1. Jonathan A. Edlow, MD, FACEP Transient Ischemic Attack Patient Update: The Optimal Management of Emergency Department Patients With Suspected Cerebral Ischemia

2. Jonathan A. Edlow, MD, FACEP Rapid TIA Patient Evaluation and Treatment: Lessons Learned from FASTER, EXPRESS, and SOS-TIA

3. Jonathan A. Edlow, MD, FACEP TIA – is it an emergency? What is the optimal management of ED patients with suspected cerebral ischemia?

4. Jonathan A. Edlow, MD, FACEP Jonathan A. Edlow, MD Vice-chairman Department of Emergency Medicine Beth Israel Deaconess Medical Center Associate Professor of Medicine Harvard Medical School Boston, MA

5. Jonathan A. Edlow, MD, FACEP Disclosures Dr. Edlow is a member of the ACEP Clinical Policies committee

6. Jonathan A. Edlow, MD, FACEP Session Objectives Evaluate which therapies might be initiated for ED TIA patients in order to minimize the subsequent stroke risk and maximize patient outcome.

7. Jonathan A. Edlow, MD, FACEP Treatment Should I start an anti-platelet drug? If so, which one? Is there a significant carotid stenosis? How is this best treated? Is there atrial fibrillation or other cardio-embolic sources of the TIA?

8. Jonathan A. Edlow, MD, FACEP Anti-platelet therapy AHA guidelines - 2006 ASA – dose 50-325mg ASA plus extended release dipyridamole (50-400mg) Clopidogrel (75mg)

9. Jonathan A. Edlow, MD, FACEP Early ASA v placebo studies ESPS-2 (1996) ASA v ASA- dipyridamole CHARISMA (2006) Clopidogrel + ASA v ASA alone CASTIA (on-going) Clopidogrel + ASA v Clopidogrel <24h ESPRIT (2007) ASA v ASA- dipyridamole PRoFESS (on- going) ASA-Dipyridamole v clopidogrel (and telmisartan v placebo) CAPRIE (1996) ASA v Clopidogrel MATCH (2006) Clopidogrel + ASA v Clopidogrel alone FASTER (2007) <24h Clopidogrel + ASA v ASA (and simvastatin v placebo)

10. Jonathan A. Edlow, MD, FACEP ASA High dose no more effective than low dose More side effects (bleeding) with high dose 20-25% RRR (compared to placebo) High quality evidence

11. Jonathan A. Edlow, MD, FACEP ASA v ASA+dipyridamole ESPS-2 (1996) ESPRIT (2006) Verro (2008) meta-analysis of these studies plus several smaller ones –Better results with extended release –~ 6% dropped out due to HA

12. Jonathan A. Edlow, MD, FACEP Clopidogrel v ASA CAPRIE (1996) –> 19,000 patients, clopidogrel 75 vs ASA 325 daily, f/u 1-3 years –ARR of 0.51, RRR of 8.7% (favors clopidogrel) –Safety equivalent

13. Jonathan A. Edlow, MD, FACEP Clopidogrel-ASA v either alone CHARISMA - (C75 + ASA) v ASA MATCH - (ASA75 + C75) v C75 FASTER – (ASA + C300/75) v ASA (and simvastatin v placebo) PRoFESS – (ASA + Di) v C (Telmisartan v placebo), a study that will enroll 20,000 patients, 8,000 within the first 7 days) C = clopidogrel ASA = aspirin Di = dipyridamole

14. Jonathan A. Edlow, MD, FACEP MATCH double-blinded placebo-controlled trial 7599 patients with recent ischemic stroke or TIA + 1 additional vascular risk factor Aspirin + clopidogrel v clopidogrel alone Primary endpoint: composite ischemic stroke, MI, vascular death, or re- hospitalization for acute ischemia (including for TIA, angina, or worsening PVD) –ARR for primary endpoint: 1% –ARI for life-threatening bleeds: 1.3% MATCH; Diener HC et al; Lancet 2004; 364: 331-337.

15. Jonathan A. Edlow, MD, FACEP MATCH EfficacySafety

16. Jonathan A. Edlow, MD, FACEP MATCH trial patient characteristics

17. Jonathan A. Edlow, MD, FACEP FASTER randomized 2x2 factorial design 392 patients enrolled < 24hours from index event Aspirin + clopidogrel v aspirin alone Primary endpoint: total 90-day stroke –7.1% with clopidogrel and aspirin –10.8% with aspirin alone –(ARR: 3.7%, 95% CI −9.4 to 1.9, p=0·19) –2 patients in the clopidogrel arm had ICH versus 0 in the placebo (aspirin only) arm (NS) FASTER; Kennedy, G; Lancet Neurology; 2007.

18. Jonathan A. Edlow, MD, FACEP FASTER v MATCH Enrollment time window –FASTER ≤ 24 hours –MATCH < 3 months Proportion of patients with LAA v small vessel disease –Both required AIS or TIA as qualifying event but MATCH required 1 additional risk factor What’s being compared? –FASTER: Clopidogrel + aspirin v aspirin –MATCH: Clopidogrel + aspirin v clopidogrel

19. Jonathan A. Edlow, MD, FACEP Stroke Risk Depends on the Location of the Disease Rothwell PM et al. Lancet Neurology 2006;5:323–31.

20. Jonathan A. Edlow, MD, FACEP Anti-platelet therapy Early intervention trials Except for FASTER, only 2 other trials have enrolled patients “early” –IST and CAST showed a reduced recurrence of stroke and/or death in the near term (14d in IST and 30d in CAST) ARR of about 1% when ASA given in the first 48 hrs CAST; Lancet 1997;349:1641–1649 IST; Lancet 1997; 349: 1569-1581

21. Jonathan A. Edlow, MD, FACEP Supporting evidence that clopidogrel + ASA helps? EXPRESS SOS-TIA Lavellee PC et al. Lancet Neurology; 2007;6:953-960. Rothwell PM et al. Lancet 2007;370:1432-1442.

22. Jonathan A. Edlow, MD, FACEP EXPRESS Before v After method –Phase 1 (4-1-02 to 9-30-04) treatment initiated in Primary Care with appointment required to TIA clinic –Phase 2 (10-1-04 to 3-31-07) treatment initiated in TIA clinic, no appointment necessary Nested in ongoing Oxford Vascular Study so other factors same; “before” group prospectively collected data

23. Jonathan A. Edlow, MD, FACEP EXPRESS Phase 1 – 634 pts -> 310 to EXPRESS Phase 2 – 644 pts -> 281 to EXPRESS (Other patients went directly to ED or hospital) Baseline characteristics similar Time to Rx – 20 days to 1 day 90 day stroke rate – 10.3% to 2.1%

24. Jonathan A. Edlow, MD, FACEP EXPRESS

25. EXPRESS

26. EXPRESS

27. SOS-TIA 24 hour access hospital-based clinic for TIA patients Assessment began ≤ 4 hours 1-3-03 to 12-31-05, 1085 patients admitted to the clinic Median symptom duration : 15 minutes 53% seen ≤ 24 hours of symptom onset

28. Jonathan A. Edlow, MD, FACEP SOS-TIA 787 patients with definite or possible TIA

29. Jonathan A. Edlow, MD, FACEP SOS-TIA outcomes

30. Jonathan A. Edlow, MD, FACEP SOS-TIA outcomes Patients with confirmed or possible TIA All started a stroke prevention program –824/845 (98%) got “anti-thrombotic” meds –43 (5%) had urgent carotid revascularization (median delay 6 days) –44 (5%) were anticoagulated for Afib –808 (74%) were sent home same day

31. Jonathan A. Edlow, MD, FACEP CEA – Faster is better For patients with ≥ 50% stenosis, the NNT to prevent 1 ipsilateral ischemic stroke was: CEA ≤ 2 weeks – 5 CEA > 12 weeks – 125 Rothwell; Lancet March 20, 2004

32. Jonathan A. Edlow, MD, FACEP AFib and other cardioembolic sources Full anti-coagulation A heparin followed up by an oral anti-coagulant

33. Jonathan A. Edlow, MD, FACEP Anti-platelet agents AHA 1 st line – ASA, ASA-dipyridamole or clopidogrel ASA failure –no evidence that increasing dose helps –no evidence to switch to warfarin ASA intolerance – use clopidogrel Individualize

34. Jonathan A. Edlow, MD, FACEP Individualizing therapy Cost Side effects Other co-morbidities (eg, CAD needing stent) PRoFESS, CASTIA may give us more answers soon regarding ASA- dipyridamole v clopidogrel Clopidogrel + ASA may work, if started early and stopped after a few months

35. Jonathan A. Edlow, MD, FACEP TIA in the ED – big picture We are there 24x7 We can begin most of the interventions Emergency Medicine is well placed to prevent strokes in these patients

36. Jonathan A. Edlow, MD, FACEP Questions? www.ferne.org jedlow@bidmc.harvard.edu www.ferne.org ferne_clindec_2008_tia_edlow_clintrials_extended_062508_final