Migraine Intervention with STARFlex Technology (MIST) Trial

1. MIST Trial Migraine Intervention with STARFlex Technology (MIST) Trial Presented at The American College of Cardiology Scientific Session 2006 Presented by Dr. Andrew Dowson

2. MIST Trial: Background • Prior retrospective studies have shown that closure of a PFO may be associated with reductions in the frequency and intensity of migraines • The STARFlex Septal Repair Implant is used to non-surgically close the Patent Foramen Ovale (PFO) and is deployed via a catheter • It was hypothesized that closure of a PFO will be associated with reductions in migraines among patients with a PFO who suffer from migraines Presented at ACC 2006

3. MIST Trial: Study Design 432 patients screened age 18-60: One year medical history of migraines with aura; migraine with aura at least 5 times per month; free of headaches at least 7 days per month; failed to achieve therapeutic effect with two classes of prophylactic medication Placebo-controlled. Randomized. 84% female, mean age 44 years, mean follow-up 6 months Transesophageal echocardiogram to confirm that PFO is suitable for closure (n=147) PFO closure with the STARFlex Septal Repair Implant (n=74) Sham procedure control group (n=73) Aspirin and clopidogrel (3 months) • Primary Endpoint: Absence of migraine during three month follow-up after clopidogrel discontinuation Presented at ACC 2006

4. MIST Trial: Migraine Screening • Among the 432 patients screened for this trial, 60.2% had an atrial right-to-left shunt, a value that is much higher than in the general population. • A large atrial shunt was seen in 37.7% of patients, a small shunt in 16.7% , and no shunt in 39.8%. • Prior population studies have shown that PFOs are present in 27% of the population and large PFOs are present in 7%. • The mean diameter of PFO in this trial was 9.21 mm. Presented at ACC 2006

5. MIST Trial: Primary Endpoint Complete Cessation of Migraines (n) p=NS • There was no difference between groups in the primary endpoint of complete cessation of migraines with 3 patients in each group. # of patients Presented at ACC 2006

6. MIST Trial: PCI Reduction in headache days by at least 50 percent (%) p=0.038 Reduction in headache burden (%) p=0.033 • Reduction in headache days by 50% was significantly greater in the PFO closure group than in the sham procedure group (42% vs. 23%, p=0.038). • Reduction in headache burden, defined as the frequency of headaches times the duration, was significantly greater in the PFO closure group than in the sham procedure group (37% vs. 17%, p=0.033). Presented at ACC 2006

7. MIST Trial: Limitations • The primary endpoint of headache cessation, a relatively difficult end point to reach, may have been too ambitious for such a small trial with only a 6 month follow-up. • Migraine improvement tends to increase over time so a longer follow-up may be warranted. • It may be necessary to identify the type of headache that is most affected by PFOs. • Also it may be of importance to identify the type of aura, frequency of aura, and migraine triggers for further examination. Presented at ACC 2006

8. MIST Trial: Summary • Among migraine sufferers, PFO closure was not associated with a difference in total migraine cessation compared with the sham procedure. • Reduction of headache frequency by 50% occurred more often in the PFO closure group and reduction in headache burden was also greater in the PFO closure group. Presented at ACC 2006