The European Society of Cardiology
New advances in stroke prevention in atrial fibrillation: ximelagatran and direct thrombin inhibition
Department of Cardiology, University Hospital, Lund, Sweden
* S. Bertil Olsson, Department of Cardiology, University Hospital, Lund, Sweden. Tel: +46-46-17-35-17; fax: +46-46-17-78-57
bertil.olsson{at}kard.lu.se
Abstract
Ximelagatran is the first oral agent in a new class of direct thrombin inhibitors and is under investigation for the prevention and treatment of a range of thromboembolic disorders. Atrial fibrillation (AF) is associated with a markedly increased risk of stroke and, while study results have consistently demonstrated that anticoagulant therapy with warfarin reduces this risk, there are substantial unmet needs in the management of AF-associated thrombotic risk. In particular, warfarin has unpredictable activity leading to the risk of bleeding complications and the need for routine anticoagulant monitoring.
Ximelagatran has a range of potential benefits over warfarin in the prevention of AF-associated stroke, including predictable anticoagulant activity that is not affected by food and a low potential for drug–drug interactions. Consequently, the risk of bleeding complications may be reduced and there is a fixed-dose regimen with no requirement for routine anticoagulant monitoring. The SPORTIF (Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) series of studies is investigating the extent to which these potential advantages translate into clinical benefits.
SPORTIF III is a Phase III study of the efficacy and safety of ximelagatran compared with warfarin in the prevention of stroke in 3407 patients with AF. The results demonstrate that ximelagatran has effectiveness non-inferior to well-controlled warfarin in the prevention of stroke and is associated with a lower risk of bleeding complications. With its predictable anticoagulant effect and the enhanced convenience offered by a fixed-dose regimen and with no requirement for routine coagulation monitoring, these results indicate that ximelagatran promises clinical benefits over warfarin that could improve the management of stroke risk in patients with AF.
Key Words: Stroke prevention • Oral direct thrombin inhibitors • Oral vitamin K antagonists • Ximelagatran • Non-valvular atrial fibrillation • SPORTIF lll
Atrial fibrillation is a leading risk factor for stroke
Non-valvular atrial fibrillation (AF) is the most common persistent cardiac arrhythmia, affecting more than 2 million adults in the United States and this figure is expected to rise to more than 5 million by 2050.1 The prevalence of AF increases markedly with advancing age, rising from 2.3% in people older than 40 to 5.9% in those older than 65, with the majority (
70%) of people with AF aged between 65 and 85.2 Other risk factors for the development of AF include hypertension, diabetes, and previous myocardial infarction (MI).3
AF was once regarded as a relatively benign condition, but it is now recognized as one of the strongest independent risk factors for stroke. A 34-year follow-up of 5070 patients in the Framingham study indicated that, while the incidence of stroke was doubled by coronary heart disease and more than trebled by hypertension, AF was associated with more than a 5-fold increase in the risk of stroke.4 AF has also been found to double the risk of recurrent stroke compared with patients with normal sinus rhythm.5 Estimates of the proportion of stroke cases attributable to AF rise from less than 2% in people aged between 50 and 59 to approximately 25% in those aged between 80 and 89.4 Given the strong association between AF and stroke, prophylactic antithrombotic therapy is critical to reducing the burden of stroke-related morbidity, disability, and mortality in this high-risk population.
Benefits and limitations of warfarin therapy for stroke prevention in atrial fibrillation
The ability of antithrombotic therapy to reduce the risk of stroke in patients with AF was first reported at the end of the 1980s.6 In the Copenhagen Atrial Fibrillation, Aspirin, AntiKoagulation (AFASAK) study, 1007 patients with chronic AF were randomized to treatment with the oral vitamin K antagonist warfarin (dose-adjusted to achieve an international normalized ratio [INR] of 1.8–4.2), aspirin (75 mg once daily) or placebo. Thromboembolic complications including stroke, transient cerebral ischaemic attack (TIA), and embolic complications in the viscera or extremities were monitored over 2 years of follow-up. Treatment with warfarin reduced the annual rate of thromboembolic events by nearly 60% compared with placebo (annual rate of thromboembolic events: warfarin=2.3%; placebo=5.6%).6
The benefits of long-term anticoagulation in patients with AF first demonstrated in the AFASAK study have subsequently been confirmed in further primary prevention trials7–10 as well as a secondary prevention trial in patients with AF and a previous minor stroke or TIA.11 A meta-analysis of these six trials indicated that oral anticoagulation with warfarin for patients with AF reduces the risk of stroke by 62% and the risk of all-cause mortality by 26% compared with placebo. Based on the same meta-analysis, treatment with aspirin also reduces the risk of stroke compared with placebo, but less effectively than warfarin (risk reduction=22%).12 It should be noted though that while all six trials showed a trend towards a reduced risk of stroke with aspirin, only in the Stroke Prevention in Atrial Fibrillation (SPAF) study was the reduction statistically significant.9 While aspirin may have benefits related to its activity against arteriothrombotic mechanisms, it is clearly a less effective than warfarin in protecting against stroke.
The benefits of reducing the risk of stroke in patients with AF must be balanced against the well-known and troublesome problem of bleeding complications associated with warfarin therapy. The meta-analysis of key trials also indicated an annual rate of severe bleeding of 1.2% among the patients treated with warfarin.12 In the AFASAK study, 6.3% of patients in the warfarin group were withdrawn because of non-fatal bleeding complications, compared with 0.6% and 0% of patients in the aspirin and placebo groups, respectively.6 The narrow therapeutic window for warfarin means that careful monitoring and dose adjustment is necessary to achieve therapeutically effective plasma levels of warfarin while minimizing the potential for bleeding complications. Increasing the warfarin INR beyond 3 provides no further reduction in the risk of stroke, but the risk of haemorrhage rises rapidly as INR increases above 4. Consequently, an INR of 2–3 has been identified as offering the best efficacy-to-safety ratio.13 In practice, INRs in the therapeutic range are often not achieved; and even when they are, patients are still at risk of bleeding complications. Furthermore, the need for monitoring and dose adjustment is inconvenient for patients and makes increased demands on the time and resources of healthcare professionals.
The reductions in the risk of stroke seen with warfarin clearly demonstrate the beneficial role of prophylactic antithrombotic therapy in patients with AF. At the same time, the reductions highlight the considerable limitations of current treatment options and the need for new antithrombotic agents with the potential to improve the management of AF-associated thrombotic risk. Specifically, new agents are needed that offer efficacy that is equivalent to or greater than that of warfarin in reducing the risk of stroke in patients with AF, but with a reduced risk of bleeding complications and without the need for anticoagulation monitoring.
Direct thrombin inhibition with ximelagatran
In the search for new antithrombotic therapies that may offer an improved efficacy-to-safety profile compared with warfarin, agents that act directly to inhibit thrombin have been identified as a promising target for development. Thrombin is the key enzyme responsible for the conversion of fibrinogen to fibrin and so plays a central role in the initiation and propagation of thrombus development. All of the direct thrombin inhibitors developed before ximelagatran have required parenteral administration, and this is a particular problem in terms of prevention of stroke in AF patients where long-term use and self-administration are required. Ximelagatran, in contrast, is the first orally administered direct thrombin inhibitor to be developed and, furthermore, potentially the first new oral anticoagulation therapy since the introduction of warfarin more than 50 years ago.
Ximelagatran is rapidly absorbed after oral administration and converted to the active form or moiety, melagatran.14 It offers many potential benefits over warfarin, including a fixed dosing regimen that does not need to be adjusted according to weight. Pharmacokinetic properties after oral administration are stable and reproducible, with no requirement for coagulation monitoring.15 While warfarin is subject to numerous interactions with drugs and foods,16 ximelagatran (melagatran) pharmacokinetics are unaffected by food intake and there is a low potential for drug–drug interactions.15
Consequently, ximelagatran may have important benefits over warfarin for the prevention of stroke in patients with AF. The efficacy and safety of ximelagatran in this indication has been investigated as part of the ongoing development programme for ximelagatran in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) series of trials.17 SPORTIF III and V studies are large-scale (3407 and 3922 patients, respectively) phase III studies of the efficacy and safety of ximelagatran 36 mg twice daily compared with warfarin (target INR 2–3) in the prevention of stroke in AF patients. SPORTIF III is a randomized, open-label, and parallel-group study that was conducted at 259 sites in 23 European, Asian, and Australasian countries. SPORTIF V was conducted at 409 sites in North America and has an identical design to SPORTIF III, except that treatment was double-blinded.18 Results from the SPORTIF III study are considered here.19
SPORTIF III: study design
In SPORTIF III, patients with AF and at least 1 additional risk factor for stroke (previous cerebral ischaemic attack, previous systemic embolism, hypertension, left ventricular dysfunction, age 
75 years or age 65 years with coronary artery disease, and/or diabetes mellitus) were recruited and randomized to treatment with either ximelagatran (
) or warfarin (
). The baseline characteristics of patients in the two groups were well matched in terms of the profile of stroke risk factors as well as age, sex, length of history of AF, and pattern of AF (paroxysmal vs. persistent). Patients were exposed to active treatment for between 12 and 26 months with an aggregate exposure of more than 4000 patient years.
The primary objective of SPORTIF III was to determine non-inferiority of ximelagatran to dose-adjusted warfarin in the prevention of all strokes and systemic embolic events (SEE) in patients with AF. While treatment was open-label, the assessment of events by local study-affiliated neurologists and the central events adjudication committee was blinded.
Quality of warfarin management
For patients randomized to warfarin, the dose was adjusted to maintain the INR between 2 and 3. INR was measured at least every 31 days and the dose titrated according to local clinical practice. Over the course of SPORTIF III, the mean INR was 2.5 and values were within the therapeutic range (INR 2–3) for 66% of the time. In practice, the warfarin dose is often not adjusted if it falls only slightly outside the therapeutic range and, considering an extended INR range of 1.8–3.2, values were within this range for 88% of the follow-up period. These results indicate that the quality of warfarin management in SPORTIF III was substantially more rigorous than that generally achieved in routine clinical practice.12,20 This may account for the relatively low rate of stroke and SEE in warfarin-treated patients in SPORTIF III as compared with other trials in patients at comparable risk.12
Ximelagatran has efficacy comparable to warfarin in preventing stroke in patients with atrial fibrillation
SPORTIF III followed patients for up to 25 months, with a median period of 18 months. There were no primary events beyond 21 months when few patients remained in the study. Ximelagatran had comparable efficacy to warfarin in the prevention of stroke over 21 months of treatment, based on an intention-to-treat (ITT) analysis (Fig. 1). The number of cases of stroke or SEE was higher with warfarin (56 events) than ximelagatran (40 events), the difference in annual event rates between the warfarin and ximelagatran groups (2.3% and 1.6%, respectively) was 0.7%, 95% CI; –0.1 to 1.4, a result well within the predefined non-inferiority margin (Fig. 2). Ximelagatran was effective irrespective of patient age, with similar annual event rates for stroke and SEE compared with warfarin in both patients aged 75 or older (3.00% for ximelagatran vs. 3.73% for warfarin) and in patients aged younger than 75 (0.93% vs. 1.59%). Considering the incidence of stroke alone in the ITT analysis, 54 patients in the warfarin group experienced stroke (9 haemorrhagic and 46 ischaemic) compared with 36 patients (4 haemorrhagic and 32 ischaemic) in the ximelagatran group. One patient in the warfarin group experienced a non-fatal ischaemic stroke first and a fatal haemorrhagic stroke later.
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An on-treatment (OT) analysis of the primary end point of stroke and SEE was also carried out and indicated annual event rates of 2.2% for warfarin and 1.3% for ximelagatran. The OT analysis demonstrated statistically significant (
) superiority for ximelagatran over warfarin in the prevention of stroke and SEE in the AF patients. The improvement in the primary end point was principally due to a reduction in the incidence of ischaemic stroke with ximelagatran compared with warfarin (22 vs. 42 events), rather than haemorrhagic stroke (4 vs. 8 events) or SEE (3 vs. 2 events).
A secondary objective of SPORTIF III was to compare the efficacy of ximelagatran and warfarin against the composite end point of stroke, SEE, MI, and death. In the OT analysis, the number of events was numerically lower with ximelagatran compared with warfarin (96 and 116 events, respectively; 
). Similarly, with the composite end point of ischaemic stroke, SEE, and TIA there was a numerical reduction with ximelagatran as compared with warfarin (48 vs. 67 events; 
).
Taken together, the results clearly and consistently demonstrate that ximelagatran is as effective as well-controlled warfarin in the prevention of stroke in patients with AF (Fig. 3). In all cases, there were fewer events in the ximelagatran as compared with the warfarin group of patients.
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SPORTIF III also compared the effects of ximelagatran and warfarin on all-cause mortality. There was no significant difference between the two treatments, with an almost identical number of deaths with ximelagatran and warfarin (78 and 79 deaths, respectively). The composite measure of primary events, major bleedings, and deaths can provide an indication of the net clinical benefit of treatment. Ximelagatran significantly reduced the relative risk of this composite measure by 25% compared with well-controlled warfarin (OT analysis; annual event rates of 4.6% and 6.1% for ximelagatran and warfarin, respectively;
). This provides a strong indication that ximelagatran promises important clinical benefits particularly when compared with warfarin in clinical practice and has the potential to improve the management of stroke risk associated with AF. Ximelagatran is associated with a lower risk of bleeding complications than warfarin
As discussed, the risk of bleeding complications is a frequent and potentially serious limitation of warfarin therapy. Treatment with ximelagatran is associated with a reduced risk of bleeding complications. Compared with warfarin, ximelagatran provided numerical reductions in the annual rates of intracranial haemorrhage (0.2% for ximelagatran vs. 0.4% for warfarin) and major bleeding (1.3% vs. 1.8%), and a statistically significant reduction in the rate of major plus minor bleeding (25.8% vs. 29.8%; 
).
Liver enzyme elevations with ximelagatran are typically transient and generally occur within the first few months of treatment
Transient elevations in liver alanine transaminase (ALAT) levels have been reported in association with ximelagatran therapy.21–23 The mechanisms underlying this effect and its clinical significance are currently being investigated. In SPORTIF III, the incidence of elevated ALAT levels (
the upper limit of normal [ULN]) was significantly higher with ximelagatran than with warfarin (6.3% and 0.8%, respectively; 
). Seven patients in the ximelagatran group and 1 in the warfarin group had elevated bilirubin levels (
ULN) within one month following ALAT levels ULN. Elevated ALAT levels associated with ximelagatran treatment typically occurred in the first 6 months of treatment, peaking in the third month after initiation of treatment (Fig. 4). In total, 107 of the 1704 patients randomized to ximelagatran therapy developed elevated ALAT levels. Of these, 59 patients continued on therapy, while 48 patients discontinued treatment, prompted by a rise in ALAT to greater than 
the ULN (a predefined criteria for immediate discontinuation of study medication). ALAT levels returned to normal in most patients, irrespective of whether they continued or discontinued ximelagatran therapy.
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There were no other significant differences between the safety profiles of ximelagatran and warfarin, including the development of congestive heart failure (2.9% and 3.9%, respectively;
) or MI (1.0% and 0.5%, respectively; 
). Conclusions
Effective antithrombotic therapy is critical to reducing the risk of stroke associated with AF, but current therapeutic options are very limited and associated with significant drawbacks. Prior to the development of ximelagatran, the only oral therapy shown consistently to provide substantial reductions in the risk of stroke associated with AF is warfarin. However, warfarin has a narrow therapeutic index, unpredictable anticoagulant activity that is affected by a wide range of interfering factors including numerous drug–drug and food interactions. Consequently, routine coagulation monitoring is required to balance the need for efficacy against the risk of side effects, particularly bleeding.24
The results of SPORTIF III demonstrate that ximelagatran, the first oral direct thrombin inhibitor, is a promising alternative to warfarin in the prevention of stroke and SEE in patients with AF. It shows effectiveness non-inferior to well-controlled warfarin in reducing the incidence of stroke in patients with AF and reduces the risk of bleeding complications. Elevations in liver enzyme levels sometimes occur with ximelagatran treatment but are generally transient, typically normalizing with either continued treatment or discontinuation of therapy. Unlike warfarin, ximelagatran has a fixed dosing regimen and does not require routine coagulation monitoring, thus bringing predictable anticoagulant activity and improved convenience to long-term treatment. By combining antithrombotic efficacy with a reduced risk of bleeding complications compared with warfarin ximelagatran has the potential to increase the proportion of patients receiving appropriate prophylactic therapy, and to reduce the considerable burden of morbidity and mortality resulting from stroke. Moreover, for those patients where warfarin is contraindicated or poorly tolerated, ximelagatran provides a new treatment option for effective anticoagulant therapy.
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