Warfarin replacements on the horizon

MAGDEBURG, GERMANY. Although there is no evidence that otherwise healthy lone afibbers have an increased risk of ischemic stroke, it is clear that atrial fibrillation (AF) patients with heart failure, diabetes or hypertension have a significantly increased risk and this risk is further magnified if the patient has already suffered a heart attack or stroke. To date, oral anticoagulation with vitamin K antagonists such as warfarin (Coumadin) is still considered to be the best preventive therapy for patients at risk for stroke. Unfortunately, warfarin interacts with many foods and drugs and treatment requires constant, costly monitoring and substantially increases the risk of hemorrhagic stroke and major internal bleeding, particularly in older people, a group that, ironically, is also most at risk for an ischemic stroke. It is therefore not surprising that a vast amount of medical research is being directed at finding a replacement for warfarin.

Warfarin acts by inhibiting the activation of the vitamin K-dependent coagulation factors V, VII, and X in the extrinsic and common pathways of the coagulation cascade. Research aimed at replacing warfarin essentially focuses on developing new pharmaceutical drugs which will inhibit specific coagulation factors. Among the more promising agents are:

  • Direct thrombin inhibitors – The first of these, ximelagatran, showed great promise as a one-size-fits-all, once-a-day effective anticoagulant. Unfortunately, it was found to be toxic to the liver and is now only approved (in Europe) for short-term use such as after knee replacement surgery. A newer direct thrombin inhibitor dabigatran etexilate (Pradax) has successfully undergone 3 large-scale phase III trials for the treatment of deep vein thrombosis (DVT). A recent trial involving 502 AF patients with at least one additional risk factor for stroke found that 150 mg of dabigatran twice a day is as effective and safe as standard warfarin therapy. A very large phase II trial has just finished enrolment of 18,000 AF patients. In this study 2 doses of dabigatran (110 and 150 mg twice a day) will be compared to warfarin therapy. Results are expected by 2009. It is noteworthy that no studies, so far, have observed any excess liver toxicity associated with dabigatran.

  • Direct inhibitors of activated factor X – two drugs, rivaroxaban and apixaban, are currently being investigated for stroke prevention in AF patients in 2 very large clinical trials involving 14,000 and 15,000 patients respectively. Rivaroxaban would appear to be the most promising of the two. Trials in over 1,000 patients with DVT found that 10-30 mg twice a day and 40 mg once a day were equally effective and had a low rate of bleeding and adverse events, and no sign of liver toxicity. However, lower doses may be required for patients with renal (kidney) impairment. Other activated factor X inhibitors include otamixaban and betrixaban and an extract from the nematode hookworm (NAP5), which is actually the most potent inhibitor identified so far.

  • Inhibitors of endocardial remodeling – there is some indication that inhibitors of endocardial remodeling (fibrosis) may be useful in stroke prevention either alone or in combination with one of the above-mentioned drugs. Foremost in the research in this area are the angiotensin II type I receptor blockers (ARBs) which have been found to help block atrial thrombus formation.

The researchers conclude that, “novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodeling like angiotensin II receptor blockers appear to be attractive future perspective approaches”.

Hammwohner, M and Goette, A. Will warfarin soon be passé? New approaches to stroke prevention in atrial fibrillation. Journal of Cardiovascular Pharmacology, Vol. 52, July 2008, pp. 18-27

Editor’s comment: It is indeed encouraging to see that a substantial research effort is being directed at replacing warfarin which, in my opinion, is very far from being an ideal stroke prevention remedy. I would not be surprised if a combination of dabigatran and an ARB such as losartan or irbesartan would turn out to be a winner with perhaps rivaroxaban being the “dark horse”. It is very unfortunate that equal effort is not being put into carrying out phase III trials with such natural stroke prevention agents as magnesium, potassium, fish oils, nattokinase, vitamin C, vitamin E, niacin, and vitamin B6.