Atrial fibrillation is a strong and independent risk factor for stroke because it predisposes to thrombus formation in the left atrial appendage, and subsequent embolism to the brain.1 Each year, at least 6000 cardioembolic ischaemic strokes occur among an estimated 150 000 Australians with atrial fibrillation,2,3 and these numbers are expected to rise substantially with the ageing of the Australian population and associated increase in the prevalence of atrial fibrillation.

The only two treatments proven to reduce the risk of stroke among patients with atrial fibrillation are aspirin and adjusted-dose warfarin.4 However, both have limitations. Aspirin is only modestly effective, reducing the risk of stroke by about a fifth compared with placebo (absolute risk reduction [ARR], 1.7% per year; number of patients needed to treat for one year to prevent one stroke [NNT], 59). Warfarin reduces the risk of stroke by about two-thirds compared with placebo (ARR, 3.1% per year; NNT, 32) and by about a third compared with aspirin (ARR, 0.8% per year; NNT, 125), but causes at least twice as many intracranial and extracranial bleeds as aspirin, particularly in patients at increased risk of bleeding (eg, those aged over 75 years, those with a history of bleeding; see Box 1).4 Warfarin is also inconvenient to use because it has a narrow therapeutic index, interacts with numerous drugs and food, and requires close laboratory monitoring (Box 2).5 Consequently, only a third to a half of patients with atrial fibrillation who are appropriate candidates for warfarin therapy actually receive it.6 Reducing the intensity of warfarin therapy to an international normalised ratio (INR) of less than 2.0 lowers the risk of bleeding, but is associated with an increased incidence of ischaemic stroke and worse stroke outcomes compared with standard-intensity warfarin therapy (INR ≥ 2.0).7

Direct thrombin inhibitors are a new class of anticoagulant drugs that bind directly to thrombin and block its interaction with substrates, thus inhibiting fibrin formation, thrombin-mediated activation of coagulation, and thrombin-induced platelet aggregation. Hirudin is the only direct thrombin inhibitor currently available for use in Australia, but must be given parenterally and is approved only for the treatment of heparin-induced thrombocytopenia. Ximelagatran, a pro-drug of melagatran, is an orally administered direct thrombin inhibitor and the newest drug in this class. It is rapidly absorbed from the gut and converted to its active form, melagatran. Melagatran is not metabolised or bound to plasma proteins. It is cleared predominantly (about 80%) by the kidneys, and has a half-life of 4–5 hours, which means ximelagatran needs to be administered twice daily (Box 2).

Two large phase III randomised trials have recently evaluated ximelagatran as a replacement for warfarin to prevent thrombotic complications in patients with non-valvular atrial fibrillation.8,9 The primary objective of the Stroke Prevention using the ORal direct Thrombin Inhibitor ximelagatran in patients with non-valvular atrial Fibrillation (SPORTIF) III and V trials was to determine whether ximelagatran given in a fixed dose of 36 mg twice daily without laboratory monitoring was non-inferior to adjusted-dose warfarin (INR, 2.0–3.0) for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation and at least one additional major risk factor for stroke. The prespecified criterion for non-inferiority required that the lower confidence interval for the difference in the rate of stroke or systemic embolism between ximelagatran and warfarin did not exceed the prespecified threshold of 2% per year.10 Establishment of non-inferiority would imply that ximelagatran has either equivalent or superior effectiveness to warfarin and would allow clinicians to select ximelagatran over warfarin for convenience or safety.

The design of the two SPORTIF trials was identical, except that SPORTIF III (3407 patients) was conducted in Europe, Asia, Australia and New Zealand and treatment allocation was open label, while SPORTIF V (3922 patients) was conducted in North America and treatment allocation was double blinded.

The pooled results of the SPORTIF III and V trials (which had mean follow-up periods of 17 or 20 months, respectively) showed no significant difference in the risk of stroke or systemic embolism between ximelagatran (2.5%) and warfarin (2.5%; Box 1). In both trials, findings for ximelagatran fulfilled the criterion for non-inferiority.

However, the pooled results of the SPORTIF trials also showed that ximelagatran significantly reduced the risk of major bleeding compared with warfarin (2.5% for ximelagatran; 3.4% for warfarin; estimated annualised ARR, 0.6%; NNT for 1 year to avoid one major bleed, 167) and increased the risk of transiently elevated levels of liver alanine aminotransferase (ALT) enzymes (6.1% for ximelagatran; 0.8% for warfarin; absolute risk increase [ARI], 5.3%; number of patients needed to treat with ximelagatran to harm [NNH] with increased ALT, 19). Raised ALT levels typically occurred 2–6 months after initiation of ximelagatran therapy, but produced no symptoms, were transient (returning to baseline spontaneously or after cessation of treatment), and without sequelae in all cases reported in the SPORTIF trials.

These results suggest the beginning of the end of warfarin, because ximelagatran is not only associated with less major bleeding than warfarin, but it also has a predictable pharmacokinetic profile (uninfluenced by the patient’s age, sex, weight, ethnicity or diet). Therefore, it is not necessary to monitor anticoagulation activity or adjust the dose of ximelagatran (except in patients with renal dysfunction, in whom a decrease in dose or longer dosing interval is likely to be required). Furthermore, ximelagatran has a wider therapeutic margin than warfarin, and a low potential for drug interactions (Box 2). Although the cost of ximelagatran is likely to be substantially higher than the cost of warfarin, it may prove to be more cost effective because of its lower risk of bleeding and superior convenience (eg, no laboratory monitoring).

Yet, important questions remain. First, there was significant heterogeneity between the two SPORTIF trials (P = 0.02). In the SPORTIF III trial, random allocation to open-label ximelagatran was associated with an absolute reduction in stroke or systemic embolism of 0.7% per year compared with warfarin, whereas in the SPORTIF V trial allocation to double-blinded ximelagatran was associated with an absolute increase in stroke or systemic embolism of 0.4% per year compared with warfarin. The cause of this heterogeneity remains uncertain, but might, at least in part, be accounted for by diagnostic suspicion or reporting bias in the open-label SPORTIF III trial. Second, the 2% per year threshold that was chosen as the criterion for non-inferiority does not reliably exclude even a near doubling of risk of stroke or systemic embolism with ximelagatran compared with warfarin. Third, unexpected hepatic side-effects of ximelagatran are an important concern given their high incidence in the short-term (6%), the large population potentially eligible for ximelagatran, and the likely long-term exposures to ximelagatran (and possibility of other long-term adverse effects). Monitoring of liver function is likely to be required during the first 6 months of treatment, and additional long term outcome data are required.

The SPORTIF data signal the emergence of ximelagatran as an effective, safe and more convenient long-term alternative to warfarin for preventing stroke in patients with non-valvular atrial fibrillation. Safety concerns and cost issues are likely to delay its approval and eventual uptake by clinicians in Australia. In the meantime a range of other new antithrombotic drugs are also being evaluated for this indication. Both idraparinux (a selective clotting factor Xa inhibitor administered by once-weekly subcutaneous injection) and the combination of aspirin and clopidogrel are being tested in clinical trials, and novel oral preparations of direct-thrombin inhibitor and factor Xa inhibitors are in clinical development. This is heartening news for patients with atrial fibrillation, their doctors, and also public health professionals and governments faced with a looming epidemic of morbidity caused by atrial fibrillation in the ageing Australian community.