Cryptogenic Stroke/PFO with Thrombophilia and VTE: Do We Know What To Do?

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1 Cryptogenic Stroke/PFO with Thrombophilia and VTE: Do We Know What To Do? Robert J. Sommer, MD Columbia University Medical Center New York, NY

2 Disclosure Statement of Financial Interest Within the past 12 months, I, Robert Sommer, have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Consulting Fees National PI ASSURED Trial Company W.L. Gore W.L. Gore W.L. Gore

3 FDA Labeling for Amplatzer PFO 10/29/2016 The Amplatzer PFO Occluder is indicated for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of years, who have a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.

4 Cryptogenic Stroke Work-up Acute onset neurologic symptoms with corresponding ischemic Infarct by cerebral imaging without other identifiable stroke source: Cerebral vascular anomalies Atrial Fibrillation Carotid artery disease Aortic atheroma LAA thrombus LV mural thrombus L sided AV valve anomalies

5 Hypercoagulable Work-up Inherited Thrombophilas: Prothrombin Gene Mutation (G20210A) Factor V Leiden Mutation (G1691A) Protein S, Protein C, Anti-thrombin III deficiencies MTHFR Mutations with elevated homocysteine levels Others Acquired Thrombophilias Anti-phospholipid Syndrome Generally require OAC

6 Do we know what to do when thrombophila (TP) is identified in a patient with CS/PFO without other known sources? No. There is no RCT data to guide us. What we do know

7 Blood thinners reduce PFO/stroke risk In all PFO RCT s, OACs and antiplatelet therapy both reduce recurrent stroke risk, compared with historical controls - PICSS Trial. Homma et al. Circulation. 2002;105: CLOSURE I Trial. Furlan et al. N Engl J Med 2012;366: RESPECT Trial. Carrol et al. 5 Year data presented at TCT PC Trial. Khattab et al. Trials. 2011;12: By reducing the clot burden returning to the RA, lessening chance of paradoxical embolization

8 Inherited Thrombophilia Inherited thrombophilias are associated with venous thrombus formation (not intraarterial) and are known to increase the risk of VTE events - Rosendaal FR. The Lancet.1999;353: Salomon et al. Arterioscler Thromb Vasc Biol. 1999;19: Couturaud et al. Blood. 2014;124(13): Increased RA clot burden will increase the risk of paradoxical embolization across a PFO

9 RESPECT 5 Year Follow-up Data Recurrent cryptogenic stroke with PFO is more strongly associated with: - Atrial septal aneurysm - Large R to L flow by bubble contrast Consistent with the accepted mechanism of paradoxical embolization through the PFO In this high risk population, closure of the PFO was 75% better than on-going blood thinners Carroll et al. Presented at TCT, October 2015

10 Thrombophilia Conditions Meta-analysis: - 6 studies, 856 pts with CS/PFO, 1001 controls - In CS/PFO group, the PT (G20210A) more prevalent {OR = 3.85 (CL )} - FV (G1691A) less strong (OR = 1.28 (CL ) - Carrying either PT or FV mutation increased CS risk - OR 1.98 (CL ), OR 1.62 (CL ) Thromb Haemost 2009;101:813-7.

11 Recurrent CVA +/- Thrombophilia Before PFO Closure Normal Thrombophilia Giardini et al. Am J Cardiol 2004;94:

12 Recommendation Thresholds should be lower for closing CS/PFO in patients with TP than in the general CS/PFO population, especially in those with higher risk PFO anatomy

13 What were they thinking??? Kernan et al. Stroke. 2014;45:

14 AHA/ASA Recommendations? Kernan et al. Stroke. 2014;45:

15 Oral Anticoagulation has never been shown to be superior to antiplatelet therapy in the CS/PFO population in preventing recurrent CS. WARSS Trial (p = NS) PICSS Trial (p = NS) CLOSURE I Trial (p = NS) PC Trial (p = NS) RESPECT Trial (p = NS)

16 IVC Filter Multiple catheters passed through an IVC filter

17 Is it safe to implant a PFO device with a known thrombophilia?

18 Is PFO Closure Safe with TP? Does TP increase the risk of device thrombosis? Personal experience: Over 4000 devices implanted over 20 yrs All have had TP work-up, positive in ~ 15-20% Five clinical cases of device thrombosis, none with documented TP

19 Is PFO Closure Safe with TP? 72 consecutive patients with PFO and Stroke/TIA 28% documented thrombophilia No outcomes difference post closure at (20 +/- 11 mos) Am J Cardiol 2004;94:

20 Is PFO Closure Safe with TP? 98 Consecutive Patients with PFO and Stroke/TIA 31% had documented thrombophilia No difference in device thrombosis or recurrent CVA events Minerva Cardioangiol 2009;57:285-9.

21 Recommendation With standard post-implant anti-platelet therapy, there is no clear additional risk of device thrombosis in patients with TP

22 Conclusions (Editorial): Cryptogenic stroke/pfo with: Documented TP: should have a lower threshold for PFO closure than the non-tp CS/PFO population Venous source: OAC X 6 months only, then longterm anti-platelet therapy, or closure with antiplatelet therapy, depending on presence/absence of high-risk PFO features. No venous source: long-term antiplatelet Rx or closure with antiplatelet therapy depending on presence/absence of high-risk PFO features.