CANOA: Fewer Migraines With Clopidogrel Plus Aspirin Post-ASD Closure

ORLANDO, FL—Three months of clopidogrel on top of aspirin appears to reduce the number and severity of migraines following atrial septal defect (ASD) closure, a new study suggests. The findings, while specific to ASD-closure patients, raise the possibility that dual antiplatelet therapy may have been a confounding factor in past, negative studies that investigated ASD/PFO closure as a potential treatment for migraines.

Migraines, adding up to as much as one week per month, affect approximately 15% of patients in the first few months after ASD closure, the researchers note.

Josep Rodés-Cabau, MD, of the Quebec Heart and Lung Institute (Laval, Canada) presented the results of the CANOA randomized, controlled, multicenter trial here at the American Heart Association 2015 Scientific Sessions. The results were published simultaneously in the Journal of the American Medical Association.

For the study, investigators randomized 220 patients who had undergone ASD closure at 1 of 6 Canadian hospitals to aspirin plus clopidogrel or aspirin plus placebo. After 3 months, patients in the dual antiplatelet group had a reduced number of migraine days and a lower incidence of new migraine attacks than patients in the aspirin-only group. Among the patients who experienced migraines, those migraines were less severe if patients were taking DAPT than in those in the aspirin-only group, although there was no difference between groups in the rate of patients with at least 1 adverse event.

In an interview with TCTMD, Rodés-Cabau stressed that the type of migraine headaches studied represent a specific type of migraine well-known to be associated with transcatheter ASD closure and typically seen in both the adult and pediatric congenital heart disease populations following defect closure. That means clopidogrel is unlikely to have any effect in patients with migraines who have not had ASD procedures. As well, closure of intra-atrial shunts has been studied as a potential treatment for migraine but here again, Rodés-Cabau said “the mechanisms are likely different.”

Mechanisms of Action

Indeed, the discussant following the CANOA presentation, J. Dawn Abbott, MD, of Brown University (Providence, RI) listed the potential mechanisms behind migraine following ASD closure, most of which would be unlikely to respond to clopidogrel therapy. These include liberation of vasoactive substances via atrial stretch, nickel release from the device itself, and the change in stroke volume or cardiac output influencing ocular hemodynamics.

A fourth possibility, however, and the rationale behind the research question, is whether migraine may be caused by microthrombi formation on the left atrial surface of the device that is not detectable on imaging. These, said Abbott, may cause microembolization and also platelet release of serotonin, which is a vasoactive substance.

Rodés-Cabau agreed that while clopidogrel may play a role in improving endothelial function and has some anti-inflammatory properties, the main properties of the drug are antithrombotic and antiplatelet. “I think the study suggests that the mechanism behind at least some of these migraine headaches is related to some prothrombotic status.”

And while the results can’t be generalized to a broader population of migraine sufferers, they at least raise the possibility that “in some specific patients, with some specific triggers, migraine may be [influenced] by prothrombotic status and patients may be at least partially protected by the addition of more antithrombotic agents.

Other Considerations

Investigators did not do any tests for clopidogrel responsiveness, but it’s possible that the lack of response in some trial patients treated with DAPT may be linked to a lack of clopidogrel effect. The study also did not address whether clopidogrel could be of value in pediatric patients undergoing ASD closure; mean age of patients in CANOA was 49.

Abbott noted that many institutions, including her own, have already been using DAPT in patients undergoing ASD closure and the CANOA results now reinforce the safety and efficacy of this practice. Rodés-Cabau, however, cautioned against a blanket application of the strategy, particularly in patients at higher bleeding risk.

One final point raised by the CANOA investigators relates to the significance of their results to past trials exploring PFO/ASD closure as a treatment for migraine. Those studies were prompted by observations that migraine sufferers appeared to find relief from their headaches after undergoing PFO/ASD closure for other indications. The 2 major studies in this space, however, PRIMA and MIST, both of which missed their primary end points, included a requirement that patients undergoing closure take DAPT for 3 months post-procedure.

“Although the pathophysiology linking interatrial shunts and chronic migraine headaches is probably different from the one linking ASD closure with new-onset migraines, the results of this trial should be considered when designing or analyzing the results of past, current, and future studies assessing the efficacy of interatrial shunt closure for the treatment of migraines,” they write.