Shelley Wood

September 16, 2014

WASHINGTON, DC — Another door is creaking shut on the hypothesis that patent foramen ovale PFO closure can help reduce migraine, with final results from the PRIMA trial using the Amplatzer device (St Jude Medical) showing no significant differences in its primary end point at one year. Long-time optimists for this approach, however, point to positive secondary end points and say certain subgroups are worth studying, namely patients with migraine with aura.

PRIMA "didn't meet its primary end point," principal investigator Dr David Hildick-Smith conceded in a morning press conference at TCT 2014 , but he said the secondary end points are worth a closer look. "If I were a migraine-with-aura patient whose life is blighted by migraine, I'd be really interested in these results and think this a therapy that warrants further investigation."

The problem? PRIMA specifically enrolled patients with migraine with aura refractory to medical treatment, based on earlier studies suggesting that this was the group that was most likely to benefit. The trial's primary end point, however, was reduction in migraine days at one year, not migraine-with-aura days, a secondary end point in the study.

As press conference moderator, Dr George Dangas, put it, "One could presume that if you study migraine with aura, you are supposed to also measure migraines with aura, but somehow, instead, they measured total migraines."

But he tentatively agreed with Hildick-Smith, saying: "This is a small study, and the primary analysis does not support the primary hypothesis, but they identified a subgroup, which is very commonly used, that might benefit from treatment, and this subgroup now [could] be the focus of further investigation."

"Had the primary end point been set differently, this would have been a positive trial," Hildick-Smith said ruefully.

Primary Results From PRIMA

PRIMA investigators found 705 patients who consented to participate in the trial, which speaks to the number of people desperate for a solution to their incapacitating headaches: an estimated 55 million people across the US and Europe experience migraine, Hildick-Smith noted.

But of those 705 patients, a full 598 were not enrolled, having been found to have no PFO or no right-to-left shunt or because they subsequently decided against proceeding with the study or found that they responded to medication after all. That left just 107 who were randomized to either PFO closure or medical therapy where, again, there was further attrition, with only 45 of 53 randomized to the device actually agreeing to undergo the procedure. Of these, only 41 actually underwent PFO closure (patients withdrew consent, a PFO could not be found and, in one case, the implantation was aborted after atrial tachycardia developed).

At one year, mean reduction in headache days from baseline was 2.9 in the closure group and 1.7 in the medical-treatment group, a nonsignificant difference. For the secondary end point, however, reduction in migraine-with-aura days, closure patients saw reductions of 2.4 (from 4.1 at baseline), significantly more (p=0.01) than patients whose migraine-with-aura days declined just 0.6 from 4.0.

In other secondary end points, the "responder rate" was significantly greater in the PFO-closure group, as was the number of patients "free from migraine" and "free from migraine with aura."

A key message from PRIMA, said Hildick-Smith, is that interventional trials in migraine and migraine with aura are extremely difficult to do. He should know: Hildick-Smith was a coinvestigator for the controversial Migraine Intervention with Starflex Technology (MIST) trial that, when it was presented in 2006, appeared to have both negative and positive findings, depending on the end point used. The subsequent publication of the data, however, confirmed that none of the end points were positive. Trial sponsor NMT Medical, which had initially planned to continue with the MIST II trial, canceled the study and subsequently went out of business. A second manufacturer, St Jude Medical, closed down its ESCAPE PFO/migraine trial six years ago.

Dr Horst Sievert , a pioneer and long-time proponent in the field of PFO closure, said in today's press conference that he believes PRIMA was a "positive trial" and that further studies are still warranted, focused on the migraine-with-aura group.

"This shows for the first time that something is really going on," Sievert told the press.

PRIMA was not sham controlled—this was by design, Hildick-Smith told heartwire , saying it was deemed unethical to subject patients to the general anesthetic that a sham procedure would have necessitated, since the procedure can be done with a local anesthetic.

But this does raise the possibility of a powerful placebo effect among patients who received the intervention—a possibility Hildick-Smith agreed was conceivable but unlikely to last the full 12 months.

"If that's placebo effect, that's pretty impressive. Quite often you might expect that to wear off after the euphoria of having something done wears off and reality kicks in."

Of note, none of the secondary end points used to gauge patient satisfaction or quality of life were any different between the medically treated and PFO-closure groups.

Hildick-Smith disclosed grants/research support and consulting rees/honoraria from St Jude Medical. Dangas disclosed consultant fees/honoraria/speakers' bureau payments from AstraZeneca, the Medicines Company, Abbott Vascular, Medtronic, and Sanofi. Sievert disclosed grant support/research contracts from Abbott, Access Closure, AGA, Angiomed, Aptus, Atrium, Avinger, Bard, Biosense Webster, Boston Scientific, Bridgepoint, Carag, Cardiac Dimensions, CardioKinetix, CardioMEMS, Cardiox, Celonova, Coherex, Contego, Covidien, CSI, CVRx, EndoCross, ev3, FlowCardia, Gardia, Gore, GTIMD Medical, Guided Delivery Systems, Hemoteq, InSeal Medical, InspireMD, Lumen Biomedical, HLT, Lifetech, Lutonix, Maya Medical, Medtronic, NDC, Occlutech, Osprey, Ostial, PendraCare, pfm Medical, Recor, ResMed, Rox Medical, SentreHeart, Spectranetics, SquareOne, Svelte Medical Systems, Trireme, Trivascular, Vascular Dynamics, Venus Medical, Veryan, and Vessix.

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