Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta®, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Nonchannel drug targets in atrial fibrillation

Atrial fibrillation (AF) is the most common clinical arrhythmia and one of the most important factors for ischemic stroke. In general, AF is treated with "channel-blocking drugs" to restore sinus rhythm and warfarin is recommended in the majority of patients to prevent atrial thrombus formation and thromboembolic events. In the recent years, a tremendous amount has been learned about the pathophysiology and molecular biology of AF. Thus, pharmacologic interference with specific signal transduction pathways with "non-channel-blocking drugs" appears promising as a novel antiarrhythmic approach to maintain sinus rhythm and to prevent atrial clot formation. Therefore, this review will highlight some novel "nonchannel drug targets" for AF therapy.     

Atrial fibrillation: diagnosis and treatment

Atrial fibrillation is the most common cardiac arrhythmia. It impairs cardiac function and increases the risk of stroke. The incidence of atrial fibrillation increases with age. Key treatment issues include deciding when to restore normal sinus rhythm, when to control rate only, and how to prevent thromboembolism. Rate control is the preferred management option in most patients. Rhythm control is an option for patients in whom rate control cannot be achieved or who have persistent symptoms despite rate control. The current recommendation for strict rate control is a resting heart rate of less than 80 beats per minute. However, one study has shown that more lenient rate control of less than 110 beats per minute while at rest was not inferior to strict rate control in preventing cardiac death, heart failure, stroke, and life-threatening arrhythmias. Anticoagulation therapy is needed with rate control and rhythm control to prevent stroke. Warfarin is superior to aspirin and clopidogrel in preventing stroke despite its narrow therapeutic range and increased risk of bleeding. Tools that predict the risk of stroke (e.g., CHADS2) and the risk of bleeding (e.g., Outpatient Bleeding Risk Index) are helpful in making decisions about anticoagulation therapy. Surgical options for atrial fibrillation include disruption of abnormal conduction pathways in the atria, and obliteration of the left atrial appendage. Catheter ablation is an option for restoring normal sinus rhythm in patients with paroxysmal atrial fibrillation and normal left atrial size. Referral to a cardiologist is warranted in patients who have complex cardiac disease; who are symptomatic on or unable to tolerate pharmacologic rate control; or who may be candidates for ablation or surgical interventions.     

Antithrombotic therapy in atrial fibrillation: ximelagatran,an oral direct thrombin inhibitor

The oral direct thrombin inhibitor ximelagatran (Exanta?, AstraZeneca) is rapidly absorbed, is efficiently bioconverted to the active form, melagatran (AstraZeneca) and has shown efficacy and relative safety as an anticoagulant for prophylaxis and therapy of thromboembolism. Two Phase III trials, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF V), have tested the hypothesis that oral ximelagatran, administered 36 mg twice daily without coagulation monitoring or dose adjustment, prevents stroke and systemic embolism at least as effectively as adjusted-dose warfarin (international normalized ratio, 2.0–3.0) in patients with nonvalvular atrial fibrillation. Both were randomized, multicenter trials (n > 3000 per trial) with blinded end-point assessment. The open-label SPORTIF III trial confirmed the noninferiority of ximelagatran versus warfarin. Publication of the full results from SPORTIF V is pending.     

Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor

The oral direct thrombin inhibitor ximelagatran (Exanta, AstraZeneca) is rapidly absorbed, is efficiently bioconverted to the active form, melagatran (AstraZeneca) and has shown efficacy and relative safety as an anticoagulant for prophylaxis and therapy of thromboembolism. Two Phase III trials, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF V), have tested the hypothesis that oral ximelagatran, administered 36 mg twice daily without coagulation monitoring or dose adjustment, prevents stroke and systemic embolism at least as effectively as adjusted-dose warfarin (international normalized ratio, 2.0-3.0) in patients with nonvalvular atrial fibrillation. Both were randomized, multicenter trials (n > 3000 per trial) with blinded end-point assessment. The open-label SPORTIF III trial confirmed the noninferiority of ximelagatran versus warfarin. Publication of the full results from SPORTIF V is pending.     

Ximelagatran for stroke prevention in atrial fibrillation

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.     

Preventable stroke and stroke prevention

Stroke is a major cause of death and disability in the world. The main causes of stroke are atherothromboembolism and cardiogenic embolism. The main causal and treatable risk factors for atherothromboembolic ischemic stroke are increasing blood pressure (BP), increasing cholesterol, cigarette smoking and diabetes; and the main risk factors for cardiogenic ischemic stroke are atrial fibrillation (AF) and ischemic heart disease. Strategies to reduce the incidence of stroke include prevention of first-ever and recurrent stroke, and treatment of patients with acute stroke to reduce death and disability. The two main strategies of stroke prevention are the 'population' (or 'mass') approach and the 'high risk' approach. The 'population' approach aims to reduce stroke by lowering the prevalence and mean level of causal risk factors in the community, by means of public education and government legislation. The 'high risk' approach aims to reduce stroke by identifying individuals at high risk of stroke, and lowering their risk by means of optimal medical therapies. Level 1 evidence from randomized controlled trials indicates that effective treatments for high risk patients include control of causal risk factors (lowering BP, lowering blood cholesterol), antithrombotic therapy (antiplatelet therapy with aspirin, clopidogrel, or the combination of aspirin and dipyridamole for patients in sinus rhythm, and anticoagulation with warfarin or ximelagatran for patients in AF) and, where appropriate, carotid revascularization for patients with severe carotid stenosis.     

Stroke risk, cholesterol and statins.

The natural statins should be used as first line agents in the prevention of stroke. The effects of the synthetic statins on the prevention of coronary events and stroke have not been reported at this time. The National Stroke Association's Stroke Prevention Advisory Board has prepared a consensus statement on risk reducing intervention. The Board identified hypertension, MI, atrial fibrillation, hyperlipidemia and asymptomatic carotid artery stenosis (60% to 99% occlusion) as proven stroke risk factors. The Board's recommendations for the prevention of a first stroke are: 1. Hypertension should be treated with lifestyle, pharmacologic and multidisciplinary management strategies. 2. Aspirin post MI and warfarin (international normalized ratio, 2 to 3) for patients with atrial fibrillation, left ventricular thrombus or significant left ventricular dysfunction. Statin agents should be used post MI. 3. Atrial fibrillation patients age 75 or older should be treated with warfarin. Younger patients 65 to 75 with atrial fibrillation and risk factors should be treated with warfarin [corrected]. Younger patients 65 to 75 with atrial fibrillation without risk factors should be treated with warfarin or aspirin [corrected]. 4. Patients with hyperlipidemia and coronary artery disease should be on statin agents. 5. Carotid endarterectomy is recommended for asymptomatic carotid stenosis (60% to 99%) when surgical morbidity and mortality are less than 3%. 6. Adherence to a low-fat diet, smoking avoidance, mild alcohol use, and physical activity should follow published guidelines.     

Potential role of oral anticoagulants in the treatment of patients with coronary artery disease: focus on dabigatran

The pharmacologic management of patients with high-risk coronary artery disease consists of aspirin and a P2Y₁₂ receptor inhibitor. Chronic oral anticoagulation with warfarin is the major treatment strategy to attenuate thromboembolism or stroke in patients with deep vein thrombosis, pulmonary embolism, heart failure and atrial fibrillation. A substantial percentage of the latter group of patients have coronary artery disease and may require stenting with long-term dual antiplatelet therapy in addition to therapy with warfarin to reduce arterial ischemic events in addition to stroke. These new oral anticoagulants have been developed for long-term therapy to overcome the limitations of warfarin. Dabigatran is a direct thrombin inhibitor and its role in patients with acute coronary syndrome is being explored.     

The increasing need for anticoagulant therapy to prevent stroke in patients with atrial fibrillation

Ischemic stroke, a major complication of atrial fibrillation (AF), is believed to result from atrial thrombus formation caused by ineffective atrial contraction. Oral anticoagulant therapy effectively reduces the risk of ischemic stroke in patients with AF; this therapy is recommended for patients with any frequency or duration of AF and other risk factors for stroke, such as increased age (>75 years), hypertension, prior stroke, left ventricular dysfunction, diabetes, or heart failure. Recently published data comparing rate-control and rhythm-control strategies in AF emphasized the importance of maintaining an international normalized ratio higher than 2.0 during warfarin therapy and the need for continuing anticoagulant therapy to prevent stroke in high-risk patients, even if the strategy is rhythm control. Hemorrhagic complications can be minimized by stringent control of the international normalized ratio (particularly in elderly patients) and appropriate therapy for comorbidities such as hypertension, gastric ulcer, and early-stage cancers. Undertreatment of patients with AF is a continuing problem, particularly in the elderly population. Patients perceived as likely to be noncompliant, such as the functionally impaired, are less likely to receive warfarin therapy. However, stroke prevention with anticoagulants is cost-effective and improves quality of life, despite the challenges of maintaining appropriate anticoagulation with monitoring and warfarin dose titration. New medications in development with more predictable dosing and fewer drug-drug interactions may reduce the complexities of achieving optimal anticoagulation and increase the practicality of long-term anticoagulant therapy for patients with AF at risk of stroke.     

Acute anticoagulation adjustment in patients with atrial fibrillation at risk for stroke: approaches, strategies, risks and benefits

The acute management of anticoagulation in patients with atrial fibrillation to prevent stroke and other thromboembolic complications includes the use of individualized strategies tailored to the patient and based on the situation (cardioversion, surgeries, dental procedures, cardiac interventions, other invasive procedures and initiation of, or adjustment to, warfarin dosing). The vast range of choices can cause confusion and few randomized controlled clinical trials in this area provide adequate guidance. Chronic anticoagulation management is more straightforward since clinical evidence is ample, randomized clinical trial data provides cogent informaiton and guidelines have been established. Acute management of anticoagulation in patients with atrial fibrillation to prevent thromboembolic complications is often unrecognized but is emerging as a crucial, but challenging, and increasingly complex aspect of the care of patients with atrial fibrillation. This review addresses issues regarding such patients who may be at risk for stroke and require acute adjustments of anticoagulation (in light of, or in lieu of, chronic anticoagulation). Several promising new strategies are considered in light of established medical care. This analysis provides practical recommendations based on available data and presents results from recent investigations that may provide insight into future strategies.     

Acute anticoagulation adjustment in patients with atrial fibrillation at risk for stroke: approaches,strategies, risks and benefits

The acute management of anticoagulation in patients with atrial fibrillation to prevent stroke and other thromboembolic complications includes the use of individualized strategies tailored to the patient and based on the situation (cardioversion, surgeries, dental procedures, cardiac interventions, other invasive procedures and initiation of, or adjustment to, warfarin dosing). The vast range of choices can cause confusion and few randomized controlled clinical trials in this area provide adequate guidance. Chronic anticoagulation management is more straightforward since clinical evidence is ample, randomized clinical trial data provides cogent informaiton and guidelines have been established. Acute management of anticoagulation in patients with atrial fibrillation to prevent thromboembolic complications is often unrecognized but is emerging as a crucial, but challenging, and increasingly complex aspect of the care of patients with atrial fibrillation. This review addresses issues regarding such patients who may be at risk for stroke and require acute adjustments of anticoagulation (in light of, or in lieu of, chronic anticoagulation). Several promising new strategies are considered in light of established medical care. This analysis provides practical recommendations based on available data and presents results from recent investigations that may provide insight into future strategies.     

New blood thinner offers first potential alternative in 50 years: ximelagatran

Traditional anticoagulants employed in the treatment of thrombosis include the injectable heparins and oral warfarin. Though effective, these traditional agents are fraught with limitations in their ease of use in the clinical setting. Warfarin, for example, has many pharmacokinetic properties and food-and-drug interactions that result in unpredictable patient response and the need for expensive and time-consuming monitoring of coagulation status. Ximelagatran is a novel, promising, orally active, direct thrombin inhibitor currently in development that, for the first time in 50 years, offers a potential alternative to the mainstay oral agent "warfarin." Advantages of ximelagatran over warfarin include predictable pharmacokinetics and pharmacodynamics, a broad therapeutic window, no routine anticoagulant monitoring, no clinically significant drug interactions, and fixed-dose administration. Ximelagatran has been evaluated for thromboprophylaxis following orthopedic surgery, acute treatment and secondary prevention of venous thrombosis, stroke prevention in atrial fibrillation, and acute coronary syndromes. Results of clinical trials suggest that ximelagatran is equally or more efficacious than warfarin and/or low-molecular-weight heparin therapy without increasing rates of minor or major bleeding. Although postmarketing surveillance will provide the final test of this drug, the future looks promising for addition of a new anticoagulant with the potential to provide excellent efficacy, predictable response, and reduced adverse effects. Pending regulatory approval, ximelagatran may help overcome barriers to appropriate anticoagulant therapy, thereby decreasing morbidity and mortality associated with thrombotic diseases.     

Atrial Fibrillation: Maintaining Stability of Sinus Rbythm or Ventricular Rate Control? The Need for Prospective Data: The PIAF Trial

Atrial fibrillation is one of the most commonly encountered clinical arrhythmias. Different treatment options for this rhythm disorder exist with the electrical and/or pharmacological cardioversion to sinus rhythm with subsequent antiarrhythmic drug therapy to prevent recurrences being one of the primary therapeutic goals. Another alternative, however, is represented by the control of the ventricular rate in patients with persistent atrial fibrillation. The question of which of these two strategies should be preferred in the majority of patients with atrial fibrillation has not been studied in a prospective way. Given the background of conflicting data with respect to the prognostic impact of atrial fibrillation and of the increasing evidence concerning the risks of antiarrhythmic drug treatment in atrial fibrillation, a prospective multicenter trial has been initiated to compare these two therapeutic alternatives prospectively. Patients will be randomly assigned to cardioversion with subsequent antiarrhythmic drug therapy to prevent recurrent atrial fibrillation or to a therapy aiming exclusively at control of the ventricular rate during persistent atrial fibrillation. All patients will receive anticoagulation by means of warfarin (target INR 2.5-3.5) to prevent thromboembolic complications. The rationale and the design of the PIAF trial (Pharmacological Intervention in Atrial Fibrillation) are discussed below. The pilot phase of this study has begun patient enrollment in the spring of 1995.     

Anticoagulant therapy for atrial fibrillation. Recommendations from major studies.

The role of antithrombotic therapy in reducing thromboembolic complications in patients with chronic atrial fibrillation has been clarified by the results of four major randomized and placebo-controlled trials. Patients with rheumatic heart disease complicated by atrial fibrillation should receive long-term warfarin therapy to reduce the risk of stroke unless an absolute contraindication exists. Patients with nonrheumatic atrial fibrillation should also be treated with low-dose warfarin therapy, especially if high-risk features for thromboembolism exist. In patients who have contraindications to warfarin therapy and in young patients with lone atrial fibrillation or paroxysmal atrial fibrillation, therapy with 325 mg of aspirin a day is preferred. Ongoing trials directly comparing aspirin and warfarin will provide additional insight into the optimal role of these antithrombotic agents in patients with atrial fibrillation.     

ATRIAL FIBRILLATION,THROMBOEMBOLISM AND ANTITHROMBOTIC THERAPY

Atrial fibrillation is the commonest sustained disorder of cardiac rhythm and is associated with increased risk of stroke and thromboembolic events. Warfarin (dose-adjusted to a target INR of 2.0-3.0) has been well established to reduce this risk of stroke by 68% (95% CI 50-79%), while aspirin provides a risk reduction of 21% (95% CI 0-38%). Nevertheless, warfarin confers a risk of bleeding and the inconvenience of regular monitoring checks, while aspirin seems effective only for certain low-risk subgroups. Thus there have been strenuous efforts to improve thromboprophylaxis in atrial fibrillation, by using low-intensity anticoagulation regimens, combination antiplatelet therapy and refinement of risk stratification strategies. Attempts at using a low-intensity, fixed-dose warfarin regimen have, however, been disappointing. For now, a strategy of risk stratification should be adopted to identify highest risk patients with atrial fibrillation who would benefit from anticoagulation.     

New anticoagulants

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.     

Risk of Complications of Atrial Fibrillation

Atrial fibrillation is associated with three major risk of complications: thromboembolism, hemodynamic compromise, and arrhythmogenesis. In patients with chronic atrial fibrillation the incidence of embolization is about 5% per year. The risk of embolism and in particular of stroke can be reduced by warfarine anticoagulation. Aspirin is generally less effective than warfarin, although it is probably more effective than placebo. The hemodynamic complications which may occur during atrial fibrillation are mainly due to the loss of effective atrial contraction, the irregular ventricular rhythm, and the possible excessively rapid ventricular rate. Sudden death is a recognized manifestation of Wolff-Parkinson-White syndrome and is considered to be precipitated by atrial fibrillation in the majority of patients. Torsades de pointes is perhaps the most widely recognized proarrhythmia associated with treatment of atrial fibrillation, especially with 1A antiarrhythmic drugs and sotalol. The chronic treatment with type 1C drugs in 3.5%–5% of patients may induce atrial flutter with 1:1 conduction with significant hemodynamic compromise.     

Rhythm or rate control in atrial fibrillation: insights from the randomized controlled trials

Pharmacologic treatment remains the mainstay of therapy in patients with atrial fibrillation for the maintenance of normal sinus rhythm. Initial therapy of atrial fibrillation is often directed toward the maintenance of sinus rhythm by means of cardioversion and the use of antiarrhythmic drugs. Heart rate control is often only pursued when rhythm control fails. Four randomized controlled trials have carefully evaluated the yield of these two treatment strategies as the initial approach to patients with paroxysmal or persistent atrial fibrillation. In essence, all four trials demonstrated that an initial strategy of rate control is equally effective compared to the rhythm control approach in terms of clinically important outcome measures including mortality, stroke prevention, or quality of life. Accordingly, rate control can be considered as an initial approach to therapy in patients with paroxysmal or persistent atrial fibrillation. The four randomized trials clearly demonstrate that continuous anticoagulation is mandatory in all patients with atrial fibrillation and risk factors for stroke, irrespective of the initial therapeutic approach of rhythm or rate control.     

Radiofrequency ablation in the pulmonary veins for paroxysmal, drug-resistant atrial fibrillation.

For select individuals with chronic, drug-resistant, paroxysmal atrial fibrillation, who have failed pharmacologic suppression or mechanical cardioversion, radiofreqency ablation of ectopic foci in and around the ostia of the pulmonary veins can restore normal sinus rhythm, prevent recurrence of the arrhythmia, and improve the quality of life. Radiofrequency ablation of these sites is an evolving process as improvements are made in the catheters and procedure. Major complications include pulmonary vein stenosis, stroke, and cardiac tamponade.