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Thrombin inhibitors: What can we learn from SPORTIF III and SPORTIF V: Ximelagatran versus Warfarin?
Gudrun Boysen
Dept. of Neurology, Bispebjerg Hospital, Copenhagen NV, Denmark
Abstract
Atrial fibrillation (AF) is associated with a fivefold increased risk of stroke compared to sinus rhythm. Anticoagulation to an INR of 2.0 – 3.0 reduces stroke risk significantly and in this condition anticoagulation is clearly superior to antiplatelet therapy. Anticoagulation is, however, markedly underused. The direct thrombin inhibitor ximelagatran provides an alternative to vitamin-K antagonists.
SPORTIF III and V demonstrated non-inferiority of ximelagatran compared to warfarin in the prevention of cerebral and systemic embolism in patients with AF. The risk of major and minor bleeding was lower with ximelagatran. The main problem was increase in serum alanine aminotransferase to more than three times upper normal level in 6% of the patients. Liver function tests normalized after cessation of treatment.
Direct thrombin inhibitors may herald a new era for stroke prevention in atrial fibrillation. We are awaiting approval of ximelagatran.
Introduction
Intracavitary mural thrombi frequently develop in patients with atrial fibrillation, dilated cardio-myopathy, acute myocardial infarction, and other cardiac diseases. Thrombosis in the cardiac chambers has the potential for systemic embolism. Stasis of blood and low shear rate may lead to activation of coagulation factors. Thrombin is the key enzyme in the thrombotic process. One of its main functions is to convert fibrinogen to insoluble fibrin. A stable fibrin network is essential to form a thrombus. This is the predominant pathogenic mechanism for intracavitary thrombi. Therefore, anticoagulation is more effective in preventing cardioembolic events than antiplatelet drugs.
Anticoagulation with vitamin K antagonist, such as warfarin alters the synthesis of factor II (prothrombin), VII, IX, protein C, and protein S, and thereby inhibits formation of fibrin.
The thrombin inhibitor ximelagatran, when converted to the active metabolite melagatran, is an alternative way of inhibiting fibrin formation and thereby thrombus generation.
Atrial fibrillation and anticoagulation
The annual incidence of stroke in patients with atrial fibrillation (AF) without antithrombotic therapy is increased 5-fold compared with patients without AF (1). Anticoagulant therapy with warfarin decreased the risk of stroke 42% to 86% compared with no treatment. The pooled data from the five primary prevention trials reduced the risk of all strokes by 68% (2). The absolute stroke reduction was from 4.5% in the control group to 1.4% in the warfarin group. There is strong evidence that the optimal International Normalized Ratio (INR) level is in the interval 2.0 – 3.0. Anticoagulation is recommended for patients with any duration or frequency of AF, also for intermittent AF. Other risk factors such as previous stroke, increasing age, hypertension, diabetes, left ventricular dysfunction, and coronary artery disease strengthen the indication for anticoagulant therapy. In spite of the strong evidence of anticoagulant therapy in AF patients, it is alarmingly underused. Many studies have shown that only half or less of those, suitable for anticoagulation are actually treated (3).
Fear of bleeding complication, the burden of repeated blood tests, problems with food interactions are among the main reasons for not using anticoagulation. Therapeutic alternatives to anticoagulant therapy will therefore be most welcome.
Rhythm or rate control.
Intuitively conversion of atrial fibrillation to sinus rhythm would be the optimal treatment, which might render anticoagulation superfluous. However, recent trials have shown that rate control achieved with digoxin, calcium channel blocker or betablocker is as important as or more important than rhythm control obtained by electrical cardioversion or by antiarrhythmic agents (4, 5) under the precondition of sustained anticoagulant therapy to INR 2.0 – 3.0.
SPORTIF III
The direct thrombin inhibitor ximelagatran, which is rapidly converted to its active form melagatran, has been shown to have excellent antithrombotic effect. The aim of SPORTIF III (Stroke Prevention with the ORal direct Thrombin Inhibitor Ximelagatran compared with warfarin in patients with non-valvular atrial Fibrillation) (7), like in SPORTIF V, was to demonstrate non-inferiority of ximelagatran as compared to warfarin. Non-inferiority implies that ximelagatran is either equivalent or superior to warfarin. For these studies an absolute difference of 2% per year in primary event rates was adopted as margin for non-inferiority. This means that the measured difference in primary event rates must be below 2%. (6)
In SPORTIF III 3410 patients with atrial fibrillation and one or more additional stroke risk factor were randomized to open-label warfarin, INR 2.0 – 3.0, or to ximelagatran 36 mg twice daily. Mean age was 70,2 years. The primary events were stroke and systemic embolism. Only 96 patients suffered primary events, 56 in the warfarin group versus 40 in the ximelagatran group. The primary event rate was 2.3% per year with warfarin and 1.6% per year with ximelagatran (fig.). Rate of disabling or fatal stroke, mortality, and major bleeding were similar between groups. The combined risk of minor and major haemorrhages were lower with ximelagatran than with warfarin.
Increases in liver function test, serum alanine aminotransferase, more than 3 x upper normal level was observed in 6% of patients with ximelagatran versus 1% in the warfarin group. This rise in abnormal liver function tests occurred mainly between 2 and 6 months after start of treatment and returned towards baseline after cessation of treatment, or even during continued ximelagatran treatment. Elevations of liver function test greater than five times the upper limit of normal was seen in 3.4% of patients assigned to ximelagatran. There was no incidence of liver necrosis or fatal liver disease.
and intention to treat. SPORTIF III
SPORTIF V
SPORTIF V included 3,922 patients with AF and one or more additional stroke risk factors (8). The mean age was 72 years. They were randomized into double-blind adjusted dose warfarin, INR 2.0 – 3.0, or to ximelagatran 36 mg twice daily. The aim was to demonstrate non-inferiority according to intention to treat. Primary events developed in 88 patients with an event rate of 1.6%/year with ximelagatran and 1.2%/year with warfarin, p = 0.13. Major bleeding episodes were equal, but total bleeding was lower with ximelagatran. Also in this study serum alanine aminotransferase levels rose to more than 3 times the upper limit of normal in 6.0% in patients with ximelagatran, and the levels decreased whether or not ximelagatran was continued. The composite endpoint of stroke, systemic embolism, myocardial infarction, or death occurred in 4.3%/year in patients on warfarin, and 4.2%/year in patients on ximelagatran. One patient on ximelagatran developed hepatic necrosis and died 145 days after randomization.
SPORTIF III and SPORTIF V
Taken together the primary event rate with ximelagatran was 1.62% per year versus 1.65% per year with warfarin. The pooled analysis has shown that ximelagatran is noninferior to optimal warfarin treatment for the prevention of thromboembolism in patients with atrial fibrillation. The main problem with ximelagatran is its influence on the liver with high rise in lever enzymes in 6% of the patients. This will necessitate measurement of liver enzymes at intervals during the first year of treatment and probably cessation of treatment in those who show significant elevation. The advantage of a treatment option like ximelagatran would be that many more patients with AF could be properly treated (9)
However, the results of SPORTIF III and V cannot be extended to patients not eligible for anticoagulation, since such patients were not included in the studies.
Monitoring
Ximelagatran does give increases in INR and activated partial thromboplastin time (aPTT), but the relation to the plasma concentration of melagatran is non-linear and treatment effectiveness cannot be monitored by these tests (10) which need not to be made. There is no specific antidote, but reversal of anticoagulant effects of ximelagatran can be obtained by NovoSevenâ (recombinant factor VIIa). Melagatran is excreted in the urine and plasma levels of melagatran can be lowered by haemodialysis.
Other drugs
Other drugs for prevention of thromboembolism in patients with AF are under investigation. A pentasaccharide is being compared with warfarin in the Amadeus study of 5700 patients. In the ACTIVE study 6500 patients with atrial fibrillation are randomized to either clopidogrel + aspirin or to warfarin (11). These trials, if positive, may lead to more treatment options being available in the future.
Discussion
SPORTIF III and V have demonstrated non-inferiority of ximelagatran compared to warfarin in patients with atrial fibrillation. The risk of major bleeding may be slightly lower with ximelagatran and the risk of minor bleeding is significantly lower. There is a problem with raised liver enzymes, however, life-threatening liver toxicity seems to be exceedingly rare. All patients in SPORTIF III and V were eligible for warfarin. The results therefore cannot be extended to patients who are ineligible for warfarin.
Warfarin treatment will not be outdated in the foreseeable future even after approval of ximelagatran, because it will continue to be an option for those who do not tolerate the drug.
Another issue is the price of the drug. Anticoagulation is expensive due to the frequent lab. test and monitoring; the costs involved with ximelagatran treatment are unknown.
Ximelagatran has not yet been approved for patients with AF.
References
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