1. Why Treat Patent Forman Ovale Clifford J Kavinsky, MD, PHD Professor of Medicine and pediatrics Associate Director, Center for Congenital and Structural Heart Disease Rush University Medical Center

2. Conclusions PFO has been clearly demonstrated to be a source of Paradoxical thrombo-embolic stroke PFO is clearly more common in cryptogenic stroke patients PFO incidence decreases with age perhaps due to steady attrition secondary to PFO-mediated stroke Medical therapy seems ineffective in eliminating stroke risk Recurrent stoke is reduced after PFO device closure The recent RESPECT trial provides randomized clinical data to support PFO closure

3. The Case for PFO-Mediated Stroke The association between PFO and cryptogenic stroke has been identified in multiple epidemiological studies. In 1877, Cohnheim described the association of PFO with stroke in a young woman with cerebral arterial embolism. prevalence of PFO in the general population ranges from 15% to 25% In patients with cryptogenic stroke prevalence of PFO is 40% to 60%.

4. Thrombus “in-situ” Arch Intern Med. 1998;158(5):438-448

5. Relationship between PFO and stroke Circulation. 2005;112:1063-1072

6. Cryptogenic stroke in the general population Two population-based studies with 1,072 and 585 patients, have failed to demonstrate a relationship between PFO and stroke J Am Coll Cardiol. 2006;47:440-445.

7. Cryptogenic stroke in the general population These studies are underpowered given that there are only 50,000 estimated cases of cryptogenic stroke per year the United States Based on available census data, that computes to an incidence of one case per 6,000 individuals per year Much larger study populations would be needed to evaluate the relationship between cryptogenic stroke and PFO in the general population

8. Association of PFO with mortality Autopsy data of nearly 1,000 normal hearts from the Mayo Clinic reported an overall 27% incidence of PFO –The incidence of PFO in patients younger than 30 years was 34% –Patients aged 31 to 80 years, the PFO incidence decreases to 25% –Patients aged 81 to 99 years, the incidence of PFO was 20% –Conclusion: PFO is associated with ongoing excess mortality with increasing age Hagen et al 1984 May Clin Proc 59:17

9. Medical Management Multiple nonrandomized, prospective follow-up studies have suggested that there is no benefit associated with anticoagulation therapy (Warfarin) over antiplatelet therapy PICSS study remains the only randomized controlled trial comparing Aspirin to Warfarin as medical therapy for PFO-associated stroke 2-year recurrent stroke/TIA rates were similar in the warfarin and aspirin cohorts (16.5% vs 13.2%; P =.65).

10. Device Closure Evidence for a decrease in the recurrent stroke and TIA rates in patients with a history of cerebral events who subsequently undergo PFO closure can be found in a large number of nonrandomized single-center experiences Event rate in the year before closure is compared to the event rate in the year after closure. The event rates before closure range from 2% to 26%, and the range of recurrent events after closure is between 1% and 2.5%

11. Device Closure Landzberg and Khairy reported a compilation of 20 studies with 2,250 patients with an adjusted 1-year stroke and TIA rate of – 7.07% before closure and – 2.71% in the year after closure – 62% reduction Homma and Sacco meta-analysis of 26 studies involving 2,534 patients with recurrent event rates per 100 patient years of – 4.86% in the medical therapy group – 2.95% in the percutaneous closure group – 39% reduction Wöhrle reported an analysis of 20 studies involving 3,014 patients.1-year recurrence rate for stroke or TIA was – 5.6% in the medical therapy group – 1.3% in the device closure group – 77% reduction Homma S and Sacco R 2005 Circ 112:1263 Landzberg M and Khairy 2004 Heart 90:219 Whorle J 2006 Lancet 368:350

12. CLOSURE I Multicenter, randomized, open label trial comparing percutaneous PFO device closure to medical therapy Cryptogenic stroke or transient ischemic attack (TIA) in patients 18-60 y/o Primary Endpoint- Stoke/TIA during 2 year followup, death from any cause during first 30 days, neurologic death to two years

13. CLOSURE I Trial 909 patients enrolled –447 underwent closure with StarFlex, then treated with Clopidogrel 75 mg daily x 6 mo and Aspirin 81 or 325 mg x 2 years –462 patients received medical therapy alone: Warfarin (target INR 2-3), aspirin 325 or both at the discretion of the operator

14. Results Primary Endpoint- 5.5% in device closure group 6.8% in medical therapy group P=0.37

15. Multicenter: 69 Sites (62 US, 7 Canada) –Prospective, 1:1 Randomized Closure with the AGA AMPLATZER™ PFO Occluder plus medical therapy Medical Treatment Regimens: Aspirin, Warfarin, Clopidogrel, Aspirin + Dipyridomole, Aspirn + Clopidogrel (removed from protocol in 2006) 980 patients enrolled with clinical stroke confirmed by CT/MRI imaging age 18-60 within 9 months TEE documented PFO Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment

16. Primary Endpoint Recurrence of a nonfatal ischemic stroke or fatal ischemic stroke or early post-randomization death defined as all-cause mortality –Device Group – within 30 days after implant or 45 days after randomization, whichever occurs latest –Medical Group – within 45 days after randomization

17. Results

21. REDUCE Multicenter prospective randomized trial – 2:1 Randomization Closure with Gore Helex device Standardized medical therapy

22. Other Diseases Migraine headaches, Decompression sickness Peripheral embolism including myocardial and renal infarction Alzheimer’s dementia. Worsen symptoms in patients with chronic lung diseases associated with hypoxemia, or obstructive sleep apnea/sleepdisordered breathing.

23. Conclusions PFO has been clearly demonstrated to be a source of Paradoxical thrombo-embolic stroke PFO is clearly more common in cryptogenic stroke patients PFO incidence decreases with age perhaps due to steady attrition secondary to PFO-mediated stroke Medical therapy seems ineffective in eliminating stroke risk Recurrent stoke is reduced after PFO device closure The recent RESPECT trial provides randomized clinical data to support PFO closure