1. PFO Closure: Review of the Trials for Migraine CRT 2013
Washington, DC, USA, Feb 23-26, 2013
10min
PFO Closure:
Review of the Trials
for Migraine .
Horst Sievert, Ilona Hofmann,
Laura Vaskelyte, Stefan Bertog,
Simon Lam, Sameer Gafoor
CardioVascular Center Frankfurt - CVC
Frankfurt, Germany

2. Horst Sievert, MD Consulting:
AccessClosure, Inc., AGA Medical Corporation, Ardian, Inc., Arstasis, Inc., Atritech Atrium Medical Corporation, Avinger, Inc., Bard Peripheral Vascular, Inc., Boston Scientific Corporation, Bridgepoint, CardioKinetix Inc., CardioMEMS, Inc., Coherex, Inc., Contego, CSI, EndoCross, Endotex Interventional Systems, Epitek, Evalve, Inc. and ev3, Inc.

3. Horst Sievert, MD Consulting:
FlowCardia, Inc., Gore, Guidant, Lumen Biomedical,
Inc., HLT, Kensey Nash Corporation, Kyoto Medical, Lifetech,
Lutonix, Inc., Medinol, Medtronic, Inc., NDCNMT Medical, Inc.,
OAS, Occlutech Osprey Medical, Inc., Ovalis, Inc., Pathway
Medical Technologies, Inc., PendraCare International B.V., Pfm
Medical, Inc., Rox Medical, Recor, Sadra Medical, Sorin
Biomedica Cardio S.R.L.,and Spectranetics Corporation, Trireme, Trivascular and Viacor, Inc.

4. Horst Sievert, MD
Honoraria: Veryan, Ardian, Inc., Atritech, Atrium Medical Corporation, Boston Scientific Corporation, CardioKinetix Inc.,
CardioMEMS, Inc., Coherex, Inc., Contego, Epitek, Evalve, Inc.,
Guidant,Gore,Kyoto Medical, Lutonix, Inc., Medinol, Medtronic, Inc., Pfm Medical, Inc., and Spectranetics Corporation.

5. Horst Sievert, MD
Honoraria: Viacor, Inc., HLT, Lifetech, Recor, Trivascular, Veryan, CVRx, GDS and InSeal Medical.

6. Facts about Migraine 12 % of the population Women: Men 3:1
Economic cost
in UK 1992: >£650 million/year Cull et al, Br Med Econ, 1992
In US 1999: $14.6 billion (medication, missed work days, and lost productivity)
Lipton, Bigal et al, Am J Med 2005;118:3S-10S
Cull et al, Br Med Econ, 1992
Hu et al. Arch Intern Med 1999;159:813-8

7. Migraine is More Common than Asthma & Diabetes Combined
The pervasiveness of migraine becomes more understandable when its prevalence is considered in the context of the prevalence of other common diseases. Data from the Centers for Disease Control show that migraine is more prevalent than several other common chronic diseases including rheumatoid arthritis, asthma, diabetes, and osteoarthritis. With a prevalence of 12% in the United States, migraine is more common than asthma and diabetes combined.
Data from the Centers for Disease Control and Prevention, US Census Bureau, and the Arthritis Foundation.

8. PFO PFO and Migraine? Stroke PFO is frequent in stroke
Migraine is frequent in stroke
PFO is frequent in Migraine
Causal or coincidental ?
PFO
Migraine

9. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke?
Is PFO associated with migraine?
Does migraine improve after PFO closure?

10. Is PFO associated with stroke?
Yes!

11. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke?
Is PFO associated with migraine?
Does migraine improve after PFO closure?

12. Migraine in cryptogenic stroke
No PFO
PFO
Lamy et al 2002
14%
27%
Sztajzela et al 2002
13%
52%
Cryptogenic stroke patients without PFO  Average incidence of migraine
Cryptogenic stroke patients with PFO  High incidence of migraine

13. Migraine in cryptogenic stroke
No PFO
PFO
Lamy et al 2002
14%
27%
Sztajzela et al 2002
13%
52%
Cryptogenic stroke patients without PFO  Average incidence of migraine
Cryptogenic stroke patients with PFO  High incidence of migraine

14. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke? – Yes!
Is PFO associated with migraine?
Does migraine improve after PFO closure?

15. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke?
Is PFO associated with migraine?
Does migraine improve after PFO closure?

16. PFO in Migraine Patients%

17. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke?
Is PFO associated with migraine? – Yes!
Does migraine improve after PFO closure?

18. PFO and Migraine? Is PFO associated with stroke?
Is Migraine associated with cryptogenic stroke?
Is PFO associated with migraine?
Does migraine improve after PFO closure?

19. Wilmshurst PT et al. Lancet 2000; 356: 1648-1651
37 patients with PFO/ASD closure
due to stroke (4), diving (29), ASD (4)
21 had migraine (16 aura, 6 without)
18 improved
10 cured

20. Migraine without aura (n=12) 62 % 15 % 23 %
Migraine reduction after PFO closure Reisman et al. J Am Coll Cardiol 2005; 45: 493-5
Complete Resolution
>50% Reduction
< 50% Reduction
Overall (n=50)
56 %
14 %
30 %
Migraine/Aura (n=38)
54 %
32 %
Migraine without aura (n=12)
62 %
15 %
23 %
PFO closure performed to prevent recurrent stroke
Mean FU 37±23 weeks

21. 215 patients with PFO closure
Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks Schwerzmann et al Neurology 2004 Apr 27; 62 (8):
215 patients with PFO closure
for stroke prevention
48 with migraine
With aura: 54% decrease of no. of attacks
Without aura: 62% decrease
Non-migraine headaches:
PFO closure had no effect

22. Azarbal B et al JACC 2005;45:489-92 89 stroke pts 42% with Migraine
66 PFO & 23 ASD
42% with Migraine
60% cured (75% Migraine with aura)
40% had improvement

23. Morandi E et al. J Interven Cardiol 2003; 1: 39-42
P<0.01
Migraine Score
PFO Closure

24. Number of Migraine Attacks and MIDAS Score
Duration of follow-up 4.8±1.4 years
p<0.0001
N=38
Giardini A et al. Catheter Cardiovasc Interv 2006;67:625-9.

25. … in particular if the PFO was closed to prevent recurrent stroke
Several other case series and also prospective non-randomized trials have shown a benefit of PFO closure in migraine …
Autor
Year N
Resolved
improved
Post
2004 26
84%
Kimmelsteil
2007 41
83%
Dubiel 46
24%
87%
Vigna
2009 82
34%
89%
… in particular if the PFO was closed to prevent recurrent stroke

26. How might PFO Closure help against Migraine?
Paradoxical microemboli?
Vasoactive chemicals bypassing lung filtration?
amino acid ??
steroid??
Prostaglandin 2 ??
Wilmshurst et al. Clin Sci 2001;100:215-20
Tobis & Azarbal Curr Issues in Cardiol 2005;32:362-5:

27. The MIST trial was the first randomized trial PFO closure vs sham procedure in migraine patients who did not have a stroke …
… and it was negative

28. MIST: Very high prevalence of PFO in migraine
result
total # %
total studied
432
100
small shunts (atrial and pulmonary) 72
16.7
large pulmonary shunt 22
5.1
ASD 3
0.7
large PFO
163
37.7
large shunts (all types)
188
43.5
total shunts
260
60.2
Prevalence of large shunts was approximately six times greater than in the general population

29. MIST - Cure of Migraine Primary Endpoint
% of patients
n.s.

30. 50% Reduction in Headache Days
% of patients
n.s.
Exploratory analysis

31. 50% Responder rates 60% Drug Trial – Active 54% Drug Trial – Placebo
MIST – Active
49%
50%
49%
MIST – Control
44%
43%
42%
40%
37%
30%
20%
21%
23%
23%
23%
23%
23%
16%
10% 0%
Gabapentin
Divalproex
Topiramate I
Topiramate II
Topiramate III
Propanolol
MIST
Mathew NT, et al. Headache. 2001;41: Brandes JL, et al. JAMbA. 2004;291: Klapper J. et al. Cephalalgia. 1997;17: Silberstein SD,, et al.. Arch Neurol. 2004;61: Diener HC, et al., J. Neurol. 2004;251: b

32. MIST – Adverse Events
Dowson et al, Circulation 2008

33. MIST II ESCAPE US ESCAPE EU
3 other migraine trials have been stopped due to slow enrolment and/or lack of funding
MIST II
ESCAPE US
ESCAPE EU

34. PRIMA Amplatzer PFO occluder for migraine therapy
Randomized multicenter study, unblinded
Primary endpoint: Reduction of migraine days
Ongoing

35. So should we routinely close PFOs to prevent migraine?
Not yet!

36. But we do it occasionally

37. Catheter Interventions
in Congenital
and Structural
Heart Disease
Case 19
Patent Foramen Ovale, Migraine
J.R., male,51 y.
Jan 2006
"I have had migraines since I was about 10. Aura, blindness, the lot. Starting about 18 years ago, I got them every single day for 8 years. After getting some relief with medications, I’ve managed to survive and continue a productive life, but the pain every week is truly debilitating. But I have now tried over 30 medications, some with disastrous side effects, and have now pretty much run out of options. Over the last 5 years I am getting migraines typically 4-5 times a week, not always with an aura and blindness, and of variable intensity (from annoying but tolerable to force 10 (where I can’t control screaming in private). About 10 per month are considered to be of disruptive pain level……
In case you are worried that I have my hopes so set on this that I will not fare well should it not be the cure I seek, please be assured that I am indeed optimistic and hopeful, but am realistic about the prospects. ….!"
Patient no 19 is a 51 years old patient from the US who has a PFO and is suffering from migraine since decades.
He send a letter some months ago and I will just read a few sentences of this letter:
DANN DEN TEXT LESEN
You will found the letter in the syllabus with more details of the patients history and symptoms

38. Jan 2007
It is irrefutable that it has made a HUGE improvement. Of course I was hoping for a total cure, but this partial relief has helped enormously. Again, the most important factor for me is not so much the severity or length but the number of totally migraine-free days. When I recall that for 8 years, that number was ZERO, this change to as many as 50 in a 3-month period is just HUGE

39. The migraine – PFO story will continue to cause headache
There is no question:
The migraine – PFO story will continue to cause headache