Clinical Topic A-Z Clinical Speciality

Atrial fibrillation

Atrial fibrillation
D001281Atrial Fibrillation
Cardiovascular
2009-08-24Last revised in August 2009

Atrial fibrillation - Summary

Atrial fibrillation (AF) is an arrhythmia. It results from irregular, disorganized electrical activity in the atria. In many people, this is thought to arise from rapidly firing cells at the junction of the pulmonary veins in the left atrial musculature. The rapidly firing impulses cause disorganized atrial depolarization and ineffective atrial contractions. The atrioventricular node receives more electrical impulses than it can conduct. This results in an irregular ventricular rhythm; the ventricular rate of untreated AF often averages 160–180 beats per minute (although this is typically slower in elderly people).

The most common causes of AF are ischaemic heart disease, hypertension, mitral stenosis, and hyperthyroidism.

Complications of AF include:

Stroke and thromboembolism.

Heart failure.

Tachycardia-induced cardiomyopathy and critical cardiac ischaemia.

Reduced quality of life.

Atrial fibrillation should be suspected in people with an irregular pulse. If AF is present, an ECG will show no P-waves, a chaotic baseline, and an irregular ventricular rate.

Management of AF includes:

Rate control with drugs (beta-blockers, rate-limiting calcium-channel blockers, or digoxin) to slow the ventricular heart rate, in an attempt to minimize symptoms and associated morbidity of AF. Rate control will not stop the atria from fibrillating.

Rhythm control (usually specialist treatment) with the aim of restoring and maintaining sinus rhythm. Options include cardioversion and/or treatment with drugs (such as amiodarone, flecainide, and sotalol). More recently, catheter ablation is being used for this purpose.

Antithrombotic treatment (e.g. aspirin and warfarin), the choice of which should be based on the person’s risk of stroke.

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This CKS topic is based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

This CKS topic covers the management of people with atrial fibrillation (AF), including people with paroxysmal AF, and covers management issues, such as rate control, antithrombotic treatment, and when to refer to a cardiologist.

This CKS topic does not cover the management of AF in children, AF causing haemodynamic instability, postoperative AF, or atrial flutter.

There are separate CKS topics on Anticoagulation - oral, Antiplatelet treatment, and Palpitations.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

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Changes

Last revised in August 2009

March 2014 — minor update. Text about assessing stroke risk in people with AF has been updated to include the CHA2DS2VASc tool which takes a risk factor-based approach to guide decisions about antithrombotic treatment, in line with updated European Society of Cardiology guidelines [Camm et al, 2012].

July 2013 — minor update. Links to the DVLA website have been updated.

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic [BMA and NHS Employers, 2013].

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic [BMA and NHS Employers, 2012]. Issued in April 2012.

May 2011 — minor update. The 2011/2012 QOF indicators have been added to this topic [BMA and NHS Employers, 2011]. Issued in June 2011.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

October 2010 — minor update. Information on fitness to drive from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive has been added [DVLA, 2010]. Advice about flying for people with atrial fibrillation, based on the British Heart Foundation Factfile, Fitness to fly for passengers with cardiovascular disease, which is derived from the British Cardiovascular Society Working Group's expert guidance has also been included [BHF, 2010]. Issued in October 2010.

May to August 2009 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There have been no major changes to the recommendations.

Previous changes

March 2009 — minor update. The Quality and Outcomes Framework (QOF) indicators for atrial fibrillation have been updated in the Goals and outcome measures section. Issued in April 2009.

September 2008 — minor correction to the Changes section. Issued in September 2008.

June 2007 — updated to include a link to the recent Patient Safety Alert from the National Patient Safety Agency (NPSA) on actions that can make anticoagulant therapy safer. Advice from the British Committee for Standards in Haematology on the management of patients on oral anticoagulants requiring dental surgery also included. Issued in June 2007.

July-September 2006 — reviewed. Validated in December 2006 and issued in January 2007.

This guidance has been reviewed, restructured and updated following a full literature review and includes an implementation of the 2006 guidance on atrial fibrillation from the National Institute for Health and Care Excellence (NICE).

October 2005 — minor update. Reference made to new CKS topic Aspirin for prevention of cardiovascular events, which outlines gastrointestinal issues that need to be considered in the prescribing of low-dose aspirin for the prevention of cardiovascular events. Issued in November 2005.

December 2002 — reviewed. Validated in March 2003 and issued in April 2003.

November 2000 — reviewed. Validated in March 2001 and issued in June 2001.

June 1998 — written and validated.

Update

New evidence

Evidence-based guidelines

Evidence-based guidelines published since the last revision of this topic:

CADTH (2012) New oral anticoagulants for the prevention of thromboembolic events in patients with atrial fibrillation. Canadian Agency for Drugs and Technologies in Health. www.cadth.ca [Free Full-text (pdf)]

Heidbuchel, H., Verhamme, P., Alings, M., et al. (2013) European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 15, 625-651. [Free Full-text (pdf)]

ICSI (2011) Antithrombotic therapy supplement. Institute for Clinical Systems Improvement. www.icsi.org [Free Full-text]

SIGN (2012) Antithrombotics: indications and management. Scottish Intercollegiate Guidelines Network. www.sign.ac.uk [Free Full-text]

The Regional Drug and Therapeutics Centre has published a drug evaluation of apixaban:

RDTC (2012) Apixaban [black triangle] in atrial fibrillation. Regional Drug and Therapeutics Centre. www.rdtc.nhs.uk [Free Full-text (pdf)]

HTAs (Health Technology Assessments)

HTAs published since the last revision of this topic:

NICE (2010) Dronedarone for the treatment of non-permanent atrial fibrillation. NICE technology appraisal guidance 197. National Institute for Health and Clinical Excellence www.nice.org.uk [Free full-text]

NICE (2012) Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. NICE technology appraisal guidance 249. National Institute for Health and Care Excellence www.nice.org.uk [Free Full-text]

NICE (2012) Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation. NICE technology appraisal guidance 256. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2013) Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. NICE technology appraisal guidance 275. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Economic appraisals

A cost-effectiveness analysis has been published since the last revision of this topic:

Freeman, J.V., Zhu, R.P., Owens, K., et al. (2010) Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Annals of Internal Medicine 154(1), 1-11. [Abstract] [Free Full-text]

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Abdulla, J. and Nielsen, J.R. (2009) Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis. Eurospace 11(9), 1156-1159. [Abstract] [Free Full-text]

Adam, S.S., McDuffie, J.R., Ortel, T.L., and Williams, J.W. (2012) Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Annals of Internal Medicine 157(11), 796-807. [Abstract]

Agarwal, S., Hachamovitch, R., and Menon, V. (2012) Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation. A meta-analysis. Archives of Internal Medicine 172(8), 623-631. [Abstract]

Albertsen, I.E., Rasmussen, L.H., Overvad, T.F., et al. (2013) Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis. Stroke 4(5), 1329-1336. [Abstract]

Baker, W.L. and Phung, O.J. (2012) Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circulation. Cardiovascular Quality and Outcomes 5(5), 711-719. [Abstract]

Bang, C.N., Greve, A.M., Abdulla, J., et al. (2013) The preventative effect of statin therapy on new-onset and recurrent atrial fibrillation in patients not undergoing invasive cardiac interventions: a systematic review and meta-analysis. International Journal of Cardiology 167(3), 624-630. [Abstract]

Biondi-Zoccai, G., Malavasi, V., D'Ascenzo, F., et al. (2013) Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proceedings in Intensive Care & Cardiovascular Anesthesia 5(1), 40-54. [Abstract]

Bonanno, C., Paccanaro, M., La Vecchia, L., et al. (2009) Efficacy and safety of catheter ablation versus antiarrhythmic drugs for atrial fibrillation: a meta-analysis of randomized trials. Journal of Cardiovascular Medicine 11(6), 408-418. [Abstract]

Calkins, H., Reynolds, M.R., Spector, P. et al. (2009) Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circulation Arrhythmia and Electrophysiology 2(4), 349-361. [Abstract] [Free Full-text]

Chatterjee, S., Ghosh, J., Lichstein, E., et al. (2012) Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. American Journal of Cardiology 110(4), 607-613. [Abstract]

Chatterjee, S., Sardar, P., Lichstein, E., et al. (2013) Pharmacologic rate versus rhythm-control strategies in atrial fibrillation: an updated comprehensive review and meta-analysis. Pacing and Clinical Electrophysiology 36(1), 122-133. [Abstract]

Dagres, N., Varounis, Cl., Flevari, P., et al. (2009) Mortality after catheter ablation for atrial fibrillation compared with antiarrhythmic drug therapy. A meta-analysis of randomized trials. American Heart Journal 158(1), 15-20. [Abstract]

Dentali, F., Riva, N., Crowther, M., et al. (2012) Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 126(20), 2381-2391. [Abstract]

Dogliotti, A., Paolasso, E., and Giugliano, R.P. (2013) Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. Clinical Cardiology 36(2), 61-67. [Abstract]

Fauchier, L., Clementy, N., and Babuty, D. (2013) Statin therapy and atrial fibrillation: systematic review and updated meta-analysis of published randomized controlled trials. Current Opinion in Cardiology 28(1), 7-18. [Abstract]

Freemantle, N., Lafuente-Lafuente, C., Mitchell, S., et al. (2011) Mixed treatment comparison of dronedarone, amiodarone, sotalol, flecainide and propafenone, for the management of atrial fibrillation. Europace 13(3), 329-345. [Abstract] [Free Full-text]

Giacomantonio, N.B., Bredin, S.S., Foulds, H.J., and Warburton, D.E. (2013) A systematic review of the health benefits of exercise rehabilitation in persons living with atrial fibrillation. Canadian Journal of Cardiology 29(4), 483-491. [Abstract]

Guijian, L., Jinchuan, Y., Rangzeng, D., et al. (2013) Impact of body mass index on atrial fibrillation recurrence: a meta-analysis of observational studies. Pacing and Clinical Electrophysiology 36(6), 748-756. [Abstract]

He, Z., Yang, L., Tian, J., et al. (2013) Efficacy and safety of omega-3 fatty acids for the prevention of atrial fibrillation: a meta-analysis. Canadian Journal of Cardiology 29(2), 196-203. [Abstract]

Jabre, P., Roger, V.L., Murad, M.H., et al. (2011) Mortality associated with atrial fibrillation in patients with myocardial infarction: a systematic review and meta-analysis. Circulation 123(15), 1587-1593. [Abstract] [Free Full-text]

Kalantarian, S., Stern, T.A., Mansour, M., and Ruskin, J.N. (2013) Cognitive impairment associated with atrial fibrillation: a meta-analysis. Annals of Internal Medicine 158(5 part 1), 338-346. [Abstract]

Kwok, C.S., Loke, Y.K., Hale, R., et al. (2011) Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis. Neurology 76(10), 914-922. [Abstract]

Kwong, J.S., Lam, Y.Y., Yan, B.P. and Yu, C.M. (2013) Bleeding of new oral anticoagulants for stroke prevention in atrial fibrillation: a meta-analysis of randomized controlled trials. Cardiovascular Drugs and Therapy 27(1), 23-35. [Abstract]

Lane, D., Raichand, S., Moore, D., et al. (2013) Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review and individual patient meta-analysis. Health Technology Assessment 17(30). [Abstract] [Free Full-text]

Limone, B.L., Baker, W.L., Kluger, J. and Coleman, C.I. (2013) Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models. PLoS One 8(4), e62183. [Abstract] [Free Full-text]

Liu, T., Korantzopoulos, P., Li, L. and Li, G. (2013) Preventive effects of rosuvastatin on atrial fibrillation: a meta-analysis of randomized controlled trials. International Journal of Cardiology 167(6), 3058-3060.

Liu, T., Korantzopoulos, P., Shehata, M., et al. (2011) Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart 97(13), 1034-1040. [Abstract]

Marshall, S., Fearon, P., Dawson, J., and Quinn, T.J. (2013) Stop the clots, but at what cost? Pharmacoeconomics of dabigatran etexilate for the prevention of stroke in subjects with atrial fibrillation: a systematic literature review. Expert Reviews of Pharmacoeconomics and Outcomes Research 13(1), 29-42. [Abstract]

McKenna, C., Palmer, S., Rodgers, M., et al. (2009) Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom. Heart 95(7), 542-549. [Abstract] [Free Full-text]

Miller, C.S., Grandi, S.M., Shimony, A., et al. (2012) Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. American Journal of Cardiology 110(3), 453-460. [Abstract]

Moran, P.S., Flattery, M.J., Teljeur, C., et al. (2013) Effectiveness of systematic screening for the detection of atrial fibrillation (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Neidecker, M., Patel, A.A., Nelson, W.W., and Reardon, G. (2012) Use of warfarin in long-term care: a systematic review. BMC Geriatrics 12(1), 14. [Abstract] [Free Full-text]

O’Dell, K.M., Igawa, D., and Hsin, J. (2012) New oral anticoagulants for atrial fibrillation: a review of clinical trials. Clinical Therapeutics 34(4), 894-901. [Abstract]

Ofman, P., Khawaja, O., Rahilly-Tierney, C.R., et al. (2013) Regular physical activity and risk of atrial fibrillation: a systematic review and meta-analysis. Circulation. Arrhythmia and Electrophysiology 6(2), 252-256. [Abstract]

Ogilvie, I.M., Newton, N., Welner, S.A., et al. (2010) Underuse of oral anticoagulants in atrial fibrillation: a systematic review. American Journal of Medicine 123(7), 638-645. [Abstract]

Pepine, C.J. (2013) Effects of pharmacologic therapy on health-related quality of life in elderly patients with atrial fibrillation: a systematic review of randomized and nonrandomized trials. Clinical Medical Insights. Cardiology. 7, 1-20. [Abstract]

Piccini, J.P., Hasselblad, V., Peterson, E.D., et al. (2009) Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. Journal of the American College of Cardiology 54(12), 1089-1095. [Abstract]

Rahimi, K., Emberson, J., McGale, P., et al. (2011) Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ 342, d1250. [Abstract] [Free Full-text]

Ruff, C.T., Giugliano, R.P., Braunwald, E., et al. (2013) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet epub ahead of print. [Abstract]

Saborido, C.M., Hockenhull, J., Bagust, A., et al. (2010) Systematic review and cost-effectiveness evaluation of 'pill-in-the-pocket' strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy. Health Technology Assessment 14(31), 1-104. [Abstract] [Free Full-text]

Samokhvalov, A.V., Irving, H.M. and Rehm, J. (2010) Alcohol consumption as a risk factor for atrial fibrillation: a systematic review and meta-analysis. European Journal of Cardiovascular Prevention and Rehabilitation 17(6), 706-712. [Abstract] [Free Full-text]

Schmitt, J., Duray, G., Gersh, B.J., and Hohnloser, S.H. (2009) Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. European Heart Journal 30(9), 1038-1045. [Abstract] [Free Full-text]

Seshasai, S.R.L., Wijesuriya, S., Sivakumaran, R., et al. (2012) Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Archives of Internal Medicine 172(3), 209-216. [Abstract]

Sobieraj, D.M., White, C.M., Alikhanov, S., et al. (2012) The impact of antiplatelet and anticoagulant therapies on gastrointestinal symptoms in patients with atrial fibrillation: a systematic review. Annals of Pharmacotherapy 46(9), 1220-1231. [Abstract]

Sullivan, S.D., Orme, M.E., Morais, E., and Mitchell, S.A. (2013) Interventions for the treatment of atrial fibrillation: a systematic literature review and meta-analysis. International Journal of Cardiology 165(2), 229-236. [Abstract]

Uchino, K. and Hernandez, A.V. (2012) Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Archives of Internal Medicine 172(5), 397-402. [Abstract]

Wasserlauf, G., Grandi, S.M., Filion, K.B., and Eisenberg, M.J. (2013) Meta-analysis of rivaroxaban and bleeding risk. American Journal of Cardiology 112(3), 454-460. [Abstract]

Webb, A.J., and Rothwell, P.M. (2010) Blood pressure variability and risk of new-onset atrial fibrillation. A systematic review of randomized trials of antihypertensive drugs. Stroke 41(9), 2091-2093. [Abstract] [Free Full-text]

Zhang, Y., Zhang, P., Mu, Y., et al. (2010) The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clinical Pharmacology and Therapeutics 88(4), 521-531. [Abstract]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

ACTIVE Investigators (2011) Irbesartan in patients with atrial fibrillation. New England Journal of Medicine 364(10), 928-938. [Abstract] [Free Full-text]

Connolly, S.J., Camm, A.J., Halperin, J.L., et al. (2011) Dronedarone in high-risk permanent atrial fibrillation. New England Journal of Medicine 365(24), 2268-2276. [Abstract] [Free Full-text]

Connolly, S.J., Crijns, H.J.G.M., Torp-Pedersen, C., et al. (2009) Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Circulation 120(13), 1174-1180. [Abstract] [Free Full-text]

Connolly, S.J., Eikelboom, J., Joyner, C., et al. (2011) Apixaban in patients with atrial fibrillation. New England Journal of Medicine 364(9), 806-817. [Abstract] [Free Full-text]

Connolly, S.J., Ezekowitz, M.D., Yusuf, S. et al. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine 361(12), 1139-1151. [Abstract] [Free Full-text]

Enajat, M., Teerenstra, S., van Kuilenburg, J.T., et al. (2009) Safety of the combination of intensive cholesterol-lowering therapy with oral anticoagulation medicine in elderly patients with atrial fibrillation: a randomized, double-blind, placebo-controlled study. Drugs & Aging 26(7), 585-593. [Abstract]

Holmes, D.R., Reddy, V.Y., Turi, Z.G., et al. (2009) Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 374(9689), 534-542. [Abstract]

Kowey, P.R., Reiffel, J.A., Ellenbogen, K.A., et al. (2010) Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA 304(21), 2362-2372. [Abstract] [Free Full-text]

Schulman, S., Parpia, S., Stewart, C., et al. (2011) Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Annals of Internal Medicine 155(10), 653-659. [Abstract] [Free Full-text]

Van Gelder, I.C., Groenveld, H.F., Crijns, H.J., et al. (2010) Lenient versus strict rate control in patients with atrial fibrillation. New England Journal of Medicine 362(15), 1363-1373. [Abstract] [Free Full-text]

Wilber, D.J., Pappone, C., Neuzil, P., et al. (2010) Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 303(4), 333-340. [Abstract] [Free Full-text]

A secondary analysis of a randomised controlled trial:

Lopes, R.D., Al-Khatib, S., Wallentin, L., et al. (2012) Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 380(9855), 1749-1758. [Abstract]

Observational studies published since the last revision of this topic:

Christiansen, C.F., Christensen, S., Mehnert, F., et al. (2009) Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case-control study. Archives of Internal Medicine 169(18), 1677-1683. [Abstract] [Free Full-text]

Connolly, S.J., Eikelboom, J.W., Ng, J., et al. (2011) Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable. Annals of Internal Medicine 155(9), 579-586. [Abstract]

Connolly, S.J., Wallentin, L., Ezekowitz, M.D., et al. (2013) The long term multi-center observational study of dabigatran treatment in patients with atrial fibrillation: (RELY-ABLE) study. Circulation 128(3), 237-243. [Abstract]

Danchin, N., Faucher, L., Marijon, E., et al. (2010) Impact of early statin therapy on development of atrial fibrillation at the acute stage of myocardial infarction: data from the FAST-MI register. Heart 96(22), 1809-1814. [Abstract]

De Caterina, R., Ruigomez, A., and Rodriquez, L.A. (2010) Long-term use of anti-inflammatory drugs and risk of atrial fibrillation. Archives of Internal Medicine 170(16), 1450-1455. [Abstract] [Free Full-text]

Friberg, L., Rosenqvist, M., and Lip, G.Y.H. (2012) Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 125(19), 2298-2307. [Abstract]

Gomes, T., Mamdani, M.M., Holbrook, A.M., et al. (2013) Rate of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ 185(2), E121-E127. [Abstract]

Hansen, M.L., Sorensen, R., Clausen, M.T., et al. (2010) Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Archives of Internal Medicine 170(16), 1433-1441. [Abstract] [Free Full-text]

Hobbs, F.D., Roalfe, A.K., Lip, G.Y., et al. (2011) Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial. BMJ 342, d3653. [Abstract] [Free Full-text]

Holt, T.A., Hunter, T.D., Gunnarsson, C., et al. (2012) Risk of stroke and oral anticoagulant use in atrial fibrillation: a cross-sectional survey. British Journal of General Practice 62(603), 710-717. [Abstract]

Ionescu-Ittu, R., Abrahamowicz, M., Jackevicius, C.A., et al. (2012) Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Archives of Internal Medicine 172(13), 997-1004. [Abstract]

Kanthan, G.L., Wang, J.J., Rochtchina, E., and Mitchell, P. (2009) Use of antihypertensive medications and topical beta-blockers and the long-term incidence of cataract and cataract surgery. British Journal of Ophthalmology 93(9), 1210-1214. [Abstract]

Kim, M.H., Smith, P.J., Jhaveri, M., et al. (2011) One-year treatment persistence and potential adverse events among patients with atrial fibrillation treated with amiodarone or sotalol: a retrospective claims database analysis. Clinical Therapeutics 33(11), 1668-1681. [Abstract]

Lee, S., Monz, B.U., Clemens, A., et al. (2012) Representativeness of the dabigatran, apixaban and rivaroxaban clinical trial populations to real-world atrial fibrillation patients in the United Kingdom: a cross-sectional analysis using the General Practice Research Database. BMJ Open 2, e001768. [Abstract] [Free Full-text]

Lubitz, S.A., Yin, X., Fontes, J.D., et al. (2010) Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA 304(20), 2263-2269. [Abstract] [Free Full-text]

Oldgren, J., Alings, M., Darius, H., et al. (2011) Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Annals of Internal Medicine 155(10), 660-667. [Abstract]

Poli, D., Antonucci, E., Grifoni, E., et al. (2009) Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. Journal of the American College of Cardiology 54(11) 999-1002. [Abstract]

Nilsson, K.R., Al-Khatib, S.M., Zhou, Y., et al. (2010) Atrial fibrillation management strategies and early mortality after myocardial infarction: results from the Valsartan in Acute Myocardial Infarction (VALIANT) Trial. Heart 96(11), 838-842. [Abstract]

Schaer, B.A., Schneider, C., Jick, S.S. et al. (2010) Risk for incident atrial fibrillation in patients who receive antihypertensive drugs: a nested case-control study. Annals of Internal Medicine 152(2), 78-84. [Abstract]

Schmidt, M., Christiansen, C.F., Mehnert, F., et al. (2011) Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ 343, d3450. [Abstract] [Free Full-text]

Scrowcroft, A.C.E., Lee, S., and Mant, J. (2013) Thromboprophylaxis of elderly patients with AF in the UK: an analysis using the General Practice Research Database (GPRD) 2000-2009. Heart 99(2), 127-132. [Abstract] [Free Full-text]

Singer, D.E., Chang, Y., Fang, M.C., et al. (2009) The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of Internal Medicine 1151(5), 297-305. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 March 2009.

New safety alerts

Dronedarone

October 2011: Following a review of the risks and benefits of dronedarone, the Committee for Medicinal Products for Human Use (CHMP) recommended that dronedarone should now be used only for the maintenance of sinus rhythm after successful cardioversion in people with paroxysmal or persistent atrial fibrillation (AF). Because of safety concerns, dronedarone should only be prescribed after alternative treatment options have been considered. Dronedarone should not be given to people with left ventricular systolic dysfunction, or to patients with current or previous episodes of heart failure.

The CHMP considered that treatment with dronedarone should be initiated and monitored only under specialist supervision.

The following advice has been issued to healthcare professionals:

Contraindications:

Dronedarone is now contraindicated in patients with:

Unstable haemodynamic conditions.

History of, or current, heart failure or left ventricular systolic dysfunction.

Permanent AF (ie, duration ≥6 months or unknown, and attempts to restore sinus rhythm no longer considered by physician).

Liver and lung toxicity related to previous use of amiodarone.

Cardiovascular monitoring:

Patients should receive regular cardiac examinations, including an ECG at least every 6 months, to identify those who revert to AF. Discontinuation of dronedarone should be considered for these patients.

Discontinue treatment if the patient develops permanent AF.

Patients should be carefully evaluated for symptoms of heart failure during treatment.

Patients should be appropriately anticoagulated as per clinical AF guidelines. International Normalised Ratio (INR) should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per the prescribing information for these products.

Hepatic monitoring:

Liver-function tests should be done:

Before starting treatment with dronedarone.

After 1 week of treatment.

After 1 month of treatment.

Every month for 6 months, then at month 9, at month 12, and periodically thereafter.

Renal monitoring:

Plasma creatinine values should be measured before and 7 days after initiation of dronedarone, and renal function should be monitored periodically afterwards. Discontinue treatment in any patients with further elevations of serum creatinine.

Pulmonary monitoring:

Cases of interstitial lung disease, including pneumonitis and pulmonary fibrosis, have been reported in association with dronedarone. Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity. If pulmonary toxicity is suspected during treatment, relevant lung examinations should be considered and treatment discontinued if confirmed.

Advice for patients:

Patients should be advised to make a routine appointment to discuss their treatment with the treating physician, but should not stop taking dronedarone unless told to do so.

Reference: MHRA (2011) Dronedarone (Multaq [black triangle]): cardiovascular, hepatic and pulmonary adverse events - new restrictions and monitoring requirements. Drug Safety Update 5(3), A1. [Free Full-text]

February 2011: Dronedarone may be associated with an increased risk of worsening or precipitating heart failure.

People should be advised to consult their doctor if they develop signs or symptoms of new or worsening heart failure (weight gain, oedema, shortness of breath).

Consider discontinuing or suspending dronedarone in these people.

Dronedaraone is contraindicated in those who are haemodynamically unstable, including those with symptoms of heart failure at rest or on minimal exertion.

Dronedarone is not recommended for people with recent (less than 3 months) clinically stable New York Heart Association class III heart failure, or with left ejection fraction < 35%, because of limited clinical experience in these groups.

Reference: MHRA (2011) Dronedarone: risk of cardiac failure and risk of hepatotoxicity. Drug Safety Update 4(7), A1. [Free Full-text].

January 2011: Following rare reports of liver injury in people taking dronedarone for atrial fibrillation, the manufacturer has advised that liver function tests should be performed:

Prior to treatment

On a monthly basis for six months

At months 9 and 12, and periodically thereafter.

If ALT levels are more than three times the upper limit of normal, they should be checked within 48 to 72 hours. If ALT levels more than three times the upper limit of normal are confirmed, dronedarone should be withdrawn.

Reference: MHRA (2011) New information on possible risk of liver injury with dronedarone (Multaq). Medicines and Healthcare products Regulatory Agency. www.mhra.gov.uk [Free Full-text]

Dabigatran (Pradexa®)

MHRA (2011) Dabigatran (Pradaxa®): risk of serious haemorrhage — need for renal function testing. Drug Safety Update 5(5), A2. [Free Full-text]

MHRA (2011) Direct Healthcare Professional Communication on the importance of assessing renal function in patients treated with [black triangle] Pradaxa® (dabigatran etexilate). Medicines and Healthcare Products and Regulatory Agency. www.mhra.gov.uk [Free Full-text (pdf)]

MHRA (2012) Dabigatran (Pradaxa [black triangle]): risk of serious haemorrhage - contraindications clarified and reminder to monitor renal function. Drug Safety Update 5(12), A1. [Free Full-text]

MHRA (2013) Dabigatran (Pradaxa): contraindicated in patients with prosthetic heart valve(s) requiring anti-coagulant treatment, because of the risk of thrombosis and haemorrhage. Drug Safety Update 6(8), A1. [Free Full-text (pdf)]

Changes in product availability

Dronedarone

Dronedarone (MULTAQ®) tablets are indicated in clinically stable adults with non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate.

Dabigatran

Dabigatran (Pradaxa®) tablets have recently been granted a license extension for the prevention of stroke and systemic embolism (SEE) in adult patients with atrial fibrillation (AF) with one or more of the following risk factors:

Previous stroke, transient ischemic attack, or SEE

Left ventricular ejection fraction less than 40 %

Symptomatic heart failure, New York Heart Association (NYHA) Class 2 or worse

Age 75 years or older

Age 65 years or older associated with one of the following: diabetes mellitus, coronary artery disease, or hypertension

The National Institute for Health and Care Excellence is expected to publish a technology appraisal on the use of dabigatran in AF in December 2011. This CKS topic will be updated following publication of the NICE appraisal.

Goals and outcome measures

Goals

To establish the diagnosis of atrial fibrillation

To control ventricular rate

To identify those people who may benefit from rhythm control and refer appropriately

To identify those people suitable for attempted cardioversion

To identify those people suitable for antithrombotic medication to reduce the risk of stroke

QOF indicators

Table 1 . Indicators related to atrial fibrillation in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
AF001 The contractor establishes and maintains a register of patients with atrial fibrillation. 5
AF002 The percentage of patients with atrial fibrillation in whom stroke risk has been assessed using the CHADS2 risk stratification scoring system in the preceding 15 months (excluding those whose previous CHADS2 score is greater than 1). 10 40–90%
AF003 In those patients with atrial fibrillation in whom there is a record of a CHADS2 score of 1 (latest in the preceding 15 months), the percentage of patients who are currently treated with anti-coagulation drug therapy or anti-platelet therapy. 6 57–97%
AF004 In those patients with atrial fibrillation whose latest record of a CHADS2 score is greater than 1, the percentage of patients who are currently treated with anti-coagulation therapy. 6 50–90%
Data from: [BMA and NHS Employers, 2013]

Background information

Definition

What is it?

Atrial fibrillation (AF) is an arrhythmia.

AF results from irregular, disorganized electrical activity in the atria. In many people, this is thought to arise from rapidly firing cells at the junction of the pulmonary veins in the left atrial musculature [BHF, 2004].

The rapidly firing impulses cause disorganized atrial depolarization and ineffective atrial contractions [NICE, 2006].

The atrioventricular node receives more electrical impulses than it can conduct. This results in an irregular ventricular rhythm; the ventricular rate of untreated AF often averages 160–180 beats per minute (although this is typically slower in elderly people) [AHA, 2006].

AF is classified according to the pattern of episodes [Levy et al, 2003; Fuster et al, 2006a].

Paroxysmal AF — episodes that last longer than 30 seconds but less than 7 days (often less than 48 hours) and are self-terminating and recurrent.

Persistent AF — episodes lasting longer than 7 days (spontaneous termination of the arrhythmia is unlikely to occur after this time).

Permanent AF — AF that fails to terminate using cardioversion, or is terminated but relapses within 24 hours, or longstanding AF (usually longer than 1 year) in which cardioversion has not been indicated or attempted (sometimes called accepted permanent AF).

Causes

What causes it?

Most people with atrial fibrillation (AF) have an identifiable cause. Lone AF (where there is no obvious cause and all investigations are normal) occurs in up to 11% of people with AF [Lip et al, 1995]. Lone AF is more common in people with paroxysmal AF, occurring in 30–40% of people [Fuster et al, 2006a].

The most common causes of AF are ischaemic heart disease, hypertension, mitral stenosis, and hyperthyroidism [Iqbal et al, 2005].

Other conditions thought to cause or be associated with AF include [National Collaborating Centre for Chronic Conditions, 2006]:

Cardiac or valve conditions:

Rheumatic heart disease.

Sick sinus syndrome.

Pre-excitation syndromes (such as Wolff–Parkinson–White syndrome).

Heart failure [Peters et al, 2002].

Less commonly, cardiomyopathy, pericardial disease, atrial septal defect, congenital heart disease, and atrial myxoma.

Non-cardiac conditions:

Drugs (such as thyroxine or bronchodilators).

Acute infection.

Electrolyte depletion.

Lung cancer.

Pulmonary embolism.

Diabetes [Aksnes et al, 2008].

Dietary and lifestyle factors:

Excessive caffeine intake.

Excessive alcohol intake (especially in susceptible individuals, such as those with structural heart disease) [Balbão et al, 2009].

Obesity [Fuster et al, 2006a].

Prevalence

How common is it?

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the UK [BHF, 2004].

In the UK, more than 46,000 new cases of AF are diagnosed each year [Iqbal et al, 2005].

The prevalence of AF increases with age [National Collaborating Centre for Chronic Conditions, 2006].

At 50–59 years of age, the prevalence is around 0.5%.

At 80–89 years of age, the prevalence is around 9%.

In UK hospitals, 3–6% of people admitted with acute medical conditions have AF [National Collaborating Centre for Chronic Conditions, 2006].

More men than women have AF, when data are adjusted for age [Snow et al, 2003; National Collaborating Centre for Chronic Conditions, 2006].

Complications

What are the complications?

Stroke and thromboembolism

Stroke and thromboembolism are the main complications of atrial fibrillation (AF) [National Collaborating Centre for Chronic Conditions, 2006].

People with AF have a five-fold greater risk of stroke and thromboembolism than people without AF [NICE, 2006].

The incidence of stroke attributable to AF increases from 1.5% in people 50–59 years of age to 23.5% in people 80–89 years of age [NICE, 2006].

Stroke risk is influenced by associated comorbidities, not by the type of AF [Choudhury et al, 2005].

Peripheral thromboembolism can occur.

Heart failure

Heart failure is commonly associated with AF (see the CKS topic on Heart failure - chronic).

Heart failure can occur because the disorganized electrical conduction in the atria results in ineffective ventricular filling [Fuster et al, 2006a]. The cardiac output can be reduced by as much as 10–20%, pushing an already compromised ventricle into failure [National Collaborating Centre for Chronic Conditions, 2006].

Tachycardia-induced cardiomyopathy and critical cardiac ischaemia

Both conditions may result from the persistently elevated ventricular rate seen in uncontrolled AF [National Collaborating Centre for Chronic Conditions, 2006].

Quality of life

AF can result in reduced exercise tolerance and impaired cognitive function [Cordina and Mead, 2005; National Collaborating Centre for Chronic Conditions, 2006].

A review (49 studies) found that people with AF have significantly poorer quality of life than healthy controls, the general population, and other people with coronary heart disease [Thrall et al, 2006].

Prognosis

What is the prognosis?

People with atrial fibrillation (AF) are nearly twice as likely to die than people in sinus rhythm [Fuster et al, 2006a].

Most deaths seen in AF occur early after diagnosis [National Collaborating Centre for Chronic Conditions, 2006].

The mortality rate of people with AF seems to be associated with the presence and severity of concomitant cardiovascular disease [Fuster et al, 2006b].

In a post hoc analysis of a study with 4736 participants that investigated antihypertensive treatment in elderly people with isolated systolic hypertension [Vagaonescu et al, 2008]:

People with hypertension and AF had significantly more cardiovascular events, deaths, and fatal and nonfatal left ventricular failure episodes than people with hypertension in sinus rhythm.

People with AF had a significantly increased risk of all-cause mortality at 14.3 years of follow up (hazard ratio [HR] 2.33, 95% CI 1.83 to 2.98) and total cardiovascular deaths (HR 2.21, 95% CI 1.54 to 3.17) compared with people with hypertension without AF.

In a subgroup analysis of a prospective randomized trial with 5251 participants that investigated antihypertensive treatment on cardiac morbidity and mortality in people older than 65 years of age [Aksnes et al, 2008]:

People with new-onset diabetes and AF had a significantly higher rate of heart failure (HR 3.56, 95% CI 2.86 to 4.44, p < 0.0001) and hospitalization than people with diabetes in sinus rhythm.

The risks from paroxysmal AF are thought to be similar to those from persistent or permanent AF.

In a hospital-based prospective trial with 2824 participants which followed up people being treated for AF over 4.6 years [Friberg et al, 2007]:

People with paroxysmal AF (888 participants, mean 73 years of age) had an annual mortality rate of 7%.

Compared with the general population, people with paroxysmal AF had a standardized mortality ratio of 1.6 (95% CI 1.4 to 1.8) for all-cause mortality, 2.4 (95% CI 1.4 to 3.7) for death from myocardial infarction, and 2.6 (95% CI 1.3 to 5.2) for death from heart failure.

Diagnosis

Diagnosis of atrial fibrillation

Suspecting atrial fibrillation

When should I suspect atrial fibrillation?

Suspect atrial fibrillation (AF) in people with an irregular pulse, with or without any of the following:

Breathlessness.

Palpitations.

Chest discomfort.

Syncope or dizziness.

Reduced exercise tolerance, malaise, or polyuria.

A potential complication of AF, such as stroke, transient ischaemic attack, or heart failure.

Absence of an abnormal pulse makes a diagnosis of AF unlikely, but its presence does not reliably indicate AF — see sensitivity and specificity values in Table 1 in Additional information.

Suspect paroxysmal AF if symptoms are episodic and last less than 48 hours (see Definition).

Additional information

Table 1 . Diagnostic accuracy of pulse palpation for detecting atrial fibrillation.
Diagnostic accuracy Men 65–74 years Men 75+ years
Sensitivity 100% (54 to 100) 95% (75 to 100)
Specificity 79% (74 to 84) 71% (65 to 77)
Positive predictive value 12% (4 to 23) 23% (14 to 34)
Negative predictive value 100% (98 to 100) 99% (96 to 100)
All values are percentages with 95% confidence intervals. Values for women are not included but are similar to those for men.
Data from: [National Collaborating Centre for Chronic Conditions, 2006]

Basis for recommendation

Basis for recommendation

The National Institute for Health and Care Excellence reviewed evidence from nine studies. All studies included people with atrial fibrillation (AF) presenting to secondary care, and as most people presenting to hospital with AF have more severe symptoms, these findings may not be generalizable to primary care [National Collaborating Centre for Chronic Conditions, 2006].

Irregular pulse

In one UK study of 916 people older than 65 years of age, an irregular pulse was found to be sensitive (93–100%) to the presence of AF. The negative predictive values ranged from 99–100% depending on age. In other words, AF can be confidently excluded if the person does not have an irregular pulse.

Symptoms

Many people with AF have no symptoms, and the irregular pulse is detected incidentally.

In two studies with 410 participants, breathlessness, chest pain, and palpitations were found to be the most common presenting symptoms in emergency admissions with newly diagnosed or previously diagnosed AF.

In one study with 756 participants, breathlessness was the most commonly reported symptom in chronic and recent onset AF (47%) and palpitations was the most commonly reported symptom in paroxysmal AF (79%).

Reduced exercise tolerance and malaise may occur due to a rapid heart rate or to a complication, such as heart failure [MeReC, 2002; Snow et al, 2003].

Polyuria may occur owing to the release of atrial natriuretic peptide during episodes of AF [Fuster et al, 2006a].

Complication of AF

In two studies, stroke was reported as a presenting symptom of AF at rates of 5% and 3%.

Diagnostic tests

What tests should I do to diagnose atrial fibrillation?

If an irregular pulse is detected, organize an electrocardiogram (ECG) to determine whether this is due to atrial fibrillation (AF).

If atrial fibrillation (AF) is present, the ECG will show no P-waves, a chaotic baseline, and an irregular ventricular rate.

The ventricular rate is often 160–180 beats per minute, but can be lower. A lower rate is frequently found in people who are asymptomatic.

The ventricular complexes look normal unless there is a ventricular conduction defect.

See a typical tracing from the ECG library.

If paroxysmal AF is suspected and AF is not detected on standard electrocardiography, organize for the person to have ambulatory electrocardiography.

A 24-hour ambulatory ECG monitor is normally used in people with suspected asymptomatic episodes of paroxysmal AF (incidental finding of an intermittent irregular pulse) or symptomatic episodes that are less than 24 hours apart.

An event recorder ECG is normally used in people who have symptomatic episodes more than 24 hours apart.

In some centres, a 7-day Holter monitor is used as an alternative to an event recorder, especially when asymptomatic paroxysms of AF are suspected.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

Standard electrocardiography (ECG)

An ECG will not only confirm a diagnosis of atrial fibrillation (AF) [ICSI, 2008] but also help indicate a possible underlying cause (such as old myocardial infarction, left ventricular hypertrophy, or a pre-excitation syndrome) [Fuster et al, 2006a].

Interpretation of ECG

NICE makes no recommendations on ECG interpretation.

A recent prospective study with 2595 participants concluded that many primary care professionals cannot accurately detect AF on ECG. For example, general practitioners detected 79 of 99 cases of atrial fibrillation on 12-lead ECG (sensitivity 80%, 95% CI 71 to 87) and misinterpreted 114 of 1355 cases of sinus rhythm as atrial fibrillation (specificity 92%, 95% CI 90 to 93) [Mant et al, 2007a].

Ambulatory ECG

In one study with 139 participants, 11% of people presenting to hospital for stroke or transient ischaemic attacks who were not in AF on their initial standard ECG were diagnosed with AF after ambulatory monitoring [Jabaudon et al, 2004].

In a systematic review (five studies, 736 participants), screening people with ischaemic stroke with routine Holter monitoring identified new AF or flutter in approximately one in 20 people (4.6%, 95% CI 0 to 12.7) [Liao et al, 2007].

Differential diagnosis

What else might it be?

Differential diagnoses include:

Atrial flutter — characterized by a saw-tooth pattern of regular atrial activation on the electrocardiogram.

Atrial extrasystoles — common, and may cause an irregular pulse.

Ventricular ectopic beats.

Sinus tachycardia — sinus rhythm more than 100 beats per minute.

Supraventricular tachycardias, including atrial and junctional tachycardias.

Multifocal atrial tachycardia.

For more information, see the CKS topic on Palpitations.

Basis for recommendation

Basis for recommendation

This recommendation is based on US guidelines on the management of patients with atrial fibrillation [Fuster et al, 2006a] and expert opinion in a textbook [Lip and Watson, 1995].

Management

Management

Scenario: First or new presentation of AF : covers the management of a first or new presentation of atrial fibrillation (AF), including what investigations to carry out, when to refer to a cardiologist, when and what rate control treatment to start, how to make a stroke risk assessment, and what antithrombotic treatment to start.

Scenario: Reviewing established AF : covers the review of people with AF, including what assessment is needed and what information should be provided.

Scenario: Paroxysmal AF : covers the management of paroxysmal AF, including what rate control treatment and antithrombotic treatment to start prior to referral to a cardiologist.

Scenario: First or new presentation of AF

Scenario: First or new presentation of atrial fibrillation

192months3060monthsBoth

When to admit/refer

When should I admit or refer someone with atrial fibrillation?

Admit (or refer) for urgent assessment and intervention if the person has any of the following:

A rapid pulse (greater than 150 beats per minute) and/or low blood pressure (systolic blood pressure less than 90 mmHg).

Loss of consciousness, severe dizziness, ongoing chest pain, or increasing breathlessness.

A complication of atrial fibrillation (AF), such as stroke, transient ischaemic attack, or acute heart failure.

Refer people with new-onset AF to a specialist in cardiology if:

The person is young (for example less than 50 years of age).

Paroxysmal AF is suspected.

Rhythm control is the preferred treatment, or there is uncertainty regarding this (see Rate or rhythm control).

Drug treatment for rate control or antithrombotic treatment that can be used in primary care are contraindicated.

The person is found to have valve disease or left ventricular systolic dysfunction on echocardiography.

Wolff–Parkinson–White syndrome or a prolonged QT interval is suspected on the electrocardiogram.

Heart rate is difficult to control, or the person continues to have symptoms despite rate-control treatment (see Management after starting rate-control treatment).

Basis for recommendation

Basis for recommendation

The National Institute for Health and Care Excellence (NICE) makes no specific recommendations regarding referring people with atrial fibrillation (AF) from primary to secondary care. The following recommendations are inferred from the NICE guidance [NICE, 2006] or are based on expert opinion [NHS Scotland, 2005].

Admission

Most people presenting with AF are not haemodynamically compromised. If the person is compromised, admission to hospital is needed for urgent intervention to prevent further deterioration.

NICE states that the following people in AF are those at highest risk from haemodynamic instability:

People with a ventricular rate greater than 150 beats per minute.

Those with ongoing chest pain.

After reviewing the evidence (three small studies), NICE concluded that rate-control drugs (such as beta-blockers and rate-limiting calcium-channel blockers) and pharmacological and electrical cardioversion are effective treatment options for the management of people presenting with haemodynamic instability.

Usually, electrical cardioversion is the treatment of choice for people with haemodynamic instability, and amiodarone is only used when there is an unacceptable delay to cardioversion.

Referral

Type of AF

It may be difficult to categorize AF. For example, different types of AF are not mutually exclusive, and the person may have episodes of paroxysmal AF and occasional persistent AF. Specialist input may be needed to categorize the person on their most frequent presentation [Fuster et al, 2006a].

Paroxysmal AF

Paroxysmal AF requires antiarrhythmic drugs that are not usually started in primary care (such as amiodarone or sotalol).

Advice given in the British National Formulary is that class I and III drugs (such as flecainide) should usually only be started by a specialist [BNF 57, 2009].

Deciding between rhythm or rate control

Some people with persistent AF will satisfy criteria for both rate and rhythm control (for example, older than 65 years of age but also symptomatic); therefore, specialists may consider additional investigations (echocardiography) and take into account the person's comorbidities before deciding on the most appropriate treatment.

Failed primary care treatment, electrocardiogram abnormality, or cardiac dysfunction

If the person with AF has persistent symptoms despite maximum treatment given in primary care, a specialist may consider the use of drugs that are not routinely started in primary care (such as amiodarone or sotalol).

In addition to drug treatment, a specialist may consider further interventions depending on the person's age, severity of symptoms, type of AF, and presence of cardiac dysfunction (for example such interventions as pulmonary vein isolation, pacemaker therapy, arrhythmia surgery, catheter ablation, or use of atrial defibrillators).

Investigations

What investigations should I do in someone with new-onset atrial fibrillation?

An electrocardiogram should already have been done to confirm the diagnosis of atrial fibrillation. An electrocardiogram may also indicate a possible underlying cause (such as an old myocardial infarction, left ventricular hypertrophy, or a pre-excitation syndrome).

Do the following tests:

Thyroid function tests (to exclude hyperthyroidism).

Full blood count (to exclude anaemia).

Blood urea and electrolytes, calcium, and glucose measurement (to exclude electrolyte disturbances, which may precipitate atrial fibrillation).

Liver function tests and clotting screen (to assess suitability for warfarin).

Chest radiography (to assess a suspected lung abnormality, such as lung cancer; this test may also help to detect heart failure).

For people not being referred to a cardiologist, consider organizing transthoracic echocardiography if:

There is a high risk or a suspicion of underlying heart disease (for example signs of heart failure or a cardiac murmur).

Information on cardiac structure or function is needed to make a decision about starting antithrombotic treatment.

Most decisions about starting antithrombotic treatment should be based on clinical judgement. Do not routinely organize echocardiography solely for risk stratification if the person meets the clinical criteria to start warfarin.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: National clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006] and published expert opinion [MeReC, 2002; NHS Scotland, 2005; Fuster et al, 2006a; ICSI, 2008].

NICE does not give specific recommendations on when to refer for echocardiography in those people who present to primary care with atrial fibrillation (AF).

After reviewing good-quality evidence (29 studies) on the ability of echocardiographic findings to predict outcomes in AF (such as recurrence of AF after cardioversion, stroke, or vascular death), NICE gave general advice on which people should undergo echocardiography.

NICE states that the decision to start appropriate antithrombotic treatment can be made clinically. However, the risk may be unclear in some people (such as those with suspected left ventricular dysfunction without overt heart failure), in which case echocardiography may be useful in refining their risk for stroke.

Rate or rhythm control

How should I decide whether rate or rhythm control is needed?

Rate control can be started in primary care, but rhythm control should only be started following specialist assessment.

Rate control is the preferred treatment for permanent atrial fibrillation (AF) and in people with persistent AF and any of the following:

More than 65 years of age.

With coronary artery disease.

With contraindications to antiarrhythmic drugs.

Unsuitable for cardioversion.

Rhythm control is the preferred treatment for paroxysmal AF and in people with persistent AF and any of the following:

Symptomatic.

65 years of age or less.

Presenting for the first time with lone AF.

Presenting with AF secondary to a treated or corrected precipitant (such as infection).

With congestive heart failure.

If there is uncertainty about which option is best (for example the person may be older than 65 years of age with lone AF), seek specialist advice.

For more information on the purpose of both types of treatment, see Aims of rate and rhythm control.

Aims of rate and rhythm control

Aims of rate and rhythm control

Rate control involves the use of drugs to slow the ventricular heart rate, in an attempt to minimize symptoms and associated morbidity of atrial fibrillation (AF). Rate control will not stop the atria from fibrillating.

Rhythm control involves the use of drugs to maintain normal sinus rhythm once AF has terminated (spontaneously or after electrical or pharmacological cardioversion). Rhythm control is often needed long term to help prevent recurrence of AF. For more information, see Rhythm control treatments used by specialists.

Cardioversion is unsuitable for people with:

Contraindications to anticoagulation.

Structural heart disease (for example a large left atrium greater than 5.5 cm or mitral stenosis) that makes it unlikely that sinus rhythm would be maintained following successful cardioversion. 

A long duration of AF (usually greater than 12 months).

A history of multiple failed attempts at cardioversion and/or relapses, even with concomitant use of antiarrhythmic drugs or non-pharmacological approaches.

An ongoing but reversible cause of AF, until the precipitant has been effectively treated (such as thyrotoxicosis).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

After reviewing the evidence (five randomized controlled trials and one meta-analysis) comparing rate control with rhythm control on different outcomes, NICE concluded that overall there is no difference between rhythm control and rate control in terms of mortality or quality of life.

NICE states that rate control is the preferred treatment in people with permanent AF (as by definition rhythm control has been tried and failed, or is not an option), and in people with persistent AF who are older than 65 years of age, have evidence of coronary heart disease, or have no evidence of heart failure, as there is some evidence that rate control may be superior in these groups.

In one study, there was a significant difference in favour of rate control in terms of all-cause mortality in people older than 65 years of age and in people with coronary artery disease.

In three studies, rhythm control compared with rate control resulted in a higher rate of adverse effects and hospital admissions and a higher incidence of arrhythmias in people with recurrent AF.

In one study, rhythm control was associated with a lower incidence of all-cause mortality in people with heart failure.

However, CKS found a subsequent prospective, open-labelled trial (n = 1376) with 2 years of follow-up which suggests that in people with AF and symptoms of heart failure, rhythm control and rate control may result in similar cardiovascular outcomes [Roy et al, 2008].

When to offer drug treatment in primary care

When should I offer drug treatment in primary care?

Rate-control treatments (beta-blockers, rate-limiting calcium-channel blockers, and digoxin) can be started in primary care, but rhythm-control treatments (such as amiodarone, flecainide, and sotalol) should only be started on specialist advice.

Start a rate-controlling drug  if the person does not require admission, regardless of whether they are to be managed in primary care or have been referred to a specialist for consideration of rhythm control, if:

The resting heart rate is 90 beats per minute or more, or

The heart rate is fast on exertion, resulting in a limited exercise tolerance.

Heart rate control

Heart rate control

Heart rate control

The National Institute for Health and Care Excellence (NICE) recommends that resting heart rate should be controlled to less than 90 beats per minute, and that heart rate on exercise should be controlled to less than 110 beats per minute in people who are inactive or 200 beats per minute minus their age in active people [NICE, 2006].

A consensus statement from the Royal College of Physicians of Edinburgh suggests a target resting heart rate of less than 90 beats per minute and less than 180 beats per minute during exercise [RCGP, 1999].

An international guideline states that criteria for rate control vary with age and suggests that ventricular rate should be controlled between 60–80 beats per minute at rest and between 90–115 beats per minute during moderate exercise [Fuster et al, 2006b].

In clinical practice, the target heart rate during exercise may need to be adjusted depending on the level of exercise the person can manage. For example, a rate of 170 beats per minute is inadequate rate control if the person has only walked up the corridor.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

The aim of rate control is to minimize symptoms associated with excessive heart rate (such as breathlessness) and prevent tachycardia-associated cardiomyopathy [Fuster et al, 2006b].

Adequate rate control has not been well studied with respect to quality of life, or symptoms or development of cardiomyopathy, and no standard method for assessment of rate control has been established to guide management.

CKS has outlined the suggested rate control targets from several guideline groups [RCGP, 1999; Fuster et al, 2006a; National Collaborating Centre for Chronic Conditions, 2006].

Initial drug treatment for rate control

Which initial drug treatment should I offer for rate control of atrial fibrillation?

Offer a beta-blocker or rate-limiting calcium-channel blocker (diltiazem or verapamil), unless this is contraindicated.

The choice between beta-blocker and calcium-channel blocker will depend on the person's current medication and comorbidities.

Diltiazem (off-licence use for atrial fibrillation) is preferred to verapamil because verapamil has a greater negative inotropic effect on the heart and interacts with digoxin.

For further information, see the prescribing sections on beta-blockers and calcium-channel blockers.

If the person has a sedentary lifestyle, digoxin is an alternative option.

Digoxin is only adequate for older, sedentary people in whom rate control is not needed during exercise.

For further information, see the prescribing section on digoxin.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

After reviewing 12 small randomized or serial crossover trials comparing beta-blockers and calcium-channel blockers for atrial fibrillation (AF), NICE concluded that:

Both calcium-channel blockers and beta-blockers are more effective than digoxin in controlling heart rate at high levels of physical exertion, but there is no difference during normal daily activities.

There is no significant difference between calcium-channel blockers and beta-blockers in terms of heart rate control.

Beta-blockers versus calcium-channel blockers

One crossover study found no difference between diltiazem and atenolol in terms of heart rate over 24 hours or during exercise.

A second crossover study found no difference between verapamil and atenolol in heart rate at rest or after exercise.

Calcium-channel blockers versus digoxin

Seven studies found no difference in heart rate between verapamil or diltiazem and digoxin, either at rest or during normal daily activity.

Seven studies found that verapamil or diltiazem resulted in a lower heart rate during exercise compared with digoxin.

Beta-blockers versus digoxin

Three studies found no difference in average heart rate between digoxin and beta-blockers while at rest or during normal daily activity.

Atenolol and labetalol controlled heart rate during exercise more effectively than digoxin.

One study found that atenolol significantly reduced heart rate compared with digoxin both at rest and after exercise.

Management after starting rate-control treatment

How should I manage someone after starting initial rate-control treatment?

Within 1 week, check whether the person is tolerating the drug and review symptoms, heart rate, and blood pressure.

If the person cannot tolerate the drug, prescribe an alternative (see Initial drug treatment for rate control).

If the person's symptoms and/or heart rate are not controlled:

If they are not taking the maximum drug dose, consider increasing the dose to control symptoms, or

If they are taking the maximum drug dose, consider combining drug treatments:

To control symptoms during normal activities only, use a beta-blocker or calcium-channel blocker (diltiazem or verapamil) with digoxin.

To control symptoms during normal activities and during exercise, use a calcium-channel blocker (diltiazem or verapamil) with digoxin. If the person is already taking a beta-blocker, it may be more practical to add in digoxin first, and if symptoms are still not controlled, then switch the beta-blocker with a calcium-channel blocker.

Do not use a combination of a beta-blocker and a rate-limiting calcium-channel blocker to control atrial fibrillation in primary care.

If symptoms are not controlled with a beta-blocker plus digoxin or a calcium-channel blocker plus digoxin, refer to a specialist in cardiology.

For detailed prescribing information, see the prescribing sections on beta-blockers, calcium-channel blockers, and digoxin.

Heart rate control

Heart rate control

Heart rate control

The National Institute for Health and Care Excellence (NICE) recommends that resting heart rate should be controlled to less than 90 beats per minute, and that heart rate on exercise should be controlled to less than 110 beats per minute in people who are inactive or 200 beats per minute minus their age in active people [NICE, 2006].

A consensus statement from the Royal College of Physicians of Edinburgh suggests a target resting heart rate of less than 90 beats per minute and less than 180 beats per minute during exercise [RCGP, 1999].

An international guideline states that criteria for rate control vary with age and suggests that ventricular rate should be controlled between 60–80 beats per minute at rest and between 90–115 beats per minute during moderate exercise [Fuster et al, 2006b].

In clinical practice, the target heart rate during exercise may need to be adjusted depending on the level of exercise the person can manage. For example, a rate of 170 beats per minute is inadequate rate control if the person has only walked up the corridor.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006]. Rate control is not always achieved with a single drug, and combination drug treatment may be required.

Beta-blocker with digoxin versus beta-blocker alone

One crossover study with 12 participants found that atenolol used in combination with digoxin resulted in a lower heart rate over 24 hours than that achieved with atenolol alone [Farshi et al, 1999]. This study found no statistically significant difference in heart rate during periods of exercise.

Calcium-channel blocker with digoxin versus calcium-channel blocker alone

Four crossover studies (with about 15 participants in each study) found that diltiazem or verapamil used in combination with digoxin was more effective in controlling heart rate over 24 hours, as well as during periods of exercise, than either diltiazem or verapamil alone.

Combination of beta-blocker and calcium-channel blocker

NICE does not recommend the use of a beta-blocker and rate-limiting calcium-channel blocker for atrial fibrillation in primary care owing to the increased risk of bradycardia with this combination.

Referral

If digoxin with a beta-blocker, or digoxin with a calcium-channel blocker, is ineffective or not tolerated, a specialist may consider the use of amiodarone, or diltiazem with a beta-blocker, to control atrial fibrillation. Alternatively, a non-pharmacological approach (mainly atrioventricular node ablation coupled with pacing) might be considered.

Rhythm control treatments used by specialists

What rhythm control treatments are used by specialists?

Persistent atrial fibrillation (AF)

Cardioversion is performed as part of a rhythm-control strategy in people with persistent AF and, if successful, will restore sinus rhythm.

Cardioversion can be carried out either with the use of drugs (pharmacological cardioversion) or electrical shock (electrical cardioversion).

Not all attempts at cardioversion are successful, and at 1 year after cardioversion, approximately 50% of people will be back in AF.

Paroxysmal AF

If the person has infrequent paroxysms and few symptoms, the specialist may offer:

A no-drug treatment strategy, or

A pill-in-the-pocket strategy (self-administration of an antiarrhythmic drug if an episode of AF occurs).

If the person has symptomatic paroxysms, a standard beta-blocker (such as atenolol) will usually be offered first-line:

If a standard beta-blocker does not adequately control paroxysms, sotalol may be used, or if there is no structural heart disease or coronary artery disease, a class Ic antiarrhythmic drug (such as flecainide or propafenone) may be tried.

If none of these are effective, the specialist may use amiodarone, or refer for non-pharmacological intervention (such as surgical ablation and pacemaker).

Failed treatment, lone AF, or an electrophysiological disorder causing AF

In people in whom pharmacological treatment has failed, those with lone AF, and those with evidence of an underlying electrophysiological disorder (for example, Wolff–Parkinson–White syndrome), a specialist may consider such interventions as pulmonary vein isolation, pacemaker therapy, arrhythmia surgery, catheter ablation, or atrial defibrillators [Fuster et al, 2006b; ICSI, 2008].

Basis for recommendation

Basis for recommendation

Persistent and paroxysmal atrial fibrillation

This information is based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006]

Failed treatment, lone AF, or an electrophysiological disorder causing AF

This information is based on expert opinion in US guidelines on the management of atrial fibrillation [Fuster et al, 2006b] and a guideline from the Institute for Clinical Systems Improvement [ICSI, 2008].

When to offer antithrombotic treatment

When should I offer antithrombotic treatment?

Most people with atrial fibrillation (whether paroxysmal, persistent, or permanent) should be offered antithrombotic treatment to reduce their risk of stroke.

Offer either aspirin or warfarin, without delay, after confirming a diagnosis of atrial fibrillation.

The choice of either aspirin or warfarin should be based on the person's risk of stroke (see Which antithrombotic treatment).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

Antithrombotic treatment for all people with atrial fibrillation (AF)

AF is an independent risk factor of stroke; the annual risk for stroke is five to six times higher in people with AF than in people in sinus rhythm.

Strokes that occur in association with AF are more likely to result in greater mortality, morbidity, and disability and longer hospital stays than strokes that occur in people without AF.

Good evidence indicates that antithrombotic treatment reduces the risk of stroke in all people with AF.

Starting antithrombotic treatment after a diagnosis of AF

Provided that the person has no contraindications to antithrombotic treatment (such as uncontrolled hypertension), NICE states that treatment should be started as soon as possible after a diagnosis of AF to minimize the risk of stroke.

Stroke risk stratification can be easily performed in primary care on the basis of clinical criteria; therefore, a primary healthcare professional should not delay antithrombotic treatment by waiting for a cardiology opinion.

Antithrombotic treatment compared with placebo or no treatment

After reviewing the evidence, NICE concluded that treatment with warfarin or an antiplatelet drug is more effective than placebo or no treatment in the prevention of cardioembolic stroke in people with AF.

Two systematic reviews found evidence that aspirin was associated with a statistically non-significant reduction in stroke risk. However, a statistically significant risk reduction in a combined outcome of stroke, myocardial infarction, or vascular death was seen.

Three systematic reviews found evidence that compared with placebo, warfarin significantly reduced the risk of stroke by two-thirds in people with AF. Compared with placebo, warfarin was associated with an increased risk of extracranial bleeding, but there was no increased incidence of intracranial bleeding.

Which antithrombotic treatment

Which antithrombotic treatment should I offer?

Treatment decisions should be made on an individual basis; the person's bleeding risk, likelihood of compliance with treatment, and preferred options should always be fully assessed before starting treatment.

Offer people with atrial fibrillation (AF) treatment options depending on their CHA2DS2VASc score:

Score 0 (low risk of stroke [aged less than 65 years with lone AF and no additional risk factors, irrespective of gender]) — no antithrombotic treatment.

Score 1 (at moderate risk of stroke) — either aspirin or warfarin.

Score 2 or more — (at high risk of stroke) — warfarin.

If there is uncertainty about stroke risk, start aspirin whilst awaiting specialist assessment.

CKS does not recommend the use of clopidogrel or a combination of aspirin and clopidogrel for AF in primary care.

For detailed information on the use of aspirin and warfarin in AF, including contraindications, starting doses and titration, monitoring, and adverse effects, see the CKS topics on Antiplatelet treatment and Anticoagulation - oral.

The National Institute for Health and Care Excellence does not state that a formal bleeding risk assessment is necessary before starting antithrombotic treatment, but it provides a list of risk factors that increase the risk of bleeding with warfarin:

More than 75 years of age.

Use of antiplatelet drugs (such as aspirin or clopidogrel).

Use of nonsteroidal anti-inflammatory drugs.

Use of multiple other drugs (polypharmacy).

Uncontrolled hypertension.

History of bleeding (for example bleeding peptic ulcer or cerebral haemorrhage).

History of previously poorly controlled anticoagulation therapy.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006] and expert opinion in the 2012 focused update of the ESC Guidelines for the management of atrial fibrillation published by the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology [Camm et al, 2012].

No antithrombotic treatment

The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology states that antithrombotic treatment is not recommended for people who are truly 'low risk' with lone AF who are aged less than 65 years, irrespective of gender, as they have very low absolute event rates, and are unlikely to benefit from treatment [Camm et al, 2012].

Warfarin versus aspirin

Good evidence indicates that warfarin is more effective than aspirin for preventing stroke or vascular events in people with atrial fibrillation (AF) but is associated with a higher risk of intracranial and extracranial bleeding.

For people without prior stroke or transient ischaemic attack (TIA), a Cochrane systematic review (eight randomized controlled trials [RCTs]) found that warfarin reduced the risk of stroke and other major vascular events in people with AF by about one-third compared with antiplatelets [Aguilar et al, 2007].

For people who have had a stroke or TIA, a Cochrane systematic review (two RCTs) found that warfarin reduced the risk of stroke by a half, and the risk of any vascular event by one-third, compared with antiplatelets [Saxena and Koudstaal, 2004b].

For people 75 years of age or older, an open-label RCT (973 participants) found that warfarin (target international normalized ratio 2.0–3.0) reduced the risk of stroke by half and the risk of vascular events by two-thirds, compared with aspirin 75 mg daily [Mant et al, 2007b].

Clopidogrel alone

NICE do not recommend the use of clopidogrel in AF. Clopidogrel is not licenced for AF and there is no trial evidence to support its use. However, a number of CKS expert reviewers do state that they would use clopidogrel as an alternative treatment option in people with a true aspirin allergy.

Combining antithrombotic treatment

NICE states that if warfarin is offered, aspirin should not be taken concomitantly to prevent stroke, as it provides no additional benefit and may increase the risk of bleeding.

CKS does not recommend the use of aspirin plus clopidogrel in primary care to reduce the risk of stroke in AF.

There is evidence that warfarin significantly reduces the risk of stroke, myocardial infarction, and vascular events compared with clopidogrel plus aspirin [Connolly et al, 2006]. Warfarin did not increase the risk of bleeding compared with clopidogrel plus aspirin.

A recently published trial found evidence that combined treatment with clopidogrel plus aspirin reduces the risk of major vascular events compared with aspirin alone [ACTIVE Investigators et al, 2009]. However, this trial also found evidence that combined treatment with clopidogrel plus aspirin was associated with a two-fold increased risk of major bleeding.

Assessing stroke risk

How should I assess stroke risk in a person with atrial fibrillation?

Assess the person's risk of stroke using a risk factor-based approach using the CHA2DS2VASc score tool. This defines 'major' and 'clinically relevant non-major' risk factors, which increase the risk of stroke. Adding together the points allocated to each risk factor gives a total CHA2DS2VASc score, which then guides the decision to offer antithrombotic treatment:

Congestive heart failure/left ventricular dysfunction (heart failure with reduced ejection fraction, or people with recent decompensated heart failure requiring hospitalization, irrespective of ejection fraction) = 1

Hypertension = 1

Age older than or equal to 75 years = 2

Diabetes = 1

Stroke/TIA/thromboembolism = 2

Vascular disease (such as myocardial infarction and peripheral arterial disease) = 1

Age 65–74 years = 1

Sex category (female) = 1

See Which antithrombotic treatment for information about specific drug treatments to offer, following a stroke risk assessment.

If there is uncertainty about the person's risk of stroke, consider referral to a cardiologist.

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006] and expert opinion in the 2012 focused update of the ESC Guidelines for the management of atrial fibrillation published by the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology [Camm et al, 2012].

Risk factors for stroke

A systematic review (search date October 2005, seven studies) suggests that prior stroke or transient ischaemic attack (TIA), advancing age, hypertension, and diabetes are independent risk factors for stroke in people with AF [Stroke Risk in Atrial Fibrillation Working Group, 2007].

Absolute stroke rates were in the range 6–9% per year for prior stroke or TIA, 1.5% to 3% per year for history of hypertension, 1.5–3% per year for age more than 75 years, and 2.0–3.5% per year for diabetes [Stroke Risk in Atrial Fibrillation Working Group, 2007].

In the systematic review, evidence for heart failure and coronary artery disease as independent risk factors for stroke is inconclusive. However, NICE includes heart failure and vascular disease as independent risk factors for stroke on the basis that left ventricular dysfunction is associated with an increased risk of stroke. Atherosclerotic vascular disease is also a risk factor for stroke, with a poor prognosis when associated with AF [Goto et al, 2008].

The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology emphasizes that stroke risk is a continuum and the previous approach of categorizing people as 'low', 'moderate', or 'high' risk of stroke had only modest predictive value of identifying people at truly high risk who subsequently suffered a stroke [Camm et al, 2012].

CHA2DS2VASc score for stroke risk

The previously recommended CHADS2 score (congestive heart failure, hypertension, age older than 75 years, diabetes, stroke [doubled]) tool for assessing stroke risk was limited in that it did not include several common stroke risk factors. It has been replaced by the CHA2DS2VASc score which takes a risk factor-based approach, defining 'major' and 'clinically relevant non-major' risk factors which are additive in indicating a person's stroke risk [Camm et al, 2012].

The CHA2DS2VASc score has been validated in multiple cohorts, and it has been found to be possibly better than CHADS2 at identifying people who develop stroke and thromboembolism [Camm et al, 2012].

The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology recommends this new CHA2DS2VASc score tool to enable a shift of focus to identifying people who are truly at low risk of stroke, who do not require any antithrombotic treatment [Camm et al, 2012].

Driving

What advice should I give about driving?

Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.

The DVLA's medical rules regarding atrial fibrillation are:

For group 1 entitlement (cars, motorcycles):

Driving must cease if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the underlying cause has been identified and controlled for at least 4 weeks

The DVLA need not be notified unless there are distracting or disabling symptoms.

For group 2 entitlement (lorries, buses):

Disqualified from driving if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the arrhythmia is controlled for at least 3 months; the left ventricular ejection fraction is equal to or greater than 0.4; there is no other disqualifying condition.

The person should check with their insurer that they are still covered for driving.

The latest information from the DVLA regarding medical fitness to drive can be obtained at www.gov.uk/government/publications/at-a-glance.

Basis for recommendation

Basis for recommendation

This information on medical rules is from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

Flying

What advice should I give about flying?

Advise the person that there are no flying restrictions provided they have stable atrial fibrillation which has not recently worsened or become more symptomatic.

Basis for recommendation

Basis for recommendation

These recommendations are based on the British Heart Foundation Factfile: Fitness to fly for passengers with cardiovascular disease, which is based on the British Cardiovascular Society Working Group's expert guidance [BHF, 2010].

Scenario: Reviewing established AF

Scenario: Reviewing established atrial fibrillation

192months3060monthsBoth

Reviewing established AF

How should I review someone with established atrial fibrillation?

Check for ongoing symptoms (at rest or with exercise) and assess heart rate.

If the person is taking rate-control treatment and has persistent symptoms or a fast heart rate, consider increasing the drug dose (if they are not taking the maximum dose), combining drug treatments (if this has not already been done), or referring to a cardiologist. For more information on heart rate control, see Heart rate control.

If the person is taking rhythm-control treatment and has recurring or persistent symptoms, refer back to a cardiologist for further assessment (for example for development of persistent atrial fibrillation [AF] or failed rhythm-control treatment).

Assess stroke and cardiovascular disease (CVD) risk.

If the person is not taking warfarin, reassess risk of stroke if they develop diabetes, hypertension, or cardiovascular disease or when they reach 65 and 75 years of age.

If the person is taking warfarin, reassess risk of bleeding (such as risk of falling).

For information on how to assess CVD risk, see the CKS topic on CVD risk assessment and management.

Check for complications of AF and assess blood pressure.

Identify and manage existing heart failure or hypertension — see the CKS topics on Heart failure - chronic and Hypertension - not diabetic.

Review the person's medication.

Check compliance, and identify and manage drug interactions and complications (such as dyspepsia with aspirin).

Give advice on known drug interactions and which drugs should be avoided with aspirin or warfarin (see Prescribing information).

Provide information on AF.

Provide written information (if this has not already been given).

Explain when to seek further medical advice (such as worsening symptoms).

For more information on patient education and support groups, see www.atrialfibrillation.org.uk.

Heart rate control

Heart rate control

Heart rate control

The National Institute for Health and Care Excellence recommends that resting heart rate should be controlled to less than 90 beats per minute, and that heart rate on exercise should be controlled to less than 110 beats per minute in people who are inactive or 200 beats per minute minus their age in active people [NICE, 2006].

A consensus statement from the Royal College of Physicians of Edinburgh suggests a target resting heart rate of less than 90 beats per minute and less than 180 beats per minute during exercise [RCGP, 1999].

An international guideline states that criteria for rate control vary with age and suggests that ventricular rate should be controlled between 60 and 80 beats per minute at rest and between 90 and 115 beats per minute during moderate exercise [Fuster et al, 2006b].

In clinical practice, the target heart rate during exercise may need to be adjusted depending on the level of exercise the person can manage. For example, a rate of 170 beats per minute is inadequate rate control if the person has only walked up the corridor.

Basis for recommendation

Basis for recommendation

These recommendations are based in part on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006], the Institute for Clinical Systems Improvement health care guideline Atrial fibrillation [ICSI, 2008], and a guideline produced jointly by US and European specialist groups [Fuster et al, 2006a].

Driving

What advice should I give about driving?

Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.

The DVLA's medical rules regarding atrial fibrillation are:

For group 1 entitlement (cars, motorcycles):

Driving must cease if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the underlying cause has been identified and controlled for at least 4 weeks

The DVLA need not be notified unless there are distracting or disabling symptoms.

For group 2 entitlement (lorries, buses):

Disqualified from driving if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the arrhythmia is controlled for at least 3 months; the left ventricular ejection fraction is equal to or greater than 0.4; there is no other disqualifying condition.

The person should check with their insurer that they are still covered for driving.

The latest information from the DVLA regarding medical fitness to drive can be obtained at www.gov.uk/government/publications/at-a-glance.

Basis for recommendation

Basis for recommendation

This information on medical rules is from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

Flying

What advice should I give about flying?

Advise the person that there are no flying restrictions provided they have stable atrial fibrillation which has not recently worsened or become more symptomatic.

Basis for recommendation

Basis for recommendation

These recommendations are based on the British Heart Foundation Factfile: Fitness to fly for passengers with cardiovascular disease, which is based on the British Cardiovascular Society Working Group's expert guidance [BHF, 2010].

Scenario: Paroxysmal AF

Scenario: Paroxysmal atrial fibrillation

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Paroxysmal AF

How should I manage someone with paroxysmal atrial fibrillation?

Refer all people with paroxysmal atrial fibrillation (AF) to a cardiologist for management.

While the person is waiting to see a specialist:

Start either aspirin or warfarin (if they are not contraindicated), to reduce the person's risk of stroke.

The choice of antithrombotic treatment should be based on the person's risk of stroke and not on the frequency or duration of paroxysms of AF.

For further information, see Which antithrombotic treatment.

If the person is having frequent, symptomatic paroxysms but does not require admission, consider starting a beta-blocker (unless this is contraindicated).

Seek advice if uncertain whether to start drug treatment.

For further information, see the prescribing section on beta-blockers.

If a specialist initiates rhythm-control treatment, initial follow up and drug monitoring will be carried out by the specialist. However, primary healthcare professionals will be involved in the longer-term follow up (for example, monitoring of drugs and identifying complications of AF).

Basis for recommendation

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Atrial fibrillation: national clinical guideline for management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

The aims of treating paroxysmal atrial fibrillation (AF) are to prevent paroxysms of AF and maintain sinus rhythm, to control heart rate during paroxysms of AF, and to prevent complications (such as stroke).

Drugs used to manage paroxysmal AF (such as amiodarone or sotalol) are not usually started in primary care; therefore, referral to a cardiologist is necessary.

Antithrombotic treatment

Controlling the symptoms of paroxysmal AF does not necessarily mean abolition of the AF (asymptomatic episodes may still occur). Evidence indicates that people with paroxysmal AF are at the same risk of stroke as people with persistent or permanent AF and should be assessed in the same way as people with persistent AF. For more information see Assessing stroke risk in the Scenario: First or new presentation of AF.

After reviewing limited evidence (subgroup analyses of two meta-analyses), NICE concluded that the efficacy of antithrombotic treatment in reducing the risk of ischaemic stroke is similar in people with paroxysmal AF and non-paroxysmal AF. The incidence of major bleeding was also similar between both groups.

One meta-analysis (six randomized trials, 4052 participants) found that in people treated with aspirin, the incidence of stroke was similar in people with paroxysmal AF and non-paroxysmal AF [van Walraven et al, 2002].

One meta-analysis (29 trials, 28,044 participants) found warfarin to be associated with a reduced incidence of ischaemic stroke compared with aspirin (1.5% compared to 4.7% respectively, p < 0.05) in people with AF [Hart et al, 2007]. These results were similar for people with paroxysmal AF and non-paroxysmal AF.

Rhythm-control treatment

NICE recommends starting treatment with a standard beta-blocker to control frequent paroxysms of AF, especially if paroxysms are associated with symptoms. Therefore, starting a beta-blocker in primary care will help reduce the number of paroxysms, help with symptoms, and possibly maintain sinus rhythm while awaiting specialist assessment.

Follow up

The specialist will usually follow up the person to assess whether they are still continuing to have paroxysms of AF and determine whether further treatment is necessary.

Driving

What advice should I give about driving?

Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.

The DVLA's medical rules regarding atrial fibrillation are:

For group 1 entitlement (cars, motorcycles):

Driving must cease if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the underlying cause has been identified and controlled for at least 4 weeks

The DVLA need not be notified unless there are distracting or disabling symptoms.

For group 2 entitlement (lorries, buses):

Disqualified from driving if the arrhythmia has caused or is likely to cause incapacity.

Driving may be permitted when the arrhythmia is controlled for at least 3 months; the left ventricular ejection fraction is equal to or greater than 0.4; there is no other disqualifying condition.

The person should check with their insurer that they are still covered for driving.

The latest information from the DVLA regarding medical fitness to drive can be obtained at www.gov.uk/government/publications/at-a-glance.

Basis for recommendation

Basis for recommendation

This information on medical rules is from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

Flying

What advice should I give about flying?

Advise the person that there are no flying restrictions provided they have stable atrial fibrillation which has not recently worsened or become more symptomatic.

Basis for recommendation

Basis for recommendation

These recommendations are based on the British Heart Foundation Factfile: Fitness to fly for passengers with cardiovascular disease, which is based on the British Cardiovascular Society Working Group's expert guidance [BHF, 2010].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Beta-blockers

Beta-blockers

Contraindications

Who should not receive a beta-blocker?

Beta-blockers are contraindicated in people with:

A history of asthma or bronchospasm.

Severe bradycardia.

Second- or third-degree heart block.

Uncontrolled heart failure.

Severe hypotension.

Severe peripheral vascular disease (including intermittent claudication).

Sick sinus syndrome.

Cardiogenic shock or phaeochromocytoma (without a concomitant alpha-blocker).

Beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe.

Basis for recommendation

This information is taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b; ABPI Medicines Compendium, 2010].

History of asthma or bronchospasm

The Commission on Human Medicines (formerly the Committee on Safety of Medicines) has advised that beta-blockers (including those considered to be cardioselective) should not be given to people with a history of asthma or bronchospasm [CSM, 1996; BNF 57, 2009].

Choice of beta-blocker

Which beta-blocker should I use?

Atenolol, acebutolol, metoprolol, nadolol, oxprenolol, and propranolol are licensed to treat atrial fibrillation.

The choice of beta-blocker will usually depend on the person's comorbidities, local recommendations, and cost.

For people with atrial fibrillation alone, atenolol may be preferred because it may be taken once a day and is less expensive than other beta-blockers.

For people with hypertension and angina, atenolol or metoprolol may be preferred. For more information, see the CKS topic on Angina.

For people who have atrial fibrillation and have had a previous myocardial infarction (without heart failure), metoprolol (standard release), propranolol (standard release), or atenolol may be preferred. For more information, see the CKS topic on MI - secondary prevention.

For people with atrial fibrillation and heart failure, bisoprolol, carvedilol, and nebivolol may be preferred. For more information, see the CKS topic on Heart failure - chronic.

Basis for recommendation

The National Institute for Health and Care Excellence (NICE) does not specify which beta-blocker should be used to treat atrial fibrillation. This recommendation is based on practical advice. The choice of beta-blocker will ultimately depend on the person's comorbidities, local recommendations, and cost [National Collaborating Centre for Chronic Conditions, 2006].

Dose and titration

What dose of beta-blocker should I prescribe and how should the dose be titrated?

Atenolol

Start with a low dose (25 mg daily).

The usual maintenance dose is 50–100 mg daily.

Check pulse and blood pressure 1 week after each dose titration to assess response to treatment.

Basis for recommendation

These doses are based on information taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2008b].

Adverse effects

What are the adverse effects of beta-blockers, and how can they be managed?

Cold extremities, paraesthesiae, and numbness can occur and are more common in people with peripheral vascular disease. If troublesome, beta-blockers might need to be stopped — this is most likely in people with severe peripheral vascular disease.

Sleep disturbance or nightmares can occur but are less likely with water-soluble beta-blockers, such as atenolol, because these drugs are less likely to cross the blood–brain barrier.

Fatigue: an incidence of approximately 18 per 1000 people treated with a beta-blocker has been reported, but in clinical trials, only 0.4% of people stopped taking their beta-blocker for this reason.

Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people on treatment, leading to discontinuation of treatment in 2 people per 1000 person-years. The person should be directly questioned about whether they are having sexual problems because this adverse effect is often not volunteered owing to embarrassment.

Depression has been claimed to be an adverse effect of beta-blockers, but a recent meta-analysis found no significant increased risk of depressive symptoms in people taking beta-blockers.

Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers. A selective beta-blocker is therefore preferred in people with diabetes. Avoid beta-blockers in people who experience frequent hypoglycaemia.

Basis for recommendation

These recommendations are based on the British National Formulary [BNF 57, 2009], published expert opinion [Ko et al, 2002; Lopez-Sendon et al, 2004], and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007e].

Drug interactions

What key drug interactions should I be aware of for beta blockers?

Verapamil and diltiazem

The combination of a beta-blocker and verapamil should not be prescribed in primary care because bradycardia, asystole, severe hypotension, and heart failure can occur.

The combination of a beta-blocker and diltiazem should not be prescribed in primary care because bradycardia and atrioventricular (AV) block can occur. Asystole and sudden death have also been reported.

Combining a beta-blocker with either verapamil or diltiazem may be initiated in secondary care.

Class I antiarrhythmics (for example quinidine and flecainide)

The combination of a beta-blocker and a class I antiarrhythmic is not recommended in primary care because bradycardia and myocardial depression can occur. This combination may be initiated in secondary care.

Class III antiarrhythmics (for example amiodarone)

The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure and check for signs of worsening heart failure, as there is an increased risk of bradycardia, AV block, and myocardial depression.

Digoxin

Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.

Other drugs that reduce blood pressure (for example angiotensin-converting enzyme inhibitors)

An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

Basis for recommendation

These recommendations are based on the manufacturer's Summary of Product Characteristics, and the British National Formulary [ABPI Medicines Compendium, 2007c; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2010; BNF 57, 2009].

Rate limiting calcium-channel blockers

Rate limiting calcium-channel blockers (diltiazem and verapamil)

Contraindications

Who should not receive a rate-limiting calcium-channel blocker?

People with the following conditions should not receive a rate-limiting calcium-channel blocker:

Heart failure — they may precipitate heart failure.

Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy) — vasodilatation may result in reduced cardiac output.

High-degree atrioventricular block — verapamil and diltiazem may induce complete atrioventricular block.

People taking beta-blockers should avoid verapamil and diltiazem. They can be co-prescribed but only on specialist advice.

Basis for recommendation

These recommendations are based on published expert opinion [Eisenberg et al, 2004; Thadani, 2004] and information published by the product manufacturers [ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2009d].

Choice of calcium-channel blocker

Which rate-limiting calcium-channel blocker should I use?

Diltiazem (off-label) or verapamil (standard release) may be used to treat atrial fibrillation. Diltiazem is preferred because verapamil causes a negative inotropic effect (decrease in myocardial contractility) and interacts with digoxin.

Basis for recommendation

This recommendation is based on guidance issued by the National Institute for Health and Care Excellence [National Collaborating Centre for Chronic Conditions, 2006].

Dose and titration

What dose of calcium-channel blocker should I prescribe and how should the dose be titrated?

Start with a low dose and titrate upwards until atrial fibrillation is controlled.

Diltiazem (off-label)

The usual starting dose is 60 mg three times a day (60 mg twice a day in elderly people).

Maintenance doses range from 60 mg to 180 mg three times a day.

Once-daily preparations may also be used.

Verapamil (standard-release)

The usual starting dose is 40 mg three times a day.

The maximum dose is 120 mg three times a day.

Check the person's pulse and blood pressure 1 week after each dose titration to assess response to treatment.

Basis for recommendation

The dosing information for verapamil is taken from the British National Formulary [BNF 57, 2009].

Diltiazem is not licensed for treating atrial fibrillation. The recommended doses for diltiazem are based on published US guidelines [Fuster et al, 2006a] and from doses used in clinical trials [Roth et al, 1986; Farshi et al, 1999; Hohnloser et al, 2000].

CKS expert reviewers agreed with the doses of diltiazem recommended here and suggested that once-daily preparations could be used to improve compliance.

Adverse effects

What are the adverse effects of calcium-channel blockers, and how should they be managed?

Verapamil commonly causes constipation.

Advise the person to eat more fibre (for example fruit, vegetables, cereals, and wholemeal bread), to try to drink at least 12 cups (equivalent to eight glasses or eight mugs) of liquid a day, and to avoid drinks with a high caffeine content because these may make constipation worse.

Bradycardia can result from taking diltiazem or verapamil.

Vasodilatory adverse effects (flushing, headaches, and ankle swelling) are less common with rate-limiting calcium-channel blockers than with dihydropyridine calcium-channel blockers and often improve with continued use. Diuretics should not be routinely prescribed to relieve ankle swelling, but they may help if there is marked oedema.

Basis for recommendation

This information is taken from the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007b; ABPI Medicines Compendium, 2008a] and the British National Formulary [BNF 57, 2009].

The recommendation regarding managing constipation is a pragmatic recommendation based on published expert opinion [Kumar and Hall, 2003; Eisenberg et al, 2004].

Drug interactions

What key drug interactions should I be aware of for calcium-channel blockers?

Grapefruit may inhibit the metabolism of verapamil, resulting in increased plasma concentrations which could be clinically important.

Verapamil should not be used with a beta-blocker because of the risk of reduced cardiac output and heart failure.

Diltiazem should not be prescribed with a beta-blocker because bradycardia and atrioventricular block can occur. Asystole and sudden death have also been reported.

Basis for recommendation

This information is taken from: the manufacturers' Summary of Product Characteristics [ABPI Medicines Compendium, 2007b]; Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008]; and the Commission on Human Medicines (formerly the Committee on Safety of Medicines) [CSM, 1997].

Digoxin

Digoxin

Contraindications

Who should not receive digoxin?

Digoxin should be avoided in people with:

Some supraventricular arrhythmias, such as Wolff–Parkinson–White syndrome.

Heart conduction problems, such as intermittent complete heart block or atrioventricular heart block.

Ventricular tachycardia.

Hypertrophic obstructive cardiomyopathy.

Basis for recommendation

These recommendations are taken from information published by the manufacturer [ABPI Medicines Compendium, 2009c].

Dose and titration

What dose of digoxin should I prescribe and how should the dose be titrated?

Prescribe a loading dose of 250 micrograms to 500 micrograms daily for 1–2 days, followed by a maintenance dose.

A clinical response is usually seen within 1 week.

Seek specialist advise for people who are elderly and who have renal impairment. The loading dose of digoxin will need to be reduced.

The usual maintenance dose is 62.5 micrograms to 250 micrograms daily; this is adjusted according to the heart rate response.

Check the person's pulse rate and apical rate 1 week after initiation and after any change in dose.

Basis for recommendation

This information is taken from the British National Formulary [BNF 57, 2009] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c].

A more rapid response may be achieved by prescribing 1–1.5 mg in divided doses over 24 hours [BNF 57, 2009], although CKS expert reviewers suggest that usually no more than 1000 micrograms (1 mg) is needed in 24 hours. If a more rapid clinical response is required, consider referral to secondary care.

Adverse effects

What are the adverse effects of digoxin?

Non-cardiac adverse effects are usually associated with overdose and include:

Nausea, vomiting, and (less commonly) diarrhoea. Nausea in particular is indicative of overdose.

Visual abnormalities (blurred or yellow vision).

Central nervous system effects, such as weakness, dizziness, confusion, apathy, malaise, headache, depression, and psychosis.

Cardiac adverse effects are usually associated with overdose, although electrolyte imbalances may predispose the person to cardiac adverse effects so that they occur even at therapeutic concentrations. They include various conduction and rhythm disturbances, such as:

Sinoatrial and atrioventricular block.

Premature ventricular contractions (resulting in bigeminy or trigeminy).

PR prolongation and ST-segment depression.

Basis for recommendation

This information is taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c], the British National Formulary [BNF 57, 2009], and published expert opinion [European Society of Cardiology, 2008].

Digoxin has a narrow therapeutic window — there is only a small range of plasma concentrations between which the drug is ineffective because of underdosing and toxic because of overdosing. Adverse effects usually occur at serum concentrations above the upper limit of the therapeutic window, and they are dose-dependent. If significant adverse effects occur, serum levels of digoxin should be measured.

Monitoring

How should I monitor someone taking digoxin?

Digoxin has a narrow therapeutic window, and measurement of serum levels may be considered in the following instances:

Shortly after initiation, to check that drug levels are in the correct therapeutic range (not standard practice).

When there is a dose change.

When there are adverse effects suggestive of overdosing.

When there are factors that may affect digoxin serum levels, such as use of a concomitant drug that affects digoxin serum levels, or deteriorating renal function.

When noncompliance is suspected.

The therapeutic range of digoxin is between 0.7 nanograms/mL and 2.0 nanograms/mL.

Blood samples should be taken at least 6 hours after the previous dose, but ideally 8–12 hours afterwards.

Monitoring should be performed several days after the last dose change.

The likelihood of toxicity depends on the serum concentration of digoxin.

Levels less than 1.5 nanograms/mL in the absence of hypokalaemia indicate that digoxin toxicity is unlikely.

Levels greater than 3.0 nanograms/mL indicate that digoxin toxicity is likely.

With levels between 1.5 nanograms/mL and 3.0 nanograms/mL, digoxin toxicity should be considered a possibility.

In addition, blood chemistry measurements (electrolytes, urea, and creatinine) should be done at least annually. These tests will often be done routinely, as renal function is likely to be monitored owing to the use of nephrotoxic drugs (such as diuretics and drugs affecting the renin-angiotensin system).

Basis for recommendation

These recommendations are taken from the National Institute of Health and Clinical Excellence guidance Chronic heart failure: management of chronic heart failure in adults in primary and secondary care [NICE, 2003].

Drug interactions

What key drug interactions should I be aware of for digoxin?

Beta-blockers

Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong atrioventricular (AV) conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.

An increase in plasma digoxin levels has been noted with carvedilol — monitor for signs of digoxin toxicity (confusion, anorexia, nausea, and disturbance of colour vision) when starting, adjusting, or stopping carvedilol.

Calcium-channel blockers

The plasma concentration of digoxin is increased by diltiazem and verapamil and possibly by nifedipine — monitor for signs and symptoms of toxicity.

There is an increased risk of AV block and bradycardia with verapamil.

Amiodarone

The plasma concentration of digoxin is increased by amiodarone — halve the dose of digoxin and monitor for signs and symptoms of toxicity.

Antimicrobials

The plasma concentration of digoxin is increased by itraconazole, macrolide antibiotics, tetracycline, and trimethoprim — monitor for signs and symptoms of toxicity.

St John's wort

The plasma concentration of digoxin may be reduced by St John's wort — advise people taking digoxin that they should not use St John's wort, and that they should check with their pharmacist before using any other over-the-counter medications.

Basis for recommendation

These recommendations are based on guidance on heart failure published by the National Institute for Health and Care Excellence [NICE, 2003]; the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009c]; and Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008].

Warfarin

Warfarin

See the CKS topic on Anticoagulation - oral for a detailed discussion on how to initiate warfarin, how to monitor people who take warfarin, and for other prescribing information on warfarin.

Aspirin

Aspirin

See the CKS topic on Antiplatelet treatment for a detailed discussion on the medicines management of aspirin.

Amiodarone

Amiodarone

Usual maintenance dose

What are the usual maintenance doses of amiodarone?

Amiodarone is usually initiated in secondary care. Primary care practitioners may be expected to continue prescribing amiodarone and monitor the person for adverse effects (depending on locally agreed shared care guidelines).

The usual maintenance dose is 200 mg daily, or less if appropriate.

Basis for recommendation

This information is taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a].

Monitoring

How should I monitor someone taking amiodarone?

Amiodarone is always initiated in secondary care, where the following baseline assessments are performed:

Thyroid function tests.

Liver function tests.

Serum electrolyte and urea measurement.

Chest radiography.

Electrocardiography.

Regular monitoring is required for the following:

Thyroid function tests — every 6 months and for 12 months after discontinuation.

Seek specialist advice if thyroid function tests are abnormal.

Liver function tests — every 6 months.

Serum electrolyte and urea measurement — every 6 months.

Electrocardiography — every 12 months.

The manufacturer recommends annual eye examinations; however, expert opinion suggests that these are only necessary for people with visual symptoms.

Regular monitoring may be performed in primary or secondary care (depending on locally agreed shared care guidelines).

Basis for recommendation

These recommendations are based on published expert opinion [Vanderpump et al, 1996; DTB, 2003; BTA et al, 2006; London and South East Medicines Information Service et al, 2008] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a].

Eye examinations

This recommendation is based on published expert opinion [DTB, 2003].

Adverse effects

What adverse effects are associated with amiodarone?

Nausea, vomiting, and taste disturbance commonly occur with loading doses but resolve with dose reduction.

Pulmonary toxicity

Pulmonary toxicity may present as dyspnoea (which may be severe and unexplained by the current cardiac status), non-productive cough, and deterioration in general health (fatigue, weight loss, and fever). If pulmonary toxicity is suspected, seek immediate specialist advice; the person may require admission.

Thyroid dysfunction

Approximately 4% of people taking maintenance doses of amiodarone may develop hypothyroidism or hyperthyroidism. People taking amiodarone should have their thyroid function checked every 6 months. If thyroid function tests are abnormal, seek specialist advice.

Hepatotoxicity

An asymptomatic increase in liver function test values is common in people taking amiodarone. Persistent elevation of liver function test values greater than 2 to 3 times the upper limit of normal (or twice previously elevated levels) occurs in 1.2% of people taking maintenance doses of amiodarone. Hepatotoxicity is rare, and death caused by severe hepatotoxicity is rarer still. Liver function should be monitored evey 6 months, and treatment with amiodarone should be stopped if severe liver function abnormalities or clinical signs of liver disease (for example jaundice) develop.

Cardiac toxicity

Maintenance doses of amiodarone may cause dose-dependent sinus bradycardia and conduction disturbances.

Visual disturbances

Most people develop corneal microdeposits; these rarely interfere with vision, but drivers may be dazzled by headlights at night. If vision is impaired or if optic neuritis (very rare) or neuropathy occurs, amiodarone must be stopped, to prevent blindness, and expert opinion sought. The manufacturer recommends annual eye examinations; however, expert opinion suggests that these are only necessary for people with visual symptoms.

Neurological symptoms

Amiodarone has been associated with neurological symptoms, such as tremor, ataxia, and (rarely) peripheral neuropathy. These are usually seen with loading doses and improve when maintenance treatment is started. Peripheral neuropathy may occur in people who have been taking amiodarone for a long time.

Skin toxicity

A blue-grey skin discolouration has been reported in approximately 2% of people taking amiodarone. This discolouration occurs in unprotected light-exposed skin and is slowly (and occasionally incompletely) reversible after stopping amiodarone.

Advise the person to:

Shield their skin from light during treatment and for several months after stopping treatment.

Use a wide spectrum sunscreen with a sun protection factor of at least 30 (for example Uvistat® or Sunsense® Ultra).

Basis for recommendation

These recommendations are based on information taken from the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2009a], published expert opinion [DTB, 2003], the British National Formulary [BNF 57, 2009], and an evidence database [Micromedex, 2009].

Drug interactions

What key drug interactions should I be aware of for amiodarone?

Beta-blockers

Only specialists should co-prescribe beta-blockers and amiodarone. Hypotension, bradycardia, ventricular fibrillation, and asystole have been seen in a few people given amiodarone with propranolol, metoprolol, or sotalol.

Calcium-channel blockers

Amiodarone should be avoided or used with caution with diltiazem or verapamil because cardiac depression can occur.

Drugs that prolong the QT interval

Only specialists should co-prescribe drugs that prolong the QT interval. This is because of the risk of additive effects, which may lead to serious and potentially life-threatening torsades de pointes arrhythmias. Examples of drugs that are known to have a high risk of causing QT prolongation include:

Antiarrhythmics, such as sotalol, disopyramide, and quinidine.

Antihistamines, such as astemizole.

Antipsychotics, such as amisulpride, haloperidol, and droperidol.

Simvastatin

Rarely, myopathy and rhabdomyolysis have been reported in people taking amiodarone with high doses of simvastatin. The dose of simvastatin should not exceed 20 mg each day in people taking amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis.

Warfarin

The anticoagulant effects of warfarin are increased by amiodarone. The onset of this interaction may be slow (up to 2 weeks), with the peak effect occurring about 7 weeks after warfarin treatment is started. The dose of warfarin should be reduced by one-third to two-thirds if amiodarone is added. The international normalized ratio should be monitored once a week for the first 7 weeks of concurrent treatment.

Digoxin

Amiodarone increases levels of digoxin because of reduced renal digoxin clearance. The dose of digoxin should be reduced by half, and concentrations of digoxin should be monitored closely in view of potential toxicity.

Grapefruit

People taking amiodarone should not eat grapefruit or drink grapefruit juice. Grapefruit appears to completely inhibit the metabolism of amiodarone to its major active metabolite.

Amiodarone has a long half-life (25–100 days); thus, interactions may occur for some time after drug withdrawal.

Basis for recommendation

These recommendations are based on Stockley's drug interactions: a source book of interactions, their mechanisms, clinical importance and management [Baxter, 2008] and published expert opinion [DTB, 2003].

Sotalol

Sotalol

Dose

What dose of sotalol should I prescribe?

Sotalol is usually initiated and titrated up to an appropriate dose in secondary care. A primary care practitioner may be expected to continue prescribing sotalol and monitor for adverse effects.

The usual maintenance dose of sotalol is 80 mg to 160 mg twice a day.

Basis for recommendation

This recommendation is based on the British National Formulary [BNF 57, 2009].

Adverse effects

What adverse effects are associated with sotalol?

Sotalol may aggravate a preexisting arrhythmia or provoke a new arrhythmia and may cause torsades de pointes. Women may be at increased risk of torsades de pointes. In addition, sotalol may cause similar adverse effects to those of other beta-blockers:

Cold extremities, paraesthesiae, and numbness can occur and are more common in people with peripheral vascular disease. If troublesome, beta-blockers might need to be stopped — this is most likely in people with severe peripheral vascular disease.

Sleep disturbance or nightmares can occur but are less likely with water-soluble beta-blockers such as atenolol, because these drugs are less likely to cross the blood–brain barrier.

Fatigue: an incidence of approximately 18 per 1000 people treated with a beta-blocker has been reported, but in clinical trials, only 0.4% of people stopped taking their beta-blocker for this reason.

Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people on treatment, leading to discontinuation of treatment in 2 people per 1000 person-years. The person should be directly questioned about whether they are having sexual problems because this adverse effect is often not volunteered owing to embarrassment.

Depression has been claimed to be an adverse effect of beta-blockers, but a recent meta-analysis found no significant increased risk of depressive symptoms in people taking beta-blockers.

Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers. A selective beta-blocker is therefore preferred in people with diabetes. Avoid beta-blockers in people who experience frequent hypoglycaemia.

Basis for recommendation

This information is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007e].

Drug interactions

What key drug interactions should I be aware of for sotalol?

Sotalol prolongs the QT interval, and only specialists should co-prescribe drugs that prolong the QT interval. This is because of the risk of additive effects, which may lead to serious and potentially life-threatening torsades de pointes arrhythmias. Examples of drugs that are known to have a high risk of causing QT prolongation include:

Antiarrhythmics, such as amiodarone, disopyramide, and quinidine.

Antipsychotics, such as amisulpride, haloperidol, and droperidol.

Antibiotics, such as erythromycin and clarithromycin.

In addition, sotalol may interact with other drugs (in common with other beta-blockers).

Verapamil and diltiazem

The combination of a beta-blocker and verapamil should not be prescribed in primary care because bradycardia, asystole, severe hypotension, and heart failure can occur.

The combination of a beta-blocker and diltiazem should not be prescribed in primary care because bradycardia and atrioventricular block can occur. Asystole and sudden death have also been reported.

Combining a beta-blocker with either verapamil or diltiazem may be initiated in secondary care.

Class I antiarrhythmics (for example quinidine and flecainide)

The combination of a beta-blocker and a class I antiarrhythmic is not recommended in primary care because bradycardia and myocardial depression can occur. This combination may be initiated in secondary care.

Class III antiarrhythmics (for example amiodarone)

The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure and check for signs of worsening heart failure, as there is an increased risk of bradycardia, atrioventricular (AV) block, and myocardial depression.

Digoxin

Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.

Other drugs that reduce blood pressure (for example angiotensin-converting enzyme inhibitors)

An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

Basis for recommendation

These recommendations are based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2007c; ABPI Medicines Compendium, 2007d; ABPI Medicines Compendium, 2007e; ABPI Medicines Compendium, 2010] and the British National Formulary [BNF 57, 2009].

Evidence

Evidence

Supporting evidence

This section reviews the evidence for drugs used to control heart rate (for example beta-blockers and rate-limiting calcium-channel blockers [diltiazem and verapamil]).

This section does not review the evidence for drugs which control heart rhythm (sotalol, flecainide, or amiodarone) because these drugs are usually initiated under specialist advice in secondary care.

[Lip et al, 2002]

Rate control compared with rhythm control

Evidence on rate control compared with rhythm control

The National Institute for Health and Care Excellence (NICE) found a non-significant difference between rate control and rhythm control in terms of all-cause mortality and quality of life. NICE concluded that a rate-control strategy was more cost-effective than rhythm control but stated that it is unclear in the UK setting whether costs of inadequate anticoagulation would affect this conclusion. Antithrombotic therapy was administered to all people in the rate-control groups, whereas it was given to people in the rhythm-control groups only if the treating physician felt that this was appropriate. Subsequent to the publication of the NICE guidance, CKS identified two randomized controlled trials (RCTs) and a subgroup analysis from a third trial, the results of which are consistent with the NICE conclusions.

The individual studies that NICE identified were the Pharmacological Intervention in Atrial Fibrillation (PIAF), Strategies of Treatment of Atrial Fibrillation (STAF), RAte Control versus Electrical cardioversion for persistent AF (RACE), Atrial Fibrillation Follow up Investigation of Rhythm Management (AFFIRM), and How to Treat Chronic AF (HOT CAFE) studies (5239 participants).

None of the studies found either rate or rhythm control to be inferior in terms of mortality or quality of life.

For people older than 65 years of age or those with coronary artery disease, a significant difference was found in favour of rate control in terms of all-cause mortality (from the AFFIRM trial). However, overall, a nonsignificant difference between rate control and rhythm control was found in terms of all-cause mortality (13.0% compared to 14.6%, p = 0.09).

In people with recurrent atrial fibrillation (AF), compared with rate control, rhythm control was associated with a higher incidence of:

Proarrhythmic events (torsades de pointes: 0.8% with rhythm control compared to 0.2% with rate control, p = 0.007).

QT prolongation (1.9% compared to 0.3%, p =< 0.001).

Bradycardiac events.

Adverse pulmonary events (7.3% compared to 1.7%, p =< 0.001).

Gastrointestinal events (2.7% compared to 2.1%, p =< 0.001).

Other noncardiac adverse events (25.4% compared to 14.0%, p =< 0.001).

In people with recurrent AF, compared with rate control, rhythm control was associated with a higher rate of hospital admission.

STAF study: 54% in the rhythm-control group compared to 26% in the rate-control group, p =< 0.001.

HOT CAFE study: 74% compared to 12%, p =< 0.001.

AFFIRM study: 80% compared to 73%, p =< 0.001.

The rate-control strategy was found to cost $5077 USD less per person than rhythm control (mean follow up 3.5 years).

CKS identified two randomized controlled trials (RCTs) and a subgroup analysis from the AFFIRM trial that compared the effectiveness of rhythm control with that of rate control. The results of these studies are consistent with the NICE conclusions.

A subgroup analysis from the AFFIRM trial compared the effectiveness of rate control with that of rhythm control in 788 people with left ventricular dysfunction [Freudenberger et al, 2007]. At 5-year follow up, there was no significant improvement in mortality, hospitalization, and New York Heart Association class with rhythm control compared with rate control. When the data were analysed by final rhythm status, there was no significant benefit for people in the rhythm control arm.

A small RCT with 221 participants randomized people with hypertension and AF to rate control or rhythm control [Yildiz et al, 2008]. After 3 years of treatment, there was no significant difference between rate control and rhythm control in terms of total mortality and embolic event rates.

A larger study randomized 1376 people with heart failure (left ventricular ejection fraction of 35% or less, and symptoms of congestive heart failure) and a history of AF to rate control or rhythm control [Roy et al, 2008]. After 3 years of treatment, there was no significant difference between the groups for the primary outcome of time to death from cardiovascular causes.

Antiplatelets

Evidence on antiplatelets

Two systematic reviews found evidence that antiplatelets are associated with a non-significant reduction in stroke risk and a significant reduction of a combined outcome of stroke, myocardial infarction (MI), or vascular death.

A Cochrane systematic review (search date: August 2004) identified three randomized controlled trials with 1965 participants which investigated the effectiveness of antiplatelet agents (low-dose aspirin: 75 mg daily, 325 mg daily, or 125 mg every other day) compared with placebo for the prevention of stroke in people with atrial fibrillation (AF) [Aguilar and Hart, 2005a]. The primary outcome was all strokes (ischaemic and hemorrhagic) because it was deemed the most relevant outcome for a disorder for which the main health risk is stroke. The people included in this review were adults with non-valvular AF and no history of stroke or transient ischaemic attack (TIA). The antiplatelet agent used in the included trials was low-dose aspirin. No trials for clopidogrel, ticlopidine, or dipyridamole were identified that met the inclusion criteria. Two of these trials were double blinded, and the third trial was an open-label study. The main results were as follows:

Stroke (all cause)

Pooled results from three RCTs found that low-dose aspirin was associated with a non-significant lower risk of stroke (odds ratio 0.70, 95% CI 0.47 to 1.07).

Stroke, MI, or vascular death

The combined endpoint of stroke, MI, or vascular death was significantly reduced in the antiplatelet treatment group compared with the placebo group (odds ratio 0.71, 95% CI 0.51 to 0.97).

The authors concluded that for the primary prevention of stroke in people with AF, for every 1000 people treated with aspirin for a year, about 10 strokes would be prevented.

There was no difference in the incidence of intracranial bleeding or major extracranial bleeding.

CKS identified one systematic review published after the above Cochrane systematic review.

A systematic review assessed antiplatelet agents for stroke prevention in people with non-valvular AF [Hart et al, 2007]. This review identified one randomized controlled trial that was published after the Cochrane systematic review and also included trials which looked at secondary prevention (unlike the Cochrane systematic review). Pooled results from seven trials with 3990 participants found evidence that aspirin was associated with a non-significant reduction in stroke risk (relative risk 19%, 95% CI –1 to +35). This is consistent with the results of the Cochrane systematic review.

For an evidence summary on combined antiplatelet agents compared with antiplatelets alone, see Combining antiplatelets.

Oral anticoagulation

Evidence on oral anticoagulation compared with placebo

Compared with placebo, oral anticoagulants significantly reduce the risk of stroke by two-thirds in people with atrial fibrillation (AF) with or without a history of stroke or transient ischaemic attack (TIA). Compared with placebo, oral anticoagulants are associated with an increased risk of extracranial bleeding.

A Cochrane systematic review (search date: June 2004) assessed the effectiveness of oral anticoagulants compared with placebo for the prevention of stroke. People included in this review had non-valvular AF and no history of stroke or TIA [Aguilar and Hart, 2005b]. Five trials with 2313 participants that were suitable for inclusion in the review were identified. Pooled data from these trials found that after 1.5 years of treatment:

Oral anticoagulants significantly reduced the risk of ischaemic stroke by about two-thirds compared with placebo (OR 0.34, 95% CI 0.23 to 0.52).

The combined endpoint of all stroke, myocardial infarction, or vascular death was reduced by nearly half in the oral anticoagulant group compared with the placebo group (OR 0.56, 95% CI 0.42 to 0.76).

The rate of stroke in the placebo group was 4% per year.

There was no difference in the incidence of intracranial bleeding or major extracranial bleeding, but the confidence intervals were wide.

Primary prevention of stroke in people with AF: for every 1000 people treated with oral anticoagulants for 1 year, about 25 strokes and about 12 disabling or fatal strokes would be prevented.

A second Cochrane systematic review (search date: June 2003) assessed the effectiveness of oral anticoagulants compared with placebo or no treatment [Saxena and Koudstaal, 2004a]. The people included in this review had prior TIA or stroke. Two trials suitable for inclusion in the review were identified.

Pooled results from two randomized controlled trials with 485 participants found that anticoagulants reduced the odds of having a stroke by about two-thirds compared with placebo (OR 0.36, 95% CI 0.22 to 0.58) or of any vascular event by almost a half (OR 0.55, 95% CI 0.37 to 0.82).

The odds of major extracranial bleeding were increased four-fold in the warfarin group compared with the placebo group (OR 4.32, 95% CI 1.55 to 12.10), but the absolute difference in bleeding rates was small. No intracranial bleeding occurred.

The rate of stroke in the placebo group was 12% per year.

The authors concluded that for the secondary prevention of stroke in people with AF, for every 1000 people treated with oral anticoagulants for a year, 90 vascular events (mainly strokes) would be prevented.

After both Cochrane systematic reviews were published, two systematic reviews were published that assessed the effectiveness of anticoagulation compared with placebo in people with AF.

The first review identified 13 trials with 14,423 participants that compared the effectiveness of aspirin, warfarin, and ximelagatran (not licensed in the UK) as thromboprophylaxis in people with non-valvular AF [Lip and Edwards, 2006]. The results of this systematic review were consistent with the previously published Cochrane systematic reviews.

The second systematic review was written by the same authors as one of the Cochrane systematic reviews and used the same randomized controlled trials as the previously published Cochrane review [Hart et al, 2007]. The results from this systematic review were consistent with the previously published Cochrane systematic reviews.

Antiplatelets compared with oral anticoagulants

Evidence on antiplatelets compared with oral anticoagulants

Oral anticoagulants are more effective than antiplatelets, for preventing stroke or vascular events in people with atrial fibrillation (AF). Oral anticoagulants reduce the risk of stroke, disabling stroke, and other major vascular events for people with AF by about one-third compared with antiplatelets in people without prior stroke or transient ischaemic attack (TIA). For people who have had a stroke or TIA, compared with antiplatelets, oral anticoagulants reduce the risk of stroke by half and the risk of any vascular event by one-third. Compared with antiplatelets, oral anticoagulants are associated with a higher risk of intracranial and extracranial bleeding.

A Cochrane systematic review (search date: June 2006) identified eight randomized controlled trials (RCTs) that assessed the effectiveness of oral anticoagulants (warfarin) compared with aspirin (dosages ranging from 75 mg to 325 mg daily) in people with chronic non-valvular AF without prior stroke or TIA [Aguilar et al, 2007]. The people in this review were followed up after approximately 1.9 years of treatment.

Pooled data from eight RCTs with 9598 participants found evidence that, compared with aspirin, warfarin was associated with a significantly lower risk of:

All stroke (odds ratio [OR] 0.68, 95% CI 0.54 to 0.85).

Ischaemic stroke (OR 0.53, 95% CI 0.41 to 0.68).

Systemic emboli (OR 0.48, 95% CI 0.25 to 0.90).

Pooled data from the same eight trials found no significant differences between aspirin and warfarin for vascular death (OR 0.93, 95% CI 0.75 to 1.15) and all-cause mortality (OR 0.99, 95% CI 0.83 to 1.18).

Compared with placebo, warfarin increased the risk of intracranial haemorrhage two-fold (OR 1.98, 95% CI 1.20 to 3.28).

A Cochrane systematic review (search date: June 2003) investigated the effectiveness of antiplatelet drugs compared with oral anticoagulants for the prevention of stroke in people with prior TIA or ischaemic stroke [Saxena and Koudstaal, 2004b]. Two trials suitable for inclusion in the review were identified (one of aspirin and one of indobufen).

Pooled results from two RCTs with 1371 participants found that, compared with antiplatelet agents, oral anticoagulants significantly reduced the risk of stroke (OR 0.49, 95% CI 0.33 to 0.72) and all vascular events (OR 0.67, 95% CI 0.50 to 0.91).

Major extracranial bleeding complications occurred more often in people taking oral anticoagulants (OR 5.16, 95% CI 2.08 to 12.83), but the absolute difference was small. In one trial, the incidence of major extracranial bleeding was 2.8% per year in the anticoagulant group and 0.9% in the aspirin group. In the other trial, the rate was 0.9% per year in the anticoagulant group and 0% in the aspirin group.

A primary care open-label RCT with 973 participants compared the use of warfarin with low-dose aspirin (75 mg daily) in people 75 years of age or older with atrial fibrillation [Mant et al, 2007b]. People in this study were followed up for 2.7 years. The primary outcomes were fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention-to-treat. The results were presented as percentage risk per year.

Compared with low-dose aspirin, warfarin significantly reduced the risk of stroke (relative risk [RR] 0.46, 95% CI 0.26 to 0.79) and systemic emboli (RR 0.32, 95% CI 0.01 to 3.99).

The authors found no significant difference between aspirin and warfarin for the yearly risk of extracranial haemorrhage (RR 0.87, 95% CI 0.43 to 1.73). However, a third of people randomly assigned to the warfarin treatment did not start treatment or started it but later stopped it, and 17% of people in the aspirin group were also taking warfarin by the end of the study.

For an evidence summary on combined antiplatelets compared with oral anticoagulants, see Combining antiplatelets.

Combining antiplatelets

Evidence on combining antiplatelets

Oral anticoagulants significantly reduce the risk of stroke, non-central nervous system (CNS) embolism, myocardial infarction, and vascular events compared with combined therapy with clopidogrel plus aspirin, without an increase in the risk of bleeding. Some evidence indicates that combined therapy with clopidogrel plus aspirin reduces the risk of major vascular events (stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular causes) compared with aspirin alone; however, combined antiplatelet therapy was associated with a two-fold increase in major bleeding.

Combined antiplatelets compared with anticoagulants

A large non-inferiority trial with 6706 participants assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation for prevention of vascular events [Connolly et al, 2006]. People with atrial fibrillation (AF) and a high risk of stroke were randomized to receive oral anticoagulation therapy or clopidogrel (75 mg per day) plus aspirin (75 mg to 100 mg daily). The primary outcome was a composite of stroke, non-CNS embolism, myocardial infarction, and vascular events. Results were reported as annual risk. This trial was stopped early because of clear evidence of superiority of oral anticoagulation therapy without any increase in the risk of bleeding.

Clopidogrel plus aspirin was associated with a higher risk of stroke, non-CNS embolism, myocardial infarction, and vascular events. The annual incidence of the primary outcomes was 3.9% in the warfarin group and 5.6% in the aspirin plus clopidogrel group (relative risk [RR] 1.44, 95% CI 1.18 to 1.76; p = 0.0003).

There was no difference between the groups in the rate of major haemorrhage (RR 1.10, 95% CI 0.83 to 1.45; p = 0.53), but more minor bleeding occurred with aspirin plus clopidogrel than with warfarin (RR 1.23, 95% CI 1.09 to 1.39; p = 0.0009).

Combined antiplatelets compared with aspirin alone

A post hoc subgroup analysis of 593 participants from the Clopidogrel and aspirin versus aspirin alone for the prevention of stroke in patients with a history of atrial fibrillation (CHARISMA) trial has been published [Hart et al, 2008]. People with a history of AF received a combination of clopidogrel (75 mg daily) plus aspirin (75 mg to 162 mg daily) or aspirin alone (75 mg to 162 mg daily). Compared with aspirin alone, aspirin plus clopidogrel did not significantly reduce the risk of stroke (hazard ratio 1.03; 95% CI 0.49 to 2.1) or all-cause mortality (hazard ratio 1.1, 95% CI 0.6 to 1.9) after 2.3 years of treatment.

A large randomized controlled trial with 7554 participants investigated the hypothesis that clopidogrel plus aspirin may reduce the risk of vascular events in people with AF [ACTIVE Investigators et al, 2009]. People with AF and a high risk of stroke, who were unsuitable for anticoagulant treatment, were randomized to receive aspirin (75 mg to 100 mg daily) plus clopidogrel (75 mg) or aspirin (75 mg to 100 mg daily) plus placebo. The primary outcome was the composite of any major vascular event (stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular causes).

After 3.6 years of treatment, clopidogrel plus aspirin was associated with a significant reduction in major vascular events compared with aspirin alone (relative risk [RR] 0.89, 95% CI 0.81 to 0.98; p = 0.01). This difference was mainly due to a reduced risk of stroke associated with clopidogrel plus aspirin compared with aspirin alone (RR 0.72, 95% CI 0.62 to 0.83; p < 0.001).

Compared with aspirin alone, clopidogrel plus aspirin was associated with a two-fold increase in major bleeding (RR 1.57, 95% CI 1.29 to 1.92; p < 0.001).

The number of people that would need to be treated with aspirin plus clopidogrel for 3.6 years to prevent one vascular event was 42 (NNT 42). The number of people that would need to take clopidogrel plus aspirin for 3.6 years for one person to have one major vascular bleeding event was 42 (NNH 42).

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on the primary care management of Atrial fibrillation, with additional searches in the following areas:

Diagnosis

Assessment

RHYTHM vs. RATE control

Referral criteria

Stroke risk vs. GI bleeding risk

Search dates

Medline and Embase: January 2006 – August 2009

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Atrial Fibrillation/, atrial fibrillation.tw

exp Diagnosis/, exp Diagnosis, Differential/, exp Electrocardiography/, exp Echocardiography/, exp Radiography, Thoracic/, exp Thyroid Function Tests/, exp Hematologic Tests/, blood test$.tw

exp Platelet Aggregation Inhibitors/, exp Aspirin/, exp Warfarin/

exp Anti-Arrhythmia Agents/, exp Calcium Channel Blockers/, exp Verapamil/, exp Diltiazem/, exp Nifedipine/

exp Adrenergic beta-Antagonists/, exp Atenolol/, exp Bisoprolol/, exp Metoprolol/, exp Acebutolol/, exp Nadolol/, exp Oxprenolol/, exp Propranolol/

exp Digoxin/, exp Amiodarone/

exp Stroke/

exp Hemorrhage/

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSH subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

British Heart Foundation

British Cardiovascular Society

European Society of Cardiology

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

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