<International Circulation>: The optimal pharmacological antiplatelet regimen to balance ischemic efficacy with the risk of periprocedural bleeding remains in flux. What’s new in stroke prevention especially in the area of antiplatelet therapy?

    Prof. Lip: Firstly， in terms of stroke patients it has been well-established for a long time that the use of aspirin reduces the risk， not only of recurrent stroke， but other cardiovascular events. That is based on data derived from huge meta-analysis from the Anti-thrombotic Trialists’ Collaboration and with the caveat that many of these studies were done a decade or more ago in the absence of some of the modern therapies like statins and ACE inhibitors. The role of aspirin has certainly been re-examined recently in light of recent studies for primary prevention， for example: the J-PAD study; POPADAD， which looked at diabetics; the AAA study， and these have shown that aspirin is no better than control or placebo in terms of reducing mortality and some cardiovascular events. One could make the argument that the incremental effect of aspirin on top of other effective secondary cardiovascular preventive strategies such as statins and ACE inhibitors， may well be quite small. So， it begs the question， if aspirin is not so wonderful for stroke prevention or， for that matter， the reduction of other cardiovascular events， whether there is something else that is better? There has certainly been initial interest in combination antiplatelet therapy， and from the ESPS-2  (the second European Stroke Prevention Study)， aspirin-dipyridamole was useful in the post-stroke setting to prevent recurrent stroke. More recently the PRoFESS study compared aspirin-dipyridamole versus clopidogrel and both were equally effective in terms of stroke prevention. So this has made it into guidelines， that for secondary stroke prevention， at least in general stroke populations， that combination antiplatelet therapy of aspirin-dipyridamole or clopidogrel should be used. More specifically， what about a cardiovascular condition very much predisposing to stroke， ie. atrial fibrillation， and does antiplatelet therapy have a role? In atrial fibrillation， a lot of clot is cardio-embolic; the mechanism of clot is more fibrin-enriched clot or “red” clot. Because it is fibrin-enriched， anti-coagulation works well and there have been many studies showing that anti-coagulation is superior to aspirin for prevention of stroke in patients with atrial fibrillation. One of the clearest examples most recently was the BAFTA trial， Birmingham Atrial Fibrillation Treatment of the Aged study. This was a trial done in elderly patients in the primary care setting because there was the perception that elderly patients do not do well on anti-coagulation and that aspirin was a safer drug. What BAFTA showed was that warfarin is superior to aspirin for stroke prevention and the risk of major bleeding was similar between warfarin and aspirin. So， why should we continue to give aspirin， which is an inferior drug for stroke prevention in patients with atrial fibrillation， when it is not any safer than warfarin? The BAFTA trial is also supported by a much smaller trial in octogenarians called the WASPO trial， and then more recently in the meta-analysis from the Atrial Fibrillation Investigators showing that， particularly in the elderly patients， the effect of anti-platelet therapy diminishes whilst the greater benefit for anti-coagulation is even more marked for elderly patients. The evidence for aspirin in atrial fibrillation has also been under a bit of scrutiny. If we look at Robert Hart’s meta-analysis of all atrial fibrillation trials， if you can find the data for antiplatelet therapy compared to control/placebo for aspirin-only trials， the stroke reduction was 19% with 95% confidence intervals， that include zero (in other words， the possibility of no or non-significant effect). What about dual antiplatelet therapy? Dual antiplatelet therapy with aspirin-clopidogrel has been looked at in two trials. One was the ACTIVE-W trial， where it was compared to warfarin. That trial was stopped early because warfarin was superior to aspirin-clopidogrel for stroke prevention and in terms of bleeding risk， they were virtually the same. For aspirin-clopidogrel compared to aspirin alone in the ACTIVE-A trial， in terms of the composite primary endpoint， aspirin-clopidogrel was better than aspirin. For the stroke end-point alone， there was a 28% difference in favor of combination aspirin-clopidogrel over aspirin alone， but that comes at a cost. The major bleeding rate on aspirin-clopidogrel was 2% per year which is in the general level of what is seen in anti-coagulation. The other point about the ACTIVE-A trial is that if you look at the patients who went into the trial， approximately 25% was by patient-preference (they absolutely refused to go onto warfarin) but 50% of the patients were included in ACTIVE-A on the basis of physician perception that the patient was unsuitable. Our work and other people’s studies has shown that physicians’ assessment of bleeding risk and stroke risk is abysmal and you could argue that physician’s perception is fairly nebulous anyway， so it is still very hard to be precise what segment of the atrial fibrillation population would benefit from aspirin-clopidogrel combination therapy. In summary， in general stroke populations， I think there is certainly some evidence for antiplatelet therapy but post-stroke combination antiplatelet therapy， as aspirin-dipyridamole， is certainly recommended on the basis of some decent large trials. In patients with atrial fibrillation in the post-stroke setting， the evidence is really clear， that antiplatelet therapy is an inferior choice. In atrial fibrillation patients and certainly for atrial fibrillation post-stroke， which is a very high risk category of patients， the default treatment should be anti-coagulation in the absence of contra-indications.