Caveat Emptor: The Prospect of PFO Closure for Migraine

December 1, 2006

On March 13 at this year's meeting of the American College of Cardiology (ACC) in Atlanta, investigators from the United Kingdom unveiled the results of the Migraine Intervention with STARflex Technology (MIST) trial. The MIST trial is the first controlled study to examine the effect of patent foramen ovale (PFO) closure on migraine headache.

On March 13 at this year's meeting of the American College of Cardiology (ACC) in Atlanta, investigators from the United Kingdom unveiled the results of the Migraine Intervention with STARflex Technology (MIST) trial. The MIST trial is the first controlled study to examine the effect of patent foramen ovale (PFO) closure on migraine headache. Although the results were inconclusive, the MIST study marks a new phase in the PFO migraine story.

Since 1998, when Del Sette and colleagues1 reported a high prevalence of PFO in persons prone to migraine headache, the idea that PFO may be linked to migraine has been gathering steam. After the report by Del Sette and colleagues, several replications followed that showed a higher prevalence of PFO in persons with migraine--particularly those with migraine with aura--than those without migraine.2

PFO LINKED TO MIGRAINE WITH AURA

The foramen ovale, a flaplike aperture in the atrial septum, allows blood to flow directly from the right to left atrium during fetal life. It usually closes after birth but remains open in about 25% of the general population.3 In persons who have migraine headaches with aura, the prevalence of PFO approaches 50%.2 The strength of the association between migraine and PFO is not entirely clear; the types of patients and methods for assessing both PFO and migraines vary from study to study and, not surprisingly, so does the prevalence of PFO. But the published findings, now involving close to 1000 patients, consistently confirm that PFOs are more common in persons who experience migraine with aura.2

Intriguing though it is, this association does not in itself indicate that PFOs play a part in migraine headache, although what got the ball rolling was a series of independent observations that suggested that PFO closure relieved migraine headaches.4

For the majority of persons with PFO, this little gap in the atrial septum--more accurately a potential gap--has no hemodynamic or clinical significance. Because of its anatomic structure, blood does not usu-ally shunt through it from left to right, and right-to-left shunting occurs only when right atrial pressure rises, as in a Valsalva maneuver. But there is some evidence of a relatively high prevalence of PFO in persons who experience cryptogenic stroke and that presence of PFO is a risk factor for stroke.5 The theory is that a PFO allows blood clots to bypass the filtering capacity of the lungs and go directly to the left heart and then to the cranial circulation.6 Although there are no controlled data (clinical trials are under way but a long way from completion), the available clinical experience suggests that PFO closure reduces stroke recurrence.7

Recurrent cryptogenic stroke is the major indication for PFO closure. Although there is as yet no firm evidence to support the value of PFO closure in recurrent stroke, thousands of stroke patients have undergone this procedure. Some were migraineurs. In the late 1990s, a few cardiologists who had carried out percutaneous PFO closures received reports from patients that after PFO closure, migraine headaches decreased; in some instances they went away completely.

John Rhodes, MD, chief of clinical cardiology in the Department of Pediatrics at Duke University Medical College in Durham, North Carolina, is one such cardiologist. About 12 patients in whom he carried out PFO closure for cryptogenic stroke told him that after the procedure, their migraine headaches improved. Some patients said that their headaches stopped entirely. These accounts of headache improvement were "notable,"said Rhodes, who is now an investigator for the Effect of Septal Closure of Atrial PFO on Events of Migraine with Premiere (ESCAPE) trial. It is one of the controlled sham closure trials that just got under way.

The spontaneous reports of migraine improvement were followed by a series of systematic studies in which patients who had a history of migraine headache and were undergoing PFO closure for either cryptogenic stroke or decompression sickness were queried about the effect of PFO closure on their headaches. The published studies have been consistent in showing that most patients with migraine, with or without aura, experience substantial headache re- lief after PFO closure.4 On average, 55% of mi- graineurs reported that their headaches went away. However, these studies have been uncontrolled and retrospective.

Jonathan Tobis, MD, clinical professor of medicine and director of interventional cardiology research at the University of California at Los Angeles has had the same experience as Rhodes. Tobis is among the investigators who have examined migraine changes after percutaneous PFO closure. He found that after closure, 75% of migraineurs with aura and 40% of those without aura experienced complete headache resolution.8 Tobis told Applied Neurology that he has followed up with some patients for as many as 5 years and found that their migraine headaches do not return.

Others in the neurology community are still skeptical about the role of percutaneous PFO closure for the treatment of migraine. "The data are intriguing but we're dealing with anecdotal, unblinded, self-reported data--not to mention a possible placebo effect and the effect of postclosure aspirin and clopidogrel, which in and of itself can have an effect on migraines," Lawrence Wechsler, MD, professor of neurology and neurological surgery at the University of Pittsburgh School of Medicine, told Applied Neurology. He had made the same comment in October 2005 during a debate at the Cardiovascular Research Foundation's 17th annual Transcatheter Cardiovascular Therapeutics scientific symposium in Washington, DC.9

To the credit of all those who have a stake in the PFO-migraine connection, no one is yet suggesting that patients with migraine should start lining up for percutaneous PFO closure. Interventional cardiologists and the medical technology companies that make the closure devices are moving quickly to conduct rigorously controlled studies. In addition to the first MIST trial, at least 6 additional trials are either under way or in the planning stages.

The stakes are high. About 28 million persons in the United States experience migraine headache.10 Available preventive medications, including beta-blockers, antidepressants, and anticonvulsants, may produce uncomfortable adverse effects and do not necessarily resolve chronic migraine. If PFO closure proves to stop or substantially relieve migraine headache in even a minority of patients, the number of percutaneous PFO closures--now probably less than 5000 a year--could increase exponentially.

MIST TRIAL RESULTS DISAPPOINTING

The MIST trial results were, at first glance, disappointing. The study involved 147 patients who had treatment-refractory migraine with aura. Patients were randomly selected to receive either percutaneous closure or sham closure that involved general anesthesia and a femoral incision. As is routine after PFO closure, all patients received aspirin and clopidogrel for 3 months; researchers followed up with the patients for an additional 3 months. On the primary outcome measure, which was headache cessation, the closure and sham procedures yielded the same results: 3 patients in each group experienced complete headache cessation.

With respect to secondary measures, more patients in the closure group than the sham closure group experienced a 50% reduction in headache days (42% vs 23%, respectively; P < .038) and a decrease in headache "burden" (frequency 3 duration) (37% vs 17%, respectively; P < .038).11 Speaking for many, William H. Maisel, MD, MPH, a cardiologist at Harvard University, remarked, "This is clearly not the home run people were hoping for." In light of these findings, NMT Medical, the manufacturer of STARFlex, recently changed the primary end point for its second MIST trial from cessation of migraine headache to reduction of headache.

Tobis acknowledges that the MIST trial was not successful on its primary end point, but he remains hopeful about the potential benefit of PFO closure. The results of the MIST trial are "as good as you get with drugs," he said. He remarked that the trial had some serious shortcomings. The closure device used in the trial "is not as effective as some others," according to Tobis. He also mentioned that no data were presented on the adequacy of the closure, making it unclear whether the closures were in fact successful in all cases.

Rhodes commented that a longer follow-up period is needed. "In the first few months all sorts of things go on that could obscure the results," he said.

The new trials, including MIST II, are using different closure devices that may be more effective. The minimum follow-up period for the new trials is 1 year, and the trials include a more rigorous sham procedure, objective criteria for preclosure headache frequency and type, and a less ambitious primary end point of a reduction in headache frequency rather than complete cessation of headaches.

The results of the new controlled trials should be available within 2 years. These trials are noteworthy for the attention given to maintaining the double-blind design, the presence of independent boards to plan and monitor the studies and evaluate the data, and the rigor of the sham procedure. For example, in the Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the AMPLATZER PFO Occluder Compared to Medical Management (PREMIUM) trial, the sham procedure includes a right heart catheterization, intracardiac echocardiography for sizing of the PFO, and a guide wire inserted through the PFO. The sham surgery in previous studies has been far less invasive.

Institutional review boards have expressed concerns over the ethics of subjecting participants to this invasive sham procedure but have agreed that the studies should go forward. The general sentiment seems to be that every effort should be made to ensure that the results are interpretable and unambiguous.

But what if the results mirror those of the MIST trial? Will the concept of PFO closure for treatment of migraine be shelved? Vlad Zayas, MD, a clinical neurologist with a full-time private practice in East Providence, Rhode Island, doubts that PFO has anything to do with migraine. If there is a connection, "we would need to completely rethink the pathophysiology of migraine," he remarked. He said that he would not consider PFO closure as an intervention for migraineurs who present to him. "It's a procedure with significant morbidity and mortality for a condition that is not life-threatening; the gun is too big for the target," he commented.

Zayas is following the PFO migraine story "with great fascination." He told Applied Neurology that he had one patient with cryptogenic stroke who underwent PFO closure. The patient also happened to have migraine headaches. After PFO closure, the patient reported that his headaches stopped completely.

REFERENCES1. Del Sette M, Angeli S, Leandri M, et al. Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis. 1998; 8:327-330.
2. Schwedt TJ, Dodick DW. Patent foramen ovale and migraine--bringing closure to the subject. Headache. 2006;46:663-671.
3. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17-20.
4. Tsimikas S. Transcatheter closure of patent foramen ovale for migraine prophylaxis: Hope or hype? J Am Coll Cardiol. 2005;45:496-498.
5. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000;55:1172-1179.
6. Maisel WH, Laskey WK. Patent foramen ovale closure devices: moving beyond equipoise. JAMA. 2006;294:366-369.
7. Khairy P, O'Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med. 2003;139:753-760.
8. Azarbal B, Tobis J, Suh W, et al. Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol. 2005;45: 489-492.
9. Wood S. Use and abuse of PFO-closure devices: the debate goes on. Available at: www.theheart.org/article/583033.do. Accessed November 3, 2006.
10. Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41:646-657.
11. Wood S. Mixed results for PFO closure in migraine cloud interpretation of MIST. Available at: www.theheart.org/viewArticle.do?primaryKey=666025. Accessed November 3, 2006.