1. PFO closure: Review of the Trials for Migraine
Saibal Kar, MD, FACC, FAHA, FSCAI
Heart Institute, Cedars-Sinai Medical Center,
Los Angeles, CA
CRT 2015

2. Conflicts
Research Grants from Gore Medical
Consultant : Gore Medical

3. Association of Migraine and PFO
1. Migraine headache affects 12% of population (18%F - 6%M) or 27 million people in USA
2. Incidence of PFO in pts with migraine:
48% if migraine with aura 1
23% if migraine w/o aura and % in controls
3. Incidence of Migraine in pts with Cryptogenic Stroke and PFO:
52% had migraine with aura2
10 of 14 (71%) had suppression post closure3
4. Migraine pts have 13x incidence of MRI lesions4
Anzola, Neurology 52(8):1622-5, 1999
Sztajzel, CV Diseases 13(2):102-6, 2002
Wilmshurst, Lancet 356(9242): , 2000
Kruit, JAMA 294(4): , 2004

4. PFO and Migraine Association of Migraine and PFO
Association of migraine and stroke
PFO closure reduced headaches in stroke pts with a history migraine
PFO
Paradoxical
Embolism
Shunted Hypoxic Blood
Unidentified Neuropeptides
Migraine
Stroke & White Matter Lesions

5. PFO closure for Migraine : Clinical evidence
Observational Studies
Studies showing the incidence of PFO in Migraine patients
Studies showing relief of Migraine in patients who had PFO closed for other indications
Randomized Clinical trials
MIST Trial ( completed)
PREMIUM Trial ( Ongoing)

6. Observational Studies Effect of PFO closure on migraine
Study
Incidence of Migraine
% migraine improved or cured
Length of follow up (months)
Wilmshurst 2000
21/ (57%)
86%
up to 30
Morandi 2003
17/ (27%)
88%
all 6
Schwerzmann 2004
48/ (22%)
81%
all 12
Post 2004
26/ (39%)
65% cured
Reisman 2005
57/ (35%)
70%
Azarbal, Tobis 2005
37/ (42%)
76%
mean 18
Total: 206/631 (33%) %

7. MIST Trial
Circulation Mar 18;117(11):

8. MIST Trial 135 Migraine with Aura pts with PFO randomized
Primary Endpoint: Cessation of Migraine attack(MHA)
3 pts in device and 3 in control group
Secondary Endpoint: 50% reduction of MHA days
Device : 42% of pts
Control: 23 % of pts
PFO closure effectiveness data: controversial
p < 0.04
Circulation Mar 18;117(11):

9. MIST Migraine Intervention with StarFlex Technology Adverse Events
Study Arm
(N=74)
Adjudicated Relationship to Device, Procedure, or Medications
A Fib with aberrant conduction
Implant
Possible Device
Tamponade
Procedure
Pericardial Effusion
Retroperitoneal Bleed
Chest Pain
A Fib
Possible Device, Procedure, Meds
Stroke
Sham
None
Groin Ooze
Procedure/Possible Meds
Dowson et al. Circulation Mar 18;117(11):

10. Predictors of clinical improvement following PFO closure: a retrospective survey OBJECTIVES
Major Objective:
Identify a candidate population of migraineurs in whom PFO closure may be ideally studied
Specific Objective:
Determine the influence of migraine phenotype on headache response to PFO closure

11. Survey Structure Institutional IRB Approved
Patients with PFO Closure > 6 mos before survey
- Intermountain Medical Center
- UCLA
Mailed invitation directing them to internet based survey
Unique identifier linked to medical record
Informed consent acknowledgement required to begin survey
Patients reporting migraine and who answered migraine disability questions included

12. Baseline Variables for Analysis
Definition
Gender
Age
Interval Between Procedure and Survey
< 2 yrs vs. > 2 yrs
IHS Defined Migraine
Affirmative response to a) two of the following four questions: unilateral location, pulsating quality, moderate or severe intensity and aggravation with movements, and b) associated with nausea, vomiting, photophobia or phonophobia.
Frequency
Episodic
Chronic
0-1, 1-5, or 6-15 migraine days/month
16-25 , or > 25 migraine days/month
Aura
Migraine with aura
Aura without headache
Migraine without aura
Affirmative response to inquiries regarding any of the following visual disturbances: a) zig-zag lines, b) distortion in size or shape of objects, c) tunnel vision, d) kaleidoscope effect, and e) dark or blind spots
Affirmative response to aura defined above without headache
IHS defined migraine but no aura
Triggers
Potential shunt related
Agitated Saline
No Trigger or non-shunt
Exercise, sexual intercourse, bending, lifting, straining, agitated saline
Bubble echo or TCD
Menses, alcohol
Baseline HIT 6 Score
< HIT-6 56 vs. > HIT-6 56

13. Endpoints Primary Composite Endpoint: Clinical Improvement
Improvement of HIT-6 Score > 5 points &
Improvement of migraine frequency > 1 category
Secondary Endpoints:
1) Change in HIT-6 defined disability
2) Change in migraine frequency categories
3) Aggregate Population changes in disability and frequency

14. Migraine Frequency & Migraine Associated Disability
Endpoints
Migraine Frequency & Migraine Associated Disability
How many days in an average month did you experience migraine headaches?
Before PFO closure
0-1
2-5
6-15
16-25
>25
How many days in an average month do you experience migraine headaches?
Now?
0-1
2-5
6-15
16-25
>25

15. HIT-6 and Freq Improvement % Did not have improvement %
Primary Composite Endpoint - Clinical Improvement
(HIT-6 reduction > 5 & > 1 Migraine Frequency Category Improvement)
HIT-6 and Freq Improvement %
Did not have improvement %
p-value
Total Population (n=236) 67 33
Gender
Female (n=184)
Male (n=52) 64 36
0.613
Age
Age >44 years old (n=82)
Age ≤44 years old (n=82) 63 60 37 40
0.72
Closure to Survey Interval
>2years
≤2years 61 39
1.000

16. Summary Observations I
This is a unique retrospective report given sample size, frequent primary indication of migraine, long-term follow up.
The majority of patients (75%) demonstrated both diminished migraine frequency and clinically meaningful improved migraine disability following PFO closure.
With a mean follow up of 1235 days and no difference between patients closed < or > 2 years before the survey, the benefits of PFO closure were durable.
Relative benefit among those with agitated saline induced migraine and potentially shunt associated triggers is consistent with a shunt hypothesis of migraine.

17. Summary Observations II
Patients with International Headache Society defined migraine demonstrated greater benefit than those with self-reported migraine who failed to meet the IHS definition.
Patients suffering migraine with aura demonstrated a trend towards greater benefit than those without aura. The power to detect this benefit was limited by the small population without aura (17%).

18. Conclusions
Patients suffering with chronic migraine and marked migraine associated disability:
- were most likely to derive clinical benefit
- derived the greatest magnitude of clinical benefit
Additional research of PFO closure among patients with chronic migraine and severe migraine associated disability is warranted.

19. PREMIUM Trial

20. The PREMIUM Trial randomize
A Randomized Double Blind Trial of PFO Closure for Severe Migraine Headaches
230 patients with migraine ± aura
assess for PFO with TCD, if +, TTE
Usual HA Rx +
Sham Procedure
PFO Closure
randomize
1o Endpoint: 50% reduction in migraine attacks
2o Endpoints: % pts with resolution of HA, # days with HA
Adverse Events: due to Amplatzer device, procedure, or meds

21. Conclusions
There is an association of severe migraine and presence of a Patent Foramen Ovale
Observational studies have shown improvement of migraine following closure of the PFO for other indications
One randomized study did not show a clear cut benefit of PFO closure with the StarFlex Device compared to sham procedure
Issues regarding device effectiveness and side effects
The end points bar was set to high

22. Conclusions
The PREMIUM Study using the Amplatzer PFO occluder is still ongoing and will shed further information regarding the role of PFO closure for patients with severe Migraine