Atrial fibrillation: current approaches to drug therapy Jaspal Taggar MRCP and Gregory Lip MD, FRCP, FACC, FESC

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1 Drug Atrial review fibrillation : current approaches to drug therapy Jaspal Taggar MRCP and Gregory Lip MD, FRCP, FACC, FESC Effective treatment of atrial fibrillation is now a realistic goal as a result of recent advances in drug therapy. Our Drug review considers the properties of the drugs now available to achieve rhythm and rate control and prevent thromboembolism, followed by sources of further information and the Datafile. (AF) is the most commonly encountered arrhythmia in the population. Importantly, AF increases the risk of ischaemic stroke by up to five times and is associated with increased morbidity and mortality. Thanks to current advances in drug development, however, effective treatment is possible in almost all cases. Pharmacological treatment of AF has two main goals: rate or rhythm control and prevention of thromboembolism. These goals depend upon the clinical subgroups of AF, a classification based on the temporal pattern of the arrhythmia. AF is considered recurrent when a patient develops two or more episodes; these episodes may be paroxysmal if they terminate spontaneously, defined by consensus as within seven days, or persistent if the arrhythmia requires electrical or pharmacological cardioversion for termination (see Table 1). Successful termination of AF does not 48 Prescriber 5 April

2 Terminology Clinical features Pattern Initial event (first symptomatic may or may detected episode) asymptomatic (first detected) not reoccur onset unknown (first detected) Paroxysmal spontaneous termination <7 days, recurrent most often <48 hours Persistent not self-terminating, lasting >7 recurrent days or prior cardioversion Permanent not terminated established ( accepted ) terminated but relapsed no cardioversion attempt Table 1. Classification of atrial fibrillation 1 alter the classification of persistent AF in these patients. Longstanding AF (defined as over a year) not successfully terminated by cardioversion, or when cardioversion is not pursued, is classified as permanent. Regardless of the eventual classification, patients with AF should be assessed for symptomatic and haemodynamic features, which will guide subsequent management, the identification and correction of associated co-morbidities and/or precipitants, and assessment of stroke and thromboembolic risk. In this article we will discuss the common drugs available, with a brief account of their mechanisms of action and side-effects, the newer therapies offering promise but not yet in common use, and a treatment algorithm illustrating a brief overview of management. Drug Interactions Side-effects/caution Class Ia quinidine increased serum digoxin levels; potentiates dosage reduced in hepatic and renal anticoagulant effect of warfarin dysfunction; QTc interval prolonged procainamide increased levels in patients taking H 2 -antagonists, caution in patients with reduced LV function beta-blockers, amiodarone, trimethoprim and quinidine; may increase effect of skeletal muscle relaxants and neuromuscular blockers; ofloxacin inhibits renal tubular secretion of procainamide Class Ic propafenone rifampicin decreases plasma levels; quinidine renal and hepatic dysfunction; increased increases drug effects; increases levels of mortality seen in those with underlying LV beta-blockers, ciclosporin, warfarin and digoxin; dysfunction or CHF; rarely positive ANA CYP4502D6 inhibitors may cause cardiotoxicity titres; reversible flecainide may increase toxicity of other rate-limiting drugs due caution in pre-existing sinus node dysfunction; to additive inotropic effects; CYP4502D6 inhibitors underlying cardiac disease; increases increase serum levels and cardiotoxicity endocardial pacing thresholds; renal or hepatic impairment Class III amiodarone increased levels of theophylline, methotrexate, digoxin, photosensitivity; pulmonary toxicity (3-7%), ciclosporin, beta-blockers and anticoagulants; rare with doses <400mg daily; thyroid additive effect with calcium-channel blockers; and liver dysfunction; pulmonary fibrosis; cimetidine may increase levels caution in patients with severe pulmonary disease; rare optic neuritis sotalol class Ia and other class III agents can enhance K channel blocking effect Table 2. Interactions and side-effects of drugs used for pharmacological cardioversion to sinus rhythm 50 Prescriber 5 April

3 Drug Side-effects Contraindications Comments Beta-blockers bisoprolol, hypotension; bradycardia, heart history of asthma; effective in controlling exercise esmolol, block; bronchospasm; impotence; reversible airway heart rates in physically active nadolol peripheral vasoconstriction; disease; acute stages individuals; drugs of first choice exacerbation of psoriasis of heart failure (NYHA class 3-4) Calcium-channel blockers diltiazem, hypotension; negative inotropic hypotensive patients; effective options in patients verapamil effect; bradycardia; constipation, AV block or brady- in whom beta-blocker use is especially in older people; cardia; acute heart contraindicated or not tolerated flushing, headache, dizziness, failure gingival hyperplasia Cardiac glycosides digoxin narrow therapeutic index; GI renal impairment useful in achieving rate control at upset; lethargy, dizziness and (severe); low or high rest; preference to other agents confusion; cardiac arrhythmias; K levels only in patients with severe digoxin toxicity, especially in LV dysfunction or poorly mobile renal impairment older patients; useful in combination for rate control; reduced efficacy, especially in the setting of sympathetic activation, eg acute heart failure, sepsis, MI Amiodarone photosensitivity; alopecia; thyroid torsades de pointes; useful in patients with heart failure dysfunction; hepatitis; peripheral long QT syndromes; or hypotension neuropathy, musculopathy; interstitial lung cardiac arrhythmias and torsades disease de pointes; numerous drug interactions; pulmonary fibrosis with long-term high doses Table 3. Side-effects and contraindications of common agents used for rate control in atrial fibrillation Rhythm control Rhythm control is a strategy used in the management of recurrent AF, which includes those with paroxysmal and persistent AF. In paroxysmal AF, the objective of drug therapy is a reduction of paroxysms and long-term maintenance of sinus rhythm. Thus, appropriate use of antiarrhythmic drugs is recommended in addition to antithrombotic therapy. In some patients, paroxysms may be so short and/or infrequent that antiarrhythmic drugs are not needed; alternatively, some selected patients find a pill in the pocket strategy to be useful, whereby antiarrhythmic drugs are only used as and when paroxysms occur. However, many require the long-term prophylactic use of antiarrhythmic drugs to suppress recurrences of AF, and patients should be made aware that these drugs do not abolish AF but merely suppress the arrhythmia. In persistent AF, the objective of management is cardioversion to sinus rhythm. While there are plausible benefits for the conversion and maintenance of sinus rhythm with a rhythm-control strategy, recent randomised trials have failed to demonstrate the superiority of this approach over a rate-control strategy. Conversion to sinus rhythm is best considered in symptomatic patients who have recent-onset (less than one year) persistent AF, where there is no underlying structural heart disease or where AF was initially due to a precipitant, eg thyroid disease or fever, which has been corrected. 52 Prescriber 5 April

4 Co-morbid condition Drug options for rate control Comments Hypertension beta-blockers, calcium-channel these agents also help in controlling blood pressure blockers Ischaemic heart disease beta-blockers, calcium-channel provide IHD symptom relief blockers COPD/bronchospasm calcium-channel blockers, beta-blockers are avoided in the presence of amiodarone evidence of hyper-reactive airways: this is tested by performing lung function tests; underlying interstitial disease could worsen with amiodarone: this needs to be ruled out and pulmonary functions monitored regularly if necessary Thyrotoxicosis nonspecific beta-blocker helps control thyrotoxic symptoms Postmyocardial infarction beta-blockers prognostic benefits in MI patients amiodarone minimal negative inotropic effects, especially in patients with acute heart failure Heart failure (stable, digoxin reduced morbidity and rehospitalisations; however, chronic) no prognostic benefits amiodarone beta-blockers minimal negative inotropic effect beneficial in chronic stable heart failure due to systolic dysfunction, after optimisation on standard heart failure therapies Table 4. Rate control agents of choice in patients with atrial fibrillation and associated co-morbidities Some pharmacological agents are capable of achieving cardioversion and maintenance of sinus rhythm. The choice of agent depends on factors such as the presence of underlying structural heart disease, cardiac function and other co-morbidities. Broadly speaking, class Ic agents such as flecainide and propafenone (Arythmol) are used in those without underlying structural or functional heart disease, while amiodarone is employed in those with heart failure or other structural heart disease. Cardioversion is less likely to be successful in those with underlying valve disease, uncontrolled hypertension, poor left ventricular function and long (over 12 months) duration of AF. Urgent cardioversion often requires intravenous administration of antiarrhythmics in an inhospital setting with ECG monitoring. In subjects where rapid cardioversion is not an issue, oral flecainide or propafenone can be used, the basis for pill in the pocket management. Digoxin is no better than placebo for cardioversion of AF and is not a good drug for paroxysmal AF: there is evidence for an increase in paroxysms that are more sustained when digoxin is used. Table 2 lists the interactions and side-effects of drugs used for cardioversion to sinus rhythm. Rate control In patients with permanent AF, the objective of management is appropriate heart rate control and prevention of thromboembolism. Table 3 provides details of side-effects and contraindications of drugs commonly used for rate control in AF. The choice of rate-controlling agents is determined by co-morbid conditions, tolerability, physical activity and patient preference. Table 4 illustrates a few examples of co-morbid conditions where certain rate-control agents may be preferred. Prescriber 5 April

5 High risk previous ischaemic stroke or TIA or thromboembolic event age 75 years with hypertension, diabetes or vascular disease* clinical evidence of valve disease or heart failure; impaired left ventricular function on echocardiography Treatment give warfarin (target INR 2-3) if no contraindications and possible in practice Moderate risk age 65 years with no high-risk factors age <75 years with hypertension, diabetes or vascular disease* Treatment either warfarin (INR 2-3) or aspirin mg daily; owing to lack of sufficient clear-cut evidence, treatment may be decided on an individual basis, and the physician must balance the risks and benefits of warfarin versus aspirin; as stroke risk factors are cumulative, warfarin may (for example) be used in the presence of 2 or more risk factors; referral and echocardiography may help in cases of uncertainty Low risk age <65 years with no moderate- or high-risk factors Treatment give aspirin mg daily assess risk, and reassess regularly risk factors are not mutually exclusive, and are additive in producing a composite risk *vascular disease peripheral or coronary artery disease echocardiogram not needed for routine risk assessment but refines clinical risk stratification in cases of moderate or severe left ventricular dysfunction and valve disease; a large atrium per se is not an independent risk factor on multivariate analysis thyrotoxicosis: since the incidence of thromboembolic events in patients with thyrotoxicosis appears similar to other aetiologies of AF, antithrombotic therapies should be chosen based on the presence of validated stroke risk factors Table 5. High-, moderate- and low-risk groups and guidelines for the use of antithrombotic therapy in nonvalvular atrial fibrillation 3 Digoxin monotherapy is not a good drug for rate control, as it essentially controls the resting heart rate but not the rate during exercise or in conditions of Factor history of previous bleeding drugs co-morbidity poor compliance psychosocial trauma Examples GI blood loss, epistaxis, haematuria NSAIDs, drugs potentiating warfarin action heart failure, liver disease poor cognition or lack of support alcohol abuse, psychiatric disorders falls, especially older people Table 6. Factors that increase the risk of bleeding high catecholamine drive, such as fever or heart failure. More often, digoxin is used as an adjunct to betablocker or rate-limiting calcium channel blocker therapy and tends only to be used as first-line therapy in patients with acute heart failure or sedentary lifestyle, eg immobile older patients. Antithrombotic therapy AF leads to increased atrial thrombus formation, which is one of the main pathophysiological mechanisms underlying the morbidity and mortality associated with AF. The risk of having a stroke in patients with AF is not homogeneous, and is increased further with the presence of other risk factors, so that high-, moderate- and low-risk categories can be identified (see Table 5). Treatment should be tailored based on the individual patient s risk category for having a stroke and the likelihood of complications from anticoagulation. The risk-benefit assessment should also include the risk of haemorrhage and co-morbidities (see Table 6). 54 Prescriber 5 April

6 Drug Mechanism of action Contraindications/ Interactions side-effects Warfarin inhibits hepatic synthesis of documented hypersensitivity; griseofulvin, carbamazepine, vitamin K-dependent severe liver or kidney disease; phenytoin, rifampicin, coagulation factors; target INR bleeding tendency colestyramine, colestipol, range of 2-3 vitamin K, spironolactone, oral contraceptives and sucralfate decrease anticoagulant effects; oral antibiotics, salicylates, sulphonamides, steroids, antifungals, sulphonylureas, allopurinol, metronidazole and phenytoin increase anticoagulation effects Aspirin inhibits platelet aggregation by bleeding diathesis; previous GI antiplatelet drugs, NSAIDS and irreversible cyclo-oxygenase bleed, active bleeding or steroids increase bleeding; acetylation and decreased hypersensitivity to NSAIDs decreased effect of uricosurics thromboxane A 2 levels are contraindications Clopidogrel inhibits ADP binding to platelet as above; an alternative to causes increased risk of receptor preventing platelet aspirin in those who are bleeding when used with other aggregation intolerant of aspirin; gastric antiplatelet drugs or NSAIDs side-effects similar to aspirin; neutropenia, aplastic anaemia Table 7. Properties of oral antithrombotic agents used in atrial fibrillation Anticoagulation is mainly based on the use of antiplatelet agents, such as aspirin or clopidogrel (Plavix), or vitamin K antagonists, usually warfarin (see Table 7). Choice of therapy depends on risk stratification, ability to adhere to a medication schedule, cognitive state, safety and mobility and risk of GI bleeding. Unfractionated heparin and low-molecular-weight heparin (LMWH) are options, especially when oral antithrombotic therapy is impossible, eg postsurgery, swallowing difficulties, etc; inadequate, eg immediate anticoagulation needed or warfarin loading; or contraindicated, eg first and last trimester of pregnancy. Heparin acts by augmenting antithrombin III activity and preventing conversion of fibrinogen to fibrin. More evidence for LMWH, which reduces Factor Xa levels, is still awaited in AF populations, though fractionated heparin is considered to be as efficacious as unfractionated heparin. Newer therapies The need for more effective and less toxic antiarrhythmic drugs has lead to the development of new agents. For example, ibutilide is now in use in the USA as an intravenous antiarrhythmic agent that is effective in cardioverting AF to sinus rhythm; the most significant adverse effect is the induction of polymorphic ventricular tachycardia or torsades de pointes. Dofetilide is another promising agent, available as both intravenous and oral preparations and used for cardioverting AF, with adverse effects similar to that of ibutilide. Azimilide shows early promise in preventing attacks of paroxysmal AF. Of the antithrombotic drugs, ximelagatran is an effective antithrombotic therapy in AF. It was the first oral direct thrombin inhibitor, but increased risk of hepatic toxicity led to withdrawal from clinical trials. However, this has led to the development of new oral direct thrombin inhibitors that have now entered phase 3 clinical trials, the results of which are eagerly anticipated. Conclusion The evidence for the pharmacological treatment of patients with AF is strong and the benefits are established. Prescriber 5 April

7 Patient with AF Is it AF? Confirm and document assess for underlying cause and associated complications in acute situations, ensure haemodynamic stability Acute AF Chronic AF Haemodynamic instability urgent cardioversion Haemodynamic stability may be self-limiting anticoagulate with iv heparin ± warfarin treat associated complications like heart failure consider rate or rhythm control Paroxysmal AF objective is reduction of paroxysms and to maintain sinus rhythm antithrombotic therapy in resistant cases consider nonpharmacological methods Sustained AF Persistent AF objective is cardioversion to sinus rhythm anticoagulate patient consider antiarrhythmic therapy to maintain sinus rhythm Permanent AF objective is heart rate control antithrombotic therapy warfarin or aspirin rate-control drugs in resistant cases consider nonpharmacological methods Figure 1. Recommended management of atrial fibrillation Thanks to advances in drug therapeutic options, treating patients with AF effectively is now a realistic goal. With further clinical trials underway involving both antithrombotic and antiarrhythmic therapies, the future looks promising. References 1. National Collaborating Centre for Chronic Conditions. : national clinical guidelines for management in primary and secondary care. Royal College of Physicians, Lip GYH, Lim HS. and stroke prevention. Lancet Neurology 2007;6: Lip GYH, Tse HF. Management of atrial fibrillation. Lancet 2007;370: Dr Taggar is a research fellow in cardiology and Gregory Lip is consultant cardiologist, professor of cardiovascular medicine and director of the Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham Prescriber 5 April

8 Datafile Resources Further reading National Institute for Health and Clinical Excellence. The management of atrial fibrillation. Clinical guideline 36. June CG036niceguideline.pdf. Groups and organisations National Heart Forum, Tavistock House South, Tavistock Square, London WC1H 9LG. Tel: , fax: , website: Produces policy documents, reports, teaching resources and a catalogue of key resources on coronary heart disease prevention. British Heart Foundation, 14 Fitzhardinge Street, London W1H 6DH. Tel: , fax: , website: Produces books, pamphlets, videos, posters and factsheets for patients and health professionals. Chest, Heart and Stroke Scotland, 65 North Castle Street, Edinburgh EH2 3LT. Tel: , advice line: am-4.30pm Monday to Friday, website: Produces books, pamphlets and videos. Heart UK, 7 North Road, Maidenhead, Berkshire SL6 1PE. Tel: , fax: , ask@heartuk.org.uk, website: Produces leaflets, booklets and factsheets. Primary Care Cardiovascular Society, 36 Berrymede Road, London W4 5JD. Tel: , fax: , office@pccs.org.uk, website: Provides meetings and a newsletter for general practitioners. Useful websites Patient UK: Information leaflets: Atrial Fibrillation and Atrial Fibrillation and Warfarin. Bandolier atrial fibrillation: bandolier/booth/booths/af.html. This site compiles the best evidence available about AF and heart failure. Contain stories from Bandolier, plus abstracts of systematic reviews, meta-analyses or other studies about AF. Atrial Fibrillation resources for patients: www. a-fib.com. Internet resource site written from a patient s point of view. Includes disease information, FAQs, discussion group and links. Drugs used in atrial fibrillation Drug Available as Form/strength Adult dosage Cost 1 Class I disopyramide Rythmodan 100mg, 150mg caps mg daily in divided doses Rythmodan Retard 250mg sust-rel tabs mg twice daily disopyramide 100mg, 150mg caps mg daily in divided doses flecainide Tambocor 50mg, 100mg tabs supraventricular arrhythmias: flecainide 50mg, 100mg tabs mg twice daily mexiletine Mexitil 50mg, 200mg caps mg 3-4 times daily propafenone Arythmol 150mg, 300mg tabs 300mg twice daily NHS cost of 28 days treatment at usual maintenance dosage. Prices MIMS, Drug Tariff February Prescriber 5 April

9 Datafile Drugs used in atrial fibrillation (cont.) Drug Available as Form/strength Adult dosage Cost 1 Class II Noncardioselective beta-blockers nadolol Corgard 80mg tabs mg daily oxprenolol Trasicor 20mg, 40mg, 80mg tabs mg daily in 2 or divided doses propranolol Syprol 5mg, 10mg, 50mg/5ml soln 10-40mg 3 or 4 times daily propranolol 10mg, 40mg, 80mg, 160mg tabs sotalol Beta-Cardone 40mg, 80mg, 200mg tabs mg daily in 2 divided Sotacor 80mg, 160mg tabs doses sotalol 160mg tabs mg daily Cardioselective beta-blockers acebutolol Sectral 100mg, 200mg caps mg daily in 2 or mg tabs divided doses atenolol Tenormin 25mg, 100mg tabs mg daily 6.50 (100mg) (50mg) Tenormin LS 50mg tabs Tenormin Syrup 25mg/5ml syrup atenolol 25mg, 50mg, 100mg tabs 29p metoprolol Lopresor 50mg, 100mg tabs 50mg 2 or 3 times daily metoprolol 50mg, 100mg tabs Class III amiodarone Cordarone X 100mg, 200mg tabs 200mg daily following initial 7.27 amiodarone 100mg, 200mg tabs stabilisation 1.31 Class IV verapamil Zolvera 40mg/5ml oral solution verapamil 40mg, 80mg, 120mg, 160mg tabs Cardiac glycoside digoxin Lanoxin 62.5µg, 125µg, 250µg tabs µg daily 45p Lanoxin-PG Elixir 50µg/ml elixir digoxin 62.5µg, 125µg, 250µg tabs 1.47 (250µg) (125µg) 1 NHS cost of 28 days treatment at usual maintenance dosage. Prices MIMS, Drug Tariff February Prescriber 5 April