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. 2008 May 2;2008:0210.

Atrial fibrillation (acute onset)

Gregory Y H Lip 1,#, Timothy Watson 2,#
PMCID: PMC2907989  PMID: 19450312

Abstract

Introduction

Risk factors for acute atrial fibrillation include increasing age, cardiovascular disease, alcohol, diabetes, and lung disease. Acute atrial fibrillation increases the risk of stroke and heart failure. Acute atrial fibrillation resolves spontaneously within 24-48 hours in over 50% of people, however many people will require interventions to control heart rate or restore sinus rhythm.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions: to prevent embolism; for conversion to sinus rhythm; and to control heart rate in people with recent onset atrial fibrillation (within 7 days) who are haemodynamically stable? We searched: Medline, Embase, The Cochrane Library and other important databases up to October 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, digoxin, diltiazem, direct current cardioversion, flecainide, propafenone, quinidine, sotalol, timolol, and verapamil.

Key Points

Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of less than 48 hours' duration. It resolves spontaneously within 24-48 hours in over 50% of people. In this review we have included studies on patients with onset up to 7 days previously.

  • Risk factors for acute atrial fibrillation include increasing age, CVD, alcohol abuse, diabetes, and lung disease.

  • Acute atrial fibrillation increases the risk of stroke and heart failure.

The consensus is that people with haemodynamically unstable atrial fibrillation should have immediate direct current cardioversion. In people who are haemodynamically stable, we found no studies of adequate quality to show whether direct current cardioversion increases reversion to sinus rhythm.

  • There is consensus that antithrombotic treatment with heparin should be given before cardioversion to reduce the risk of embolism in people who are haemodynamically stable, but we found no studies to show whether this is beneficial.

Oral or intravenous flecainide,propafenone, or amiodarone increase the likelihood of reversion to sinus rhythm compared with placebo in people with haemodynamically stable acute atrial fibrillation.

CAUTION: Flecainide and propafenone should not be used in people with ischaemic heart disease as they can cause (life-threatening) arrhythmias.

We don't know whether quinidine or sotalol increase reversion to sinus rhythm in people with haemodynamically stable atrial fibrillation, as few adequate studies have been conducted.

  • Digoxin does not seem to increase reversion to sinus rhythm compared with placebo. We don't know whether verapamil increases reversion to sinus rhythm compared with placebo.

Treatment with digoxin may control heart rate in people with haemodynamically stable atrial fibrillation, despite its being unlikely to restore sinus rhythm. We don't know whether diltiazem, timolol, and verapamil are effective at controlling heart rate, but they are unlikely to restore sinus rhythm.

  • No one drug has been shown to be more effective at controlling heart rate. However, intravenous bolus amiodarone is more effective than digoxin. Verapamil may cause hypotension. We don't know whether sotalol can control heart rate in people with acute atrial fibrillation who are haemodynamically stable, but it may cause arrhythmias at high doses.

About this condition

Definition

Acute atrial fibrillation is rapid, irregular, and chaotic atrial activity of less than 48 hours' duration. It includes both the first symptomatic onset of chronic or persistent atrial fibrillation, and episodes of paroxysmal atrial fibrillation. It is sometimes difficult to distinguish new-onset atrial fibrillation from previously undiagnosed long-standing atrial fibrillation. Atrial fibrillation within 72 hours of onset is sometimes called recent-onset atrial fibrillation. Definitions of acute atrial fibrillation vary, but for the purposes of this review we have included studies where atrial fibrillation may have occurred up to 7 days previously. By contrast, chronic atrial fibrillation is more sustained, and can be described as paroxysmal (with spontaneous termination and sinus rhythm between recurrences), persistent, or permanent atrial fibrillation. This review deals with people with acute and recent atrial fibrillation who are haemodynamically stable. The consensus is that people who are not haemodynamically stable should be treated with immediate direct current cardioversion. We have excluded studies in people with atrial fibrillation arising during or soon after cardiac surgery. Diagnosis: Acute atrial fibrillation should be suspected in people presenting with dizziness, syncope, dyspnoea, or palpitations. Moreover, atrial fibrillation can contribute to a large number of other non-specific symptoms. Palpation of an irregular pulse is generally only considered sufficient to raise suspicion of atrial fibrillation: diagnosis requires confirmation with ECG. However, in those with paroxysmal atrial fibrillation, ambulatory monitoring may be required.

Incidence/ Prevalence

We found limited evidence on the incidence or prevalence of acute atrial fibrillation. Extrapolation from the Framingham study suggests an incidence in men of 3/1000 person-years at age 55 years, rising to 38/1000 person-years at age 94 years. In women, the incidence was 2/1000 person-years at age 55 years and 32.5/1000 person-years at age 94 years. The prevalence of atrial fibrillation ranged from 0.5% for people aged 50-59 years to 9% in people aged 80-89 years. Among acute emergency medical admissions in the UK, 3-6% had atrial fibrillation, and about 40% of these were newly diagnosed. Among acute hospital admissions in New Zealand, 10% (95% CI 9% to 12%) had documented atrial fibrillation.

Aetiology/ Risk factors

Common precipitants of acute atrial fibrillation are acute MI and the acute effects of alcohol. Age increases the risk of developing acute atrial fibrillation. Men are more likely than women to develop atrial fibrillation (38 years' follow-up from the Framingham Study, RR after adjustment for age and known predisposing conditions 1.5). Atrial fibrillation can occur in association with underlying disease (both cardiac and non-cardiac) or can arise in the absence of any other condition. Epidemiological surveys found that risk factors for the development of acute atrial fibrillation include ischaemic heart disease, hypertension, heart failure, valve disease, diabetes, alcohol abuse, thyroid disorders, and disorders of the lung and pleura. In a British survey of acute hospital admissions of people with atrial fibrillation, a history of ischaemic heart disease was present in 33%, heart failure in 24%, hypertension in 26%, and rheumatic heart disease in 7%. In some populations, the acute effects of alcohol explain a large proportion of the incidence of acute atrial fibrillation. Paroxysms of atrial fibrillation are more common in athletes.

Prognosis

Spontaneous reversion: Observational studies and placebo arms of RCTs found that more than 50% of people with acute atrial fibrillation revert spontaneously within 24-48 hours, especially if atrial fibrillation is associated with an identifiable precipitant such as alcohol or MI. Progression to chronic atrial fibrillation: We found no evidence about the proportion of people with acute atrial fibrillation who develop more chronic forms of atrial fibrillation (e.g. paroxysmal, persistent, or permanent atrial fibrillation). Mortality: We found little evidence about the effects on mortality of acute atrial fibrillation where no underlying cause is found. Acute atrial fibrillation during MI is an independent predictor of both short- and long-term mortality. Heart failure: Onset of atrial fibrillation reduces cardiac output by 10-20%, irrespective of the underlying ventricular rate, and can contribute to heart failure. People with acute atrial fibrillation who present with heart failure have worse prognoses. Stroke: Acute atrial fibrillation is associated with a risk of imminent stroke. One case series using transoesophageal echocardiography in people who had developed acute atrial fibrillation within the preceding 48 hours found that 15% had atrial thrombi. An ischaemic stroke associated with atrial fibrillation is more likely to be fatal, have a recurrence, or leave a serious functional deficit among survivors than a stroke not associated with atrial fibrillation.

Aims of intervention

To reduce symptoms, morbidity, and mortality, with minimum adverse effects.

Outcomes

Major outcomes include: measures of symptoms; thromboembolism; recurrent strokes, or transient ischaemic attacks; mortality; major bleeding; and adverse effects of treatment. Proxy measures include heart rhythm, ventricular rate, and time to restoration of sinus rhythm. Frequent spontaneous reversion to sinus rhythm makes it difficult to interpret short-term studies of rhythm; treatments may accelerate restoration of sinus rhythm without increasing the proportion of people who eventually convert. The clinical importance of changes in mean heart rate is also unclear.

Methods

BMJ Clinical Evidence search October 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2007, Embase 1980 to October 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 3. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). We have reported RCTs of people with atrial fibrillation of over 7 days' duration, in combined populations of less and greater than 7 days' duration, and RCTs which have not specified duration of atrial fibrillation, in the comments section, as it is unclear whether data in these populations is transferable to acute atrial fibrillation.

Table.

GRADE evaluation of interventions for atrial fibrillation (acute onset)

Important outcomes Symptoms, thromboembolic events (stroke, TIAs), restoration of sinus rhythm, adverse effects (including bleeding)
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of interventions to prevent embolism in people with recent-onset atrial fibrillation who are haemodynamically stable?
No studies found
What are the effects of interventions for conversion to sinus rhythm in people with recent-onset atrial fibrillation who are haemodynamically stable?
5 (1031) Conversion to sinus rhythm Flecainide v placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
4 (727) Conversion to sinus rhythm Flecainide v amiodarone 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for inclusion of different regimens
3 (919) Conversion to sinus rhythm Flecainide v propafenone 4 –1 –1 –1 0 Very low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for inclusion of different regimens
9 (1049) Conversion to sinus rhythm Propafenone v placebo 4 0 0 0 0 High
1 (123) Conversion to sinus rhythm Propafenone v digoxin 4 –2 0 0 0 Low Quality points deducted for sparse data and short follow-up
4 (796) Conversion to sinus rhythm Propafenone v amiodarone 4 0 –1 –1 0 Low Consistency point deducted for conflicting results. Directness point deducted for differences in endpoints and regimens
5 (736) Conversion to sinus rhythm Amiodarone v placebo 4 –1 –1 –1 0 Very low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for difference in regimens
6 (399) Conversion to sinus rhythm Amiodarone v digoxin 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (140) Conversion to sinus rhythm Amiodarone v sotalol 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (24) Conversion to sinus rhythm Amiodarone v verapamil 4 –2 0 0 +1 Moderate Quality points deducted for sparse data and short follow-up. Effect size point added for relative risk greater than 2
1 (61) Conversion to sinus rhythm Quinidine plus digoxin v sotalol 4 –1 0 0 0 Moderate Quality point deducted for sparse data
4 (438) Conversion to sinus rhythm Digoxin v placebo 4 0 0 –2 0 Low Directness points deducted for wide inclusion criteria and for use of different regimens
What are the effects of interventions to control heart rate in people with recent-onset atrial fibrillation who are haemodynamically stable?
1 (100) Control of heart rate Amiodarone v digoxin 4 –2 –1 0 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for different results at different endpoints
2 (333) Control of heart rate Digoxin v placebo 4 0 0 –1 0 Moderate Directness point deducted for wide inclusion criteria
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Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.

Glossary

Atrial flutter

A similar arrhythmia to atrial fibrillation, but the atrial electrical activity is less chaotic and has a characteristic saw tooth appearance on an electrocardiogram.

Chronic atrial fibrillation

Refers to more sustained or recurrent forms of atrial fibrillation, which can be subdivided into paroxysmal, persistent, or permanent atrial fibrillation.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Paroxysmal atrial fibrillation

If the atrial fibrillation recurs intermittently with sinus rhythm, with spontaneous recurrences or termination, it is designated as “paroxysmal”, and the objective of management is suppression of paroxysms and maintenance of sinus rhythm.

Permanent atrial fibrillation

If cardioversion is inappropriate, and has not been indicated or attempted, atrial fibrillation is designated as “permanent”, where the objective of management is rate control and antithrombotic treatment.

Persistent atrial fibrillation

When atrial fibrillation is more sustained than paroxysmal, atrial fibrillation is designated “persistent” and needs termination with pharmacological treatment or electrical cardioversion.

Very low-quality evidence

Any estimate of effect is very uncertain.

Wolff–Parkinson–White syndrome

Occurs when an additional electrical pathway exists between the atria and ventricles as a result of anomalous embryonic development. The extra pathway may cause rapid arrhythmias. Worldwide, it affects about 0.2% of the general population. In people with Wolff–Parkinson–White syndrome, beta-blockers, calcium channel blockers, and digoxin can increase the ventricular rate and cause ventricular arrhythmias.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Gregory Y H Lip, University Department of Medicine, City Hospital, Birmingham, UK.

Timothy Watson, University Department of Medicine, City Hospital, Birmingham, UK.

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BMJ Clin Evid. 2008 May 2;2008:0210.

Antithrombotic treatment before cardioversion

Summary

We found no clinically important results about the effects of aspirin, heparin, or warfarin as thromboprophylaxis before attempted cardioversion in people with acute atrial fibrillation of less than 7 days' duration who are haemodynamically stable.

Benefits

We found no systematic review or RCTs on the use of aspirin, heparin, or warfarin as thromboprophylaxis before cardioversion in people with acute atrial fibrillation of less than 7 days' duration.

Harms

We found no RCTs.

Comment

One RCT compared low molecular weight heparin versus unfractionated heparin (155 people with atrial fibrillation of between 2 and 19 days' duration, undergoing a transoesophageal echocardiography-guided cardioversion strategy).The RCT found no significant difference between low molecular weight heparin and unfractionated heparin in rates of thrombus observation, stroke, systemic embolism, or bleeding. However, low molecular weight heparin did allow earlier hospital discharge.

Clinical guide:

There is consensus to give heparin to people who have cardioversion within 48 hours of the onset of arrhythmia, but we found insufficient evidence from trials to support this. The decision to give anticoagulation both in the short term and after cardioversion is usually based on an individual's intrinsic risk of thromboembolism. Warfarin is not used as an anticoagulant in acute atrial fibrillation because of its slow onset of action. One transoesophageal echocardiography study in people with a recent embolic event found left atrial thrombus in 15% of people with acute atrial fibrillation of less than 3 days' duration. This would suggest that such people may benefit from formal anticoagulation, or need to be evaluated by transoesophageal echocardiography before cardioversion.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Flecainide for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with placebo: Oral or intravenous flecainide is more effective at increasing the rate of conversion to sinus rhythm at 1–24 hours in people with acute atrial fibrillation ( moderate-quality evidence ). Compared with amiodarone: Oral or intravenous flecainide may be more effective than intravenous amiodarone at increasing conversion rates to sinus rhythm at 1–12 hours ( low-quality evidence ). Compared with propafenone: Oral or intravenous flecainide may be as effective as oral or intravenous propafenone at conversion to sinus rhythm at 1–12 hours ( very low-quality evidence ). NOTE We found no clinically important results about flecainide compared with quinidine in the treatment of people with atrial fibrillation of less than 7 days' duration. ADVERSE EFFECTS Flecainide is associated with serious adverse events, such as severe hypotension, and torsades de pointes. Flecainide and propafenone are not used in people with known or suspected ischaemic heart disease because they may cause arrhythmias. Amiodarone should be used in preference to flecainide in people with structural heart disease.

Benefits

Flecainide versus placebo:

We found five RCTs. The first RCT (62 people aged over 75 years, onset of atrial fibrillation of 7 days or less) compared three treatments: oral flecainide (300 mg single dose), intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/day), and placebo. It found that oral flecainide significantly increased the rate of conversion to sinus rhythm at 8 hours compared with placebo (conversion rate: 20/22 [91%] with oral flecainide v 10/21 [48%] with placebo; P less than 0.01). The second RCT (98 people, onset of atrial fibrillation 72 hours or less) compared three treatments: intravenous flecainide (2 mg/kg, maximum dose 150 mg), intravenous amiodarone (7 mg/kg), and placebo. It found that intravenous flecainide significantly increased conversion to sinus rhythm within 2 hours compared with placebo (20/34 [59%] with iv flecainide v 7/32 [22%] with placebo; RR 2.69, 95% CI 1.32 to 5.48). The third RCT (102 people with recent-onset atrial fibrillation of less than 72 hours) also found that intravenous flecainide significantly increased the proportion of people who reverted to sinus rhythm within 1 hour (29/51 [57%] with iv flecainide v 7/51 [14%] with placebo; OR 8.3, 95% CI 2.9 to 24.8), and in whom sinus rhythm was maintained after 6 hours (34/51 [67%] with iv flecainide v 18/51 [35%] with placebo; OR 3.67, 95% CI 1.50 to 9.10) compared with placebo. Participants were randomised to receive flecainide 2 mg/kg over 30 minutes (maximum dose 150 mg) or placebo, and were monitored in intensive-care or coronary-care units. Intravenous digoxin 500 µg over 30 minutes was given to all people who had not previously received digoxin. The fourth RCT (417 people admitted to hospital with recent-onset atrial fibrillation of 7 days or less) compared five treatments: oral flecainide (300 mg single dose), intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/24 hours), intravenous propafenone (2 mg/kg bolus followed by 0.0078 mg/kg/minute), oral propafenone (600 mg single dose), and placebo. It found that oral flecainide increased the rate of conversion to sinus rhythm at 8 hours compared with placebo (cardioversion rate: 75% with oral flecainide v 37% with placebo; significance not reported). The fifth RCT (352 people with recent-onset atrial fibrillation less than 72 hours) compared three treatments: intravenous flecainide, intravenous propafenone, and control. It found that flecainide significantly increased the rate of conversion to sinus rhythm at 1, 3, 6, and 24 hours compared with control (at 1 hour: 72% with iv flecainide v 22% with control; P less than 0.0001; at 3 hours: 80% with iv flecainide v 28% with control; P less than 0.0001; at 6 hours: 86% with iv flecainide v 35% with control; P less than 0.0005; at 24 hours: 90% with iv flecainide v 46% with control; P less than 0.0001).

Flecainide versus amiodarone or propafenone:

We found five RCTs. The first RCT (417 people admitted to hospital with recent-onset atrial fibrillation 7 days' duration or less) compared five treatments: oral flecainide (300 mg single dose), intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/24 hours), intravenous propafenone (2 mg/kg bolus followed by 0.0078 mg/kg/minute), oral propafenone (600 mg single dose), and placebo. It found no significant difference in the proportion of people who converted to sinus rhythm at 1 and 3 hours between oral flecainide and intravenous amiodarone, but found a higher rate of conversion to sinus rhythm with oral flecainide at 8 hours (at 1 hour: 9/69 [13%] with oral flecainide v 3/51 [6%] with iv amiodarone, RR 2.2, 95% CI 0.6 to 7.8; at 3 hours: 39/69 [57%] with oral flecainide v 13/51 [25%] with iv amiodarone, RR 2.20, 95% CI 0.96 to 1.51; at 8 hours: 52/69 [75%] with oral flecainide v 29/51 [57%] with iv amiodarone, RR 1.30, 95% CI 1.01 to 1.74). It found no significant difference in the proportion of people who converted to sinus rhythm at 1, 3, or 12 hours between oral flecainide and oral propafenone (at 1 hour: 9/69 [13%] with oral flecainide v 10/119 [8%] with oral propafenone, RR 1.55, 95% CI 0.66 to 3.63; at 3 hours: 39/69 [57%] with oral flecainide v 54/119 [45%] with oral propafenone, RR 1.25, 95% CI 0.94 to 1.66; at 8 hours: 52/69 [75%] with oral flecainide v 91/119 [76%] with oral propafenone, RR 0.99, 95% CI 0.83 to 1.17). It found that intravenous propafenone increased the rate of conversion to sinus rhythm within 1 hour, but found similar conversion rates at 3 and 8 hours (conversion rate of about 75% at 8 hours). The second RCT (62 people aged less than 75 years, onset of atrial fibrillation 7 days or less) compared three treatments: oral flecainide (300 mg single dose), intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/day), and placebo. It found that oral flecainide significantly increased the proportion of people who converted to sinus rhythm at 8 hours compared with intravenous amiodarone (20/22 [91%] with oral flecainide v 7/19 [37%] with iv amiodarone; RR 2.47, 95% CI 1.35 to 4.51). The third RCT (98 people, onset of atrial fibrillation 72 hours or less) compared three treatments: intravenous flecainide (2 mg/kg, maximum dose 150 mg), intravenous amiodarone (7 mg/kg), and placebo. It found no significant difference between intravenous flecainide and intravenous amiodarone in the proportion of people who converted to sinus rhythm within 2 hours (20/34 [59%] with iv flecainide v 11/32 [34%] with iv amiodarone; RR 1.71, 95% CI 0.98 to 2.98). The fourth RCT (352 people with recent-onset atrial fibrillation less than 72 hours) compared three treatments: flecainide, propafenone, and control. It found significantly faster conversion to sinus rhythm with intravenous flecainide within 1 hour after treatment compared with intravenous propafenone (72% with iv flecainide v 54% with iv propafenone; P = 0.05; absolute numbers not reported). The fifth RCT (150 people, onset of atrial fibrillation 48 hours or less) compared three treatments: flecainide (2 mg/kg bolus in 20 minutes), propafenone (2 mg/kg bolus in 20 minutes), and amiodarone (5 mg/kg in 20 minutes followed by continuous infusion of 50 mg/hour). It found that intravenous flecainide significantly increased the proportion of people who converted to sinus rhythm at 1, 8, and 12 hours compared with intravenous amiodarone (at 1 hour: 29/50 [58%] with iv flecainide v 7/50 [14%] with iv amiodarone, RR 4.14, 95% CI 2.00 to 8.57; at 8 hours: 41/50 [82%] with iv flecainide v 21/50 [42%] with iv amiodarone, RR 1.95, 95% CI 1.38 to 2.77; at 12 hours: 45/50 [90%] with iv flecainide v 32/50 [64%] with iv amiodarone, RR 1.41, 95% CI 1.12 to 1.77). The RCT found no significant difference between intravenous flecainide and intravenous propafenone in the proportion of people who converted to sinus rhythm at 1 and 8 hours. It found a significantly higher conversion rate at 12 hours with flecainide compared with propafenone (at 1 hour: 29/50 [58%] with iv flecainide v 30/50 [60%] with iv propafenone, RR 0.97, 95% CI 0.70 to 1.34; at 8 hours: 41/50 [82%] with iv flecainide v 34/50 [68%] with iv propafenone, RR 1.21, 95% CI 0.96 to 1.51; at 12 hours: 45/50 [90%] with iv flecainide v 36/50 [72%] with iv propafenone, RR 1.25, 95% CI 1.03 to 1.52).

Flecainide versus quinidine:

We found no systematic review or RCTs that compared flecainide with quinidine in people with atrial fibrillation of less than 7 days' duration.

Harms

Flecainide versus placebo:

The first RCT reported an asymptomatic pause of 9.3 seconds in a person who took oral flecainide. The second RCT reported hypotension during the study period, but this was not significantly different between intravenous flecainide and placebo (8/34 [24%] with iv flecainide v 8/32 [25%] with placebo). The third RCT found that a higher proportion of people developed severe hypotension (a decrease in systolic arterial pressure by 33% or more) with intravenous flecainide compared with placebo (11/51 [22%] with iv flecainide v 3/51 [6%] with placebo; OR 4.40, 95% CI 1.03 to 18.60). One person in the intravenous-flecainide group with no history of ventricular arrhythmia and a normal QT interval developed torsades de pointes. The fourth RCT reported adverse effects of oral flecainide in three people, one with left ventricular decompensation, and two with atrial flutter with rapid ventricular response. One person in the placebo group had atrial flutter with rapid ventricular response. The fifth RCT found more adverse effects with intravenous flecainide compared with control (10% with flecainide v 4% with control; significance not reported).

Flecainide versus amiodarone or propafenone:

The first RCT reported left ventricular decompensation in one person receiving oral flecainide and one person receiving intravenous propafenone, and atrial flutter with rapid ventricular response in two people receiving oral flecainide. The second RCT reported no major adverse effects leading to interruption of the study. It reported superficial phlebitis in two people receiving intravenous amiodarone, and mild light-headedness in one person receiving oral flecainide. The third RCT found that a higher proportion of people developed severe hypotension with intravenous flecainide compared with intravenous amiodarone (8/34 [24%] with iv flecainide v 5/32 [16%] with iv amiodarone). It found that, overall, adverse effects were more common with flecainide compared with amiodarone. The fourth RCT found similar adverse effects with intravenous flecainide and intravenous propafenone (10% with iv flecainide v 10% with iv propafenone; significance not reported). The fifth RCT found no significant difference in adverse events between intravenous flecainide, intravenous amiodarone, and intravenous propafenone (transient junctional rhythm, symptomatic hypotension: 6/50 [12%] with iv flecainide; rash, symptomatic hypotension: 3/50 [6%] with iv amiodarone; transient junctional rhythm, atrial tachycardia: 7/50 [14%] with iv propafenone; reported as not significant).

Flecainide versus quinidine:

We found no RCTs.

Comment

Flecainide versus quinidine:

One small RCT found no difference between flecainide and quinidine for conversion to sinus rhythm (60 people aged 16–92 years, of whom 36 people had atrial fibrillation of up to 10 days; conversion to sinus rhythm, time period not reported). The RCT reported one case of severe bradycardia (after the loading dose) and one case of first-degree atrioventricular block and left bundle branch block (during the intravenous loading dose) in people taking flecainide. Adverse effects in people taking quinidine included nausea, abdominal pain, and diarrhoea. Multi-arm RCTs reported in this option are also reported in the amiodarone and propafenone options, where relevant.

Clinical guide:

Following the increased mortality observed in people who have had an MI randomised to flecainide or encainide in the Cardiac Arrhythmia Suppression Trial, flecainide is not used for the treatment of atrial fibrillation in people with known ischaemic heart disease, because of the risk of proarrhythmia. One systematic review on atrial fibrillation concluded that flecainide is the drug of choice to perform pharmacological cardioversion in those without evidence of structural heart disease (coronary artery disease or left ventricular dysfunction). However, this drug should not be used in people with haemodynamic compromise. In the presence of structural heart disease, amiodarone is first-line treatment.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Propafenone for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with placebo: Oral or intravenous propafenone is more effective at increasing the proportion of people who convert to sinus rhythm within 6 hours in people with acute atrial fibrillation ( high-quality evidence ). Compared with intravenous digoxin: Intravenous propafenone may be as effective at increasing conversion to sinus rhythm at 1 hour ( low-quality evidence ). Compared with amiodarone: We don't know whether propafenone is more or less effective at increasing conversion to sinus rhythm at 1–48 hours in people with acute atrial fibrillation (low-quality evidence). Compared with flecainide: Oral or intravenous propafenone may be as effective as oral or intravenous flecainide at increasing conversion to sinus rhythm at 1–12 hours ( very low-quality evidence ). ADVERSE EFFECTS Propafenone and flecainide are not used in people with known or suspected ischaemic heart disease, because they may cause arrhythmias.

Benefits

Propafenone versus placebo:

We found nine RCTs (see table 1 ). All RCTs found that oral or intravenous propafenone was more effective than placebo in terms of the proportion of people who converted to sinus rhythm within 6 hours (see table 1 ). Subgroup analysis of the first RCT found that, after stratification by age (up to 60 years, or over 60 years of age), conversion to sinus rhythm with propafenone was more likely in people aged under 60 years compared with older people (in people aged over 60 years: OR 3.78, 95% CI 1.80 to 7.92 at 3 hours v OR 4.74, 95% CI 2.12 to 10.54 at 8 hours; in people aged up to 60 years: OR 5.03, 95% CI 2.08 to 12.12 at 3 hours v OR 6.75, 95% CI 3.38 to 73.86 at 8 hours). The fourth RCT also found that the time to conversion to sinus rhythm was significantly shorter with intravenous propafenone compared with oral propafenone (see table 1 ).

Table 1.

RCTs comparing propafenone versus placebo in conversion to sinus rhythm in people with acute atrial fibrillation (see text).

RCT Population Intervention Control Outcome Time Result
87 people with recent-onset atrial fibrillation (7 days' duration or less) Propafenone Intravenous or oral Placebo Conversion to sinus rhythm 1 hour 8/29 (28%) with intravenous propafenone, 1/29 (3%) with oral propafenone versus 1/29 (3%) with placebo; P less than 0.05
          3 hours 12/29 (41%) with intravenous propafenone, 16/29 (55%) with oral propafenone versus 3/29 (10%) with placebo; P less than 0.02; P less than 0.001
          8 hours 19/29 (66%) with intravenous propafenone, 20/29 (69%) with oral propafenone versus 7/29 (24%) with placebo; P less than 0.005
188 people, mean age 59 years, with recent-onset atrial fibrillation Propafenone intravenous Placebo Conversion to sinus rhythm 1 hour 89/164 (54%) with propafenone versus 12/50 (22%) with placebo; P less than 0.005
          3 hours 112/164 (68%) with propafenone versus 15/50 (28%) with placebo; P less than 0.001
          6 hours 123/164 (75%) with propafenone versus 19/50 (35%) with placebo; P less than 0.0005
          24 hours 151/164 (92%) with propafenone versus 25/50 (46%) with placebo; P less than 0.0001
240 people, mean age 59 years, duration of atrial fibrillation less than 7 days Propafenone oral Placebo Conversion to sinus rhythm 3 hours 54/119 (45%) with propafenone v 22/121 (18%) with placebo (ARR 27%, 95% CI 17% to 39%)
          8 hours 91/119 (76%) with propafenone v 45/121 (37%) with placebo (ARR 39%, 95% CI 29% to 52%)
55 people, mean age 59 years, duration of atrial fibrillation less than 7 days Propafenone oral Placebo Conversion to sinus rhythm 2 hours 12/29 (41%) with propafenone v 2/26 (8%) with placebo; P = 0.005
          6 hours 65% with propafenone v 31% with placebo; P = 0.015
          12 hours 69% with propafenone v 31% with placebo; P = 0.06
          24 hours 79% with propafenone v 73% with placebo; P = 0.75
156 people aged 18–80 years, onset of atrial fibrillation less than 72 hours Propafenone intravenous Placebo Conversion to sinus rhythm 2 hour 57/81 (70%) with propafenone v 13/75 (17%) with placebo (ARR 53%, 95% CI 42% to 68%; RR 4.06, 95% CI 2.43 to 6.79)
123 people, onset of atrial fibrillation less than 72 hours Propafenone intravenous or oral Placebo Conversion to sinus rhythm 1 hour 25/81 (31%) with propafenone v 7/42 (17%) with placebo, no further statistical analysis provided
          4 hours 49/81 (61%) with propafenone v 14/42 (33%) with placebo, no further statistical analysis provided
          8 hours 53/81 (65%) with propafenone v 20/42 (48%) with placebo, no further statistical analysis provided
    Propafenone intravenous Propafenone oral   1 hour 19/40 (48%) with intravenous propafenone v 6/41 (15%) with oral propafenone; P less than 0.005
          4 hours 20/40 (50%) with intravenous propafenone v 29/41 (71%) with oral propafenone, no further statistical analysis provided
          8 hours 21/40 (53%) with intravenous propafenone v 32/41 (78%) with oral propafenone; P less than 0.03
Three-arm study, 123 people aged 18–75 years, onset of atrial fibrillation less than 72 hours Propafenone intravenous Placebo Conversion to sinus rhythm 1 hour 20/41 (49%) with propafenone v 6/42 (14%) with placebo (RR 3.42, 95% CI 1.53 to 7.63)
Three-arm study, 77 men, mean age, 63 ± 12 years, recent-onset atrial fibrillation 48 hours or less Propafenone intravenous Placebo Conversion to sinus rhythm 1 hour 36/46 (78%) with propafenone v 27/49 (55%) with placebo (RR 1.42, 95% CI 1.06 to 1.91)
75 people, aged 18–70 years, recent-onset atrial fibrillation less than 72 hours Propafenone intravenous Placebo Conversion to sinus rhythm Within 3 hours, or until conversion occurred 24/41 (59%) with propafenone v 10/34 (29%) with placebo (OR 3.2, 95% CI 1.3 to 7.9; P less than 0.01)
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Propafenone versus digoxin:

We found one RCT (123 people, aged 18–75 years, onset of atrial fibrillation less than 72 hours), which compared three treatments given as a 10-minute infusion: propafenone 2 mg/kg, digoxin 0.007 mg/kg, and placebo. It found no significant difference in the rate of conversion to sinus rhythm at 1 hour between propafenone and digoxin (49% with propafenone v 32% with digoxin; OR 1.50, 95% CI 0.87 to 2.59).

Propafenone versus amiodarone:

We found no systematic review. We found three RCTs. The first RCT (143 people, mean age 63 years, recent-onset atrial fibrillation of 48 hours or less) compared three treatments: intravenous propafenone (2 mg/kg over 15 minutes followed by 10 mg/kg over next 24 hours), intravenous amiodarone (300 mg over 1 hour followed by 20 mg/kg over next 24 hours plus 1800 mg/day orally), and placebo. Intravenous digoxin was given to all people who had not previously received digoxin. The RCT found no significant difference between intravenous propafenone and amiodarone in the proportion of people who converted to sinus rhythm within 1 hour (36/46 [78%] with iv propafenone v 40/48 [83%] with iv plus oral amiodarone; RR 0.94, 95% CI 0.77 to 1.15). The second RCT (417 people with recent-onset atrial fibrillation 7 days' or less) compared five treatments: intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/24 hours), intravenous propafenone (2 mg/kg bolus followed by 0.0078 mg/kg/minute), oral propafenone 600 mg single dose, oral flecainide 300 mg single dose, and placebo. It found that intravenous propafenone and oral propafenone increased the rate of conversion to sinus rhythm at 8 hours compared with amiodarone (75% with iv propafenone v 76% with oral propafenone v 57% with iv amiodarone; significance not reported). The third RCT (150 people, onset of atrial fibrillation 48 hours or less) compared three treatments: iv flecainide (2 mg/kg bolus in 20 minutes), iv propafenone (2 mg/kg bolus in 20 minutes), or iv amiodarone (5 mg/kg in 20 minutes followed by continuous infusion of 50 mg/hour). It found no significant difference in the rate of conversion to sinus rhythm at 12 hours between propafenone and amiodarone (36/50 [72%] with iv propafenone v 32/50 [64%] with iv amiodarone; P = 0.39). It found that propafenone significantly reduced median time to conversion to sinus rhythm compared with amiodarone (30 minutes with iv propafenone v 333 minutes with iv amiodarone; P less than 0.001).

Propafenone versus flecainide:

See benefits of flecainide.

Harms

Propafenone versus placebo:

The first RCT reported left ventricular depression in one person receiving propafenone, and atrial flutter with rapid ventricular response in one person receiving placebo.The second RCT found more adverse effects with propafenone compared with control (10% with propafenone v 4% with control; significance not reported). The fourth RCT, which included people with structural heart disease and hypertension, found no significant difference between propafenone and placebo in terms of adverse events (sustained atrial flutter or tachycardia lasting less than 1 minute: 8/119 [7%] with propafenone v 7/121 [6%] with placebo; P less than 0.2; pauses of less than 2 seconds: 1/119 [1%] with propafenone v 3/121 [2%] with placebo; P less than 0.2). No cases of ventricular proarrhythmia were reported. The eighth RCT reported discontinuation of propafenone in two people due to excessive QRS widening. The other five RCTs that compared propafenone versus placebo reported no serious adverse events.

Propafenone versus digoxin:

The RCT found no significant difference in hypotension between propafenone and digoxin (P = 0.12). It reported asymptomatic atrial flutter with 2:1 atrioventricular conduction (ventricular rates between 105 beats/minute and 130 beats/minute) in three people: one receiving propafenone as first treatment, one receiving propafenone after digoxin, and one receiving digoxin after propafenone.

Propafenone versus amiodarone:

The first RCT reported discontinuation of propafenone in two people because of excessive QRS widening, and discontinuation of amiodarone in one person because of allergy. The second RCT reported left ventricular decompensation in one person receiving propafenone. The third RCT found no significant difference in adverse events between amiodarone and propafenone (rash, symptomatic hypotension: 3/50 [6%] with amiodarone; transient junctional rhythm, atrial tachycardia: 7/50 [14%] with propafenone; reported as not significant).

Propafenone versus flecainide:

See harms of flecainide.

Other comparisons:

We found one RCT (246 people with onset of atrial fibrillation of less than 48 hours), which evaluated the safety of an oral loading dose of propafenone (600 mg for less than 60 kg body weight, then 300 mg if persistent) compared with that of digoxin plus propafenone, digoxin plus quinidine, and placebo. The RCT found no serious adverse events. The RCT found similar rates across treatment groups of transient atrial flutter (13/66 [20%] with propafenone v 12/70 [17%] with digoxin plus propafenone v 9/70 [13%] with digoxin plus quinidine v 3/40 [8%] with placebo), asymptomatic salvos of up to four ventricular beats (4/70 [6%] with digoxin plus propafenone v 1/70 [1%] with digoxin plus quinidine), transient left bundle branch block (3/66 [5%] with propafenone v 2/70 [3%] with digoxin plus propafenone v 2/70 [3%] digoxin plus quinidine), transient Wenckebach 2:1 heart block (2/66 [3%] with propafenone v 2/70 [3%] with digoxin plus quinidine), and transient mild hypotension (5/66 [8%] with propafenone v 1/70 [1%] with digoxin plus quinidine). No significance figures were reported. The RCT found no significant difference between groups for non-cardiac adverse events such as nausea, headache, gastrointestinal disturbance, dizziness, and paraesthesia.

Comment

Multi-arm RCTs reported in this option are also reported in the amiodarone, digoxin, and flecainide options, where relevant. One systematic review (search date 1997, 27 controlled clinical trials including some non-randomised trials, 1843 people) did not analyse the data for patients with acute and chronic atrial fibrillation separately. In the trials included in the systematic review, propafenone was given either intravenously (2 mg/kg as initial bolus followed by infusion) or orally (450–600 mg). The systematic review reported that people treated with propafenone were more likely to convert to sinus rhythm at 4 and 8 hours after initial treatment compared with people treated with placebo, but there was no significant difference at 24 hours. The systematic review gave no information on adverse effects. The number of RCTs was not reported clearly.One subsequent RCT (86 people, onset of atrial fibrillation less than 2 weeks) reported a faster rate of conversion to sinus rhythm with oral propafenone (600 mg in the first 24 hours, with a further 300 mg over the next 24 hours if necessary) compared with oral amiodarone (30 mg/kg for the first 24 hours and, if necessary, a repeated dose of 15 mg/kg for 24 hours). However the RCT reported no increase in the proportion of people who converted to sinus rhythm at 24 and 48 hours. The RCT found no serious adverse events.

Clinical guide:

Extrapolation of the results of the Cardiac Arrhythmia Suppression Trial, in which flecainide or encainide increased mortality in people who had had an MI, has meant that other class 1c antiarrhythmic agents, including propafenone, tend not to be used in people with ischaemic heart disease because of concerns over a possible increase in proarrhythmic effects in this group of people. In addition, the increased frequency of cardiac adverse events with long-term propafenone noted in people with structural heart disease means that trials in acute atrial fibrillation have, for the main part, excluded people with significant heart disease.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Amiodarone for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with placebo: Amiodarone may be more effective at increasing conversion to sinus rhythm at 1–8 hours in people with acute atrial fibrillation who are haemodynamically stable ( very low-quality evidence ). Compared with digoxin: Amiodarone may be as effective at increasing conversion to sinus rhythm at 1–48 hours ( low-quality evidence ). Compared with sotalol: Amiodarone may be as effective at increasing conversion to sinus rhythm at 3 hours (low-quality evidence). Compared with flecainide: Intravenous amiodarone may be less effective than oral or intravenous flecainide at increasing conversion to sinus rhythm at 1–12 hours (low-quality evidence). Compared with propafenone: We don't know whether amiodarone is more or less effective than propafenone at increasing conversion to sinus rhythm at 1–48 hours in people with acute atrial fibrillation (very low-quality evidence). Compared with verapamil: Amiodarone is more effective at increasing conversion to sinus rhythm at 3 hours ( moderate-quality evidence ). ADVERSE EFFECTS Amiodarone is associated with adverse effects including bradycardia and hypotension. NOTE We found no clinically important results about the effect of amiodarone compared with direct current cardioversion.

Benefits

Amiodarone versus placebo:

We found two systematic reviews (search dates 2001, 2 RCTs comparing amiodarone as a single agent versus placebo, 104 people with acute-onset atrial fibrillation), one additional RCT, and two subsequent RCTs. Neither RCT included in the review found a difference in rates of conversion from atrial fibrillation to sinus rhythm at 8 hours between intravenous amiodarone and placebo (first RCT: 40 people; cardioversion rate: 37% with amiodarone 5 mg/kg bolus plus 1800 mg/day v 48% with placebo; P value reported as not significant; second RCT: 64 people; cardioversion rate: 59% with amiodarone 7 mg/kg bolus v 56% with placebo; P value reported as not significant). The additional RCT (417 people with recent-onset atrial fibrillation 7 days or less) compared five treatments: intravenous amiodarone (5 mg/kg bolus followed by 1.8 g/24 hours), intravenous propafenone (2 mg/kg bolus followed by 0.0078 g/kg/minute), oral propafenone (600 mg single dose), oral flecainide (300 mg single dose), and placebo. It found that intravenous amiodarone significantly increased rates of conversion to sinus rhythm at 8 hours compared with placebo (cardioversion rate: 57% with iv amiodarone v 37% with placebo; reported as significant, P value not reported). The first subsequent RCT (72 people) found higher cardioversion rates with oral amiodarone at 8 hours compared with placebo (cardioversion rate: 50% with oral amiodarone 30 mg/kg/day v 20% with placebo; absolute numbers not reported, P less than 0.0001). The second subsequent RCT (143 people, mean age 63 years, recent-onset atrial fibrillation 48 hours or less) compared three treatments: intravenous amiodarone (300 mg over 1 hour followed by 20 mg/kg over next 24 hours plus 1800 mg/day orally), intravenous propafenone (2 mg/kg over 15 minutes followed by 10 mg/kg over next 24 hours), and placebo. Intravenous digoxin was given to all people who had not previously received digoxin. Amiodarone significantly increased the proportion of people converting to sinus rhythm within 1 hour compared with placebo (40/48 [83%] with iv plus oral amiodarone v 27/49 [55%] with placebo; P less than 0.02).

Amiodarone versus digoxin:

We found two systematic reviews (search date 2001, 3 RCTs, 148 people with acute-onset atrial fibrillation; search date 2001, 3 RCTs, 114 people, no statistical pooling of results) and two subsequent RCTs. Together, the reviews identified four small RCTs (34, 45, 50, and 30 people). None found any statistically significant difference in rates of conversion to sinus rhythm at 24–48 hours between amiodarone and digoxin. The subsequent RCT (100 people with recent-onset atrial fibrillation, heart rate less than 135 beats/minute at presentation) compared amiodarone 450 mg versus digoxin 0.6 mg given as a single bolus through peripheral intravenous access. If the person remained tachycardic after 30 minutes, a further 300 mg of amiodarone or 0.4 mg digoxin was administered to each group. The first RCT found a significantly higher rate of conversion to sinus rhythm at 30 minutes in the amiodarone group compared with the digoxin group (14/50 [28%] with iv amiodarone v 3/50 [6%] with iv digoxin; P = 0.003) and at 60 minutes (21/50 [42%] with iv amiodarone v 9/50 [18%] with iv digoxin; P = 0.012). However, the RCT found no statistically significant difference at 24 hours (significance assessment not performed, no further data reported).The second RCT (140 people, mean age 55 years, presenting with recent-onset atrial fibrillation) randomised consecutive people to intravenous amiodarone (10 mg/kg over 30 minutes), intravenous sotalol (1.5 mg/kg over 10 minutes), or intravenous digoxin (0.5 mg over 20 minutes). If pharmacological cardioversion had not occurred by 12 hours, then direct current cardioversion was attempted. Similar rates of conversion to sinus rhythm were reported in all three groups (51% with amiodarone v 44% with sotalol v 50% with digoxin; P reported as not significant). In those people in whom subsequent direct current cardioversion was required, there was no significant difference in success rate between groups (94% with amiodarone v 95% with sotalol v 98% with digoxin; P reported as not significant).

Harms

Amiodarone versus placebo:

One systematic review found that the most common adverse effects of intravenous amiodarone were phlebitis, hypotension, and bradycardia. Pooled adverse-event rates were higher with amiodarone than with placebo (AR for any adverse effect: 17% with amiodarone v 11% with placebo). Other reported adverse effects of amiodarone in the acute setting include heart failure and arrhythmia. The additional RCT found no serious adverse effects in the intravenous-amiodarone group. The first subsequent RCT reported a similar proportion of people with adverse events with amiodarone and placebo (rapid ventricular response, diarrhoea, nausea, fainting in 6/31 [19%] with amiodarone; diarrhoea, nausea, sinus arrest, transient ischaemic attack in 6/31 [19%] with placebo). In the second subsequent RCT, amiodarone was discontinued in one person (1/48 [2%]) because of an allergic reaction; there were no adverse events in the placebo group (0/49 [0%]).

Amiodarone versus digoxin:

No adverse events were reported in one of the RCTs (0/15 [0%] with amiodarone v 0/15 [0%] with digoxin). Two RCTs reported more adverse events with amiodarone than with digoxin (1/18 [6%] with amiodarone v 0/16 [0%] with digoxin; 3/26 [12%] with amiodarone v 0/24 [0%] with digoxin). One RCT reported more adverse events with digoxin than with amiodarone (major adverse events: 3/39 [8%] with amiodarone v 8/36 [22%] with digoxin). One RCT gave no information on adverse effects.One RCT compared intravenous amiodarone versus digoxin and reported a trend towards more serious adverse effects in the amiodarone group. These included one person with profound bradycardia after amiodarone infusion, and one person who had a viral cardiomyopathy and subsequently developed cardiogenic shock which required inotropic and ventilatory support. Other transient reactions included nausea and vomiting, and paraesthesia over the infusion site. Amiodarone was also more likely than digoxin to produce symptomatic hypotension (5 people; P = 0.035).

Amiodarone versus digoxin versus sotalol:

One RCT compared intravenous amiodarone, sotalol, and digoxin, and reported a trend towards more serious adverse effects in the amiodarone group. These included one person with profound bradycardia after amiodarone infusion, and one person who had a viral cardiomyopathy and subsequently developed cardiogenic shock which required inotropic and ventilatory support. Other transient reactions included nausea and vomiting, and paraesthesia over the infusion site. Amiodarone was also more likely than digoxin or sotalol to produce symptomatic hypotension (5 people; P = 0.035).

Amiodarone versus flecainide:

See harms of flecainide.

Amiodarone versus verapamil:

The RCT reported slowing of ventricular rate to 45 beats a minute and transitory hypotension in one person receiving verapamil, and hypotension without bradycardia, lasting for about 4 minutes, in one person receiving amiodarone.

Amiodarone versus propafenone:

See harms of propafenone.

Amiodarone versus direct current cardioversion:

We found no RCTs.

Comment

The RCTs that found no significant difference between treatments may have lacked power to detect clinically important effects. Multi-arm RCTs reported in this option are also reported in the flecainide and propafenone options where relevant.

Clinical guide:

One systematic review on atrial fibrillation management concluded that amiodarone should be the drug of choice to attempt pharmacological cardioversion in people with evidence of structural heart disease (coronary artery disease or left ventricular dysfunction). However, in the absence of structural heart disease, flecainide is the usual first choice.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Direct current cardioversion for rhythm control

Summary

We found no clinically important results about the effects of direct current cardioversion in acute atrial fibrillation in people who are haemodynamically stable. Consensus is that it should be used in people with haemodynamically unstable acute atrial fibrillation.

Benefits

We found no systematic review or RCTs on the use of direct current cardioversion for heart-rhythm control in people with acute atrial fibrillation of less than 7 days' duration.

Direct current cardioversion versus no cardioversion or chemical conversion:

We found no RCTs.

Harms

We found no RCTs. Adverse events from synchronised direct current cardioversion include those associated with a general anaesthetic, generation of a more serious arrhythmia, superficial burns, and thromboembolism.

Comment

Clinical guide:

The only evidence for direct current cardioversion in acute atrial fibrillation is extrapolated from its use in chronic atrial fibrillation. Direct current cardioversion has been used for the treatment of atrial fibrillation since the 1960s. It may be unethical to conduct RCTs of direct current cardioversion in people with acute atrial fibrillation and haemodynamic compromise. The consensus is that immediate direct current cardioversion for acute atrial fibrillation should be attempted if there are signs of haemodynamic compromise. If the patient is haemodynamically stable, full anticoagulation is recommended (warfarin for 3 weeks before and 4 weeks after cardioversion) to reduce the risk of thromboembolism in people with atrial fibrillation of more than 48 hours' duration. We found insufficient evidence on whether cardioversion or rate control is superior for the treatment of acute atrial fibrillation.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Quinidine for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with flecainide: Quinidine may be as effective at increasing conversion to sinus rhythm ( very low-quality evidence ). Quinidine plus digoxin compared with sotalol: Quinidine plus digoxin is more effective at increasing conversion to sinus rhythm at 12 hours ( moderate-quality evidence ). NOTE We found no direct information about whether quinidine is better than no active treatment in people with acute atrial fibrillation.

Benefits

Quinidine versus placebo:

We found no RCTs comparing quinidine versus placebo for heart-rhythm control in people with acute atrial fibrillation of less than 7 days' duration.

Quinidine plus digoxin versus sotalol:

One small RCT (61 people aged 18–75 years, mean age about 54 years, with recent-onset atrial fibrillation of less than 48 hours) found that quinidine plus digoxin significantly increased the proportion of people who converted to sinus rhythm within 12 hours compared with sotalol (24/28 [86%] with quinidine plus digoxin v 17/33 [51.5%] with sotalol; ARR 34%, 95% CI 16% to 58%; RR 1.66, 95% CI 1.16 to 2.39; NNT 3, 95% CI 2 to 6). Quinidine was given as 200 mg orally up to three times with 2 hour intervals, and up to 0.75 mg of digoxin was given intravenously if the initial heart rate was greater than 100 beats a minute. Sotalol 80 mg was given orally, and the dose was repeated at 2, 6, and 10 hours after the initial dose if sinus rhythm was not achieved.

Quinidine versus flecainide:

See benefits of flecainide.

Harms

Quinidine versus placebo:

We found no RCTs.

Quinidine plus digoxin versus sotalol:

The RCT reported broad complex tachycardia in 7/28 (27%) people with quinidine plus digoxin compared with 4/33 (13%) people with sotalol. ECG R–R interval prolongation was also reported in both groups (total 3 people, longest R–R: 3.8 seconds with digoxin plus quinidine v 6.4 seconds with sotalol).

Quinidine versus flecainide:

See harms of flecainide.

Comment

Clinical guide:

There is insufficient evidence to draw conclusions regarding the use of quinidine in acute atrial fibrillation. As with other Class I antiarrhythmic drugs, caution must be exercised when prescribing, particularly regarding the risk of proarrhythmia. Given limited data regarding the use of quinidine in acute atrial fibrillation, quinidine remains of unknown effectiveness, and it may therefore be more appropriate to use alternative drugs.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Sotalol for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with quinidine plus digoxin: Sotalol is less likely to lead to conversion to sinus rhythm at 12 hours ( moderate-quality evidence ). ADVERSE EFFECTS Sotalol can cause arrhythmias at high doses. NOTE We found no direct information about whether sotalol is better than no active treatment.

Benefits

Sotalol versus placebo:

We found no systematic review or RCTs that compared sotalol versus placebo for heart-rhythm control in people with acute atrial fibrillation of less than 7 days' duration.

Sotalol versus quinidine plus digoxin:

See benefits of quinidine.

Harms

Sotalol versus placebo:

We found no RCTs.

Sotalol versus quinidine plus digoxin:

See harms of quinidine.

Comment

We found one systematic review (search date 1998), which compared beta-blockers versus placebo in people with acute or chronic atrial fibrillation. See comment on timolol.

Clinical guide:

It should be noted that sotalol is a beta-blocker that has class III antiarrhythmic activity at high doses (240–480 mg/day). In UK clinical practice, sotalol is often used at low doses (80–160 mg/day), at which it essentially acts in a similar manner to a standard beta-blocker (class II) in terms of antiarrhythmic activity. In people with low BMI, renal impairment, etc, some class III activity may be manifest at low doses. When used as an antiarrhythmic agent, sotalol is often started at 80 mg twice daily for the first week, and thereafter titrated to 160 mg twice daily (or higher subsequently), after checking for adverse effects and QT prolongation on the ECG.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Digoxin for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with placebo: Digoxin may be no more effective at increasing conversion to sinus rhythm at 1–16 hours in people with atrial fibrillation for up to 7 days ( low-quality evidence ). Compared with amiodarone: Digoxin may be as effective at increasing conversion to sinus rhythm at 1–48 hours (low-quality evidence). Compared with propafenone: Intravenous digoxin may be as effective as intravenous propafenone at increasing conversion to sinus rhythm at 1 hour (low-quality evidence). ADVERSE EFFECTS Digoxin can cause bradyarrhythmias.

Benefits

Digoxin versus placebo:

We found four RCTs in people with atrial fibrillation of up to 7 days' duration. The first RCT (239 people within 7 days of onset of atrial fibrillation, mean age 66 years, mean ventricular rate 122 beats/minute) found that intravenous digoxin (mean 0.88 mg) did not increase the restoration of sinus rhythm at 16 hours compared with placebo (51% with digoxin v 46% with placebo; P = 0.37). The second RCT (40 people within 7 days of the onset of atrial fibrillation, mean age 64 years, 23 men) compared high-dose intravenous digoxin 1.25 mg versus placebo. Restoration to sinus rhythm was not significantly different (9/19 [47%] with digoxin v 8/20 [40%] with placebo; P = 0.6). The third RCT (36 people within 7 days of the onset of atrial fibrillation) compared oral digoxin (doses of 0.6, 0.4, and 0.2 mg at 0, 4, 8, and 14 hours, or until conversion to sinus rhythm, whichever occurred first) versus placebo. Conversion to sinus rhythm at 18 hours was not significantly different (50% with digoxin v 44% with placebo; ARR +6%, 95% CI –11% to +22%). The fourth RCT (123 people, aged 18–75 years, onset of atrial fibrillation less than 72 hours) compared three treatments given as a 10-minute infusion: propafenone (2 mg/kg), digoxin (0.007 mg/kg), and placebo. It found no significant difference in rate of conversion to sinus rhythm between digoxin and placebo within 1 hour (13/40 [33%] with digoxin v 6/42 [14%] with placebo; RR 2.28, 95% CI 0.96 to 5.40).

Digoxin versus amiodarone:

See benefits of amiodarone.

Digoxin versus propafenone:

See benefits of propafenone.

Harms

Digoxin versus placebo:

In the first RCT, some people developed asymptomatic bradycardia, and one person with previously undiagnosed hypertrophic cardiomyopathy suffered circulatory distress. In the second RCT, two people developed bradyarrhythmias. No adverse effects were stated in the third RCT. Digoxin at toxic doses could result in: visual, gastrointestinal, and neurological symptoms; heart block; and arrhythmias. The fourth RCT reported hypotension in four people receiving propafenone, and it reported asymptomatic atrial flutter with 2:1 atrioventricular conduction (ventricular rates between 105 beats/minute and 130 beats/minute) in three people: one receiving propafenone as first treatment, one receiving propafenone after digoxin, and one receiving digoxin after propafenone.

Digoxin versus amiodarone:

See harms of amiodarone.

Digoxin versus propafenone:

See harms of propafenone.

Comment

The three-arm RCT reported in this option is also reported in the propafenone option.

Clinical guide:

The evidence suggests that digoxin is no better than placebo for restoring sinus rhythm in people with recent-onset atrial fibrillation. The peak action of digoxin (oral or iv) is delayed for up to 6–12 hours.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Verapamil for rhythm control

Summary

CONVERSION TO SINUS RHYTHM Compared with amiodarone: Verapamil is less effective at increasing the conversion to sinus rhythm at 3 hours ( moderate-quality evidence ). ADVERSE EFFECTS Verapamil has been associated with ventricular arrhythmias, hypotension, and exacerbation of heart failure. NOTE We found no direct information about whether verapamil is better than no active treatment.

Benefits

Verapamil versus placebo:

We found no systematic review or RCTs on the use of verapamil versus placebo for heart-rhythm control in people with acute atrial fibrillation of less than 7 days' duration.

Verapamil versus amiodarone:

See benefits of amiodarone.

Harms

Verapamil versus placebo:

We found no RCTs.

Verapamil versus amiodarone:

See harms of amiodarone. In people with Wolff–Parkinson–White syndrome, verapamil may increase the ventricular rate, and can cause ventricular arrhythmias. Rate-limiting calcium channel blockers may exacerbate heart failure and hypotension.

Comment

We found one crossover RCT (double blind, 20 people) in people with atrial fibrillation or atrial flutter for 2 hours to 2 years, which compared intravenous low-dose verapamil (0.075 mg/kg) versus placebo. A positive response was defined as conversion to sinus rhythm, or a decrease in the ventricular response to less than 100 beats a minute, or by more than 20% of the initial rate. If a positive response did not occur within 10 minutes, then a second bolus injection was given (placebo for people who initially received verapamil, and verapamil for people who initially received placebo). The RCT reported no significant difference in the proportion of people who converted to sinus rhythm within 30 minutes compared with placebo. The RCT reported development of 1:1 flutter in one person with previous Wolff–Parkinson–White syndrome and 2:1 flutter.

Clinical guide:

One systematic review concluded that the available evidence suggests that calcium channel blockers such as diltiazem and verapamil reduce ventricular rate in acute- or recent-onset atrial fibrillation. However, these drugs are probably no better than placebo for restoring sinus rhythm. We found no studies of the effect of rate-limiting calcium channel blockers on exercise tolerance in people with acute- or recent-onset atrial fibrillation, but studies in people with chronic atrial fibrillation found improved exercise tolerance.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Amiodarone for rate control

Summary

CONTROL OF HEART RATE Compared with digoxin: Amiodarone may be as effective at controlling heart rate at 30 minutes ( very low-quality evidence ).

Benefits

Amiodarone versus digoxin:

We found one RCT (100 consecutive people, heart rate 135 beats/minute or more, at presentation) comparing amiodarone 450 mg versus digoxin 0.6 mg given as a single bolus through peripheral intravenous access. If the person remained tachycardic after 30 minutes, a further amiodarone 300 mg or digoxin 0.4 mg was administered to each group. The RCT found that amiodarone as an intravenous bolus was significantly more effective than digoxin at controlling heart rate in people with acute atrial fibrillation, and that this effect was noted from 5 minutes after administration (P = 0.008, results presented graphically, no further data reported). However, data presented for subsequent timeframes also included those people who had converted to sinus rhythm, and are therefore difficult to interpret. At 60 minutes, considering only people who remained in atrial fibrillation, no significant differences in heart rate were apparent between the two drugs (results presented graphically).

Harms

Amiodarone versus digoxin:

One RCT showed that intravenous bolus amiodarone resulted in a slight reduction in systolic blood pressure up to 5 minutes after administration. This did not require treatment, but the numbers affected were not stated. One case of superficial phlebitis was reported with amiodarone, requiring local topical treatment.

Comment

Clinical guide:

One systematic review on atrial fibrillation concluded that intravenous beta-blockers or rate-limiting calcium channel antagonists should be used for people requiring urgent pharmacological rate control. Where these drugs are ineffective or contraindicated, amiodarone should be used.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Digoxin for rate control

Summary

CONTROL OF HEART RATE Compared with placebo: Digoxin is more effective at controlling heart rate at 30 minutes to 2 hours in people with atrial fibrillation lasting up to 7 days ( moderate-quality evidence ). Compared with amiodarone: Digoxin may be as effective at controlling heart rate at 30 minutes ( very low-quality evidence ). Compared with diltiazem: Digoxin may be less effective at controlling heart rate at 5–180 minutes in people with atrial fibrillation or flutter ( low-quality evidence ).

Benefits

We found no systematic review or RCTs on the use of digoxin to control heart rate limited to people with acute atrial fibrillation of less than 7 days' duration.

Digoxin versus placebo:

We found two RCTs in people with atrial fibrillation of up to 7 days' duration. The first RCT (239 people less than 7 days of onset of atrial fibrillation, mean age 66 years, mean ventricular rate 122 beats/minute) found a rapid and clinically important reduction in ventricular rate at 2 hours (to 105 beats/minute with iv digoxin v 117 beats/minute with placebo; P = 0.0001). The second RCT (40 people with atrial fibrillation of less than 7 days' duration, mean age 64 years, 23 men) compared high-dose intravenous digoxin 1.25 mg versus placebo. The ventricular rate after 30 minutes was significantly lower with digoxin compared with placebo (data produced graphically, P less than 0.02).

Digoxin versus diltiazem:

See benefits of diltiazem.

Digoxin versus amiodarone:

See benefits of amiodarone.

Harms

Digoxin versus placebo:

In the first RCT, adverse effects included asymptomatic bradycardia, and one person with previously undiagnosed hypertrophic cardiomyopathy suffered circulatory distress. In the second RCT, two people developed bradyarrhythmias.

Digoxin versus diltiazem:

See harms of diltiazem.

Digoxin versus amiodarone:

See harms of amiodarone.

Comment

Clinical guide:

We found one systematic review (search date 1998) and two additional RCTs comparing digoxin versus placebo in people with chronic atrial fibrillation, which found that control of the ventricular rate during exercise was poor unless a beta-blocker or rate-limiting calcium channel blocker (verapamil or diltiazem) was used in combination. One systematic review on atrial fibrillation concluded that intravenous beta-blockers or rate-limiting calcium channel antagonists should be used for people requiring urgent pharmacological rate control. Where these drugs are ineffective or contraindicated, amiodarone should be used.It is not clear whether these results can be extrapolated to people with acute atrial fibrillation.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Diltiazem for rate control

Summary

CONTROL OF HEART RATE We found no clinically important results about diltiazem in the treatment of people with acute atrial fibrillation.

Benefits

We found no systematic review or RCTs on the effects of diltiazem to control heart rate in people with acute atrial fibrillation, of less than 7 days' duration, who are haemodynamically stable.

Diltiazem versus placebo:

We found no systematic review. We found no RCTs limited to people with acute atrial fibrillation.

Diltiazem versus digoxin:

We found no systematic review. We found no RCTs limited to people with acute atrial fibrillation.

Diltiazem versus verapamil:

See benefits of verapamil.

Harms

Diltiazem versus placebo:

We found no RCTs.

Diltiazem versus digoxin:

We found no RCTs.

Diltiazem versus verapamil:

See harms of verapamil. Rate-limiting calcium channel blockers may exacerbate heart failure and hypotension.

Comment

Clinical guide:

Diltiazem versus placebo:

One RCT (113 people; 89 with atrial fibrillation of unspecified duration and 24 with atrial flutter; ventricular rate of over 120 beats/minute; systolic blood pressure 90 mm Hg or more, without severe heart failure; 108 people with at least 1 underlying condition that may explain atrial arrhythmia; mean age 64 years) compared intravenous diltiazem versus placebo. After randomisation, a dose of intravenous diltiazem (or equivalent placebo) 0.25 mg/kg every 2 minutes was given; if the first dose had no effect after 15 minutes, then the code was broken and diltiazem 0.35 mg/kg every 2 minutes was given regardless of randomisation. The RCT found no difference in response rate to diltiazem in people with atrial fibrillation compared with those with atrial flutter. In the diltiazem-treated group, seven people developed asymptomatic hypotension (systolic blood pressure less than 90 mm Hg), three developed flushing, three developed itching, and one developed nausea and vomiting.

Diltiazem versus digoxin:

One RCT (30 consecutive people, 10 men, mean age 72 years, 26 with acute atrial fibrillation, 4 with atrial flutter, unspecified duration) compared intravenous diltiazem versus intravenous digoxin versus both drugs given on admission to the emergency department. Heart rate control was defined as a ventricular rate of less than 100 beats a minute. Intravenous digoxin (25 mg as a bolus at 0 and 30 minutes) and intravenous diltiazem (initially 0.25 mg/kg over the first 2 minutes, followed by 0.35 mg/kg at 15 minutes, and then a titratable infusion at a rate of 10–20 mg/hour) were given to maintain heart-rate control. The dosing regimens were the same whether the drugs were given alone or in combination. The RCT found that diltiazem decreased ventricular heart rate against baseline within 5 minutes, compared with digoxin, which was not significant until 180 minutes. No additional benefit was found with the combination of digoxin and diltiazem. The RCT was not large enough to assess adverse effects adequately, and none were apparent. The evidence suggests that calcium channel blockers such as diltiazem and verapamil reduce ventricular rate in acute- or recent-onset atrial fibrillation, but they are probably no better than placebo for restoring sinus rhythm. We found no studies of the effect of rate-limiting calcium channel blockers on exercise tolerance in people with acute- or recent-onset atrial fibrillation, but studies in people with chronic atrial fibrillation found improved exercise tolerance. One systematic review on atrial fibrillation concluded that intravenous beta-blockers or rate-limiting calcium channel antagonists should be used for people requiring urgent pharmacological rate control. Where these drugs are ineffective or contraindicated, amiodarone should be used.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Timolol for rate control

Summary

CONTROL OF HEART RATE We found no direct information about timolol in the treatment of people with atrial fibrillation.

Benefits

We found no systematic review or RCTs on the effects of timalol to control heart rate in people with acute atrial fibrillation of less than 7 days' duration who are haemodynamically stable.

Harms

Timolol versus placebo:

We found no RCTs. Beta-blockers may exacerbate heart failure and hypotension in acute atrial fibrillation and can precipitate bronchospasm. Beta-blockers plus rate-limiting calcium channel blockers (diltiazem and verapamil) may increase the risk of asystole and sinus arrest.

Comment

Timolol versus placebo:

We found one RCT (61 people with atrial fibrillation of unspecified duration, ventricular rate over 120 beats/minute), which compared intravenous timolol 1 mg (a beta-blocker) versus intravenous placebo given immediately and repeated twice at 20-minute intervals if sinus rhythm was not achieved. It found that, 20 minutes after the last injection, intravenous timolol increased the proportion of people who had a ventricular rate below 100 beats a minute compared with placebo. The most common adverse effects were bradycardia (2%) and hypotension (9%). We found one systematic review comparing beta-blockers versus placebo in people with acute or chronic atrial fibrillation. It found that, in 7/12 (58%) comparisons at rest, and in all during exercise, beta-blockers reduced ventricular rate compared with placebo.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Verapamil for rate control

Summary

CONTROL OF HEART RATE We found no direct information about verapamil in the treatment of people with acute atrial fibrillation.

Benefits

We found no systematic review or RCTs on the effects of verapamil to control heart rate in people with acute atrial fibrillation of less than 7 days' duration who are haemodynamically stable.

Harms

Verapamil versus placebo:

Comment

See comment on diltiazem.

Verapamil versus placebo:

Two RCTs found that intravenous verapamil reduced heart rate at 10 and 30 minutes compared with placebo in people with atrial fibrillation or atrial flutter. The first RCT (duration of atrial fibrillation not stated) reported that intravenous verapamil caused a transient drop in systolic and diastolic blood pressure greater than with placebo (saline), which did not require treatment, but it did not state the number of people affected. The second RCT reported development of 1:1 flutter in one person with previous Wolff–Parkinson–White syndrome and 2:1 flutter.

Verapamil versus diltiazem:

We found one small, double blind, crossover RCT (17 men, 5 with acute atrial fibrillation, 10 with atrial flutter, and 2 with a combination of atrial fibrillation and atrial flutter; ventricular rate at least 120 beats/minute, systolic blood pressure at least 100 mm Hg), which compared intravenous verapamil versus intravenous diltiazem, and found no difference in rate control or measures of systolic function. In the RCT, 3 people who received verapamil developed symptomatic hypotension and were withdrawn from the study before crossover. Two people recovered, but the episode in the third person was considered life threatening. In people with Wolff–Parkinson–White syndrome, verapamil may increase ventricular rate, and can cause ventricular arrhythmias. Rate-limiting calcium channel blockers may exacerbate heart failure and hypotension.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 May 2;2008:0210.

Sotalol for rate control

Summary

We found no clinically important results about the effects of sotalol on controlling heart rate in people with acute atrial fibrillation who are haemodynamically stable.

Benefits

We found no systematic review or RCTs on the effects of sotalol to control heart rate in people with acute atrial fibrillation of less than 7 days' duration who are haemodynamically stable.

Harms

We found no RCTs.

Comment

See comment on the antiarrhythmic effects of sotalol.

Substantive changes

No new evidence

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