PATENT FORAMEN OVALE: UPDATE IN MANAGEMENT OF RECURRENT STROKE KATRINE ZHIROFF, MD, FACC, FSCAI LOS ANGELES CARDIOLOGY ASSOCIATES

OBJECTIVES Review social burden and epidemiology of stroke Gender disparities in stroke diagnosis and management Diagnosis of cryptogenic stroke Role of PFO and gender in pathophysiology of cryptogenic stroke Indications for PFO closure in secondary stroke prevention Review of date from clinical trials supporting PFO closure

STROKE STATISTICS Stroke kills about 140,000 Americans each year 1 out of every 20 deaths Every year, more than 795,000 people in the United States have a stroke About 610,000 of these are first or new strokes About 185,00 strokes nearly 1 of 4 87% of all strokes have ischemic etiology Projections by 2030, an additional 3.4 million US adults will have had a stroke 20.5% increase in prevalence from 2012 Highest increase (29%) is projected to be in Hispanic men

STROKE ECONOMIC BURDEN US cost estimated $34 billion each year Health care services, medicines to treat stroke, and missed days of work Between 2012 and 2030, total direct medical stroke-related costs are projected to triple $71.6 billion to $184.1 billion majority of the projected increase in costs arising from those 65 to 79 years of age

fields of cardiology and stroke medicine encompass the 2 most important vascular territories affected by disease, the heart and brain. the most important overlap between cardiology and stroke medicine involves ischemic heart disease and ischemic stroke. Commonalities between these 2 frequently encountered disorders include similar epidemiological bases and risk factors, overlapping pathophysiological mechanisms, and similar approaches to acute therapy and to primary and secondary prevention.

WOMEN AND STROKE Women have a higher lifetime risk of stroke than men Lifetime risk of stroke among 55 to 75 years of age was 1 in 5 for women (20% 21%) Lifetime risk of stroke among 55 to 75 years of age 1 in 6 for men (14% 17%) Age-specific incidence rates are substantially lower in women than men in younger and middle-age groups Differences narrow in the older age groups

RISK OF STROKE IN WOMEN: EFFECT OF AGE AND GENDER

WOMEN AND STROKE Stroke is the 3 rd leading cause of death for women Stroke is the 5 th leading cause of death for men Each year 55,000 more women have a stroke than men. Stroke will have a more negative impact in women Live longer than men Live alone when they have a stroke Be more likely to live in a long term health care facility after a stroke Have a worse functional recovery after stroke

STROKE AND DISABILITY In 2003, among Medicare patients discharged from the hospital after stroke 45% returned directly home 32% used home healthcare services 24% were discharged to inpatient rehabilitation facilities 31% were discharged to skilled nursing facilities

WOMEN AND DISABILITY After stroke, women often have greater disability than men Women were half as likely to be independent in activities of daily living after stroke, after controlling for age, race, education, and marital status A meta-analysis of >25 studies found that women had worse functional recovery and greater long-term disability and handicap

STROKE AND DISABILITY

AWARENESS OF STROKE SYMPTOMS

PUBLIC AWARENESS Someone other than the patient decides to seek treatment in 66% of the cases A study was conducted of patients admitted to an ED with possible stroke to determine their knowledge of the signs, symptoms, and risk factors of stroke 39% did not know a single sign or symptom A study of patients with stroke 60.5% were able to accurately identify 1 stroke risk factor 55.3% were able to identify 1 stroke symptom Median delay time from onset of symptoms to admission in the ED was 16 hours and only 31.6% accessed the ED in <2 hours

ACUTE STROKE SYMPTOMS WOMEN VS MEN DISCOORDINATION/ATAXIA HEMIPARESIS APHASIA MENTAL STATUS CHANGE DIPLOPIA Analysis showed that the appearance of nonmotor symptoms as the primary symptom and nonuse of the 9-1-1 system were significant predictors of delay >2 hours.

NONTRADITIONAL SYMPTOMS OF STROKE 51.8% women reported 1 nontraditional stroke/tia symptom compared to 43.9% of men (p=0.09). Most prevalent nontraditional symptom was mental status change (women, 23.2%; men, 15.2%; p=0.03). The odds of reporting at least 1 nontraditional stroke/tia symptom were 1.42 times (95% CI, 0.97 2.06) greater in women than in men.

WOMEN AND STROKE SYMPTOMS Loss of consciousness or fainting General weakness Difficulty or shortness of breath Confusion, unresponsiveness or disorientation Sudden behavioral change Agitation Hallucination Nausea or vomiting Pain Seizures Hiccups

GENDER DISPARITIES IN TREATMENT OF STROKE Median time to arrival to ED longer by 1 hour Longer waiting times in ED 11% longer door-to-doctor times and 15% longer door-to-image times as men Less intensive treatment and therapeutic workup 71% males versus 62% females had carotid imaging 57% males versus 48% females had 2D ECho

WOMEN AND ACUTE STROKE CARE 10% less likely to be admitted within 3 hours of stroke 13% less likely to receive thrombolysis Discrepancies persist despite controlling for age, comorbidity, prestroke functional status, stroke severity OR 0.51 for women to receive tpa compared to men Several studies have demonstrated equal or superior effectiveness of tpa compared to men Lower Rankin scores and more substantial neurological recovery in women within 24 hours of IV tpa Worse functional outcomes in untreated women

% of patients 90 80 70 60 50 40 30 20 10 0 IDENTIFICATION OF PERSONAL RISK FACTORS 76.4 77.3 71.6 Hypertension 54 High Cholesterol 52.4 62.8 36.3 32.5 27 16.3 17.8 17.9 3.3 Smoke ever Diabetes Angina/CAD Atrial Fibrillation Identified Risk Factor 7.9 Carotid Stenosis % Have % Identified

% of Subjects AWARENESS OF SYMPTOMS IN WOMEN 80 70 Knowledge of Warning Signs 71.2 69.3 60 50 Weakness/numbness 40 30 20 10 33.6 32.2 26 Dizziness Headache Confusion Trouble talking 0 % of Subjects

STROKE RISK FACTORS UNIQUE TO WOMEN GENERAL RISK FACTORS Family history, high blood pressure, high cholesterol, atrial fibrillation, diabetes, smoking, lack of exercise, and being overweight ORAL CONTRACEPTIVES PREGNANCY HORMONE REPLACEMENT THERAPY (HRT) MIGRAINE HEADACHES WITH AURA

HORMONE THERAPY AND STROKE Menopausal state is associated with increased risk of stroke Women with natural menopause <42 yo had 2-fold increased ischemic stroke risk of women with natural menopause >42 yo Use of oral contraceptives increased prothrombotic state and increases risk of stroke Use of estrogen plus progestin, as well as estrogen alone, increases stroke risk in postmenopausal, generally healthy women Provides no protection for postmenopausal women with established and recent stroke or TIA

PREGNANCY AND STROKE The risk of ischemic stroke or intracranial hemorrhage during pregnancy and the first 6 weeks after giving birth was 2.4 times greater than for nonpregnant women of similar age and race Preeclampsia is a risk factor for ischemic stroke remote from pregnancy

MIGRAINE AND STROKE RISK Increase a woman's stroke risk two and a half times Most people in the U.S. who suffer migraines are women Migraine with aura is associated with ischemic stroke in younger women, particularly if they smoke or use oral contraceptives. The combination of Migraine+ OCP + Smoking all 3 factors increases the risk 9-fold compared with women without any of these factors

PATENT FORAMEN OVALE An anatomical interatrial communication with potential for right-to-left shunt Known since the time of Galen (130 AD-210 AD) In 1564, Leonardi Botali, an italian surgeon, was the first to describe the presence of foramen ovale at birth Function in utero was not known at that time In 1877, Cohnheim described paradoxical embolism relation to PFO https://emedicine.medscape.com/article/156863

EPIDEMIOLOGY OF PFO Flaplike opening between the atrial septa primum and secundum at the location of the fossa ovalis that persists after age 1 year In utero, serves as a physiologic conduit for right-to-left shunting Once the pulmonary circulation is established after birth, left atrial pressure increases, allowing functional closure of the foramen ovale. Anatomical closure of the septum primum and septum secundum by the age of 1 year Detected in 10-15% of the population by contrast transthoracic echocardiography Autopsy studies show a 27% prevalence of probe-patent foramen ovale https://emedicine.medscape.com/article/156863

https://my.clevelandclinic.org/health/articles/patent-foramen-ovale https://acphospitalist.org/archives/2008/02/acph-200802-expert_a1.jpg https://library.med.utah.edu/webpath/cvhtml/cv115.html

PATHOPHYSIOLOGY OF PFO The Mayo clinic autopsy study revealed that the size of a PFO increases from a mean of 3.4 mm in the first decade to 5.8 mm in the 10th decade of life, as the valve of fossa ovalis stretches with age Large enough to permit passage of emboli that may occlude MCA (~ 3 mm ) and major cortical branches (~1 mm) Any conditions that increase right atrial pressure more than left atrial pressure can induce paradoxical flow and may result in an embolic event Found in up to 50% of young adults with cryptogenic stroke https://emedicine.medscape.com/article/156863

IS PFO A FAMILIAL TRAIT?

TOAST Classification Classification Of Stroke Subtypes LARGE-ARTERY ATHEROSCLEROSIS CARDIOEMBOLISM 14 to 30 % of ischemic strokes SMALL-VESSEL OCCLUSION STROKE OF OTHER DETERMINED ETIOLOGY STROKE OF UNDETERMINED ETIOLOGY CRYPTOGENIC STROKE No large vessel stenosis ( 50 percent) or occlusion in the territory of the infarct No evidence of occult atrial fibrillation and no other high-risk cardioembolic source No radiographic acute lacunar infarction and no clinical lacunar stroke syndrome if imaging shows no infarct

CRYPTOGENIC STROKE 20-30% of all strokes are qualified as cryptogenic Low overall rate of recurrence in patients 18-55 yo with cryptogenic stroke treated with aspirin 1.9% in the first year of follow up 0.8% per year in years 2-4 of follow up Most are embolic in nature Sources include proximal arterial sources, heart and venous structure Topographic clues of etiology Infarcts in multiple territories suggest emboli from a proximal aortocardiac source Infarcts of different ages in a single territory suggest emboli of arterial origin Infarcts along the borders between brain artery territories suggest systemic hypotension or multiple emboli Small, deep infarct along with white-matter hyperintensities suggests intrinsic small-vessel disease Presenting history may point to clues for etiology Saver et al. NEJM 2016: 374;21

Saver et al. NEJM 2016: 374;21

FEATURES THAT INCREASE LIKELIHOOD OF CAUSATION Younger age Valsalva at the onset of stroke symptoms Extended travel preceding stroke Concomitant VTE Coexisting venous hypercoagulable state Atrial septal aneurysm History of migraine with aura Cortical location, multiplicity and large size of cerebral infarcts Absence of hypertension, diabetes, smoking Saver et al. NEJM 2016: 374;21

Eleni Doufekias et al. JACC 2008;51:1049-1059 American College of Cardiology Foundation

RoPE SCORE CALCULATOR (Risk of Paradoxical Embolism) IS PFO AN INCIDENTAL FINDING OR CAUSE OF STROKE? PFO prevalence increased from 23% in those with 0 to 3 points to 73% in those with 9 or 10 points Kent et al. Neurology 2013; 81: 619

Kavinsky et al. CIT 2017; 11(3):47

Published July 27, 2016 in Neurology

CLOSURE OR MEDICAL THERAPY FOR CRYPTOGENIC STROKE WITH PATENT FORAMEN OVALE Furlan et al. For the CLOSURE I investigators N ENGL J MED 2012; 366:991-999 909 patients were enrolled Starflex septal closure system I 18 and 60 years of age with a cryptogenic stroke or transient ischemic attack (TIA) and PFO The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up Closure with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke or TIA.

CLOSURE OF PATENT FORAMEN OVALE VERSUS MEDICAL THERAPY AFTER CRYPTOGENIC STROKE John D. Carroll, M.D., et al. For the RESPECT investigators N= 980 patients (mean age, 45.9 years) at 69 sites Follow-up period of 2.6±2.0 years, a median of 2.1 years Amplatzer PFO occluder was implanted in 462 In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. Carroll et al. N Engl J Med 2013; 368:1092

PERCUTANEOUS CLOSURE OF PATENT FORAMEN OVALE IN CRYPTOGENIC EMBOLISM Bernhard Meier, M.D., et al. For the PC trial investigators * N Engl J Med 2013; 368:1083-1091 414 patients randomized 1:1 Mean duration of follow-up 4.1 yrs Amplatzer PFO Closer Closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.

DEVICE CLOSURE OF PATENT FORAMEN OVALE AFTER STROKE: POOLED ANALYSIS OF COMPLETED RANDOMIZED TRIALS Kent et al. J Am Coll Cardiol. 2016 Mar 1; 67(8): 907 917 Among 2,303 patients, closure was not significantly associated with the primary composite outcome. For the outcome of stroke, all comparisons were statistically significant HR.058

Kavinsky et al. CIT 2017; 11(3):47

WHY BE MORE AGGRESSIVE WITH PFO CLOSURE IN 2018? CLOSE REDUCE RESPECT

CLOSE PFO Closure vs Anticoagulation vs Antiplatelets After Stroke Multicenter, randomized, open-label trial; 1:1:1 randomization Patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt Transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group) Antiplatelet therapy alone (antiplatelet-only group) or oral anticoagulation (anticoagulation group) (randomization group 1) Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3) The primary outcome was occurrence of stroke N=663 Study funded by the French Ministry of Health Derumeaux et al. NEJM 2017. 377;11:1011

NNT=20 To prevent one stroke

AF in PFO group detected within 1 month of the procedure No recurrence of AF in PFO group in the 4.4 years of follow up Effect on risk of stroke not known

CONCLUSIONS FROM CLOSE Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. Patients in this trial were well selected for those with cryptogenic stroke 2/2 paradoxical embolism Observed rate of strokes was lower than anticipated based on historical data

RESPECT Long Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke Multicenter, randomized, open label trial Patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended release dipyridamole at the discretion of physician). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. Saver et al. NEJM 2017. 377;11:1022

PATIENT SELECTION 980 patients (mean age, 45.9 years) at 69 sites Follow up for a median of 5.9 years. Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical therapy group Hazard ratio, 0.38; P = 0.007

CONCLUSIONS FROM RESPECT PFO CLOSURE WITH THE USE OF AMPLATZER PFO OCCLUDER WAS ASSOCIATED WITH A LOWER RATE OF RECURRENT ISCHEMIC STROKES THAN MEDICAL THERAPY ALONE DURING EXTENDED FOLLOW UP PERIOD

REDUCE Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke Multinational, randomized trial using Gore Helex/ Gore Cardioform Device Randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group) Imaging of the brain was performed at the baseline screening and at 24 months 664 patients (mean age, 45.2 years) Median follow-up of 3.2 years (min 2 years and max 5 years) Coprimary end points were freedom from clinical evidence of ischemic and 24-month incidence of new brain infarction (composite clinical and silent with + imaging). Sondergaard et al. NEJM 2017. 377; 11: 1033

Complete closure of PFO was achieved in 75% of patients by 12 months

CONCLUSIONS FROM REDUCE Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure (with Helex device) was associated with higher rates of atrial fibrillation

WHY ARE THE RECENT TRIALS POSITIVE? Required more stringent inclusion/exclusion criteria Neuroimaging requirements Longer follow up In CLOSE, patients were required to have a large interatrial shunt at rest or an atrial septal aneurysm There were ZERO strokes in the PFO closure arm REDUCE allowed patients with moderate shunting Application of RoPE score for stratification of risk of paradoxical embolism Clinically useful tool: ensuring PFO is the cause of stroke and not just a dx of exclusion Of note, size/severity of shunting are not part of the score Ropper et al. NEJM 2017. 377; 11: 1093

FDA APPROVAL OF PFO CLOSURE DEVICE: AMPLATZER PFO OCCLUDER

MacCarthy et al. CIT 2017; 11(3): 55

CONSIDERATION FOR EXCLUSIONS TO DEVICE CLOSURE VTE provoked by a known event or an identifiable transient risk factor treated with anticoagulation for 3 to 12 months PFO device closure can be postponed until anticoagulation is stopped May have an indication for chronic anticoagulation (e.g., unprovoked or recurrent deep venous thrombosis) Other considerations to percutaneous device closure include the presence of an inferior vena cava filter, elevated bleeding risk or coagulopathy, and vascular, cardiac, or PFO anatomy that is unsuitable for device placement.

CLINICAL PRACTICE UPDATE PFO closure is superior to medical therapy in patient <60 years of age presenting with embolic stroke secondary to PFO demonstrated by imaging and after extensive work up excluding other potential causes of ischemic stroke PFO closure is advised in addition to antiplatelet therapy for secondary stroke prevention

CONCLUSIONS Recent RCTs consistently demonstrate that device closure of a PFO plus antiplatelet therapy is more effective than antiplatelet therapy alone for preventing recurrent ischemic stroke Absolute risk reductions ranging from 2.2 to 6 %. Medical therapy alone is not adequate for secondary prevention of stroke Patient selection is critical RoPE score Device associated increase in post procedural AF in short term follow up that has unclear clinical significance

QUESTIONS?