Preventing strokes in atrial fibrillation: New answers to old questions

From the State University of New York Health Sciences Center, Stony Brook

Atrial fibrillation is the most common sustained arrhythmia encountered in clinical practice, affecting approximately 2 million people in the United States alone.1 The risk of developing atrial fibrillation increases with age. Although its incidence in the fifth decade of life is only 0.5%, it increases to 4% by the seventh decade and to almost 9% by the eighth decade.2 In industrialized nations, the most common predisposing factor to atrial fibrillation is hypertension, with factors such as atherosclerotic heart disease, myocardial infarction, and cardiomyopathy playing lesser roles. In the developing world, rheumatic valvular disease outweighs other predisposing causes.

Atrial fibrillation is typically characterized by an irregularly irregular R-R interval in the absence of P waves on electrocardiogram. The arrhythmia is recognized clinically by irregularly irregular heart sounds, often with variability in the intensity of S1, and a pulse deficit may be present. Disorganized atrial electrical activity may be evident, with atrial rates approaching 400 to 600 per minute.

Depending on the atrioventricular nodal conduction, the ventricular rate in atrial fibrillation can be quite rapid. Gaining control of the ventricular rate is requisite for optimizing hemodynamics and avoiding tachycardia-related cardiomyopathy; however, ventricular rate control does not confer protection from the most feared complication of atrial fibrillation, namely, embolic stroke.

Atrial fibrillation is a leading cause of stroke among Americans, accounting for an estimated 75,000 strokes annually.1 Cardioembolic strokes carry greater morbidity and mortality compared with nonembolic strokes.3

Because of the economic impact and the severe long-term morbidity associated with stroke, there has been much investigation into stroke prevention in the population with atrial fibrillation. The primary approach to prevention has been warfarin therapy for chronic thromboprophylaxis in most patients, and unfractionated heparin for acute or interim therapy. The current American College of Cardiology/American Heart Association guidelines do show a role for aspirin therapy (table)4; however, only a small minority of patients with atrial fibrillation are eligible to be treated with aspirin alone.

Until recently, restoration of sinus rhythm has been a major goal of atrial fibrillation therapy. Recent clinical trials, however, have shown rate control to be at least as effective, and, in some cases, superior to restoration of sinus rhythm. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators’ data surprised many clinicians.5 This study showed that restoration of sinus rhythm does not reduce the rate of embolic events, and, with the exception of younger patients and those with congestive heart failure, rate control and concomitant warfarin therapy were superior to rhythm control.

The effectiveness of warfarin therapy for thromboprophylaxis has been validated.6 Only about one half of the patients eligible for warfarin therapy actually receive it, however, because of its narrow therapeutic window, the need for close monitoring, and the agent’s many food and drug interactions. For these reasons, elderly patients, who are at the highest risk for embolic strokes, usually do not get warfarin therapy, whereas younger lower-risk patients with less to gain often do receive it.

A report by Sudlow and colleagues underscores this problem.7 Their group looked at almost 5,000 patients selected at random from

the general population. Of these

patients, 4.7% were found to have atrial fibrillation. Further investigation revealed that 43% of the patients with atrial fibrillation had a tem-porary contraindication to warfa-

rin therapy, and 26% had a permanent contraindication as defined by the criteria set forth in the Stroke

Prevention in Atrial Fibrillation (SPAF) trial.6

Clearly, many patients need protection from cardioembolism but cannot take warfarin. This has led to the development of anticoagulants that act directly on thrombin rather than through the antagonism of vi-tamin K-dependent factor synthesis.

Direct thrombin inhibition

Ximelagatran is an oral direct thrombin inhibitor. It is a competitive and reversible inhibitor of thrombin, and thus prevents the conversion of fibrinogen to fibrin. Ximelagatran is a prodrug that is hydrolyzed to form melagatran,

the active compound. Melagatran, however, has poor bioavailability when taken orally, a problem overcome by substituting a hydroxyamidine group and an ethyl ester in place of an amidine and carboxylic acid moiety, respectively, to form ximelagatran. When taken orally, peak plasma levels are achieved in roughly 2 hours, with a half-life of 3.5 hours. The drug is excreted by the renal system and can be taken with or without food. Because of its reliable pharmacokinetics, ximelagatran does not require the extensive titration and monitoring needed with warfarin therapy.8

The efficacy and safety of ximelagatran in the prevention of venous thromboembolism after orthopedic surgery have been validated.9 Recent studies have shown that ximelagatran is well tolerated and safe when taken by patients with atrial fibrillation for the prevention of stroke.10 In the Stroke Prevention by Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF II) trial, ximelagatran was given in three different dose schemes, each of which were compared with a control group on warfarin therapy.10 Based on the results, ximelagatran appears to be as effective as warfarin at preventing embolic stroke and is well tolerated at doses of up to 60 mg twice daily.10 Although there was a trend toward more minor bleeding in the ximelagatran group, the major bleeding episodes were similar between

the two groups. The ximelagatran group also had a higher incidence

of asymptomatic transaminase elevation (4.3% versus 0%). The transaminase elevations appeared 4 to 8 weeks into the study, and in all cases returned to baseline. Five of the patients with elevated liver function tests had a normalization of their values without stopping therapy. The mechanism and significance of these laboratory abnormalities remain under investigation. The ongoing SPORTIF III and IV trials continue to assess the efficacy and safety of ximelagatran in atrial fibrillation.

Only 34% of the patients in the warfarin arm of SPORTIF II had an ideal international normalized ratio ([INR], 2—3) at the start of the study. This value increased to 57% by the completion of the 12-week study. This finding underscores the dif-ficult and cumbersome nature of warfarin therapy and its requir-

ed monitoring. Rather than being an anomaly, these values likely reflect how well physicians are able to maintain warfarin therapy within its narrow therapeutic window, even under the best of circumstances.

Left atrial appendage occlusion

Some of the problems with warfarin therapy include this narrow therapeutic window and the drug’s contraindication in many patients. Finding an optimal therapy for patients at high risk for embolic stroke but with a contraindication to warfarin therapy has led physicians to explore new frontiers in treatment.

It has been shown that in patients with nonrheumatic atrial fibrillation, most thrombi originate in the left atrial appendage. This finding has led to the hypothesis that occlusion, obliteration, or removal of the left atrial appendage may reduce cardioembolic events in atrial fibrillation patients. This is relatively easy to accomplish as an additional procedure for those undergoing aortocoronary bypass surgery or valvular surgery; however, most atrial fibrillation patients do not need these operations.

It is feasible to perform surgical obliteration of the left atrial appendage with ligation or stapling using a thoracoscopic procedure.11 Sievert and colleagues demonstrated a technique called percutaneous left atrial appendage transcatheter occlusion, in which they achieved total occlusion of the left atrial appendage in 15 patients at risk of embolic stroke but with a contraindication to warfarin therapy.12 In a feasibility study, their group implanted a self-expanding poly-tetrafluoroethylene-coated nitinol cage into the left atrial appendage. Follow-up of these patients using transesophageal echocardiography showed the device to be well positioned and free of thrombus. Large-scale trials need to be done before further evaluation of this promising therapy can be made.

Conclusion

Strokes that arise from cardio-emboli in the setting of atrial fibrillation are a major health concern for

millions of people. Ongoing trials

of oral direct thrombin inhibitors show promise as an effective and safe alternative to warfarin therapy. For those patients who cannot tolerate any degree of anticoagulation,

percutaneous left atrial appendage transcatheter occlusion, like most catheter-based techniques, can be expected to evolve rapidly as a treatment for this population. Finally, patients who have the need for aortocoronary bypass or other open thoracotomy procedures may be treated with surgical ligation of the left atrial appendage.