Warfarin versus Dabigatran – An Overview
Warfarin is a well-established life-long therapy for patients with long-term atrial fibrillation, an irregularly irregular heart beat. In lay terms this means that the muscles in the heart, instead of beating synchronously, fibrillate or ripple across the heart. This has the effect of producing ineffective pumping of blood to the rest of the body and causes blood stasis. As a result patients with atrial fibrillation have a higher risk of thrombosis (clots) forming within the heart and a risk of these clots being sent to different organs of the body e.g. the brain where it may cause an ischemic stroke. Warfarin decreases the risk of clots forming and therefore the risk of fatal embolic events.
Warfarin works by inhibiting vitamin K and thus the clotting factors that rely on vitamin K to be formed – factors II, VII, IX and X and protein C and S. Due to its nature of stopping clots forming, it naturally predisposes the same patients to an increased risk of bleeding. Of particular concern is the risk of bleeding into the brain, a haemorrhagic stroke.
Warfarin therefore remains a concern to clinicians but also has huge lifestyle implications for patients. It interacts with a whole host of foods, drinks and other medications. This has meant a need for frequent blood tests and monitoring of patients on warfarin and discontinuation rates are high. This is unlikely to be helped by the perception held by some patients that they are taking rat poison. In addition it has been found that many patients receiving warfarin are still not adequately anticoagulated.
This has been a concern for a number of years to many clinicians and various attempts have been made to find an alternative. However, none has superseded warfarin as the drug of choice to reduce the risk of embolic events in patients with atrial fibrillation. A combination of clopidogrel and aspirin was found to be less effective than warfarin. Ximelagatran, an early direct thrombin inhibitor was found to be as effective as warfarin but also toxic to the liver. Idraparinux was found to be more effective than warfarin at stopping clots but had a much higher risk of bleeding. The search has continued for a better alternative and researchers have now found a potential answer; dabigatran.
A study published in 2009 in The New England Journal of Medicine consisting of 18,113 patients from 44 different countries aimed to appraise whether dabigatran, a thrombin inhibitor, at doses of 110mg and 150mg twice daily was not inferior to therapeutic doses of warfarin. The results showed that at both doses, dabigatran could be considered a superior medication to warfarin. Despite dabigatran at 110mg being associated with no improvement in stroke or systemic embolism outcomes compared to warfarin, there was a decreased risk of major haemorrhage. At the 150mg dose of dabigatran there was a lower risk of stroke as compared with warfarin, but the rate of major haemorrhage was no better.
In spite of the results warfarin still remains the drug of choice but there appears to be an ever increasing awareness of dabigatran amongst clinicians. It is possible that dabigatran will eventually replace warfarin as the predominant anticoagulant for atrial fibrillation, but clinicians must remember that dabigatran, like any medication, fails to tick all the boxes for an ideal drug. Dabigatran at both doses was found to have a higher risk of myocardial infarction than warfarin. Although decreasing the risk of bleeding in most areas of the body, dabigatran was found to have a higher rate of gastrointestinal bleeding when compared with warfarin.
The explanation for the dyspeptic symptoms and the increased risk of gastrointestinal bleeding with the 150mg dose may be attributed to the fact that dabigatran requires an acidic environment for absorption. Thus the tablets are formed with a tartaric acid core, perhaps contributing to the gastrointestinal symptoms.
Is dabigatran the future? Maybe. It certainly appears to tick more boxes than warfarin did for both patients and clinicians. However with research taking us forward continuously, it serves as a useful reminder that practitioners must continue to update their knowledge of the ever-changing world of medicine.
Connolly SJ, Ezekowitz MD, Phil D et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361(12):1139-1151
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