Atrial fibrillation (chronic)

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.

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 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.

About this condition

Definition

Atrial fibrillation is the most frequently encountered and sustained cardiac arrhythmia in clinical practice. It is a supraventricular tachyarrhythmia characterised by the presence of uncoordinated 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 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 unsuccessful, 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 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 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 (or even 7-day) Holter monitoring or event recorder (e.g., Cardiomemo®) may also be required. The most common presenting symptoms of chronic atrial fibrillation are palpitations, shortness 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% 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 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 approximately 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 years was 7.2%, with a higher prevalence in men (7.8%) and in people aged 75 years or more, 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. 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/ Risk factors

Atrial fibrillation is linked to a variety of risk factors such as increasing age, hypertension, and to 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 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 women, independent of other risk factors. It increases the risk of ischaemic stroke and thromboembolism 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. 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 heart failure and adversely affects quality of life, including cognitive function.

Aims of intervention

To prevent stroke and achieve ventricular rate control, with minimal adverse effects of treatments.

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 single-blinded, 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). 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).

Table.

GRADE Evaluation of interventions for Atrial fibrillation (chronic).

Important outcomes	Exercise tolerance, Heart rate control, Mortality, Symptom severity, Thromboembolic events
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of oral medical treatments to control heart rate in people with chronic (>1 week) non-valvular atrial fibrillation?
1 (47)	Mortality	Beta-blockers versus digoxin	4	–1	0	–2	0	Very low	Quality point deducted for sparse data; directness points deducted for no direct statistical comparison between groups and small number of events
1 (47)	Symptom severity	Beta-blockers versus digoxin	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (47)	Heart rate control	Beta-blockers versus digoxin	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (24)	Heart rate control	Calcium-channel blockers (rate-limiting) versus digoxin	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (24)	Heart rate control	Calcium-channel blockers (rate-limiting) plus digoxin versus calcium-channel blockers (rate-limiting) alone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (24)	Exercise tolerance	Calcium-channel blockers (rate-limiting) plus digoxin versus calcium-channel blockers (rate-limiting) alone	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (35)	Heart rate control	Beta-blockers versus rate-limiting calcium-channel blockers	4	–1	0	0	0	Moderate	Quality point deducted for sparse data

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

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.

Rate-control treatment strategies

These interventions employ beta-blockers, digoxin, and non-dihydropyridine calcium-channel blockers (verapamil or diltiazem), either alone or in combination, to maintain a resting heart rate of 70–90 beats a minute. Highly symptomatic people may also be considered for cardioversion (electrical or pharmacological), atrioventricular node/junction ablation/modification, or both, with or without pacemaker implantation.

Very low-quality evidence

Any estimate of effect is very uncertain.

Atrial fibrillation (acute onset)

Stroke prevention

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.