained to a sustained tachyarrhythmia, acceleration of tachycardia rate, the new appearance of a clinically significant brady-arrhythmia or conduction defect, sudden death, QRS or QT prolongation resulting in withdrawal from treatment).
Search methods for identification of studies
Searches for relevant trials will be conducted in the following databases:
- Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library.
- MEDLINE (OVID).
- EMBASE (OVID).
A preliminary search strategy for MEDLINE (OVID) including the Cochrane sensitivity-maximising RCT filter (Lefebvre 2011) is included in Appendix 1. This search strategy will be adapted for use in the other databases.
We will apply no language restrictions.
Searching other resources
We will search the following clinical trial registers to identify ongoing and unpublished studies:
- WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/).
- ClinicalTrials.gov (www.clinicaltrials.gov/).
We will also check the reference lists of retrieved articles, recent reviews and meta-analyses.
Data collection and analysis
Once the studies have been pooled, a fixed-effect or random-effects model will be used depending on whether there is heterogeneity observed between studies. If any outcome results are statistically significant, we will calculate a number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for a specified duration of treatment. All statistical calculations will be done using Review Manager 5 software (RevMan).
Selection of studies
Once the list of citations has been generated from the search strategy, two authors (AMT & GE) will independently assess the list of citations based on the title or abstract, or both, using the pre-defined inclusion and exclusion criteria. We will compare the two lists of possible inclusions and a third author (KL) will resolve any disagreements. We will independently check the articles selected for review to identify duplicate data that have been published. A pre-defined form will be developed for this task. We will keep a record of the study selection process for each study assessed and generate a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (PRISMA 2009) flow chart.
Data extraction and management
Two authors (KL & AMT) will extract the data. We will resolve any disagreements by discussion and consensus.
The data extraction form will include:
- study ID;
- baseline characteristics (age, gender, frequency and type of heart disease, echocardiographic measures, duration and type of atrial fibrillation);
- details of treatments (method of cardioversion employed, time interval between conversion to sinus rhythm and initiation of intervention, antiarrhythmic drugs used and dose, treatment used in control group, concomitant treatments);
- follow-up duration (patients lost to follow up and withdrawals).
Assessment of risk of bias in included studies
Two authors (KL & AMT) will conduct the risk of bias assessment based on the tools and criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011). We will resolve any disagreements by discussion and consensus.
- Random sequence generation (e.g. random number table, computer random number generator).
- Allocation concealment (e.g. centralized allocation).
- Blinding of participants and personnel (e.g. blinding of key participants and personnel clearly stated and unlikely that blinding could have been compromised). Open trials are included as electrocardioversion is difficult to blind. The presence or absence and quality of blinding will still be recorded regardless.
- Blinding of outcome assessment (e.g. presence of blinding and assessment whether outcome is likely to be influenced by blinding).
- Incomplete outcome data (e.g. no missing outcome data, missing outcome data balanced between intervention groups).
- Selective outcome reporting (e.g. all pre-specified primary and secondary outcomes were reported).
Each methodological feature will be assessed and ranked for their risk of bias as "low risk", "unclear risk" or "high risk", based on the criteria laid out in Table 8.5d of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If a judgment is ambiguous, we will provide clarification in the notes section of the pre-defined form. When no information is available to make this judgment, it will be stated explicitly (Higgins 2011). A risk of bias graph for each included trial will also be generated to assess the risk of bias. A narrative description will be given in the end to aid in the interpretation of the risk of bias assessment.
Measures of treatment effect
Studies will be pooled and relative risk (RR) and odds ratio (OR) will be calculated for dichotomous data and weighted mean differences (WMD) for continuous data (calculated to 95% confidence intervals).
Dealing with missing data
Where data are missing we will contact investigators or pharmaceutical company sponsors of eligible studies to request unpublished data. We will also contact investigators of large scale RCTs studying the use of hybrid therapies to identify additional unpublished trials. We will search the Food and Drug Administration (FDA) and European Medicines Agency websites for unpublished data. If missing data are not available, we will conduct worst-case scenario sensitivity analysis to see if effect sizes or their directions will change as a result.
Assessment of heterogeneity
We will test for heterogeneity using the I
Assessment of reporting biases
A funnel plot will be generated to screen for publication bias.
Data from antiarrhythmics will be pooled and analyzed individually as specific drugs and by their pharmacological class. We will use a fixed-effect model unless substantial heterogeneity between studies is observed, in which case a random-effects model will be used. If any outcome results are statistically significant, a number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) will be calculated for a specified duration of treatment. We will summarize in narrative form any data that cannot be meta-analyzed.
Subgroup analysis and investigation of heterogeneity
- Recent vs. persistent AF.
- Paroxysmal AF vs. persistent AF.
- Heart failure vs. structurally normal heart.
- Use of anticoagulation (comparing studies where warfarin was mandatory versus those where warfarin was discretionary).
- Atrial fibrillation vs. atrial flutter.
- Antiarrhythmic Class I & Class III: Data from antiarrhythmics will be pooled and analyzed individually as specific drugs and by their pharmacological class.
- Duration of antiarrhythmic therapy (pre- and post-cardioversion).
- Worst case scenario for intention-to-treat (ITT) (all missing patients considered as events).
- Pool studies with low risk of bias.
- Studies including the greatest number of patients.
The search strategy and methods for this review were designed by the Trial Search Coordinator, Joanne Abbott, of the Cochrane Heart Group.
Appendix 1. MEDLINE search strategy
1 Anti-Arrhythmia Agents/
4 anti arrhythmi$.tw.
5 (antifibrillatory adj2 agent$).tw.
6 (myocardial adj2 depressant$).tw.
7 (cardiac adj2 depressant$).tw.
21 Atrial Fibrillation/
22 atrial fibrillation$.tw.
23 atrium fibrillation$.tw.
24 auricular fibrillation$.tw.
26 20 and 25
27 randomized controlled trial.pt.
28 controlled clinical trial.pt.
31 drug therapy.fs.
35 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34
36 exp animals/ not humans.sh.
37 35 not 36
38 26 and 37
Contributions of authors
GE: Original conception of the research question.
KL, GE, AT: The design of the review and writing of the protocol was done in collaboration between the three authors.
AT: Guarantor of the review.
Declarations of interest
Aaron Tejani works for Lower Mainland Pharmacy Services, British Columbia and Therapeutics Initiative UBC. He has received a grant from CIHR to complete a systematic review of Daptomycin and several other knowledge translation grants. He has also received four honoraria for a variety of talks on drugs (but not the drugs discussed in this review) from Community and Rural Internal Medicine Society of BC, and REACH Private family medicine clinic, Vancouver Island Health Authority Pharmacy Services, Fraser Health Pharmacy Services (from a government CIHR grant).
There are no other known conflicts of interest.