Clopidogrel Only Needed for 3 Months After ASD Closure: CANOA Analysis

Three months of clopidogrel is sufficient to curb new-onset migraine headaches after percutaneous atrial septal defect (ASD) closure, new data from the randomized CANOA trial show. There was no rebound effect after patients stopped the P2Y12 inhibitor, continuing on aspirin alone.

By 6 and 12 months after ASD closure, both the number and the severity of migraines had decreased, Jérôme Wintzer-Wehekind, MD (Quebec Heart and Lung Institute, Laval University, Quebec City, Canada), et al report today in JAMA Cardiology. The main results from CANOA, published in JAMA back in 2015, showed that clopidogrel was effective within the first 3 months of therapy.

ASD closure has long been known to cause new-onset migraines among patients who didn’t previously have the severe headaches, but there has been debate over why this phenomenon occurs. “Nickel allergy, increased platelet aggregation, and the presence of microthrombus on the ASD closure device have been proposed as potential mechanisms,” the investigators note.

Around 15% to 20% of patients get these de novo migraines, which carry “a high burden and a huge impact on daily living,” Wintzer-Wehekind told TCTMD. “So it’s really important to limit this bad effect of closure.” As the investigators note in their paper, ASD patients with subsequent migraine are often young adults of working age “and present within the day and weeks following the procedure, leading to a significant burden of medical consultations in addition to missed work or school days and reduced productivity.”

“This study confirms that the optimal duration of dual antiplatelet therapy following transcatheter ASD closure should be no longer than 3 months,” Josep Rodés-Cabau, MD, PhD (Quebec Heart and Lung Institute, Laval University), principal investigator for CANOA and the new paper's senior author, told TCTMD in an email.

For Wintzer-Wehekind, the lack of rebound effect is the main takeaway from the latest CANOA analysis. “We need 3 months of dual antiplatelet therapy to have the device really endothelialize,” and thereafter 99% of patients are migraine free, he emphasized.

Robert Sommer, MD (NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY), who didn’t take part in the CANOA trial, said clopidogrel’s effects in this population—and in people with patent foramen ovales (PFO)—“indicate there’s clearly a platelet-mediated effect, whatever it is: whether it’s microemboli causing the headaches, whether it’s paradoxical passage of platelet activation products like vasoactive chemicals and things like that. Nobody knows exactly what it is, but it’s pretty clear that it’s a P2Y12-mediated effect, based on what we’ve done previously and also based on this.”

The study importantly “confirms the benefit of dual antiplatelet therapy not only for device thrombosis prevention but also for the elimination of migraine symptoms, which can occur de novo after closure,” Sommer commented to TCTMD.

All this brings to mind debates over PFO closure as a means of migraine prevention, though Wintzer-Wehekind specified that “it’s not the same issue.” Here, ASD closure was done to address dyspnea and shortness of breath, he said. PFO closure is recommended in patients who’ve experienced a related stroke, formerly referred to as “cryptogenic,” but it’s less clear whether closure can ameliorate migraines. Despite positive observational studies, three randomized trials have failed to show a benefit to PFO closure in this setting. More-recent data hint that complete closure may be key.

CANOA After 3 Months

CANOA, a double-blind trial, enrolled 171 migraine-free patients (mean age 49 years; 62% women) who underwent ASD closure at six Canadian hospitals between December 2008 and November 2014, randomizing them to dual antiplatelet therapy (DAPT; clopidogrel and aspirin) or to placebo plus aspirin. After 3 months, patients received only aspirin.

As previously reported, 9.5% of the DAPT group and 21.9% of controls developed new-onset migraine in the 3 months following ASD closure (P = 0.03).

Thereafter, with aspirin monotherapy, 3.5% of patients who’d developed migraines continued to have the headaches at 6 months and 1.2% (one person in each group) experienced new-onset migraines, for a total of 4.7% across the entire study cohort. At 12-month follow-up, 2.3% of patients still had recurrent migraines, but no new-onset headaches emerged between 6 and 12 months. There also were no moderate or severe migraine attacks after 3 months, with no differences in migraine rate between patients initially assigned to clopidogrel versus aspirin at either 6 or 12 months.

These results align with his clinical experience, Sommer said. “When the headaches occur after the procedure . . . by about 3 months, most of the headaches are gone and that has to do with endothelialization of the device. Once the skin grows over the device, the platelets no longer stick to it and they no longer become activated.” People who have headaches beyond 3 months likely do so because of differences in healing times, he explained, suggesting that these individuals might benefit from restarting clopidogrel.

Wintzer-Wehekind agreed that their findings indicate that increased platelet aggregation, rather than something about the device itself, is what’s behind the de novo migraines. “The antioxidant, anti-inflammatory, and vasoprotective effects of clopidogrel could also play a role on the prevention of migraine attacks,” the researchers suggest in their paper.