Updates in Cerebrovascular Disease with Underwriting Impact

1. Updates in Cerebrovascular Disease with Underwriting Impact Midwestern Underwriting Conference Dave Rengachary, MD Vice President and Medical Advisor September 10, 2014

2. Table of Contents TIA definition update and mimics Stroke in the Young Novel Oral Anticoagulants Carotid and Intracranial Stenting Underwriting of Cerebral Aneurysm and AVM

3. Transient Ischemic Attacks (versus mimics)

4. “We often receive attending physician statements where we have difficulty telling whether an individual had a TIA. We already know what TIAs are and how to apply ratings for these events. We need some guidance on situations where it is not entirely certain that a person had an actual TIA or whether it might be another condition like migraine”

5. “Sudden focal neurologic deficit lasting less than 24 hours, presumed to be of vascular origin, and confined to an area of the brain or eye perfused by a specific artery” TIA: Previous definition

6. “a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour and without evidence of acute infarction” Easton JD et al. Stroke. 2009; 40:228 1 TIA: New Definition (AHA/ASA)

7. Amort M et al. Cerebrovascular Diseases. 2011;32:60 2 Causes of TIA mimics

8. Headache - no mechanism whereby TIA should cause headache • Memory Loss (*see below!) • Blurred vision (as opposed to loss of vision or diplopia) • Syncope • Recurrent stereotyped episodes with negative workup • Symptoms that do not conform well to a single artery - generalized symptoms with a gradual or hazy onset rather than focal sudden onset symptoms ("weak" all over”, "dizzy“) • Lack of other vascular risk factors Symptoms Predictive of TIA mimic

9. Sudden onset Weakness face/arm/leg Slurred speech Able to walk Dizziness Seizure LOC Confusion Symptoms and TIA’s 0.1 1 10 MIMIC OR TIA/STROKE Stroke 2006; 37: 769-75 3 Lancet 2005; 4:727-34 4

10. “ At 3 months, stroke, recurrent TIA and myocardial infarction were absent in patients with TIA mimics but occurred in 13 (5.2%), 20 (8.1%) and 3 (1.2%) TIA patients, respectively.” Amort M et al. Cerebrovascular Diseases. 2011;32:62 1 Prognosis of TIA mimics

11. One of the most interesting neurologic phenomenon – happens in entirely normal people with little medical history • Pathogenesis unknown • Key feature is sudden and profound inability to form new memories, repetition of questions lasting on the order of hours without focal symptoms • Often follows exercise • Workup typically normal (MRI, ECHO, carotids, EEG) • Entirely different prognosis • Low rate of recurrence (4%) • Lower rate of stroke, myocardial infarction or death Pantoni Let al. European Journal of Neurology. 2005; 12: 350 5 Transient global amnesia

12. Stroke in the Young

13. Stroke in the Young

14. Increasing Incidence of Stroke in Young Adults Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) evaluated stroke incidence between 1993 and 2005. The proportion of strokes in those less than 55 increased from 13% in 1993 to 19% in 2005 6 Rates of increase were especially high between 1999 and 2005 This trend runs counter to an overall decrease in worldwide stroke incidence of 42% between 1972 and 2008 7

15. Stroke in the Young: Diverse Causes Adapted from Martin et al 8

16. Carotid Dissection Iancu et al. 9 Creative Commmons Attribution 2.0

17. Carotid Dissection Al-Ali, Firas, and Brandon C. Perry. “Spontaneous Cervical Artery Dissection: The Borgess Classification.” Stroke 4 (2013): 133. Creative Commons Attribution License

18. Dissection 1. Very common cause of stroke in the young (10-25%)8 2. Carotid and Vertebral artery dissections are different 3. Three main causes – Trauma, Connective Tissue Disease, and “I dunno” 4. Trauma and “I dunno” have the best prognosis, Connective Tissue disease has the worst prognosis but is the most rare. 5. In roughly 15% of cases multiple arteries are involved (and multiple artery involvement indicates underlying connective tissue disease)10 Top 10 things to Remember!

19. Dissection 6. Nobody knows how to treat dissection 7. The gold standard of diagnosis is changing 8. There is an increasing association with infections (but is the infection or is it the cough?!) 9. The time frame for recanalization is 3-6 months (this corresponds well with permanency of any stroke deficit). When rating pay greater emphasis upon remaining stroke deficit. 10. Watch for pseudoaneurysm as a complication Top 10 things to remember!

20. Cerebral Venous Thrombosis Munira et al. 11 Creative Commons Attribution License 2.0

21. Cerebral Venous Thrombosis Overall a rare cause of stoke (1%) but 78% of these cases are below the age of 50.12 Peak age between 20-40, women outnumbering men 3:113 Primary presenting symptom is headache as a result of increased intracranial pressure. Time course can vary significantly Focal symptoms are concerning prognostic indicator as they implicate focal infarction and hemorrhage. Risk factors are very similar to other sources of venous thrombosis: hormonal, pregnancy, oral contraceptives, cancer, dehydration and various thrombophilias (Factor V, protein C and S deficiency, anti-thrombin III deficiency, antiphospholipid antibody syndrome)

22. Cerebral Venous Thrombosis Risk factors more specific to CVT include local infections (sinusitis, mastoiditis, dental), lumbar puncture, inflammatory bowel disease, head trauma, and central lines (in jugular vein)13 MRI and in particular Magnetic Resonance Venograms– Studies within the first few days can be insensitive Treatment – 1)Heparin 2) Warfarin …. ? Xarelto! 3) Repeat MRI/MRV in 3-6 months and discontinue anticoagulants if recanalized (or continue indefinitely in those with thrombophilia or prior DVT/PE) 4) Intra-arterial lysis or surgical extraction (implies worse presentation)

23. Cerebral Venous Thrombosis “Desert” Island Underwriting Questions

24. Cerebral Venous Thrombosis Males Age > 37 Deep Cerebral Vein Thrombosis CNS infection Other Poor Prognostic Factor from International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT)14

25. The New Oral Anticoagulants

27. Warfarin Anticoagulation Time spent in the therapeutic range 60-70% 15 Frequent blood draws Medication and food interactions Major bleeding risks with labile kinetics

28. Factors in Favor of Anticoagulation CHADS Score

29. Factors that increase bleed risk HAS BLED Score

30. Stroke vs. Bleed Risk16 CHADS HAS BLED

31. Dabigatran (Pradaxa) Direct thrombin inhibitor (factor II) First of the novel oral anticogulants, FDA approved for two indications: Non-valvular atrial fibrillation (October 2010) DVT and PE after 5 days of heparin (April 2014) Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)Trial *Renal clearance

32. Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)Trial Connolly et al. 2013 17

33. Rivaroxaban (Xarelto) and Apixaban (Eliquis) Both oral direct factor 10a inhibitors Major trials for both published within a week of each other in NEJM: ROCKET AF- rivaroxaban ARISTOTLE – apixaban FDA indications: Non-valvular atrial fibrilation Treatment of DVT/PE and reduce recurrence afterwards DVT prophylaxis after surgery (Knee and Hip)

34. Rocket AF trial (Rivaroxaban) Patel et al. 2011 18

35. ARISTOTLE (Apixiban) Granger et al. 201119

36. Novel oral anticoagulants There are no currently approved ways to reverse the medication in the event of bleed or requirements for urgent surgery Premature discontinuation of these agents results in particularly high thrombotic rates (leading to black box warning) Second black box warning relates to spinal/epidural hematomas A study (RE-ALIGN) of dabigatran and mechanical heart valves was terminated early because of both excess thrombotic events and major bleeding FDA put out communication regarding analysis of “post market bleeding reports” of dabigatran BoehringerIngelheimsettled 4000 lawsuits for 650 million FDA later announced after review of 134,000 Medicare recipients that there was no exceed bleeding than expected from Re-Ly trial or versus warfarin. Caveats

37. Carotid and Intracranial Stenting

38. Carotid Stenting General Considerations

39. SAPPHIRE Trial Inclusion Criteria (334 high risk surgical patients): Symptomatic stenosis of 50% or asymptomatic stenosis of 80% High risk cardiac disease CHF Abnormal stress test Need for open heart surgery Severe COPD Contralateral Carotid Occlusion Restenosis after CEA Age >80 Gurm et al.20

40. SAPPHIRE Trial Composite endpoint – ipsilateral stroke or periprocedural death, stroke or MI Results – at three years carotid stenting (+ and emboli protection device) was noninferior to carotid endarterectomy (24.6% in stenting group versus 26.9% in CEA group) Both surgeons and interventionalists were certified with complication rates between 3-5%. Results

41. CREST Trial 2503 patients followed for an average of 2.5 years Enrolled either symptomatic or asymptomatic patients and randomized them to carotid stenting or endarterectomy Primary endpoint was a stroke, MI or death Brott et al.21

42. CREST Trial

43. Intracranial Atherosclerosis WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease)22 History of Stroke or TIA and intracranial athlerosclerosis Warfarin versus aspirin (1300 mg/day) Trial stopped early because of elevated risk of death, hemorrhage, and myocardial infarctions in warfarin group with no benefit in ischemic stroke prevention SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) 23 Compared aggressive medical management (antiplatelet plus risk factor control) with intracranial angioplasty and stenting Trial stopped early because of a higher rate of strokes (especially periprocedural) in the stenting group (14.7 vs 5.8%)

44. Underwriting of Cerebral Aneurysm and AVM

45. Cerebral Aneurysm

46. Cerebral Aneurysm Prevalence – 3.2%24 Risk factors Tobacco Female Sex Family History Polycystic kidney disease (autosomal dominant) Age Atherosclerosis Infections, endocarditis, intravenous drug use Connective Tissue Diseases – Ehlers Danlos, Marfan’s Case fatality rates 25 40% mortality within 24 hours 25% additional mortality from complications by 6 months Background

47. Zarosky26 Creative Commons Attribution License 3.0

48. Who to Screen and how often? Who to Screen?27 Patients with two first degree primary relatives PCKD (10-22%), Ehlers Danlos How often to screen?28 For high risk category every 5 years is recommended 20% had an aneurysm by 10 years after negative initial screen How to screen? CTA and MRA are fairly equivalent with high sensitivity and specificity above 3 mm.29

49. Risk of Rupture From UCAS Japan Investigators30 (5720 patients, with 6697 aneurysms studied for 3 years) Size

50. Risk of Rupture Location *Not statistically significant PICA = Posterior Inferior Cerebellar artery