To Close or Not to Close (the PFO)? That is the Question Lorna Belsky, M.D. March 31, 2004

Learning Objectives: By the end of this presentation, you will be able to: define patent foramen ovale (PFO) define atrial septal aneurysm (ASA) Discuss the association of PFO, ASA and migraine, TIA and stroke. Financial disclosures – None (I will pass the hat at the end of the talk).

Patients: Patient No. 1 - K.M., 44-year-old woman 3 separate episodes of visual clouding in right eye, “gray cloud” No headache, Left eye normal Symptoms lasted 5-8 minutes each time, occurred each evening x2, then again in the morning of the third day. Saw her primary care doctor PMH migraine, started in adolescence, worsened around age 40, associated with blurred vision Episode of vertigo 2 yrs prior, associated with sinus infection Severe, fell out of a chair, could not drive for 4 weeks, no sequelae thereafter Depressive disorder, treated

Patient No. 1 - K.M., 44-year-old woman (cont’d) Medications – fluoxetine, MVI Allergies – none SH – married, 2 boys Never smoker Wine, 1-2/weekend Stock broker FH – Mother had TIA age 68, decreased vision and paresthesias, on Aspirin, no recurrence x5 years. Sister age 36 with epilepsy Father-HTN No bleeding or clotting disorders

Patient No. 2 – A.F., 52-year-old woman New patient to clinic to establish care H/O left frontoparietal stroke 12 yrs ago at age 40 Treated with ASA. Residual slurred speech when tired. No recurrent neurological symptoms. Previous stroke workup -No hypercoaguable disorders -TEE showed PFO -High suspicion of paradoxical embolism PMH-severe migraines with aura around time of stroke Postmenopausal, migraines remitted Shoulder surgery GERD

Patient No. 3 – R.K., 48-year-old woman Called my office with new symptoms While driving, she experienced: decreased vision in left eye that followed zig-zagging visual changes in the left eye simultaneously, numbness of left face, arm and leg lasting 1-2 hours. Now resolved. associated with a minor headache located over forehead

Patient No. 3 – R.K., 48-year-old woman PMH major depressive disorder, recurrent complex regional pain syndrome right arm Dysphagia, esophageal dysmotility Former smoker Migraine headaches Hysterectomy, benign

Patient No. 3 - R.K., 48-year-old woman (cont’d) Medications – Premarin Protonix Verapamil-for migraine MVI Calcium FH – HTN, heart disease, stroke in old age

Patient No. 3 - R.K., 48-year-old woman (cont’d) Admitted to hospital-stroke workup done MRI brain-chronic infarct right caudate nucleus Hypercoaguable workup-negative at discharge. Factor V Leiden pending TEE-Atrial septal aneurysm with associated PFO trivial interatrial shunt, right to left, at rest Discharged home after two days on Aspirin 81 mg and Plavix 75 mg (Premarin was continued) Patient declined treatment with LMWH Subsequently consulted Interventional Cardiology Did not meet current FDA guidelines for percutaneous PFO closure -failed anticoagulation with recurrent neurological symptoms -significant contraindication to anticoagulation

Patient No. 3 - R.K., 48-year-old woman (cont’d) Two weeks later-called again with recurrent left face, arm, leg numbness & mild headache, partner noted left facial droop. Patient experienced mild weakness in arm and leg this time. Back to ER. Admitted. Completed right hemispheric sub-cortical stroke, residual left hemiplegia, (while on ASA/Plavix). Found heterozygous for Factor V Leiden Now-fulfills FDA criteria for PFO closure. Undergoes percutaneous PFO closure with Amplatzer closure device. Discharged home, disabled for her job, on Plavix, to receive physical and occupational therapy.

Topics for Discussion Today What is a PFO? What is an ASA? What is the association between PFO, ASA, Migraine Headaches, TIA and Stroke Who should be referred for PFO closure? Who do you refer your pt to? What is the role of medication treatment versus surgical interventions?

Embryology 101 The cardiovascular system is the first system to function in the embryo Blood begins to circulate by the end of the third week. Derived from angioblastic tissue (mesenchyme). Contractions of the heart begin by Day 22.

Partitioning of the Primitive Atrium Septum primum grows down from atrial roof Foramen primum-opening in septum primum Septum primum fuses with endocardial cushions Foramen primum closes, concurrently: Foramen secundum-forms in septum primum Septum secundum grows down from atrial roof right of septum primum The two septums overlap, incompletely, in the area of the foramen secundum-forms the foramen ovale.

Physiology/Embryology 101 Before birth-foramen ovale open-blood flows from IVC  RALA After birth-Foramen ovale closes Septum primum fuses with Septum Secundum

Atrial Septal Defects Ostium primum ASD-failure of septum primum to fuse with endocardial cushion. Ostium secundum ASD-inadequate development of septum secundum or excess resorption of septum primum Patent foramen ovale-inadequate fusion of the septum primum with the septum secundum

Prevalence and Diagnosis of PFO Hagen-1984-Autopsy study 965 pts PFO in 27.3% of hearts Varied with age 34.3% in first three decades of life 20.2% in ninth and tenth decades of life

Prevalence and Diagnosis of PFO Echocardiography PFO-echo dropout in atrial septum in more than one plane

Prevalence and Diagnosis of PFO Right-to-Left Shunt-appearance of microbubbles in left atrium within 3-5 cardiac cycles after peripheral injection of agitated saline Grading-arbitrary 10 bubbles – trivial >10-small intense opacification of LA-large

Atrial Septal Aneurysm (ASA) Associated with PFO-Kerut, Thompson Autopsy series – 16 ASA/1578 adults (1%) ASA-Definition by echo Bulging in the region of fossa ovalis Septum membrane mobility Sum of excursions at rest in both directions

Atrial Septal Aneurysm (ASA) Hanley-suggests a sum of 15 mm or more as definition of septal excursion Mugge-1995-195 pts with ASA associated PFO with shunting 33%

Transesophageal Echocardiogram TEE considered most sensitive method to detect PFO Transcranial Doppler sonography of middle cerebral artery during contrast injection has been proposed. PFO-microbubbles in MCA after peripheral injection Heckman-1999-45 pts with stroke or TIA Conclusion-both tests useful Rate of detection higher when using both tests Both tests dependent on technical expertise

Stroke and PFO Stroke-third leading cause of death in U.S. 700,000 new strokes/year $50 billion in lost productivity/total health care costs Etiology-hemorrhagic or ischemic 40% of ischemic strokes-no clear cause Termed cryptogenic

Stroke and PFO Northern Manhattan Stroke Study, 1994 Sacco, et al. Recurrence rates for all subtypes 9.4%/year Cryptogenic stroke 10%/year Lechal, et al.-1988-First reported high prevalence of PFO in cryptogenic stroke pts. 60 adults younger than 55 years All with ischemic stroke Contrast surface echocardiography PFO in 40% of study population PFO in 10% of control group without stroke PFO in 54% of pts with cyptogenic stroke

Stroke and PFO Mas, et al.-2001-New Engl J Med-598 pts Between ages 18-35 Presented with stroke of unknown origin PFO in 36% ASA in 1.7% PFO and ASA in 8.5%

Association between PFO and stroke stronger in certain subgroups. Overell, et al.-2000-Metanalysis of 9 studies Rate of stroke significantly associated with: Younger pts (< 55 years) who had: PFO odds ratio 3.10 ASA odds ratio 6.14 PFO plus ASA odds ratio 15.59 Similar association not found in older pts

Despite high prevalence of PFO in general population, Actual stroke event rate remains small Lack of understanding of pathophysiology of PFO and cryptogenic stroke Causal relationship between PFO, ASA, and Ischemic stroke is not established

Paradoxical Emboli Thrombus, fat and air all recognized Right to left shunt occurs- during coughing after release phase of Valsalva during mechanical ventilation with elevated RA pressures from PE, COPD and RV failure Suggested as main mechanism of stroke in PFO

Ranoux, et al.-1993-tested this theory 68 consecutive pts, age <55/ischemic stroke PFO-in 32 pts (47%) Valsalva provoking event present at stroke in 6 pts with PFO and in 8 pts without PFO DVT present in one pt with PFO and none of the others. Concluded—paradoxical embolization as cause of stroke in PFO—not valid.

Second Proposed Mechanism for Clot Embolization Primary Formation of Clot in PFO Canal Anecdotal data only

Other PFO Factors Size and Shunting Hausmann, et al.-1995-Shunting is more severe and PFOs are larger in pts with strokes caused by paradoxical embolism Homma, et al.-1994-74 pts/ischemic stroke Cryptogenic stroke pts had larger PFOs with more shunting than stroke pts of determined cause

PFO and ASA De Castro, et al.-2000-350 pts with acute ischemic stroke or TIA Contrast TEE High risk vs. low risk anatomy for subsequent stroke PFO and ischemic stroke pts-at high risk for recurrence if— right to left shunt at rest or high septum membrane mobility

Other Proposed Mechanisms Berthet, et al.-1999-Atrial vulnerability paroxysmal atrial arrythmia abnormal atrial septal anatomy studied 62 ischemic stroke pts <55 yrs ischemic stroke/unknown cause TEE evidence of PFO or ASA EP study-inducible atrial fibrillation Potential role of transient atrial arrythmias in thrombus formation in presence of ASA or PFO

Other Proposed Mechanisms Hypercoaguable States May promote paradoxical emboli in pts with PFO and cryptogenic stroke One small study-1998-Chaturvedi 17 pts, cryptogenic stroke and PFO 31% had hemostatic abnormalities Need further larger series

Medical Treatment of Stroke Patients with PFO Not studied extensively No studies comparing medical, surgical and/or catheter-based treatments reported. Medical therapy Antiplatelet or antithrombin drugs

Medical Treatment of Stroke Patients with PFO Mas, et al.-1995-132 pts, <60, PFO/stroke Treated with aspirin (250-500 mg/d) or oral anticoagulation (target INR 2.0-3.0) Average annual rate of recurrence 1.2% for stroke 3.4% for combined stroke/TIA endpoints No difference between 2 therapies

Medical Treatment of Stroke Patients with PFO Mas, et al.-2001-recurrent events-prospective study Young pts with PFO, ASA or both Treated with aspirin (300 mg/d) for 4 years Stroke recurrence rate 2.3% with PFO 0% with ASA 4.2% with PFO and ASA At 4 years-risk of stroke or TIA in pts with PFO and ASA was 19.2%

Warfarin-Aspirin Recurrent Stroke Study (WARSS) 2206 pts with ischemic stroke Randomized to aspirin (325 mg/d) or warfarin (INR 1.4-2.8) for two years No difference between aspirin or warfarin regarding recurrent stroke or death.

PFO in Cryptogenic Stroke Study Evaluated TEE findings in 630 pts with cryptogenic stroke within WARSS trial PFO in 39% of pts with cryptogenic stroke compared to 29.9% of pts with known cause of stroke warfarin vs. aspirin—no difference in incidence of stroke or death

Surgical Closure of PFO Open thoracotomy Mixed results Higher recurrence of neurological events in older pts with cryptogenic stroke after open surgical repair

Percutaneous Closure of PFO Braun, et al.-2002 276 consecutive pts with PFO & 1 thromboembolic event PFO closure with a PFO-star device Successful implantation in all 276 Complications- Transient ST elevation 1.8% TIA in 0.8% 15 months of follow-up 0% recurrent stroke 1.7% TIA 0% peripheral emboli

Percutaneous Closure of PFO Windecker, et al.-2000 80 pts with PFO & at least 1 parodoxical embolic event Used 1 of 5 different PFO closure devices 60 pts had PFO only 20 pts had PFO and ASA Successful implantation in 78 pts (98%) Complete PFO closure achieved in 57 (73%) Residual Right to Left Shunt 21 (27%)

Percutaneous Closure of PFO Five years of Followup Actuarial annual risk for embolic event 2.5% for TIA 0% for Stroke 0.9% for Peripheral Emboli 3.4% for Combined Endpoint of TIA/Stroke and Peripheral emboli Post-procedural shunt-predictor of recurrent event Relative risk of 4.2% Risk of recurrence-highest in the first year

PFO and Migraine Headaches Relationship between migraine with aura and cardiac right to left shunt has been reported Del Sette, et al.-1998 Case Control Study Conclusion-prevalence of right to left shunt in pts with migraine with aura is significantly higher than healthy controls and similar to the prevalence of RLS in young pts with stroke.

PFO and Migraine Headaches Wilmshurst, et al.-2000 Of 37 pts who underwent PFO closure, 21 had migraine before procedure (57%) 30 month follow-up 10 pts-no further migraine (7 w/ aura, 3 w/o) 8 pts-decreased frequency/severity of HA 3 pts-no change in migraines

Patient Follow-ups K.M.-44 y/o woman with 3 separate TIA, right eye visual loss Found to have moderate PFO with interatrial shunting AND a cerebral aneurysm Placed on warfarin Developed gross hematuria Symptomatic menorrhagia Had percutanous PFO closure with Amplatizer Device one year ago No recurrent neurological events Off Warfarin No interatrial shunting

Patient Follow-ups A.F.-52 y/o woman with stroke at age 40 Documented PFO No recurrent events in 12 years on ASA alone Not a candidate for PFO closure

Patient Follow-ups R.K.-48 y/o woman Recurrent TIAS, PFO with ASA Treated with Aspirin and Plavix Evidence of old silent caudate infarct Heterozygous for Factor V Leiden Subsequent right hemispheric sub-cortical stroke while taking Aspirin and Plavix PFO closure with Amplatizer closure device on 1-7-04. Remains hemiplegic, undergoing rehab, with no further events, no further migraine headaches

UW Health Heart and Vascular Care Interventional Cardiologist – Dr. Tim Tanke performed the first percutaneous PFO closure (K.M.) in 2002 at the University of Wisconsin. To refer a patient-(608)263-1530 or tet@medicine.wisc.edu FDA approved indications for percutaneous PFO closure -cryptogenic stroke with PFO -failure of medical therapy (recurrent event on “therapy”) or contraindication to medical therapy

Many thanks to Patty Boyle for assistance in preparing this presentation.