A replacement for warfarin as a treatment for atrial fibrillation (AF)-a major risk factor for stroke-remains a pharmaceutical holy grail. This conclusion follows the premature termination of ACTIVE-W because of an increased risk of stroke, heart attack and other vascular events in patients randomised to Plavix (clopidogrel) and aspirin compared to patients receiving warfarin.
ACTIVE-W randomised more than 6500 patients with AF and at least one other stroke risk factor to either antiplatelet therapy with Plavix plus aspirin or oral anticoagulant therapy (usually with warfarin). On the primary endpoint of stroke, heart attack, embolism and vascular death, there was an annual risk of 5.6% in the Plavix-aspirin group compared to 3.9% in the warfarin group - a relative increased risk of 47%. There was also no reduction in the risk of bleeding with the Plavix-aspirin combination.
These findings, announced yesterday at the American Heart Association annual meeting, mean that warfarin remains the standard therapy to reduce the risk of stroke in AF. An alternative to warfarin is urgently needed, since it is a difficult to administer and involves frequent monitoring. However, warfarin's effectiveness in stroke prevention is beyond doubt and, in light of ACTIVE-W and AstraZeneca's troubles with Exanta (ximelegatran), regulatory bodies will demand strong evidence of safety and efficacy of future alternatives to warfarin.
Exanta has been affected by questions over safety and efficacy, which ultimately led to its rejection by the US Food and Drug Administration last year [[11/10/04a]].
In the meantime, B-MS and Sanofi-Aventis can draw some consolation that there was some evidence in ACTIVE-W that patients new to warfarin may benefit from Plavix-aspirin. This promise may be realised in ACTIVE-A, which is comparing Plavix plus aspirin to aspirin alone in AF. The other study in the ACTIVE trial programme, ACTIVE-I, which is comparing Aprovel/Avapro (irbesartan) and placebo in AF, is also continuing and it, too, may yield more positive results.
Source: Sue Lyon at the AHA in Dallas, USA.