Atrial fibrillation (chronic) Search date May 2014 Deirdre A. Lane, Christopher J. Boos, and Gregory Y.H. Lip ABSTRACT INTRODUCTION: Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of fast and uncoordinated atrial activation leading to reduced atrial mechanical function. Risk factors for atrial fibrillation include increasing age, male sex, co-existing cardiac and thyroid disease, pyrexial illness, electrolyte imbalance, cancer, and co-existing infection. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of oral medical treatments to control heart rate in people with chronic (defined as longer than 1 week for this review) non-valvular atrial fibrillation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (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 four 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: beta-blockers (rate-limiting, with or without digoxin), calcium-channel blockers (with or without digoxin), and digoxin.
QUESTIONS What are the effects of oral medical treatments to control heart rate in people with chronic (>1 week) non-valvular atrial fibrillation?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 INTERVENTIONS ORAL TREATMENTS
Trade off between benefits and harms
Likely to be beneficial Beta-blockers versus digoxin (beta-blockers more effective than digoxin in controlling symptoms)* . . . . . . . 4 Beta-blockers plus digoxin versus beta-blockers alone (beta-blockers plus digoxin more effective than betablockers alone)* . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Beta-blockers versus rate-limiting calcium-channel blockers (selection is dependent on individual risk factors and co-existing morbidities) . . . . . . . . . . . . . . . . . . . 9 Covered elsewhere in Clinical Evidence Atrial fibrillation (acute onset)
Calcium-channel blockers (rate-limiting) versus digoxin (calcium-channel blockers more effective than digoxin for controlling heart rate)* . . . . . . . . . . . . . . . . . . . . 6
Stroke prevention
Calcium-channel blockers (rate-limiting) plus digoxin versus calcium-channel blockers (rate-limiting) alone (calcium-channel blockers plus digoxin more effective than calcium-channel blockers alone) . . . . . . . . . . . 7
*Categorisation based on consensus.
Footnote
Key points • Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of uncoordinated atrial activation and deteriorating atrial mechanical function. Risk factors for atrial fibrillation are increasing age, male sex, co-existing cardiac disease, thyroid disease, pyrexial illness, electrolyte imbalance, cancer, and acute infections. • This review examines the effects of different oral medical treatments to control heart rate in people with chronic (longer than 1 week) non-valvular atrial fibrillation. We have focused on medical treatments and have not included other types of interventions. • Overall, we found a lack of good-quality large RCTs on which to base robust conclusions. • Consensus is that beta-blockers are more effective than digoxin for controlling symptoms of chronic atrial fibrillation, but very few trials have been found. When a beta-blocker alone is ineffective, current consensus supports the addition of digoxin. • Current consensus is that calcium-channel blockers are more effective than digoxin for controlling heart rate, but very few RCTs have been found. When a calcium-channel blocker alone is ineffective, the addition of digoxin is effective in improving exercise tolerance and reducing heart rate. • The choice between using a beta-blocker or a calcium-channel blocker is dependent on individual risk factors and co-existing morbidities. Clinical context
GENERAL BACKGROUND Atrial fibrillation is the most frequently encountered and sustained cardiac arrhythmia in clinical practice. Chronic atrial fibrillation confers a significant clinical burden and personal burden to the patient. It is an independent predictor © BMJ Publishing Group Ltd 2015. All rights reserved.
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Clinical Evidence 2015;05:217
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of mortality, increases the risk of stroke, thromboembolism, heart failure, and adversely affects quality of life, including cognitive function.
FOCUS OF THE REVIEW This review examines the effects of different oral medical treatments (beta blockers [with or without digoxin], calcium channel blockers [rate-limiting, with or without digoxin], and digoxin) to control heart rate in people with chronic (longer than 1 week) non-valvular atrial fibrillation.
COMMENTS ON EVIDENCE Overall, we found a lack of good-quality large RCTs on which to base robust conclusions.
SEARCH AND APPRAISAL SUMMARY The update literature search for this review was carried out from the date of the last search, June 2011, to May 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 60 studies and the further review of four full publications. Of the four full articles evaluated, one RCT was included in the Comment section at this update but it did not meet BMJ Clinical Evidence inclusion criteria for data extraction.
ADDITIONAL INFORMATION Current consensus is that beta-blockers are more effective than digoxin alone for controlling ventricular rate in chronic atrial fibrillation. When a beta-blocker alone is ineffective, digoxin can be added. Furthermore, rate-limiting calcium-channel blockers are more effective than digoxin alone, and when a calcium-channel blocker alone is ineffective, the addition of digoxin is effective in improving exercise tolerance and reducing heart rate. The choice between using a beta-blocker or a calcium-channel blocker is dependent on individual risk factors and co-existing morbidities. DEFINITION
Atrial fibrillation is the most frequently encountered and sustained cardiac arrhythmia in clinical [1] practice. It is a supraventricular tachyarrhythmia characterised by the presence of uncoordinated [1] [2] [3] atrial activation and deteriorating atrial mechanical function. On the surface ECG, P waves are absent and are replaced by rapid fibrillatory waves that vary in size, shape, and timing, leading to an irregular ventricular response when atrioventricular conduction is intact. Classification [3] chronic atrial fibrillation is most commonly classified according to its temporal pattern. Faced with a first detected episode of atrial fibrillation, four recognised patterns of chronic disease may develop: (1) 'paroxysmal atrial fibrillation' refers to self-terminating episodes of atrial fibrillation, usually lasting less than 48 hours (both paroxysmal and persistent atrial fibrillation may be recurrent); (2) 'persistent atrial fibrillation' describes an episode of sustained atrial fibrillation (usually >7 days) that does not convert to sinus rhythm without medical intervention, with the achievement of sinus rhythm by either pharmacological or electrical cardioversion; (3) 'long-standing persistent atrial fibrillation' pertains to atrial fibrillation with a duration of 1 year or longer where a decision has been taken to implement a rhythm-control strategy; (4) 'permanent atrial fibrillation' describes episodes of persistent (usually >1 year) atrial fibrillation, in which cardioversion is not attempted or is unsuc[3] cessful, with atrial fibrillation accepted as the long-term rhythm for that person. 'Lone atrial fibrillation' is largely a diagnosis of exclusion and refers to atrial fibrillation occurring in the absence of concomitant CVD (e.g., hypertension) or structural heart disease (normal echocardiogram), with [4] an otherwise normal ECG (with the exception of atrial fibrillation) and chest x-ray. This review covers only chronic atrial fibrillation (persistent and permanent). Acute atrial fibrillation is covered in a separate review (see atrial fibrillation [acute onset]). Diagnosis in most cases of suspected [2] [3] atrial fibrillation, a 12-lead ECG is sufficient for diagnosis confirmation. However, where diagnostic uncertainty remains, such as in chronic permanent atrial fibrillation, the use of 24-hour [2] (or even 7-day) Holter monitoring or event recorder (e.g., Cardiomemo®) may also be required. [3] The most common presenting symptoms of chronic atrial fibrillation are palpitations, shortness [1] [2] [3] of breath, fatigue, chest pain, dizziness, and stroke.
INCIDENCE/ PREVALENCE
In the developed world, the prevalence of atrial fibrillation is currently estimated to be around 1.5% [5] to 2% of the general population. The prevalence of atrial fibrillation is highly age-dependent, and increases markedly with each advancing decade of age, from 0.5% at age 50–59 years to almost [6] [7] 9% at age 80–90 years. Data from the Framingham Heart Study suggest that the lifetime risk for development of atrial fibrillation for men and women aged 40 years and older is approxi[8] mately 1 in 4. This risk is similar to that reported by the Rotterdam Study investigators, who found that the lifetime risk associated with developing atrial fibrillation in men and women aged 55 years and above was 24% and 22%, respectively. The Screening for Atrial Fibrillation in the Elderly (SAFE) project reported that the baseline prevalence of atrial fibrillation in people aged over 65
© BMJ Publishing Group Ltd 2015. All rights reserved.
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Cardiovascular disorders
Atrial fibrillation (chronic)
years was 7.2%, with a higher prevalence in men (7.8%) and in people aged 75 years or more, [9] with an incidence of 0.69% to 1.64% per year, depending on screening method. The US Census Bureau reports that the number of people with atrial fibrillation is projected to be 12.1 million by 2050, assuming that there are no further increases in age-adjusted incidence of atrial fibrillation. [10] These incidence data refer to cross-sectional study data, whereby most people would have atrial fibrillation of over 7 days' duration (persistent, paroxysmal, or permanent atrial fibrillation), and do not refer to acute atrial fibrillation. AETIOLOGY/ Atrial fibrillation is linked to a variety of risk factors such as increasing age, hypertension, and to RISK FACTORS all types of cardiac conditions, including heart failure (where a reciprocal relationship exists) and cardiothoracic surgery. It is also linked to a large number of non-cardiac conditions, such as thyroid [1] [4] [11] disease, any pyrexial illness, electrolyte imbalance, cancer, and acute infections. PROGNOSIS
Chronic atrial fibrillation confers an enormous and significant clinical burden. It is an independent predictor of mortality, and is associated with an odds ratio for death of 1.5 for men and 1.9 in [12] women, independent of other risk factors. It increases the risk of ischaemic stroke and throm[13] boembolism an average of fivefold. Furthermore, the presence of chronic atrial fibrillation is linked to more severe strokes, with greater disability and lower discharge rate to patients' homes. [13] [14] [4] Chronic atrial fibrillation is a frequent (3%–6%) cause of all medical admissions and results in longer hospital stays. In addition, chronic atrial fibrillation increases the risk of developing [15] heart failure and adversely affects quality of life, including cognitive function.
AIMS OF To prevent stroke and achieve ventricular rate control, with minimal adverse effects of treatments. INTERVENTION OUTCOMES
Mortality; symptom severity (palpitations, dyspnoea, dizziness); thromboembolic events (recurrent strokes or transient ischaemic attacks, thromboembolism); heart rate control (heart rhythm, ventricular rate); exercise tolerance; adverse effects.
METHODS
BMJ Clinical Evidence search and appraisal May 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2014, Embase 1980 to May 2014, and The Cochrane Database of Systematic Reviews 2014, issue 5 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least singleblinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. All serious adverse effects, or those adverse effects that were reported as statistically significant, were data extracted for inclusion in the adverse effects tables of the review. We only included RCTs of adults aged 18 years or older, and excluded atrial fibrillation arising during or soon after cardiac surgery, 'new onset'/acute atrial fibrillation (covered by BMJ Clinical Evidence in atrial fibrillation [acute]), and people with valvular atrial fibrillation. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 16 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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Cardiovascular disorders
Atrial fibrillation (chronic)
QUESTION
What are the effects of oral medical treatments to control heart rate in people with chronic (>1 week) non-valvular atrial fibrillation?
OPTION
BETA-BLOCKERS VERSUS DIGOXIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Atrial fibrillation (chronic), see table, p 16 .
•
Consensus is that beta-blockers are more effective than digoxin for controlling symptoms of chronic atrial fibrillation, but very few RCTs have been found. When a beta-blocker alone is ineffective, the addition of digoxin is likely to be effective in improving exercise tolerance and reducing heart rate.
•
Current consensus is that beta-blockers should be used in preference to digoxin in non-sedentary people. Benefits and harms
Beta-blockers versus digoxin: [4] We found one systematic review (search date 2005), which did not perform a meta-analysis. It identified four [16] RCTs, one of which met BMJ Clinical Evidence inclusion criteria. Mortality Beta-blockers compared with digoxin We don't know whether carvedilol is more effective than digoxin at reducing mortality in people with chronic non-valvular atrial fibrillation, as we found insufficient evidence from one small RCT (very low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Mortality [16]
RCT Crossover design
47 people with per- Mortality , 6 months sistent atrial fibrilla2 deaths with carvedilol tion for >1 month and heart failure; 0 deaths with digoxin mean age 68 years In the carvedilol group, 1 death [4] In review was due to MI and 1 death was due to stroke
Significance not assessed
Symptom severity Beta-blockers compared with digoxin Carvedilol seems as effective as digoxin at 6 months at improving exercise tolerance in people with chronic non-valvular atrial fibrillation (moderate-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Symptoms [16]
RCT Crossover design
47 people with persistent atrial fibrillation for >1 month and heart failure; mean age 68 years In review
[16]
RCT Crossover design
6-minute walk distance , 6 months 374 m with carvedilol
Not significant
414 m with digoxin
[4]
47 people with per- Symptom scores , 6 months sistent atrial fibrilla6 with carvedilol tion for >1 month and heart failure; 8 with digoxin mean age 68 years In review
P = 0.49
P = 0.08 Not significant
[4]
Heart rate control Beta-blockers compared with digoxin Carvedilol seems no more effective than digoxin at reducing 24-hour ventricular heart rate or daytime and exercise heart rate at 6 months in people with chronic non-valvular atrial fibrillation (moderate-quality evidence).
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Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Control of heart rate [16]
RCT Crossover design
47 people with persistent atrial fibrillation for >1 month and heart failure; mean age 68 years In review
Average 24-hour ventricular rate per minute , 6 months 88.8 with carvedilol 75.7 with digoxin
[4]
P = 0.13 The RCT also reported on daytime and exercise-related ventricular rate and nocturnal heart rate; see Further information on studies for full details
Not significant
Thromboembolic events No data from the following reference on this outcome.
[16]
Exercise tolerance No data from the following reference on this outcome.
[16]
Adverse effects No data from the following reference on this outcome.
[16]
Further information on studies [16]
Carvedilol and digoxin were similar in controlling the daytime and exercise-related ventricular rate. However, digoxin lowered the nocturnal heart rate to a greater extent (absolute numbers and significance assessment not reported).
Comment:
OPTION
Clinical guide Based on comparative data from small (1 year; aged 30–82 years, mean age 61 years In review
[4]
Exercise-induced heart rate , at least 2 weeks' follow-up
Significance not assessed
122 beats/minute with verapamil 155 beats/minute with digoxin 0.25 mg daily 147 beats/minute with digoxin 0.5 mg daily The remaining arm assessed verapamil plus digoxin
Thromboembolic events No data from the following reference on this outcome.
[17]
Exercise tolerance No data from the following reference on this outcome.
[17]
Adverse effects No data from the following reference on this outcome.
[17]
Comment:
OPTION
Clinical guide Based on data from predominantly small (1 year; aged 30–82 years, mean age 61 years In review
[4]
Resting heart rate , at least 2 weeks' follow-up
P 1 year; aged 30–82 years, mean age 61 years In review
[4]
Exercise-induced heart rate , at least 2 weeks' follow-up
P 1 month digoxin [4] In review 0/35 (0%) with diltiazem plus digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Dizziness [18]
RCT Crossover design
35 people, mean Dizziness age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Dyspnoea [18]
RCT Crossover design
35 people, mean Dyspnoea age 52 years with 3/35 (9%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported
© BMJ Publishing Group Ltd 2015. All rights reserved.
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11
Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Doses of digoxin were similar in each group; see Further information on studies for full details
Gastric pain [18]
RCT Crossover design
35 people, mean Gastric pain age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 1/35 (3%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Headache [18]
RCT Crossover design
35 people, mean Headache age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Fatigue [18]
RCT Crossover design
35 people, mean Fatigue age 52 years with 3/35 (9%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 1/35 (3%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Nausea [18]
RCT Crossover design
35 people, mean Nausea age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Constipation [18]
RCT Crossover design
35 people, mean Constipation age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
© BMJ Publishing Group Ltd 2015. All rights reserved.
Significance not assessed
..........................................................
12
Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Oedema [18]
RCT Crossover design
35 people, mean Oedema age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Further information on studies [18]
Digoxin dose: as this was strictly a comparative combination treatment RCT, the doses of digoxin were made similar in both groups by adjusting them until the serum digoxin concentration was within 0.8 to 2.0 nanomol/L.
Comment:
We found one subsequent crossover RCT (average duration of AF 11 months, people with ischaemic heart disease or systolic heart failure excluded, people with valvular disease not reported); this reported results for 60/80 (75%) of people randomised, which is below the minimum follow-up cri[19] [20] teria for this BMJ Clinical Evidence review. It compared a single fixed daily dose of diltiazem, verapamil, metoprolol, and carvedilol administered for 3 weeks in a randomised sequence. Previous rate-reducing drugs were discontinued before the trial started (mainly metoprolol [56.7% of people]). It excluded people from the analysis who discontinued before the trial started (4 people), withdrew due to adverse effects (3 with diltiazem, 1 with verapamil, 5 with metoprolol, 3 with carvedilol), and four people with unrelated events (death; renal failure; stroke; conversion to sinus rhythm). It found that the 24-hour mean heart rate was significantly reduced from baseline in all four treatment groups [19] (P
QUESTIONS What are the effects of oral medical treatments to control heart rate in people with chronic (>1 week) non-valvular atrial fibrillation?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 INTERVENTIONS ORAL TREATMENTS
Trade off between benefits and harms
Likely to be beneficial Beta-blockers versus digoxin (beta-blockers more effective than digoxin in controlling symptoms)* . . . . . . . 4 Beta-blockers plus digoxin versus beta-blockers alone (beta-blockers plus digoxin more effective than betablockers alone)* . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Beta-blockers versus rate-limiting calcium-channel blockers (selection is dependent on individual risk factors and co-existing morbidities) . . . . . . . . . . . . . . . . . . . 9 Covered elsewhere in Clinical Evidence Atrial fibrillation (acute onset)
Calcium-channel blockers (rate-limiting) versus digoxin (calcium-channel blockers more effective than digoxin for controlling heart rate)* . . . . . . . . . . . . . . . . . . . . 6
Stroke prevention
Calcium-channel blockers (rate-limiting) plus digoxin versus calcium-channel blockers (rate-limiting) alone (calcium-channel blockers plus digoxin more effective than calcium-channel blockers alone) . . . . . . . . . . . 7
*Categorisation based on consensus.
Footnote
Key points • Atrial fibrillation is a supraventricular tachyarrhythmia characterised by the presence of uncoordinated atrial activation and deteriorating atrial mechanical function. Risk factors for atrial fibrillation are increasing age, male sex, co-existing cardiac disease, thyroid disease, pyrexial illness, electrolyte imbalance, cancer, and acute infections. • This review examines the effects of different oral medical treatments to control heart rate in people with chronic (longer than 1 week) non-valvular atrial fibrillation. We have focused on medical treatments and have not included other types of interventions. • Overall, we found a lack of good-quality large RCTs on which to base robust conclusions. • Consensus is that beta-blockers are more effective than digoxin for controlling symptoms of chronic atrial fibrillation, but very few trials have been found. When a beta-blocker alone is ineffective, current consensus supports the addition of digoxin. • Current consensus is that calcium-channel blockers are more effective than digoxin for controlling heart rate, but very few RCTs have been found. When a calcium-channel blocker alone is ineffective, the addition of digoxin is effective in improving exercise tolerance and reducing heart rate. • The choice between using a beta-blocker or a calcium-channel blocker is dependent on individual risk factors and co-existing morbidities. Clinical context
GENERAL BACKGROUND Atrial fibrillation is the most frequently encountered and sustained cardiac arrhythmia in clinical practice. Chronic atrial fibrillation confers a significant clinical burden and personal burden to the patient. It is an independent predictor © BMJ Publishing Group Ltd 2015. All rights reserved.
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Clinical Evidence 2015;05:217
Cardiovascular disorders
..................................................
of mortality, increases the risk of stroke, thromboembolism, heart failure, and adversely affects quality of life, including cognitive function.
FOCUS OF THE REVIEW This review examines the effects of different oral medical treatments (beta blockers [with or without digoxin], calcium channel blockers [rate-limiting, with or without digoxin], and digoxin) to control heart rate in people with chronic (longer than 1 week) non-valvular atrial fibrillation.
COMMENTS ON EVIDENCE Overall, we found a lack of good-quality large RCTs on which to base robust conclusions.
SEARCH AND APPRAISAL SUMMARY The update literature search for this review was carried out from the date of the last search, June 2011, to May 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 60 studies and the further review of four full publications. Of the four full articles evaluated, one RCT was included in the Comment section at this update but it did not meet BMJ Clinical Evidence inclusion criteria for data extraction.
ADDITIONAL INFORMATION Current consensus is that beta-blockers are more effective than digoxin alone for controlling ventricular rate in chronic atrial fibrillation. When a beta-blocker alone is ineffective, digoxin can be added. Furthermore, rate-limiting calcium-channel blockers are more effective than digoxin alone, and when a calcium-channel blocker alone is ineffective, the addition of digoxin is effective in improving exercise tolerance and reducing heart rate. The choice between using a beta-blocker or a calcium-channel blocker is dependent on individual risk factors and co-existing morbidities. DEFINITION
Atrial fibrillation is the most frequently encountered and sustained cardiac arrhythmia in clinical [1] practice. It is a supraventricular tachyarrhythmia characterised by the presence of uncoordinated [1] [2] [3] atrial activation and deteriorating atrial mechanical function. On the surface ECG, P waves are absent and are replaced by rapid fibrillatory waves that vary in size, shape, and timing, leading to an irregular ventricular response when atrioventricular conduction is intact. Classification [3] chronic atrial fibrillation is most commonly classified according to its temporal pattern. Faced with a first detected episode of atrial fibrillation, four recognised patterns of chronic disease may develop: (1) 'paroxysmal atrial fibrillation' refers to self-terminating episodes of atrial fibrillation, usually lasting less than 48 hours (both paroxysmal and persistent atrial fibrillation may be recurrent); (2) 'persistent atrial fibrillation' describes an episode of sustained atrial fibrillation (usually >7 days) that does not convert to sinus rhythm without medical intervention, with the achievement of sinus rhythm by either pharmacological or electrical cardioversion; (3) 'long-standing persistent atrial fibrillation' pertains to atrial fibrillation with a duration of 1 year or longer where a decision has been taken to implement a rhythm-control strategy; (4) 'permanent atrial fibrillation' describes episodes of persistent (usually >1 year) atrial fibrillation, in which cardioversion is not attempted or is unsuc[3] cessful, with atrial fibrillation accepted as the long-term rhythm for that person. 'Lone atrial fibrillation' is largely a diagnosis of exclusion and refers to atrial fibrillation occurring in the absence of concomitant CVD (e.g., hypertension) or structural heart disease (normal echocardiogram), with [4] an otherwise normal ECG (with the exception of atrial fibrillation) and chest x-ray. This review covers only chronic atrial fibrillation (persistent and permanent). Acute atrial fibrillation is covered in a separate review (see atrial fibrillation [acute onset]). Diagnosis in most cases of suspected [2] [3] atrial fibrillation, a 12-lead ECG is sufficient for diagnosis confirmation. However, where diagnostic uncertainty remains, such as in chronic permanent atrial fibrillation, the use of 24-hour [2] (or even 7-day) Holter monitoring or event recorder (e.g., Cardiomemo®) may also be required. [3] The most common presenting symptoms of chronic atrial fibrillation are palpitations, shortness [1] [2] [3] of breath, fatigue, chest pain, dizziness, and stroke.
INCIDENCE/ PREVALENCE
In the developed world, the prevalence of atrial fibrillation is currently estimated to be around 1.5% [5] to 2% of the general population. The prevalence of atrial fibrillation is highly age-dependent, and increases markedly with each advancing decade of age, from 0.5% at age 50–59 years to almost [6] [7] 9% at age 80–90 years. Data from the Framingham Heart Study suggest that the lifetime risk for development of atrial fibrillation for men and women aged 40 years and older is approxi[8] mately 1 in 4. This risk is similar to that reported by the Rotterdam Study investigators, who found that the lifetime risk associated with developing atrial fibrillation in men and women aged 55 years and above was 24% and 22%, respectively. The Screening for Atrial Fibrillation in the Elderly (SAFE) project reported that the baseline prevalence of atrial fibrillation in people aged over 65
© BMJ Publishing Group Ltd 2015. All rights reserved.
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Cardiovascular disorders
Atrial fibrillation (chronic)
years was 7.2%, with a higher prevalence in men (7.8%) and in people aged 75 years or more, [9] with an incidence of 0.69% to 1.64% per year, depending on screening method. The US Census Bureau reports that the number of people with atrial fibrillation is projected to be 12.1 million by 2050, assuming that there are no further increases in age-adjusted incidence of atrial fibrillation. [10] These incidence data refer to cross-sectional study data, whereby most people would have atrial fibrillation of over 7 days' duration (persistent, paroxysmal, or permanent atrial fibrillation), and do not refer to acute atrial fibrillation. AETIOLOGY/ Atrial fibrillation is linked to a variety of risk factors such as increasing age, hypertension, and to RISK FACTORS all types of cardiac conditions, including heart failure (where a reciprocal relationship exists) and cardiothoracic surgery. It is also linked to a large number of non-cardiac conditions, such as thyroid [1] [4] [11] disease, any pyrexial illness, electrolyte imbalance, cancer, and acute infections. PROGNOSIS
Chronic atrial fibrillation confers an enormous and significant clinical burden. It is an independent predictor of mortality, and is associated with an odds ratio for death of 1.5 for men and 1.9 in [12] women, independent of other risk factors. It increases the risk of ischaemic stroke and throm[13] boembolism an average of fivefold. Furthermore, the presence of chronic atrial fibrillation is linked to more severe strokes, with greater disability and lower discharge rate to patients' homes. [13] [14] [4] Chronic atrial fibrillation is a frequent (3%–6%) cause of all medical admissions and results in longer hospital stays. In addition, chronic atrial fibrillation increases the risk of developing [15] heart failure and adversely affects quality of life, including cognitive function.
AIMS OF To prevent stroke and achieve ventricular rate control, with minimal adverse effects of treatments. INTERVENTION OUTCOMES
Mortality; symptom severity (palpitations, dyspnoea, dizziness); thromboembolic events (recurrent strokes or transient ischaemic attacks, thromboembolism); heart rate control (heart rhythm, ventricular rate); exercise tolerance; adverse effects.
METHODS
BMJ Clinical Evidence search and appraisal May 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2014, Embase 1980 to May 2014, and The Cochrane Database of Systematic Reviews 2014, issue 5 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, at least singleblinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. All serious adverse effects, or those adverse effects that were reported as statistically significant, were data extracted for inclusion in the adverse effects tables of the review. We only included RCTs of adults aged 18 years or older, and excluded atrial fibrillation arising during or soon after cardiac surgery, 'new onset'/acute atrial fibrillation (covered by BMJ Clinical Evidence in atrial fibrillation [acute]), and people with valvular atrial fibrillation. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 16 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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3
Cardiovascular disorders
Atrial fibrillation (chronic)
QUESTION
What are the effects of oral medical treatments to control heart rate in people with chronic (>1 week) non-valvular atrial fibrillation?
OPTION
BETA-BLOCKERS VERSUS DIGOXIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
•
For GRADE evaluation of interventions for Atrial fibrillation (chronic), see table, p 16 .
•
Consensus is that beta-blockers are more effective than digoxin for controlling symptoms of chronic atrial fibrillation, but very few RCTs have been found. When a beta-blocker alone is ineffective, the addition of digoxin is likely to be effective in improving exercise tolerance and reducing heart rate.
•
Current consensus is that beta-blockers should be used in preference to digoxin in non-sedentary people. Benefits and harms
Beta-blockers versus digoxin: [4] We found one systematic review (search date 2005), which did not perform a meta-analysis. It identified four [16] RCTs, one of which met BMJ Clinical Evidence inclusion criteria. Mortality Beta-blockers compared with digoxin We don't know whether carvedilol is more effective than digoxin at reducing mortality in people with chronic non-valvular atrial fibrillation, as we found insufficient evidence from one small RCT (very low-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Mortality [16]
RCT Crossover design
47 people with per- Mortality , 6 months sistent atrial fibrilla2 deaths with carvedilol tion for >1 month and heart failure; 0 deaths with digoxin mean age 68 years In the carvedilol group, 1 death [4] In review was due to MI and 1 death was due to stroke
Significance not assessed
Symptom severity Beta-blockers compared with digoxin Carvedilol seems as effective as digoxin at 6 months at improving exercise tolerance in people with chronic non-valvular atrial fibrillation (moderate-quality evidence). Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Symptoms [16]
RCT Crossover design
47 people with persistent atrial fibrillation for >1 month and heart failure; mean age 68 years In review
[16]
RCT Crossover design
6-minute walk distance , 6 months 374 m with carvedilol
Not significant
414 m with digoxin
[4]
47 people with per- Symptom scores , 6 months sistent atrial fibrilla6 with carvedilol tion for >1 month and heart failure; 8 with digoxin mean age 68 years In review
P = 0.49
P = 0.08 Not significant
[4]
Heart rate control Beta-blockers compared with digoxin Carvedilol seems no more effective than digoxin at reducing 24-hour ventricular heart rate or daytime and exercise heart rate at 6 months in people with chronic non-valvular atrial fibrillation (moderate-quality evidence).
© BMJ Publishing Group Ltd 2015. All rights reserved.
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4
Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Control of heart rate [16]
RCT Crossover design
47 people with persistent atrial fibrillation for >1 month and heart failure; mean age 68 years In review
Average 24-hour ventricular rate per minute , 6 months 88.8 with carvedilol 75.7 with digoxin
[4]
P = 0.13 The RCT also reported on daytime and exercise-related ventricular rate and nocturnal heart rate; see Further information on studies for full details
Not significant
Thromboembolic events No data from the following reference on this outcome.
[16]
Exercise tolerance No data from the following reference on this outcome.
[16]
Adverse effects No data from the following reference on this outcome.
[16]
Further information on studies [16]
Carvedilol and digoxin were similar in controlling the daytime and exercise-related ventricular rate. However, digoxin lowered the nocturnal heart rate to a greater extent (absolute numbers and significance assessment not reported).
Comment:
OPTION
Clinical guide Based on comparative data from small (1 year; aged 30–82 years, mean age 61 years In review
[4]
Exercise-induced heart rate , at least 2 weeks' follow-up
Significance not assessed
122 beats/minute with verapamil 155 beats/minute with digoxin 0.25 mg daily 147 beats/minute with digoxin 0.5 mg daily The remaining arm assessed verapamil plus digoxin
Thromboembolic events No data from the following reference on this outcome.
[17]
Exercise tolerance No data from the following reference on this outcome.
[17]
Adverse effects No data from the following reference on this outcome.
[17]
Comment:
OPTION
Clinical guide Based on data from predominantly small (1 year; aged 30–82 years, mean age 61 years In review
[4]
Resting heart rate , at least 2 weeks' follow-up
P 1 year; aged 30–82 years, mean age 61 years In review
[4]
Exercise-induced heart rate , at least 2 weeks' follow-up
P 1 month digoxin [4] In review 0/35 (0%) with diltiazem plus digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Dizziness [18]
RCT Crossover design
35 people, mean Dizziness age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Dyspnoea [18]
RCT Crossover design
35 people, mean Dyspnoea age 52 years with 3/35 (9%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported
© BMJ Publishing Group Ltd 2015. All rights reserved.
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11
Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Doses of digoxin were similar in each group; see Further information on studies for full details
Gastric pain [18]
RCT Crossover design
35 people, mean Gastric pain age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 1/35 (3%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Headache [18]
RCT Crossover design
35 people, mean Headache age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Fatigue [18]
RCT Crossover design
35 people, mean Fatigue age 52 years with 3/35 (9%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 1/35 (3%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Nausea [18]
RCT Crossover design
35 people, mean Nausea age 52 years with 2/35 (6%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 2/35 (6%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Constipation [18]
RCT Crossover design
35 people, mean Constipation age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
© BMJ Publishing Group Ltd 2015. All rights reserved.
Significance not assessed
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12
Cardiovascular disorders
Atrial fibrillation (chronic)
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Oedema [18]
RCT Crossover design
35 people, mean Oedema age 52 years with 1/35 (3%) with betaxolol plus chronic atrial fibrilladigoxin tion of >1 month 0/35 (0%) with diltiazem plus [4] In review digoxin
Significance not assessed
Post-crossover result; no washout period was reported Doses of digoxin were similar in each group; see Further information on studies for full details
Further information on studies [18]
Digoxin dose: as this was strictly a comparative combination treatment RCT, the doses of digoxin were made similar in both groups by adjusting them until the serum digoxin concentration was within 0.8 to 2.0 nanomol/L.
Comment:
We found one subsequent crossover RCT (average duration of AF 11 months, people with ischaemic heart disease or systolic heart failure excluded, people with valvular disease not reported); this reported results for 60/80 (75%) of people randomised, which is below the minimum follow-up cri[19] [20] teria for this BMJ Clinical Evidence review. It compared a single fixed daily dose of diltiazem, verapamil, metoprolol, and carvedilol administered for 3 weeks in a randomised sequence. Previous rate-reducing drugs were discontinued before the trial started (mainly metoprolol [56.7% of people]). It excluded people from the analysis who discontinued before the trial started (4 people), withdrew due to adverse effects (3 with diltiazem, 1 with verapamil, 5 with metoprolol, 3 with carvedilol), and four people with unrelated events (death; renal failure; stroke; conversion to sinus rhythm). It found that the 24-hour mean heart rate was significantly reduced from baseline in all four treatment groups [19] (P
