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

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.

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.

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.

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

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

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.

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

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?

Is PFO associated with stroke? Yes!

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?

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

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

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?

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?

PFO in Migraine Patients %

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?

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?

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

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

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): 1399-1401 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

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

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

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.

… 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

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:

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

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

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

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

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;41:119-128. Brandes JL, et al. JAMbA. 2004;291:965-973. Klapper J. et al. Cephalalgia. 1997;17:103-108. Silberstein SD,, et al.. Arch Neurol. 2004;61:490-495.Diener HC, et al., J. Neurol. 2004;251:943-50.b

MIST – Adverse Events Dowson et al, Circulation 2008

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

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

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

But we do it occasionally

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

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

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