Migraine Intervention With STARFlex Technology - MIST

Description:

The goal of this trial was to evaluate closure of patent foramen ovale (PFO) compared with a sham procedure in patients with refractory migraine headache.

Hypothesis:

Closure of a PFO with the STARFlex device will be more effective in reducing migraine headache.

Study Design

  • Randomized
  • Blinded
  • Patients Screened: 443
  • Patients Enrolled: 147
  • Mean Follow Up: 6 months
  • Mean Patient Age: 44 years
  • Female: 84%

Inclusion criteria:

  •  Migraine headache with aura in patients 18-60 years of age
  •  At least 5 migraine days per month with 7 or more days per month headache-free
  •  Failure of at least two classes of migraine medications due to intolerability or inefficacy

Exclusion criteria:

  •  Other cardiovascular defects
  •  Intracardiac thrombus
  •  Active endocarditis or other active infection
  •  Coagulopathy
  •  Elevated serum creatinine
  •  Platelet disorder
  •  Neurological disorder
  •  History of gastrointestinal bleeding
  •  End-stage liver disease
  •  Pulmonary arteriovenous malformation
  •  Contraindication to aspirin or clopidogrel
  •  Pregnant, planning to become pregnant, or nursing
  •  Presence of another indication for PFO closure such as recurrent stroke or decompression illness

Primary Endpoints:

  • Cessation of migraine headache 91-180 days after the procedure

Secondary Endpoints:

  •  Incidence of migraine
  •  Change in severity of migraine attacks based on MIDAS and HIT-6 scores
  •  Change in the frequency of migraine attacks
  •  Change in the characteristics of migraine
  •  Change in the severity, frequency, and character of migraine relative to effective closure rate or presence or residual leak
  •  Change in the quality of life

Drug/Procedures Used:

After general anesthesia, patients underwent transesophageal echocardiography to assess the interatrial septal anatomy. Patients were then randomized to PFO closure (n = 74) or a sham procedure that consisted of a skin incision (n = 73).

Concomitant Medications:

Patients received aspirin (300 mg) and clopidogrel (300 mg) 24 hours prior to the procedure and for 90 days after the procedure at a dose of 75 mg daily for both medications. Patients continued any prophylactic medication that they were on at the start of the trial.

Principal Findings:

Of the migraine patients referred for potential study enrollment, a right-to-left shunt from a moderate-to-large PFO was documented by transthoracic echocardiography in 38%. Any type of shunt, including atrial septal defect, was present in 60%. The mean number of migraine attacks in the 30 days prior to the procedure was 4.82 in the closure group and 4.51 in the sham group. No PFO was identifiable in 7% of the closure group. Residual moderate-to-large right-to-left shunt was present in four patients at 6 months. There were more serious procedural-related adverse events in the closure group (atrial fibrillation, n = 2; pericardial tamponade, n = 2; retroperitoneal hemorrhage, n = 1; and chest pain, n = 2).

Three patients in each group reported migraine cessation (p = 1.0). Similarly, for closure versus sham, there was no difference in any of the secondary endpoints; frequency of migraine attacks per month (3.23 vs. 3.52, p = 0.14), total MIDAS headache score (17 vs. 18, p = 0.88), or headache days per 3 months (18 vs. 21, p = 0.79).

No difference in treatment effect was noted, regardless of whether a residual shunt was present at follow-up. Two patient outliers accounted for one-third of the study headache burden. When these patients were removed from analysis, there was a reduction of 2.2 headache days per month in the closure group versus 1.3 days per month in the sham group (p = 0.027).

Interpretation:

This was the first randomized sham-controlled trial to study the effect of PFO closure in patients with refractory migraine. An important finding was that among migraine patients referred for analysis, some type of right-to-left shunt was documented in 60% (in 38% due to PFO). The primary outcome, cessation of migraine, occurred in three patients in each group. Secondary outcomes such as frequency of migraines and headache scores were also similar between the two groups.

When the two patient outliers were excluded from analysis, a difference was noted in the reduction of headache days favoring PFO closure; however, this finding should only be hypothesis generating since it was a post-hoc analysis.

Failure to detect a difference between treatment groups may have been at least partly explained by lack of adequate power. It is unknown if a longer duration of follow-up to allow for more complete healing of the defect would have also been beneficial. Additionally, patients continued prophylactic medications throughout the trial, which may have made it more difficult for the PFO device to show benefit. Additional trials on the topic are forthcoming.

References:

Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) Trial. A Prospective, Multicenter, Double-Blind, Sham-Controlled Trial to Evaluate the Effectiveness of Patent Foramen Ovale Closure With STARFlex Septal Repair Implant to Resolve Refractory Migraine Headache. Circulation 2008;117:1397-1404.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Noninvasive Imaging, Pericardial Disease, Congenital Heart Disease, CHD & Pediatrics and Imaging, CHD & Pediatrics and Quality Improvement, Echocardiography/Ultrasound

Keywords: Follow-Up Studies, Chest Pain, Heart Septal Defects, Atrial, Epilepsy, Foramen Ovale, Patent, Migraine Disorders, Headache, Cost of Illness, Echocardiography, Transesophageal, Cardiac Tamponade


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