Long-Term Comparison of Medical Treatment With Percutaneous Closure of Patent Foramen Ovale for Secondary Prevention of Paradoxical Embolism: A Propensity-Score Matched Comparison Andreas Wahl*, Fabien Praz*, Bindu Kalesan †, Marie-Luise Mono #, Laura Geister #, Krassen Nedeltchev #, Lorenz Räber*, Heinrich P. Mattle #, Peter Jüni †, Stephan Windecker*, Bernhard Meier* Departments of Cardiology* and Neurology # and Clinical Trials Unit † Bern University Hospital, Switzerland

Conflicts of Interest Research grants Lecture and consultation fees –AGA Medical, Plymouth, MN, USA

Stroke and Patent Foramen Ovale Stroke remains the 3 rd leading cause of mortality and the leading cause of serious disability 40% of strokes remain cryptogenic despite extensive diagnostic evaluation PFO associated with (cryptogenic) stroke Patients with stroke presumably related to PFO are at increased risk for recurrent cerebrovascular events despite medical treatment –1-12% events per year –Higher risk among patients with associated atrial septal aneurysm –Bleeding risk associated with medical treatment –Need for long-term treatment

PFO and Cryptogenic Stroke Risk of recurrence in patients with PFO and (cryptogenic) stroke Best therapeutic measure to prevent recurrence Cause-effect relationship between PFO and (cryptogenic) stroke

PFO as Predictor of Adverse Outcome in Patients With Major Pulmonary Embolism Konstantinides S et al. Circulation 1998;97:1946 PFO as Predictor of Adverse Outcome in Patients With Major Pulmonary Embolism Konstantinides S et al. Circulation 1998;97: PFO: independent predictor of mortality - Suggested mechanism: paradoxical embolism 139 patients with major pulmonary embolism undergoing TEE 35% with PFO 59 ± 17 ( ) years Clinical endpoints death cerebral embolism arterial thrombo-embolism major bleeding

Das RR, Stroke. 2008;39: Silent Cerebral Infarctions (by MR) 2,040 Framingham Offsprings (53% female; mean age, 62±9 years)

Prevalence of PFO According to Age Age (years) PFO in 263/965 autopsies (mean 27%) Y= x R 2 =0.6, p=0.008 Hagen PT, Mayo Clin Proc 1984; 59: Selective mortality? %

Percutaneous PFO Closure Percutaneous PFO closure has been shown to be safe and efficacious using several devices - Small procedural risk - Minimal long-term risk - Satisfactory closure rate - Acceptable cost (outpatient procedure) Observational, non-randomized data suggest a lower risk of recurrence as compared to medical treatment alone No randomized trial published to date Limitations of ongoing randomized trials - High risk patients closed with device, not randomized - Follow-up too short

Objective To assess the therapeutic benefit of percutaneous PFO closure as compared to medical treatment alone in a population of consecutively treated patients with stroke presumably related to PFO during long-term follow-up to 15 years in a propensity-score matched analysis

Patient Population Inclusion Criteria All patients with ischemic stroke or TIA, confirmed clinically or radiologically at the University Hospital of Bern Stroke Center between January 1994 and August 2000 were prospectively entered into the stroke/PFO registry if they had - PFO ± atrial septal aneurysm (contrast TEE) Exclusion Criteria Obvious other cardiac, aortic, or cerebrovascular cause Treatment decision Based on consensus among neurologist and patient

Sample Size Considerations Primary Endpoint Composite of stroke, TIA, or peripheral embolism Propensity-score matching –Assumption to be able to match 75% of patients of the entire cohort (N=308) would result in 113 pairs Assumed event rates –Medical treatment: 25% at 10 years –Percutaneous PFO closure: 10% at 10 year Estimated power –80% power: detect a relative risk of 0.40 –60% power: detect a relative risk of 0.50 –40% power: detect a relativ risk of 0.60 Secondary Endpoints Death, ischemic stroke, TIA, peripheral embolism Bleeding complications

Patient Flow – Intention to Treat Analysis 308 Patients Jan – Aug Medical treatment alone 158 patients Medical treatment alone 158 patients Percutaneous PFO closure 150 patients Percutaneous PFO closure 150 patients Medical treatment alone 103 Patients Medical treatment alone 103 Patients Percutaneous PFO closure 103 Patients Percutaneous PFO closure 103 Patients Clinical Follow-up Median 10.3 years 1,170 patient-years1,011 patient-years After Propensity Score Matching 206 Patients - 6 brands used - 42% Amplatzer occluders - 6% acute complications (no sequelae), no late complications - 87% complete closure, 4% after 2nd intervention - 50% antiplatelet therapy - 50% warfarin - 27% PFO closure during follow-up All neurovascular events adjudicated by neurologist (Windecker S, JACC 44: 750-8, 2004)

PFO Closure 150 Patients Medical Treatment 158 Patients P Age 50±1251± Male, % Diabetes mellitus, % Hypertension, % Hypercholesterolemia, % Smoking, % Cerebrovascular index event, % Ischemic stroke TIA 3523 Mean number of CV events 1.8±1.11.5± More than 1 CV event, % Patient Characteristics Before Propensity Score Matching (N=308)

PFO Closure 103 Patients Medical Treatment 103 Patients P Age 49±1250± Male, % Diabetes mellitus, % Hypertension, % Hypercholesterolemia, % Smoking, % Cerebrovascular index event, % Ischemic stroke TIA 2530 Mean number of CV events 1.5±1.01.5± More than 1 CV event, % Patient Characteristics After Propensity Score Matching (N=206)

PFO Closure 150 Patients Medical Treatment 158 Patients P Atrial septal anatomy, % PFO only PFO and atrial septal aneurysm 2522 Interatrial shunt grade, % Small Moderate Large 7961 Patient Characteristics Before Propensity Score Matching (N=308)

PFO Closure 103 Patients Medical Treatment 103 Patients P Atrial septal anatomy, % PFO only PFO and atrial septal aneurysm 2621 Interatrial shunt grade, % Small 49 - Moderate Large 7470 Patient Characteristics After Propensity Score Matching (N=206)

PFO Closure 103 Patients Medical Treatment 103 Patients P Death 1.0%1.9% Cardiac death 0%1% Vascular death 0% - - Non-cardiovascular death 1.0% 1.00 Thrombo-embolic events - Stroke 0%1.9% TIA 0%5.8% Peripheral embolism 0% - Clinical Outcomes at 1 Year Propensity Score Matched Cohort

PFO Closure 103 Patients Medical Treatment 103 Patients P Bleeding 1.0%0% Life-threatening or disabling 0% - - Major 1.0%0%1.00 Composite endpoints - Stroke, TIA, or peripheral embolism 0%7.8% Stroke, TIA, peripheral embolism, or death 1.0%8.7% Stroke, TIA, peripheral embolism, death, or bleeding 1.9%8.7%0.054 Clinical Outcomes at 1 Year Propensity Score Matched Cohort

Primary Endpoint – Propensity Score Matched Cohort Hazard Ratio = % CI 0.20 – 0.94 P=0.033 Stroke, TIA, or Peripheral Embolism at 10 Years PFO Closure 10.7% Medical Treatment 21.4%

Medical Treatment 5.8% PFO Closure 5.8% Hazard Ratio = 1.00, 95% CI 0.32 – 3.10 P=1.00 Propensity Score Matched Cohort All Cause Mortality at 10 Years

Medical Treatment 7.8% PFO Closure 5.8% Hazard Ratio = 0.75, 95% CI 0.26 – 2.16, P=0.59 Ischemic Stroke at 10 Years Propensity Score Matched Cohort

Medical Treatment 13.6% PFO Closure 4.9% Hazard Ratio = % CI 0.10 – 0.94 P=0.039 Transient Ischemic Attack at 10 Years Propensity Score Matched Cohort

PFO Closure 103 Patients Medical Treatment 103 Patients P Death 5.8% Cardiac death 2.9%1.0% Vascular death 0%1.9% Non-cardiovascular death 2.9% 1.00 Thrombo-embolic events - Stroke 5.8%7.8% TIA 4.9%13.6% Peripheral embolism 0% - Clinical Outcomes at 10 Years Propensity Score Matched Cohort

PFO Closure 103 Patients Medical Treatment 103 Patients P Bleeding 1.0%2.9% Life-threatening or disabling 0%1.9% Major 1.0%1.9%1.0 Composite endpoints - Stroke, TIA, or peripheral embolism 10.7%21.4% Stroke, TIA, peripheral embolism, or death 15.5%24.3% Stroke, TIA, peripheral embolism, death, or bleeding 16.5%26.2%0.08 Clinical Outcomes at 10 Years Propensity Score Matched Cohort

PFO closure better Medical tr. better 0.43 ( ) Overall ( ) PFO only 0.61 ( )PFO and ASA ( ) Age <55 yrs ( ) Age ≥55 yrs 0.14 ( )Female ( ) Male 0.25 ( ) No severe shunt ( )Severe shunt 1.00 ( ) ≤1 event ( )>1 event 0.04 ( ) Index event TIA ( )Index event stroke HR (95% CI) P Stroke/TIA/Periph. Embol. Propensity-Matched Cohort

PFO Closure 150 Patients Medical Treatment 158 Patients P Death 0.7%1.9% Cardiac death - Vascular death - Non-cardiovascular death Thromboembolic events - Stroke 0.4%2.5% TIA 1.3%3.8% Peripheral embolism 0% Clinical Outcomes at 1 Year Intention-to-Treat Population (N=308)

PFO Closure 150 Patients Medical Treatment 158 Patients P Bleeding - Life-threatening or disabling - Major Composite endpoints - Stroke, TIA, or peripheral embolism 2.0%6.3% Stroke, TIA, peripheral embolism, or death 2.7%7.6% Stroke, TIA, peripheral embolism, death, or bleeding Clinical Outcomes at 1 Year Intention-to-Treat Population (N=308)

Primary Endpoint – Intention to Treat Population PFO Closure 9.3% Hazard Ratio = % CI 0.22 – 0.75 P=0.004 Medical Treatment 21.5% Ischemic Stroke, TIA, or Peripheral Embolism at 10 Years

Medical Treatment 8.2% PFO Closure 4.7% Hazard Ratio = 0.55, 95% CI , P=0.21 All Cause Mortality at 10 Years Intention to Treat Population (N=308)

Medical Treatment 9.5% PFO Closure 4.7% Hazard Ratio = 0.47, 95% CI 0.19 – 1.16, P=0.10 Ischemic Stroke at 10 Years Intention to Treat Population (N=308)

Medical Treatment 11.4% PFO Closure 4.7% Hazard Ratio = % CI 0.17 – 0.96 P=0.04 TIA at 10 Years Intention to Treat Population (N=308)

PFO Closure 150 Patients Medical Treatment 158 Patients P Death 4.7%8.2% Cardiac death 2.7%2.5% Vascular death 0%2.5% Non-cardiovascular death 2.0%3.2%0.52 Thromboembolic events - Stroke 4.7%9.5% TIA 4.7%11.4% Peripheral embolism 0%1.3%0.50 Clinical Outcomes at 10 Years Intention-to-Treat Population (N=308)

PFO Closure 150 Patients Medical Treatment 158 Patients P Bleeding - Life-threatening or disabling 0.7%0.6% Major 0.7%1.9%0.62 Composite endpoints - Stroke, TIA, or peripheral embolism 9.3%21.5% Stroke, TIA, peripheral embolism, or death 12.7%26% Stroke, TIA, peripheral embolism, death, or bleeding 14.0%27.9%0.003 Clinical Outcomes at 10 Years Intention-to-Treat Population (N=308)

P<0.001 Event Rates per Year (%) NS (1,796 patient-years)(1,323 patient-years) Device No Device

Strengths and Limitations Non-randomized observational study - Propensity score matching to minimize bias - Simultaneous enrollment period - Treatment protocols and medication regimen at a single institution did not change significantly - Minimizes the potential of confounding by indication Improvements in device design New antithrombotic medications including thienopyridines, oral thrombin inhibitors

Conclusions PFO closure appears more effective than medical treatment for secondary prevention of recurrent cerebrovascular events among patients with stroke or TIA presumably related to PFO. Less death, stroke, or TIA with a PFO closure device than without. Results require confirmation in randomized clinical trials.