Fewer adverse effects with aspirin than with warfarin in stroke patients with intracranial arterial stenosis

Shelley Wood

March 30, 2005

Boston, MA - A new study showing aspirin to be just as effective as warfarin (Coumadin®, Bristol-Myers Squibb) in preventing cerebrovascular eventswith fewer adverse effectsin stroke patients with intracranial arterial stenosis (IAS) should establish aspirin once and for all as the preferred therapy in this group, investigators say.[1]

"The common practice of administering warfarin rather than aspirin for symptomatic intracranial arterial stenosis is not supported by the results of this trial," Dr Marc I Chimowitz (Emory University, Atlanta, GA) and colleagues write in the March 31, 2005 issue of the New England Journal of Medicine.

Dr Don Easton (Brown University, Providence, RI), commenting on the study for heart wire , put it even more succinctly: "I think that warfarin is dead for atherothrombotic stroke, and this is the last nail in the coffin."

A stroke by any other cause
 
I think that warfarin is dead for atherothrombotic stroke, and this is the last nail in the coffin.
 

As Chimowitz et al explain in their paper, atherosclerotic intracranial arterial stenosis is a common and important cause of stroke; warfarin, an established treatment for cardioembolic stroke, is frequently used to prevent stroke in patients with intracranial arterial stenosis, despite no randomized trial evidence proving its superiority over aspirin in this setting. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial was designed to compare warfarin therapy (target INR 2.0-3.0) vs 1300-mg daily aspirin to prevent ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke (the primary end point of the trial) in people with previous TIAs or strokes and confirmed 50% to 99% stenosis of a major intracranial artery.

Enrollment had reached 569 patients when the trial's safety committee halted the study, citing concerns over adverse events in the warfarin group. Thus, at a follow-up of 1.8 years, the incidence of the combined primary end point was similar in the two groups, with approximately one in five patients in both groups experiencing ischemic stroke, brain hemorrhage, or death from vascular causes. Where differences emerged, however, were in adverse events, with a statistically higher incidence of all deaths, major hemorrhage, and deaths from nonvascular causes seen in the warfarin-treated patients.

Outcomes and adverse events in WASID

End point Aspirin (%) Warfarin (%) Hazard ratio (95% CI) p
Primary end point 22.1 21.8 1.04 (0.73-1.48) 0.83
Death 4.3 9.7 0.46 (0.23-0.90) 0.02
Death from vascular causes 3.2 5.9 0.56 (0.25-1.26) 0.16
Death from nonvascular causes 1.1 3.8 0.30 (0.08-1.07) 0.05
Major hemorrhage 3.2 8.3 0.39 (0.18-0.84) 0.01
MI 2.5 4.2 0.62 (0.24-1.58) 0.31
A strike against warfarin, not against anticoagulation

In a post hoc analysis, Chimowitz et al examined rates of ischemic or hemorrhagic events in patients assigned to warfarin treatment who were actually maintained within the target INR. (INRs were within the target range only 63% of the maintenance period in WASID, a proportion dismally similar to other trials.) The authors report that INRs <2.0 were significantly associated with ischemic stroke and major cardiac events, while INRs >3.0 were significantly associated with major hemorrhage. In patients maintained within the therapeutic level of anticoagulation, however, the number of major hemorrhages, ischemic strokes, and major cardiac events was very low.

It's a point hammered home in an editorial by Dr Walter J Koroshetz (Massachusetts General Hospital, Boston), who argues that the WASID trial results "do not preclude a trial of very carefully regulated anticoagulation in patients who continue to have recurrent ischemic events" despite being on aspirin.[2]

As he explained to heartwire , "I agree with the authors that given the way warfarin was used, this study shows that warfarin is definitely not better than aspirin, so that if you're going to use warfarin the way it is standardly used, aspirin is certainly easier and probably less dangerous. . . . Everyone knows Coumadin is the bane of the existence of the doctor and the patient. It's a terrible drug. And I think this is a good study showing that if you use Coumadin in the standard manner, you're not helping anybody."

 
Everyone knows Coumadin is the bane of the existence of the doctor and the patient. It's a terrible drug.
 

However, he continues, risk of events was actually very low in patients taking warfarin at therapeutic doses. "Anticoagulation is actually quite effective at reducing your risk, and the trouble is that Coumadin the way it is used is actually not very good at keeping people anticoagulated, and with this condition, if you go subtherapeutic, it's going to get you. So the question for the future is, how do you do better in terms of anticoagulation? The data suggest that anticoagulation is still a good thing: we just need a better way of anticoagulating."

Koroshetz suggests that carefully monitored warfarin may be principally useful during periods when symptoms are particularly "revved up," for example, after the index TIA or stroke. Use of a low-molecular-weight heparin to achieve "rapid and consistently active" anticoagulation might prevent early adverse events, he noted.

Koroshetz also told heartwire direct thrombin inhibitors are promising "because they give you smoother coverage" and, if approved for the US market, would be a welcome anticoagulation alternative.

Confusion to come over aspirin dose?

Experts interviewed by heartwire agreed that aspirin was the clear winner in what was otherwise a negative trial; where some confusion may arise is over the nonstandard aspirin dose chosen by the WASID investigators.

Easton called the dose "a bit of a holdover from an earlier time," when a similarly high daily aspirin dose was tested in the endarterectomy trials for cerebrovascular disease.

"Over the years, more and more data started coming in showing aspirin doses coming down and down and being just as effective. For cerebrovascular disease, we've gotten to the point where most people use 325 mg or 81 mg a day. So the problem we're going to be stuck with here is, this is going to make things a bit difficult for many people, who will think that aspirin was shown to be better in this trial only because it was used in a high dose," Easton explains.

Easton, however, will not be upping the aspirin. "I'm still going to use 325 mg on the grounds that there is a huge amount of other data that would suggest that 325 mg is equally as good, so it's not going to change my practice, although it will change some. We may have not yet seen the end of four aspirin a day."

Koroshetz also queried the aspirin dose. "Strictly from the study, you'd have to say that we have data only on the 1300-mg dose, but I don't think that's going to filter into clinical practice, because that high dose is not substantiated, and we do know that GI side effects are related to dose. . . . We have no evidence in stroke that one dose of aspirin is any better than any other dose. Most stroke doctors are used to that and most will use it [on the basis of these trial results] but will do so at the standard dose, 325 mg or 81 mg."

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