Author + information
- Babikir Kheiri, MD,
- Ahmed Abdalla, MD,
- Mohammed Osman, MD,
- Sahar Ahmed, MBBS,
- Mustafa Hassan, MD,
- Ghassan Bachuwa, MD and
- Deepak L. Bhatt, MD, MPH∗ ()
- ↵∗Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115
Previous studies have reported the association of patent foramen ovale (PFO) with migraine. Up to 50% of patients with migraine with aura have demonstrated evidence of a right-to-left shunt (RLS) by transcranial Doppler (1). The mechanism underpinning this association has been postulated to be paradoxical microemboli, chemicals (bypassing the lungs’ metabolism), and low blood oxygen content reaching the brain via RLS, triggering migraine (1,2). We conducted a systematic search of electronic databases for all randomized controlled trials that evaluated the efficacy and safety of PFO closure in adult patients with migraine. Two authors (B.K. and A.A.) extracted those data, and RevMan version 5.3 Windows was used for statistical analysis. Using the Mantel-Haenszel method for random effects, aggregated risk ratios and heterogeneity (I2) were calculated.
We included 3 randomized controlled trials with 448 total patients (10 months mean follow-up) (3–5). The results showed a significant reduction in the mean average of migraine attacks (mean difference: −0.54; 95% confidence interval: −0.63 to −0.45; p < 0.01) and days per month (mean difference: −1.33; 95% confidence interval: −2.32 to −0.33; p < 0.01) in the PFO closure group. However, there was no significant difference in subjects who had complete cessation of migraine attacks (p = 0.14) (Figure 1A). In addition, there was no significant difference in the development of new atrial fibrillation between both groups, although the number of events was numerically higher in the closure group (p = 0.18) (Figure 1B).
In the first trial, MIST (Migraine Intervention With STARFlex Technology) (4), 432 patients were assessed for an RLS. A shunt was detected in 260 patients (60%) and 163 patients (38%) were interpreted as having at least a moderate or large PFO. The investigators failed to demonstrate significant migraine cessation with STARFlex implant (NMT Medical Inc., Boston, Massachusetts) in comparison with a sham group (p = 0.51). However, PFO closure resulted in a greater reduction in total migraine days (p = 0.027). The PRIMA trial (Percutaneous Closure of PFO in Migraine with Aura) (5) enrolled patients with migraine with aura. Of the 705 patients, 329 patients (47%) had confirmed RLS and PFO. Although the mean monthly migraine days with and without aura were less in the Amplatzer PFO Occluder (St. Jude Medical, Plymouth, Minnesota) group versus the nonsham group by 1.2 days, the results were not significant (p = 0.17). However, the device significantly improved the responder rate (≥50% reduction of migraine days; p = 0.02) and significantly reduced the migraine with aura attacks and days per month with complete cessation in 40% (vs. 10% control group; p < 0.01, p = 0.01, and p < 0.01, respectively). In the PREMIUM trial (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the Amplatzer PFO Occluder to Medical Management) (3), 230 patients were enrolled. Although 10 of 117 (8.5%) closures resulted in complete freedom of migraine, the investigators failed to achieve their primary endpoint of significant improvement in responder rate (≥50% reduction of migraine attacks) with PFO closure (45 of 117 vs. 33 of 103; p = 0.32). Interestingly, in subgroup analysis of subjects with frequent aura migraines (>50% episodes), the device significantly improved the responder rate in 49% (vs. 23% control group; p = 0.015). In addition, this subgroup had a significant complete cessation of their migraines attacks (15.4% vs. 2.5%; p = 0.04).
The Clinical Trials Subcommittee of the International Headache Society recommends using the number of migraine attacks and days per evaluation interval as a primary efficacy measure (3). This meta-analysis demonstrated that in patients with PFO and migraine, percutaneous device closure might reduce the average migraine days and the total number of attacks (both p < 0.01). However, it should be noted that none of these trials were powered to detect these clinical outcomes. Therefore, adequately powered sham-controlled trials are warranted before use of PFO closure for migraine prevention.
The authors thank Katherine Negele, editorial assistant, research department, Hurley Medical Center/Michigan State University, for assistance with manuscript editing.
Please note: Dr. Hassan has received a research grant from Abbott. Dr. Bhatt serves on the Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; serves on the Board of Directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; is the Chair of American Heart Association Quality Oversight Committee; serves on the Data Monitoring Committees of Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); has a relationship with Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); has received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); is a Site Co-Investigator for Biotronik, Boston Scientific, and St. Jude Medical (now Abbott); is a Trustee of American College of Cardiology; and has received unfunded research from FlowCo, Merck, PLx Pharma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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