a Royal Hallamshire Hospital, Sheffield, UK
b Sheffield Centre for Health and Related Research, Sheffield, UK
c Rotherham District General Hospital, Rotherham, UK
d Barnsley District General Hospital, Barnsley, UK
e Mid Yorkshire NHS Trust, Wakefield, UK
f Calderdale Royal Hospital, Halifax, UK
* Correspondence to: Dr Kevin S. Channer MD FRCP, Consultant Cardiologist, Royal Hallamshire Hospital, Glossop Rd., Sheffield S10 2JF, UK. Tel: +44 114 271 3473; Fax: +44 114 271 2042
E-mail address: Kevin.channer{at}sth.nhs.uk
Received 3 June 2003; revised 6 October 2003; accepted 16 October 2003
Abstract
Aims The efficacy of cardioversion (DCCV) for restoration of sinus rhythm (SR) in persistent atrial fibrillation (AF) is limited by a high relapse rate. Relapse may be reduced by amiodarone but no placebo-controlled trials of efficacy have been performed and the appropriate duration of therapy is unknown.
Method and results In this double-blind study, 161 subjects with persistent AF were randomized to one of three groupsplacebo (n=38); amiodarone 400mg BD for 2 weeks prior to DCCV and 200mg daily for 8 weeks followed by placebo for 44 weeks (n=62, short-term amiodarone); amiodarone 400mg BD for 2 weeks then 200mg daily for 52 weeks (n=61, long-term amiodarone). Spontaneous reversion to SR occurred before DCCV in 21% (26/123) patients on amiodarone and none of the 38 patients on placebo (absolute difference 21%, 95% confidence interval (CI): 10 to 29%, P=0.002). At 8 weeks following DCCV, 51% (63/123) patients on amiodarone remained in SR compared to 16% (6/38) taking placebo (difference35% 95% CI: 48 to 18%, P<0.001). At 1 year, 49% (30/61) patients on long-term amiodarone were in SR compared to 33% (21/62) taking short-term amiodarone (difference15%, 95% CI: 31 to 2%, P=0.085). There was no difference in adverse event rate or quality of life scores between groups.
Conclusions Amiodarone pre-treatment before electrical DCCV for persistent AF allows chemical conversion in one-fifth of patients without altering the efficacy of subsequent DC conversion. Amiodarone is more effective than placebo in the maintenance of SR when continued for 8 weeks following successful DCCV. More patients taking long-term amiodarone remained in SR at 52 weeks, but more had serious adverse effects requiring discontinuation of therapy. Eight weeks of adjuvant therapy with amiodarone following successful DCCV may be the preferred option.
Key Words: Amiodarone Cardioversion Atrial fibrillation Duration of therapy
1. Introduction
Atrial fibrillation (AF) is the commonest arrhythmia requiring treatment, with an incidence doubling in each decade of adult life to peak at 35 new cases per 1000 population per year between the ages of 85 and 94 years.1It is common practice to attempt to restore sinus rhythm (SR), usually by direct-current cardioversion under general anaesthesia (DCCV). External DCCV establishes normal SR in 7090% of patients with a low risk of complications.2However, relapse is common and occurs in up to 75% of patients at 1 year.3Prophylactic anti-arrhythmic therapy may reduce the relapse rate, with prospective, non-blinded trials demonstrating that amiodarone may be the most effective.4,5Unfortunately, there is a risk of non-cardiac toxicity during treatment with amiodarone and routine screening for adverse effects is required.6Most recurrences of AF occur during the 3 months following DCCV of a first episode of AF but the appropriate duration of prophylactic anti-arrhythmic treatment is not known.7This study compared the efficacy of placebo versus short-term treatment with amiodarone versus long-term treatment with amiodarone in maintaining SR following successful DCCV.
2. Methods
The study was conducted in five hospitals in South Yorkshire, England (Royal Hallamshire Hospital, Sheffield, Rotherham District General Hospital, Barnsley District General Hospital, and Mid Yorkshire NHS Trust comprising Wakefield & Pontefract Hospitals). Written, informed consent was obtained from participants prior to inclusion and the Ethics Committee of each institution approved the research. Recruitment commenced in January 1999, randomization was concluded in July 2001, and follow-up was terminated in July 2002.
2.1. Inclusion and exclusion criteria
Patients aged over 18 years were recruited if they had sustained AF for more than 72h. Patients were excluded if they were thought to be suffering from AF due to an acute reversible condition. Echocardiographic exclusion criteria were: left ventricular ejection fraction less than 20%; mitral regurgitation worse than mild; mitral stenosis (valve area less than 2.0cm2); aortic stenosis (peak gradient more than 30mmHg); severe tricuspid regurgitation; or elevated pulmonary artery systolic pressure (greater than 40mmHg). Other exclusion criteria were: female of childbearing age (taken as under 50 years); previous long-term therapy with or intolerance to amiodarone; previous or active thyroid disease; abnormal liver function tests (a serum alanine aminotransferase concentration more than 2.5 times the upper limit of normal); chronic lung disease (FEV1less than 1L); and any medical condition that would make survival for 1 year unlikely. Patients were not recruited if they had a contra-indication to anticoagulation.
2.2. Randomization
Patients were anticoagulated with warfarin and the international normalized ratio (INR) was required to be >2.0 for a minimum of 2 weeks before randomization. Patients were randomized to one of three arms: matching placebo for 2 weeks prior to DCCV, continued for 52 weeks after successful DCCV; short-term amiodarone (400mg twice daily for 2 weeks prior to DCCV, then 200mg once daily for 8 weeks after successful DCCV, followed by matching placebo for 44 weeks); or long-term amiodarone (400mg twice daily for 2 weeks prior to DCCV, followed by 200mg once daily for 52 weeks). Patients were assigned their treatment group by a pharmacist using a random number sequence. No blocking or stratification was used. Subjects recruited to the trial, investigators, and physicians involved in DCCV were blinded to treatment allocation. Given the interaction with warfarin, an INR measurement was checked within 1 week of recruitment. An independent observer controlled anticoagulation, who was blinded to study drug treatment and unconnected with study follow-up.
2.3. Electrical DCCV
Cardioversion was performed during the morning hours with the patient in the fasting state. After the administration of propofol IV 1.5mg/kg, patients were shocked with R-wave synchronized monophasic discharges using the following protocol: 100J, 200J, 360J, 360J, 360J (anterolateral). If unsuccessful, a further 360J shock was delivered in the anteroposterior direction. Unsuccessful DCCV was considered to include both those who failed to revert to SR and those who reverted to AF within 1h.
2.4. Follow-up assessment
Cardiac rhythm was determined by electrocardiographs at 1, 4, 8, 12, 26 and 52 weeks after DCCV. Patients were considered to have relapsed to AF at the first electrocardiographically confirmed recurrence. Quality of life indices were measured by using the SF 36 at entry, repeated at 8 and 52 weeks. The SF-36 is the most commonly used health status measure in the world today.8It originated in the USA but has been anglicized for use in the UK.9,10It contains 36 questions measuring health across eight different dimensions-physical functioning (PF), role limitation because of physical health (RP), social functioning (SF), vitality (VT), bodily pain (BP), mental health (MH), role limitation because of emotional problems (RE) and general health (GH). Responses to each question within a dimension are combined to generate a score from 0 to 100, where 100 indicates good health. Thus, the SF-36 generates a profile of HRQoL outcomes (on up to eight dimensions).
2.5. Aims
The first primary end-point was the comparison of amiodarone versus placebo in maintaining SR at 8 weeks after successful DCCV. The second primary end-point was the comparison of the frequency of maintenance of SR after DCCV following short- and long-term treatment with amiodarone assessed at 52 weeks. Trial medication was discontinued if patients relapsed into AF during study follow-up. Secondary end-points included: the frequency of spontaneous reversion to SR with amiodarone compared to placebo; the number and charge of the shocks required to achieve SR during electrical DCCV; the frequency of adverse events (sub-divided into haemorrhagic and other); and changes in SF-36 quality of life scores.
2.6. Statistical assessment
One hundred and twenty-one patients were required per group to detect a reduction from 30% to 15% in relapse to AF at 8 weeks with 80% power at 5% (two-sided) significance. Randomization to placebo alone was terminated after a pre-specified interim analysis of the first 90 patients completing 8 weeks of follow up, for two reasons: (1) a significant improvement in maintenance of SR at 8 weeks was revealed in favour of amiodarone over placebo: 48% (25/52) on amiodarone vs 16% (6/38) on placebo, P=0.003; (2) publication of papers by Roy4and Capucci5supported the routine use of amiodarone to improve maintenance of SR during DCCV. Since we anticipated no more than two analyses (one interim and one final) for the primary response variable, then one can adopt P<0.029 as the criterion for stopping the trial, since the overall type I error (i.e. the probability of a false-positive result) will not exceed 0.05.
Thereafter, patients were randomized only to short-term or to long-term amiodarone. A further power calculation was performed specifically to establish numbers required to compare maintenance of SR at 52 weeks between the two durations of therapy with amiodarone taking into account the high relapse rate in the first 90 patients. This suggested that 58 patients per limb would be required to detect a reduction in relapse rate from 50% to 25% at 52 weeks with 80% power at 5% (two-sided) significance level.
Summary data are expressed as means±SD or numbers and percentages of patients. Analyses were performed according to the intention-to-treat principle. Independent t-tests were used to assess normally-distributed continuous data and chi-square (with Yates correction) was used to assess dichotomous data in the two group comparisons (amiodarone versus placebo; long-term amiodarone versus short-term amiodarone). One-way ANOVA was used to assess normally-distributed continuous data and chi-square was used to assess dichotomous data in the three group comparisons (long-term amiodarone versus short-term amiodarone versus placebo). Statistical analysis was performed with the use of SPSS (version 11). Significance was assumed if P<0.05, but since we performed a large number of tests of significance because of multiple testing and interim analysis, some caution should be applied to the interpretation of theP values we have reported. For the spontaneous reversion to SR outcome and other binary outcomes the rate or proportion in each group experiencing the event was calculated. Absolute (not relative differences) in event rates were calculated as the event rate in the amiodarone group minus the event rate in the placebo group. This risk difference is also called the absolute risk reduction (ARR). Ninety-five percent confidence intervals for this difference in event rates were estimated by using the recommended Wilson's method.11
The number needed to treat (NNT) was calculated as the reciprocal of the risk difference (absolute risk reduction (ARR). A confidence interval (CI) for the NNT is obtained simply by taking reciprocals of the values defining the CI for the absolute risk reduction. For example, if the risk difference in the trial is 10% with 95% CI: 5% to 10%, then the NNT is 1/0.1 and the 95% CI: for the NNT is 6.7 to 20 (i.e. 1/0.15 to 1/0.05). In the case of treatment effect that is non-significant, Altman11suggests using the terms NNTB (number needed to treat to benefit) and NNTH (number needed to treat to harm). With an ARR of zero the NNT is infinity. Therefore, a risk difference of 10% (95% CI: 5% to 25%) can be written and interpreted as NNTB 10 (95% CI: NNTH 20 to infinity to NNTB 4).
3. Results
A total of 172 patients were enrolled following anticoagulation. Subsequently, four patients were withdrawn because of protocol violations (two with iron-deficiency anaemia in whom anticoagulation was contra-indicated; two with active thyroid disease in whom study drug was contra-indicated). A further seven patients withdrew consent after randomization but before DCCV was performed. This left 161 patients available for analysis. The study population used in the final analysis comprised 38 in the placebo group, 62 in the short-term amiodarone group, and 61 in the long-term amiodarone group. Follow-up was complete for these patients.
3.1. Baseline characteristics
The clinical and echocardiographic characteristics of the patients at the time of enrolment are shown in Table 1. There were no significant differences in baseline characteristics between the treatment groups. The majority of subjects were presenting for the first time for cardioversiononly 3.7% (6/161) had previously undergone cardioversion of any type.
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3.4. Restoration of SR with DCCV
Cardioversion was then performed in 135 patients and resulted in restoration of SR in 100 (74%, 95% CI 66 to 81%). There was no significant difference in the success rate of DCCV between those pre-treated with amiodarone (70/97; 72%) compared to those receiving placebo (30/38; 79%, absolute difference 7%, 95% CI: 21 to 11%, P=0.46). There were no differences in baseline variables between those receiving amiodarone and those receiving placebo to indicate a greater or lesser likelihood of success during DCCV with either pre-treatment. There were no differences in the energy used in those receiving amiodarone compared with placebo (mean number of shocks performed: amiodarone 2.8±1.3 vs placebo 2.9±1.5, P=0.64; total amount of energy used: amiodarone 642±402J vs placebo 651±462J, P=0.91).
3.5. Maintenance of SR
The distribution of the patients through the study and the study design is displayed in Fig. 1. At 8 weeks following the planned date of DCCV, 63/123 (51%) patients who were taking amiodarone remained in SR after cardioversion compared to 6/38 (16%) taking placebo (absolute difference35%, 95% CI: 48 to 18%, chi-square 14.88, P<0.001). The number needed to treat for benefit (NNTB) is 2.8 (95% CI: 2.1 to 5.4), so that less than three patients need to be treated on amiodarone for 8 weeks compared to placebo for an extra patient to have a successful cardioversion and to remain in SR. Excluding those patients who failed to revert to SR following DCCV, 63/96 (66%) patients who were taking amiodarone maintained SR compared to 6/30 (20%) taking placebo (absolute difference 45%, 95% CI: 59 to 26%, chi-square 18.08, P<0.001). At 1 year following DCCV, 30/61 (49%) patients who were taking long-term amiodarone remained in SR compared to 21/62 (33%) taking short-term amiodarone (absolute difference or risk reduction ARR=15%, 95% CI: 31 to 2%, chi-square 2.97, P=0.085). The NNTB on long-term amiodarone is 6.5 (95% CI: NNT to Harm 3.2 to infinity to NNTB 49.1) compared to short-term amiodarone, so that if seven people were given long-term amiodorane one extra patient would remain in SR over the year. Excluding those patients who failed to revert to SR following DCCV, 30/48 patients (63%) assigned to long-term amiodarone remained in SR compared to 20 patients (42%) assigned to short-term amiodarone (absolute difference 21%, 95% CI 39 to 0%, chi-square 3.38, P=0.07). Only two (5%) subjects randomized to placebo remained in SR at the end of the study. Relapse to AF following successful DCCV was frequent in those treated with placebo (28; 93%, chi-square 23.75, P<0.001).
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There was no significant difference in the number of adverse events leading to discontinuation of therapy (excluding the events related to anticoagulation above) either between the three groups or when comparing short-term with long-term amiodarone. There were five (8%) such events in those receiving short-term amiodarone, 11 (18%) in those receiving long-term amiodarone, and one (3%) in those receiving placebo (see Table 3).
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4. Discussion
The results of this randomized, double-blind placebo-controlled trial demonstrate that amiodarone is more effective than placebo in the maintenance of SR following successful DCCV for AF. There is a trend towards greater efficacy with amiodarone continued for 1 year rather than for 8 weeks after successful DCCV. More prolonged treatment with amiodarone is not associated with a statistically significant difference in complications. Amiodarone therapy prior to DCCV chemically converted 21% patients, thus obviating the need to proceed to electrical cardioversion under anaesthesia. Pre-treatment does not alter the efficacy of DCCV or the energy required for restoration of SR in those patients with persistent AF. Electrical cardioversion to SR was achieved in 100 of the 135 patients using monophasic defibrillators, although it is possible that this success rate could have been increased by the use of biphasic defibrillators.12
Most recurrences of AF occur within the first 3 months of DCCV of a first episode of AF.7Oral prophylactic drugs are given to reduce this recurrence rate although until recently, clear efficacy data based on controlled trials has been limited. Amiodarone may be the most effective oral prophylaxis, although all randomized trials of amiodarone for long-term maintenance of SR in patients with recurrent persistent AF have used active-control groups. Amiodarone is more effective than class 1 anti-arrhythmic agents, without the purported risk of increased mortality associated with quinidine and others in this class.6,13Amiodarone is more effective than other class III agents, with maintenance of SR in 75% on amiodarone compared to only 37% on sotalol after a mean follow-up of 16 months in one large randomized comparison.4A further randomized, open-label study has demonstrated greater efficacy of amiodarone compared to the class IV agent diltiazem at 2 months (68% SR on amiodarone compared to 48% SR on diltiazem 180mg daily).5Our study is the first to demonstrate a clear benefit with amiodarone compared to placebo in the maintenance of SR at 8 weeks following DCCV, persisting to 1 year whether or not amiodarone was continued. The number needed to treat to benefit (NNTB) is 2.8 (95% CI: 2.1 to 5.4) so that less than three patients need to be treated on amiodarone for 8 weeks compared to placebo for an extra patient to avoid a failed cardioversion or first recurrence of AF. Recent evidence has suggested that rates of maintenance of SR following DCCV may be further improved either by combination therapy with angiotensin 1 type 1 receptor antagonists or by short-term treatment with verapamil around the time of DCCV.14,15
If amiodarone is a useful adjunct to DCCV of persistent AF, the most important clinical question to be answered is the appropriate duration of therapy. A trend was found towards improved maintenance of SR with long-term amiodarone at 1year. This study has over 90% power at 5% significance to detect a difference in relapse rate of more than 30% between short-term and long-term therapy assuming a long-term relapse rate of 50%, but cannot exclude a smaller difference. One of the limitations of our study is that it is underpowered to detect smaller differences in relapse rate. However, there are good clinical reasons why it may no longer be useful to perform larger studies to search for smaller differences in relapse rate. Longer durations of amiodarone therapy expose the patient to a greater risk of adverse effects which may be unacceptable in treating AF. In our study, although there was no statistical difference in the frequency of adverse events, there was a higher absolute rate of events requiring discontinuation of long-term amiodarone (18%) compared to short-term treatment (8%) or placebo (3%). In the study by Roy,4there was also no statistical difference in adverse events on amiodarone (18%) compared to sotalol or propafenone (11%), but the absolute event rate was higher. These adverse event rates are both lower than the rates in other long-term trials.16,17The bare statistics also hide a qualitative difference in the type of adverse event suffered by those on long-term amiodaronein our study, four subjects required thyroxine replacement, one required a permanent pacemaker for heart block, and one developed abnormal liver function tests. Not only does long-term amiodarone expose the patient to a greater absolute event rate of more clinically adverse effects, this may no longer be acceptable in a population of patients who may be treated safely by rate control and anticoagulation. Results from both the AFFIRM18and the Rate Control versus Electrical Cardioversion for Persistent AtrialFibrillation19studies demonstrated that rhythm control was not superior to rate control. In particular, rate control was associated with fewer adverse drug events in both studies. However, all the patients in the European study (subjects were recruited after previous DCCV) and the majority of those in the North American study had already had an episode of atrial fibrillation. Therefore, it is not clear whether the results of these studies may be generalized to those presenting for the first time with persistent AF.20Our study demonstrated improvement in outcome in patients treated with amiodarone presenting for the first time for DCCV, despite the long average duration of persistent AF in the subjects recruited. Therefore, while an attempt at DCCV may no longer be imperative for those presenting for the first time with arrhythmia, it seems reasonable to attempt to restore SR in such patients or in patients who are poorly tolerant of AF using short-term amiodarone to reduce relapse rate. However, if the attempt fails and there is recurrence of the arrhythmia, or if the maintenance of SR requires longer use of potentially toxic anti-arrhythmic agents, it may be preferable to accept rate control.
Pre-treatment with amiodarone was successful in 21% of patients in our trial prior to elective DCCV, thus avoiding the need for admission and general anaesthesia. Tielman21also found that pre-treatment with 600mg oral amiodarone successfully cardioverted 23/129 (18%) patients from refractory AF which is similar to the rate in our study. Clinical variables associated with success were desethylamiodarone plasma levels, arrhythmia duration, left atrial area, and concomitant anti-arrhythmic treatment with verapamil. In our study, there was no significant difference in duration of arrhythmia between those who cardioverted chemically and those who subsequently required DCCV. However, the rate of chemical conversion is remarkably similar across these and other studies, including those of Capucci (26%)5and Opolski (18%).22
Pre-treatment with amiodarone did not alter the success rate of electrical cardioversion or the energy required for restoration of SR in our study. There is some evidence that pre-treatment with class I and class III antiarrhythmic agents increases the success rate of direct-current shock or, at least, prevents early recurrences of AF (propafenone/ibutilide /sotalol).2325However, the data for amiodarone are less clear. No effect of amiodarone on the efficacy of electrical cardioversion was found by Sagrista-Sauleda et al., although this was a non-randomized trial including some patients with atrial arrhythmias other than AF.26Capucci et al. observed in a randomized, non-blinded study that amiodarone increased the efficacy of electrical cardioversion (20/23 successful, 87%) compared to diltiazem with (17/29, 58%) or without (19/29, 65%) glucose-insulin-potassium infusion.5In a further randomized, non-blinded study, amiodarone was found to increase the efficacy of electrical cardioversion not only compared to diltiazem but also compared to placebo.27The cardioversion success rate in this study was 100% in those receiving amiodarone compared to 83% of those receiving no antiarrhythmic drugs. In our double-blind randomized study, the rate of successful cardioversion with amiodarone was lower (72%) than in either of these positive studies. It is possible that this lower rate was due to the longer mean duration of AF in the patients in our study and that a positive effect of pre-treatment with amiodarone on efficacy of electrical cardioversion is limited to those with more recent onset persistent AF.
5. Conclusion
Amiodarone pre-treatment before electrical DCCV for persistent AF allows chemical conversion in one-fifth of patients without altering the efficacy of subsequent DC conversion. Amiodarone is more effective than placebo in the maintenance of SR when continued for 8 weeks following successful DCCV. More patients taking long-term amiodarone remained in SR at 52 weeks. Similarly, more patients treated for 52 weeks had to discontinue amiodarone because of serious adverse effects. The NNTB for long-term amiodarone is 6.5 compared to short-term amiodarone so that seven more patents would need to be treated for a year to avoid one relapse in AF. Weighing up the risks and benefits of short- versus long-term amiodarone and in the light recent trial data comparing rate versus rhythm control18,19may mean that 8-week therapy following successful DCCV is preferred.
References