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

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Presentation on theme: "Midwestern Underwriting Conference Updates in Cerebrovascular Disease with Underwriting Impact Dave Rengachary, MD Vice President and Medical Advisor September."— Presentation transcript:

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

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

3 Transient Ischemic Attacks (versus mimics) 3

4 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 TIA: Previous definition “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”

6 TIA: New Definition (AHA/ASA) “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

7 Causes of TIA mimics Amort M et al. Cerebrovascular Diseases. 2011;32:60 2 Diagnosis of MimicPercent Seizure44 Migraine23 Psychogenic7 Hypertensive encephalopathy4 Transient Global Amnesia4 Sepsis4 Hypoglycemia2 Benign Paroxysmal Vertigo2 Cerebral venous thrombosis2 Brain Neoplasm1 Subarachnoid hemorrhage1 Peripheral nerve lesion1 *Syncope??

8 Symptoms Predictive of TIA mimic 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

9 Symptoms and TIA’s Sudden onset Weakness face/arm/leg Slurred speech Able to walk Dizziness Seizure LOC Confusion MIMIC OR TIA/STROKE Stroke 2006; 37: Lancet 2005; 4:

10 Prognosis of TIA mimics “ 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

11 Transient global amnesia 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

12 12 Stroke in the Young

13 Increasing Incidence Heterogenous causes Elevated mortality but wide range Stroke in the Young 13

14  Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) evaluated stroke incidence between 1993 and  The proportion of strokes in those less than 55 increased from 13% in 1993 to 19% in 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 Increasing Incidence of Stroke in Young Adults 14

15 Atherosclerosis CardioembolicThrombophilias Cerebral Venous Thrombosis GeneticVasculitisDissection Stroke in the Young: Diverse Causes 15 Adapted from Martin et al 8

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

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

18  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 Dissection Top 10 things to Remember! 18

19  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 Dissection Top 10 things to remember! 19

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

21  Overall a rare cause of stoke (1%) but 78% of these cases are below the age of  Peak age between 20-40, women outnumbering men 3:1 13  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) Cerebral Venous Thrombosis 21

22  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) Cerebral Venous Thrombosis 22

23 Is there any underlying thrombophilia or systemic disease? Did the applicant have infarction or hemorrhage on imaging? Any Permanent Symptoms or Complications? Cerebral Venous Thrombosis 23 “Desert” Island Underwriting Questions

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

25 The New Oral Anticoagulants 25

26 Novel Oral Anticoagulants Dabigatran Exilate (Pradaxa) Rivaroxaban (Xarelto) Apixiban (Eliquis) 26

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

28 CCardiac Failure 1 point HHypertension1 point AAge 75 or greater 1 point DDiabetes1 point SStroke or TIA history 2 points Factors in Favor of Anticoagulation 28 CHADS Score

29 HHypertension (greater than 160 mm hg)1 point AAbnormal Renal or Liver function1 point EACH SStroke1 point BBleed History1 point LLabile INR1 point EElderly (age greater than 65)1 point DDrugs or alcohol1 point EACH Factors that increase bleed risk 29 HAS BLED Score

30 PointsStroke RiskPointsBleed Risk 01.9%01.13% 12.8%11.02% 24%21.88% 35.9%33.74% 48.5%48.7% 512.5% % Stroke vs. Bleed Risk 16 CHADSHAS BLED 30

31  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 Dabigatran (Pradaxa) 31

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

33  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) Rivaroxaban (Xarelto) and Apixaban (Eliquis) 33

34 Rocket AF trial (Rivaroxaban) 34 Patel et al

35 ARISTOTLE (Apixiban) 35 Granger et al

36  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  Boehringer Ingelheim settled 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. Novel oral anticoagulants Caveats 36

37 37 Carotid and Intracranial Stenting

38 Is the patient symptomatic ? Why is an endarterectomy not being performed? Who is doing the procedure? Carotid Stenting 38 General Considerations

39  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 SAPPHIRE Trial 39 Gurm et al. 20

40  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%. SAPPHIRE Trial 40 Results

41  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 CREST Trial 41 Brott et al. 21

42 CREST Trial 42

43  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%) Intracranial Atherosclerosis 43

44 Underwriting of Cerebral Aneurysm and AVM 44

45 Cerebral Aneurysm 45

46  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 Cerebral Aneurysm Background 46

47 47 Zarosky 26 Creative Commons Attribution License 3.0

48  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 Who to Screen and how often? 48

49 From UCAS Japan Investigators 30 (5720 patients, with 6697 aneurysms studied for 3 years) Risk of Rupture Size 49 SizeHazard Ratio 3-4 mmReference 5-6 mm mm mm9.09 >25 mm76.26

50 Location Middle CerebralReference Internal Carotid0.43 PICA/Vertebral Junction0.68* Basilar/Superior Cerebellar Junction1.49* Posterior Communicating/Internal Carotid 1.0 Anterior Communicating Artery2.0 Risk of Rupture Location 50 *Not statistically significant PICA = Posterior Inferior Cerebellar artery

51  Any growth - Recent study (Villablanca et al 2013) 31 showed 12 x rupture rate with growth defined as increase by 5% of volume even for small aneurysms  Age >70  Tobacco  HTN  Female Sex Risk of Rupture 51 Other Factors

52 How to treat? 52 Izar et al. 32 Creative Commons Attribution License 3.0

53  Longest term data available for larger scale trial is from extension of ISAT (International Subarachnoid Hemorrhage Trial) 33, 5 year data from 2009:  Out of 2143 patients there were a total of 24 rebleeds greater than one year after therapy  The risk of rebleeding overall was higher in the coiling group (17 versus 7 of the bleeds) – This was confirmed in large Meta-analysis published in Stroke of 4 RCTs and 23 observational studies  The risk of death was lower in the coiling group (RR 0.77)  The overall Standardized Mortality Rate for any patient with ruptured aneurysm was 1.5 Clipping versus Coiling for Aneurysm Management 53

54 54 Arteriovenous Malformation

55 55 Neacsu et al. 34 Creative Commons Attributions License

56  Multicenter (39) trial 35 where patients with unruptured AVM were randomized to interventional surgery (any combination of neurosurgery, embolization, or radiosurgery) or medical management.  The primary endpoint was death or stroke  Trial was stopped by the NINDS after 223 patients had enrolled.  At time that trial was stopped 30% had reached primary endpoint in surgical group versus 10% in medical management group  A cohort study from Scotland 36 with 12 years of follow up published in 2014 also supported better outcomes with conservative management. AVM management 56 ARUBA trial

57  Largest natural history cohort analysis to date MARS (Multicenter AVM Research Study) Kim et al

58 PredictorHazard Ratio Age at diagnosis1.10 Female Sex1.12 Associated Arterial Aneurysm1.68 Exclusively deep venous drainage2.14 Hemorrhage at presentation3.45 MARS (Multicenter AVM Research Study) 58

59 1. Easton, J. Donald, Jeffrey L. Saver, Gregory W. Albers, Mark J. Alberts, Seemant Chaturvedi, Edward Feldmann, Thomas S. Hatsukami, et al. “Definition and Evaluation of Transient Ischemic Attack A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke Council; Stroke 40, no. 6 (June 1, 2009): 2276– Amort, Margareth, Felix Fluri, Juliane Schäfer, Florian Weisskopf, Mira Katan, Annika Burow, Heiner C. Bucher, Leo H. Bonati, Philippe A. Lyrer, and Stefan T. Engelter. “Transient Ischemic Attack versus Transient Ischemic Attack Mimics: Frequency, Clinical Characteristics and Outcome.” Cerebrovascular Diseases 32, no. 1 (2011): 57– Hand, Peter J., Joseph Kwan, Richard I. Lindley, Martin S. Dennis, and Joanna M. Wardlaw. “Distinguishing between Stroke and Mimic at the Bedside: The Brain Attack Study.” Stroke; a Journal of Cerebral Circulation 37, no. 3 (March 2006): 769– Nor, Azlisham Mohd, John Davis, Bas Sen, Dean Shipsey, Stephen J. Louw, Alexander G. Dyker, Michelle Davis, and Gary A. Ford. “The Recognition of Stroke in the Emergency Room (ROSIER) Scale: Development and Validation of a Stroke Recognition Instrument.” Lancet Neurology 4, no. 11 (November 2005): 727– Pantoni, L., E. Bertini, M. Lamassa, G. Pracucci, and D. Inzitari. “Clinical Features, Risk Factors, and Prognosis in Transient Global Amnesia: A Follow-up Study.” European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies 12, no. 5 (May 2005): 350–56. doi: /j x.6. Kissela, Brett M., Jane C. Khoury, Kathleen Alwell, Charles J. Moomaw, Daniel Woo, Opeolu Adeoye, Matthew L. Flaherty, et al. “Age at Stroke Temporal Trends in Stroke Incidence in a Large, Biracial Population.” Neurology 79, no. 17 (October 23, 2012): 1781– Kissela, Brett M., Jane C. Khoury, Kathleen Alwell, Charles J. Moomaw, Daniel Woo, Opeolu Adeoye, Matthew L. Flaherty, et al. “Age at Stroke Temporal Trends in Stroke Incidence in a Large, Biracial Population.” Neurology 79, no. 17 (October 23, 2012): 1781–87. References 59

60 7. Lackland, Daniel T., Edward J. Roccella, Anne F. Deutsch, Myriam Fornage, Mary G. George, George Howard, Brett M. Kissela, et al. “Factors Influencing the Decline in Stroke Mortality A Statement From the American Heart Association/American Stroke Association.” Stroke, December 5, 2013, 8. Martin, P. J., T. P. Enevoldson, and P. R. Humphrey. “Causes of Ischaemic Stroke in the Young.” Postgraduate Medical Journal 73, no. 855 (January 1997): 8– Iancu, Daniela, Rene Anxionnat, and Serge Bracard. “Brainstem Infarction in a Patient with Internal Carotid Dissection and Persistent Trigeminal Artery: A Case Report.” BMC Medical Imaging 10, no. 1 (July 2, 2010): Mackey, Jason. “Evaluation and Management of Stroke in Young Adults.” Continuum (Minneapolis, Minn.) 20, no. 2 Cerebrovascular Disease (April 2014): 352– Munira, Yusoff, Zakariah Sakinah, and Embong Zunaina. “Cerebral Venous Sinus Thrombosis Presenting with Diplopia in Pregnancy: A Case Report.” Journal of Medical Case Reports 6 (2012): Saposnik, Gustavo, Fernando Barinagarrementeria, Robert D. Brown, Cheryl D. Bushnell, Brett Cucchiara, Mary Cushman, Gabrielle deVeber, Jose M. Ferro, and Fong Y. Tsai. “Diagnosis and Management of Cerebral Venous Thrombosis A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association.” Stroke 42, no. 4 (April 1, 2011): 1158– Bushnell, Cheryl, and Gustavo Saposnik. “Evaluation and Management of Cerebral Venous Thrombosis.” Continuum (Minneapolis, Minn.) 20, no. 2 Cerebrovascular Disease (April 2014): 335– Ferro, José M., Patrícia Canhão, Jan Stam, Marie-Germaine Bousser, and Fernando Barinagarrementeria. “Prognosis of Cerebral Vein and Dural Sinus Thrombosis Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT).” Stroke 35, no. 3 (March 1, 2004): 664– Kim, Anthony S. “Evaluation and Prevention of Cardioembolic Stroke.” Continuum (Minneapolis, Minn.) 20, no. 2 Cerebrovascular Disease (April 2014): 309–22. doi: /01.CON d. References (continued) 60

61 16. Alliance for Aging Resarch Assessing Stroke and Bleeding Risk in Atrial Fibrillation—Consensus Statement. Retrieved from df df 17. Connolly, Stuart J., Michael D. Ezekowitz, Salim Yusuf, John Eikelboom, Jonas Oldgren, Amit Parekh, Janice Pogue, et al. “Dabigatran versus Warfarin in Patients with Atrial Fibrillation.” New England Journal of Medicine 361, no. 12 (2009): 1139– Patel, Manesh R., Kenneth W. Mahaffey, Jyotsna Garg, Guohua Pan, Daniel E. Singer, Werner Hacke, Günter Breithardt, et al. “Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation.” New England Journal of Medicine 365, no. 10 (2011): 883– Granger, Christopher B., John H. Alexander, John J.V. McMurray, Renato D. Lopes, Elaine M. Hylek, Michael Hanna, Hussein R. Al-Khalidi, et al. “Apixaban versus Warfarin in Patients with Atrial Fibrillation.” New England Journal of Medicine 365, no. 11 (2011): 981– Gurm, Hitinder S., Jay S. Yadav, Pierre Fayad, Barry T. Katzen, Gregory J. Mishkel, Tanvir K. Bajwa, Gary Ansel, et al. “Long-Term Results of Carotid Stenting versus Endarterectomy in High-Risk Patients.” New England Journal of Medicine 358, no. 15 (2008): 1572– Brott, Thomas G., Robert W. Hobson, George Howard, Gary S. Roubin, Wayne M. Clark, William Brooks, Ariane Mackey, et al. “Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis.” New England Journal of Medicine 363, no. 1 (2010): 11– Chimowitz, Marc I., Michael J. Lynn, Harriet Howlett-Smith, Barney J. Stern, Vicki S. Hertzberg, Michael R. Frankel, Steven R. Levine, et al. “Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis.” New England Journal of Medicine 352, no. 13 (2005): 1305–16. References (continued) 61

62 23. Chimowitz, Marc I., Michael J. Lynn, Colin P. Derdeyn, Tanya N. Turan, David Fiorella, Bethany F. Lane, L. Scott Janis, et al. “Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis.” The New England Journal of Medicine 365, no. 11 (September 15, 2011): 993– Vlak, Monique HM, Ale Algra, Raya Brandenburg, and Gabriël JE Rinkel. “Prevalence of Unruptured Intracranial Aneurysms, with Emphasis on Sex, Age, Comorbidity, Country, and Time Period: A Systematic Review and Meta- Analysis.” The Lancet Neurology 10, no. 7 (July 2011): 626– National Institute of Neurological Disorders and Stroke Cerebral Aneurysms Fact Sheet. Retrieved from Nicholas Zaorski, MD, via Wikimedia Commons. Intracranial Aneurysms Inferior Heat Map View. Retrieved from _heat_map.jpg _heat_map.jpg 27. Bederson, Joshua B., Issam A. Awad, David O. Wiebers, David Piepgras, E. Clarke Haley, Thomas Brott, George Hademenos, Douglas Chyatte, Robert Rosenwasser, and Cynthia Caroselli. “Recommendations for the Management of Patients With Unruptured Intracranial Aneurysms A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association.” Stroke 31, no. 11 (November 1, 2000): 2742– Bor, A Stijntje E, Gabriel J E Rinkel, Jeroen van Norden, and Marieke J H Wermer. “Long-Term, Serial Screening for Intracranial Aneurysms in Individuals with a Family History of Aneurysmal Subarachnoid Haemorrhage: A Cohort Study.” The Lancet Neurology 13, no. 4 (April 2014): 385– Kelly, Adam G. “Unruptured Intracranial Aneurysms: Screening and Management.” Continuum (Minneapolis, Minn.) 20, no. 2 Cerebrovascular Disease (April 2014): 387–98. doi: /01.CON “The Natural Course of Unruptured Cerebral Aneurysms in a Japanese Cohort.” New England Journal of Medicine 366, no. 26 (2012): 2474–82. doi: /NEJMoa References (continued) 62

63 31. Villablanca, J. Pablo, Gary R. Duckwiler, Reza Jahan, Satoshi Tateshima, Neil A. Martin, John Frazee, Nestor R. Gonzalez, James Sayre, and Fernando V. Vinuela. “Natural History of Asymptomatic Unruptured Cerebral Aneurysms Evaluated at CT Angiography: Growth and Rupture Incidence and Correlation with Epidemiologic Risk Factors.” Radiology 269, no. 1 (October 2013): 258– Izar, Benjamin, Ansaar Rai, Karthikram Raghuram, Jill Rotruck, and Jeffrey Carpenter. “Comparison of Devices Used for Stent-Assisted Coiling of Intracranial Aneurysms.” PLoS ONE 6, no. 9 (September 22, 2011): e Molyneux, Andrew J., Richard S. C. Kerr, Jacqueline Birks, Najib Ramzi, Julia Yarnold, Mary Sneade, Joan Rischmiller, and ISAT Collaborators. “Risk of Recurrent Subarachnoid Haemorrhage, Death, or Dependence and Standardised Mortality Ratios after Clipping or Coiling of an Intracranial Aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): Long-Term Follow-Up.” Lancet Neurology 8, no. 5 (May 2009): 427–33. doi: /S (09) Neacsu, Angela, and A. V. Ciurea. “General Considerations on Posterior Fossa Arteriovenous Malformations (clinics, Imaging and Therapy). Actual Concepts and Literature Review.” Journal of Medicine and Life 3, no. 1 (March 2010): 26– 35. Mohr, J P, Michael K Parides, Christian Stapf, Ellen Moquete, Claudia S Moy, Jessica R Overbey, Rustam Al-Shahi Salman, et al. “Medical Management with or without Interventional Therapy for Unruptured Brain Arteriovenous Malformations (ARUBA): A Multicentre, Non-Blinded, Randomised Trial.” The Lancet 383, no (February 2014): 614– Al-Shahi Salman, Rustam, Philip M. White, Carl E. Counsell, Johann du Plessis, Janneke van Beijnum, Colin B. Josephson, Tim Wilkinson, et al. “Outcome after Conservative Management or Intervention for Unruptured Brain Arteriovenous Malformations.” JAMA: The Journal of the American Medical Association 311, no. 16 (April 23, 2014): 1661– Kim, Helen, Rustam Al-Shahi Salman, Charles E. McCulloch, Christian Stapf, and William L. Young. “Untreated Brain Arteriovenous Malformation Patient-Level Meta-Analysis of Hemorrhage Predictors.” Neurology 83, no. 7 (August 12, 2014): 590–97. References (continued) 63


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