<International Circulation>: Atrial fibrillation poses additional thorny problems in antithrombotic therapies， and some lessons have been learnt recently from ACTIVE-W and ACTIVE-A in this respect. What is your perspective on the bleeding issue with clopidogrel plus aspirin in stroke prevention in atrial fibrillation compared to bleeding with warfarin?

    Prof. Verheugt: Because of the complexity of warfarin therapy around the world， (but less so in my country， the Netherlands as I explained)， the search was for a simpler strategy. We know that aspirin on its own has a small effect on stroke prevention in atrial fibrillation but inferior to warfarin. So clopidogrel was added on top of aspirin to come closer to the effect of warfarin. This failed completely as well. However， we have patients who it is felt are ineligible for warfarin because for warfarin therapy you need a clear mind and you need to be a co-operative compliant patient with a thrombosis clinic in the vicinity of where you live. Additionally some patients refuse to take warfarin for a number of reasons and also some doctors feel uncomfortable putting patients on warfarin. In these cases， other strategies are needed and the option is often to fall back on antiplatelet therapy. Aspirin on its own is insufficient and the ACTIVE-A trial showed that aspirin and clopidogrel together was more effective than aspirin alone in stroke prevention but at a significant cost of excess bleeding. Long term aspirin-clopidogrel usage has as bad a bleeding incidence as warfarin alone which we know from ACTIVE-W. Therefore， my personal opinion is that the aspirin-clopidogrel option in warfarin ineligible patients is not good. You can ask the question – who is ineligible? It is a subjective feeling of the patient in the first place but also of the doctor. The doctor is there to advise the patient who is usually ignorant of efficacy and safety of treatment， so the physician should explain the available treatment options. Doctors may also be reluctant because they do not want the extra monitoring and an easy-going doctor may choose the simpler aspirin-clopidogrel option， while the more precise doctor may opt for warfarin. In the ACTIVE-A study for instance， warfarin ineligibility was， in 50% of patients， the decision of the doctor. This worries me a lot. It needs to be an informed doctor-patient decision and nothing to do with researchers or scientists. If the patient and the doctor decide not to use warfarin， then it is clear we need to have better antiplatelet therapies and I believe there are some possibilities on the horizon that these patients may benefit from and hopefully these newer drugs will be as good as or better than warfarin. I am also pretty optimistic that new anticoagulants may be the choice for these patients who are categorized as ineligible for warfarin.