1. ©2016 American Academy of Neurology

2. Report by: Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology Practice Advisory (Update of Practice Parameter) Recurrent Stroke with Patent Foramen Ovale

3. ©2016 American Academy of Neurology Practice Advisory Funding Slide 2 This practice advisory was developed with financial support from the American Academy of Neurology (AAN). Authors who serve as AAN subcommittee members or methodologists (S.R.M., G.G.) were reimbursed by the AAN for expenses related to travel to subcommittee meetings where drafts of manuscripts were reviewed.

4. ©2016 American Academy of Neurology Sharing This Information The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use.guidelines@aan.com Slide 3

5. ©2016 American Academy of Neurology Presentation Objectives To present the evidence systematically reviewed in the update to the 2004 AAN guideline for patients with stroke and patent foramen ovale (PFO)  Whether percutaneous closure of PFO is superior to medical therapy alone  Whether anticoagulation is superior to antiplatelet therapy for the prevention of recurrent stroke To present practice recommendations Slide 4

6. ©2016 American Academy of Neurology Overview  Introduction  Clinical questions  AAN practice advisory process  Methods  Conclusions  Practice recommendations Slide 5

7. ©2016 American Academy of Neurology Introduction In 2004, the AAN published a practice guideline addressing secondary stroke in patients with PFO. The guideline concluded that the optimal therapy for secondary stroke prevention in this population was unknown. 1 Since that time, additional studies necessitated that we update our prior guideline, addressing the following therapeutic questions: 1.In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does percutaneous PFO closure reduce the risk of stroke recurrence compared with medical therapy alone? 2.In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does anticoagulation reduce the risk of stroke recurrence compared with antiplatelet medication? This practice advisory is not intended to be a comprehensive guideline for the management of other stroke risk factors or causes. The primary audiences are neurologists, cardiologists, and other clinicians caring for patients with cryptogenic ischemic stroke and PFO. Slide 6

8. ©2016 American Academy of Neurology Clinical Questions Slide 7 In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does percutaneous PFO closure reduce the risk of stroke recurrence compared with medical therapy alone? Clinical Question 1 In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does anticoagulation reduce the risk of stroke recurrence compared with antiplatelet medication? Clinical Question 2

9. ©2016 American Academy of Neurology AAN Practice Advisory Process* Clinical Question Evidence Conclusions Modified Delphi Consensus Recommendations Slide 8 *Practice advisory developed using the 2011 AAN Clinical Practice Guideline Process Manual, as amended.

10. ©2016 American Academy of Neurology Literature Search/Review Rigorous, Comprehensive, Transparent Slide 9 Inclusion criteria: Randomized studies pertinent to the questions Primary outcomes of interest: recurrent ischemic stroke or the combination of stroke and death (or both) Exclusion criteria: Studies in animals or languages other than English TIAs from assessed outcomes when feasible because TIA is subjective 3 809 abstracts 5 rated articles Searched: EMBASE, MEDLINE (via PubMED), and Cochrane databases from 2002  2014

11. ©2016 American Academy of Neurology AAN Classification of Evidence Therapeutic Scheme (2011 amended in 2015) Slide 10 Note: Numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III *Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data). Class I  Randomized controlled clinical trial (RCT) in a representative population  Masked or objective outcome assessment*  Relevant baseline characteristics are presented and substantially equivalent between treatment groups, or there is appropriate statistical adjustment for differences  Also required: a. Concealed allocation b. No more than 2 primary outcomes specified c. Exclusion/inclusion criteria clearly defined d. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: · 1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority · 2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose, and dosage adjustments are similar to those previously shown to be effective) · 3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment · 4. The interpretation of the study results is based on a per-protocol analysis that accounts for dropouts or crossovers f. For crossover trials, both period and carryover effects examined and statistical adjustments performed, if appropriate

12. ©2016 American Academy of Neurology AAN Classification of Evidence Therapeutic Scheme (2011 amended in 2015) Slide 11 Class II An RCT that lacks 1 or 2 criteria a  e (see Class I) or a prospective matched cohort study meeting criteria b  e (see Class I) Randomized crossover trial missing 1 of the following 2 characteristics: a. Period and carryover effects described b. Baseline characteristics of treatment order groups presented All relevant baseline characteristics are presented and substantially equivalent among treatment groups, or there is appropriate statistical adjustment for differences Masked or objective outcome assessment Class III Controlled studies (including external controls) Crossover trial missing both of the following 2 criteria: a. Period and carryover effects described b. Baseline characteristics presented A description of major confounding differences between treatment groups that could affect outcome* Outcome assessment masked, objective, or performed by someone who is not a member of the treatment team Class IV Did not include patients with the disease Did not include patients receiving different interventions Had undefined or unaccepted interventions or outcome measures Had no measures of effectiveness or statistical precision presented or calculable *Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

13. ©2016 American Academy of Neurology AAN Conclusions and Recommendation Slide 12 *Italics denotes language that would appear in the conclusions or recommendations Confidence in evidence anchored to the studies’ risk of bias  Highly likely or highly probable* = high confidence level  Likely or probable = moderate confidence level  Possibly = low confidence level  Insufficient evidence = very low confidence level Recommendations informed by premises  Evidence systematically reviewed  Strong evidence derived from related conditions  Axiomatic principles of care  Inferences made from one or more statements in the recommendation rationale Clinician level of obligation assigned (modified Delphi)  Must (or must not) = Level A (strong)  Should (or should not) = Level B (moderate)  May (or may not) = Level C (weak)  Should not = Level R (restricted to research setting only)  No recommendation made = Level U (insufficient evidence)

14. ©2016 American Academy of Neurology Clinical Question 1 Slide 13 In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does percutaneous PFO closure reduce the risk of stroke recurrence compared with medical therapy alone?

15. ©2016 American Academy of Neurology From Evidence to Conclusion Slide 14 [The advisory authors] judged that the differences between the STARFlex and AMPLATZER PFO Occluder were sufficient to warrant separate evidence syntheses and conclusions.

16. ©2016 American Academy of Neurology STARFlex Slide 15 For patients with cryptogenic stroke and PFO, percutaneous PFO closure with the STARFlex device  possibly does not provide a large benefit in preventing stroke in place of medical therapy alone—RD 0.13%, 95% CI -2.2% to 2.0%; possibly increases the risk of new- onset atrial fibrillation (AF)—RD 5%, 95% CI 2%–8% (1 Class I study, confidence downgraded to low for risk of bias relative to magnitude of effect);  probably is associated with a serious periprocedural complication risk of 3.2%, 95% CI 1.9–5.2% (1 Class I study).

17. ©2016 American Academy of Neurology AMPLATZER PFO Occluder Slide 16 For patients with cryptogenic stroke and PFO, percutaneous PFO closure with the AMPLATZER PFO Occluder  possibly decreases the risk of recurrent stroke—RD -1.68%, 95% CI -3.18% to -0.19%;  possibly increases the risk of new-onset AF—RD 1.64%, 95% CI 0.07%–3.2% (2 Class I studies; confidence downgraded to low for risk of bias relative to magnitude of effect and imprecision);  is highly likely to be associated with a procedural complication risk of 3.4%, 95% CI 2.3%–5% (2 Class I studies).

18. ©2016 American Academy of Neurology Recommendations: Clinical Question 1 Slide 17 Level A Clinicians must counsel patients considering percutaneous PFO closure that having a PFO is common; it occurs in about 1 in 4 people; it is impossible to determine with certainty whether their PFOs caused their strokes or TIAs; the effectiveness of the procedure for reducing stroke risk remains uncertain; and the procedure is associated with relatively uncommon, yet potentially serious, complications.

19. ©2016 American Academy of Neurology Recommendations: Clinical Question 1 Slide 18 Level R Clinicians should not routinely offer percutaneous PFO closure to patients with cryptogenic ischemic stroke outside of a research setting. Level C In rare circumstances, such as recurrent strokes despite adequate medical therapy with no other mechanism identified, clinicians may offer the AMPLATZER PFO Occluder if it is available.

20. ©2016 American Academy of Neurology Random-effects Meta-Analyses of Risk Differences AMPLATZER PFO Occluder closure vs medical therapy alone. Outcome stroke. Risk difference in percent. Slide 19

21. ©2016 American Academy of Neurology Meta-Analysis of AMPLATZER PFO Occluder Studies Using Hazard Ratios Slide 20

22. ©2016 American Academy of Neurology Clinical Question 2 Slide 21 In patients with a PFO who have had a cryptogenic ischemic stroke or TIA, does anticoagulation reduce the risk of stroke recurrence compared with antiplatelet medication?

23. ©2016 American Academy of Neurology From Evidence to Conclusion Slide 22 Using a random-effects meta-analysis (appendix e- 9 of the published practice advisory), there was no significant difference between treatments, and the summary estimate of effect was an RD of 2% favoring antiplatelet treatment (95% CI -21% to 25%). The CI of the pooled effect included potentially substantial benefits or harms of anticoagulation compared with antiplatelets.

24. ©2016 American Academy of Neurology From Evidence to Conclusion Slide 23 For the start of the modified Grading of Recommendations Assessment, Development and Evaluation process, the confidence in evidence was anchored at moderate (appendix e-8 of the published practice advisory) and then downgraded to very low because of severe imprecision and heterogeneity (I 2 = 65%).

25. ©2016 American Academy of Neurology Anticoagulation vs. Antiplatelet Medication Slide 24 For patients with cryptogenic stroke and PFO, there is insufficient evidence to determine the efficacy of anticoagulation compared with antiplatelet therapy in preventing recurrent stroke (RD 2%, 95% CI -21% to 25% [2 Class II studies, confidence downgraded for severe imprecision and inconsistency]).

26. ©2016 American Academy of Neurology Recommendations: Clinical Question 2 Slide 25 Level C In the absence of another indication for anticoagulation, clinicians may routinely offer antiplatelet medications instead of anticoagulation to patients with cryptogenic stroke and PFO. In rare circumstances, such as stroke that recurs while a patient is undergoing antiplatelet therapy, clinicians may offer anticoagulation to patients with cryptogenic stroke and PFO.

27. ©2016 American Academy of Neurology Random-effects Meta-Analyses of Risk Differences Anticoagulation vs antiplatelet medication. Outcome stroke (Shariat 2013 14 includes 2 TIAs). Risk difference in percent. Slide 26

28. ©2016 American Academy of Neurology Recommendations for Future Research At least 3 large RCTs comparing PFO closure with medications are ongoing…it is possible that these ongoing trials may fail to provide definitive evidence for efficacy, and the aggregate data may not define a patient population with a clear reduction in stroke risk and acceptable procedural risk profile. If so, additional RCTs may be required, and these future studies should make great efforts to carefully select patients who have limited vascular risk factors and have undergone a thorough evaluation to exclude other stroke etiologies. 22 [T]hese studies should use blinded endpoint ascertainment and adjudication (as opposed to open ascertainment with blinded endpoint adjudication), assess subsequent stroke risk and safety, and follow patients over a reasonably long period to compare the near- and long-term safety fairly with any subsequent stroke risk reduction. If a PFO closure device is approved in the United States, a postmarketing prospective, observational, long-term registry should be established to further inform our understanding of long-term benefits and risks. Finally, there are ongoing studies comparing novel anticoagulants, factor Xa inhibitors, and direct thrombin inhibitors with antiplatelet medications for the prevention of recurrent embolic stroke of uncertain source. Because the novel anticoagulant medications have less bleeding risk, effective venous thrombosis prevention, and greater convenience than warfarin, these medications may be viable alternatives for patients with stroke and a PFO, and it would be reasonable to consider studies in this patient population. Slide 27

29. ©2016 American Academy of Neurology References References cited here can be found in the published practice advisory, available at AAN.com/guidelines.AAN.com/guidelines Slide 28

30. ©2016 American Academy of Neurology Access Practice Advisory and Summary Tools To access the practice advisory and related summary tools, visit AAN.com/guidelines.AAN.com/guidelines Practice advisory article Summary for clinicians and summary for patients/families Slide 29

31. ©2016 American Academy of Neurology Questions?