Updates in Cerebrovascular Disease
with Underwriting Impact
Midwestern Underwriting Conference
Dave Rengachary, MD
Vice President and Medical Advisor
September 10, 2014
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
Transient Ischemic Attacks (versus
mimics)
3
“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”
4
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”
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
Causes of TIA mimics
Diagnosis of Mimic
Percent
Seizure
44
Migraine
23
Psychogenic
7
Hypertensive encephalopathy
4
Transient Global Amnesia
4
Sepsis
4
Hypoglycemia
2
Benign Paroxysmal Vertigo
2
Cerebral venous thrombosis
2
Brain Neoplasm
1
Subarachnoid hemorrhage
1
Peripheral nerve lesion
1
*Syncope
??
Amort M et al. Cerebrovascular Diseases. 2011;32:60
2
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
0.1
Stroke 2006; 37: 769-754
Lancet 2005; 4:727-34
3
MIMIC
1
10
OR TIA/STROKE
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
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
Stroke in the Young
12
Stroke in the Young
Increasing
Incidence
Elevated
mortality but
wide range
Heterogenous
causes
13
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
14
Stroke in the Young: Diverse Causes
Adapted from Martin et al
8
Cardioembolic
Dissection
Thrombophilias
Atherosclerosis
Cerebral
Venous
Thrombosis
Vasculitis
Genetic
15
Carotid Dissection
9
Iancu et al. Creative Commmons Attribution 2.0
16
Carotid Dissection
Al-Ali, Firas, and Brandon C. Perry. “Spontaneous Cervical Artery Dissection: The Borgess Classification.” Stroke 4 (2013): 133. Creative Commons Attribution License
17
Dissection
Top 10 things to Remember!
 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
10
disease)
18
Dissection
Top 10 things to remember!
 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
19
Cerebral Venous Thrombosis
Munira et al.
11
Creative Commons Attribution License 2.0
20
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, antithrombin III deficiency, antiphospholipid antibody syndrome)
21
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)
22
Cerebral Venous Thrombosis
“Desert” Island Underwriting Questions
Is there any
underlying
thrombophilia or
systemic disease?
Any Permanent
Symptoms or
Complications?
Did the applicant
have infarction or
hemorrhage on
imaging?
23
Cerebral Venous Thrombosis
Other Poor Prognostic Factor from International Study on Cerebral
Vein and Dural Sinus Thrombosis (ISCVT)14
 Males
 Age > 37
 Deep Cerebral Vein Thrombosis
 CNS infection
24
The New Oral Anticoagulants
25
Dabigatran
Exilate
(Pradaxa)
Novel Oral
Anticoagulants
Rivaroxaban
(Xarelto)
Apixiban
(Eliquis)
26
Warfarin Anticoagulation




Time spent in the therapeutic range 60-70% 15
Frequent blood draws
Medication and food interactions
Major bleeding risks with labile kinetics
27
Factors in Favor of Anticoagulation
CHADS Score
C Cardiac
Failure
1 point
H Hypertension
1 point
A Age 75 or
greater
1 point
D Diabetes
1 point
S Stroke or TIA
history
2 points
28
Factors that increase bleed risk
HAS BLED Score
H
Hypertension (greater than 160 mm hg)
1 point
A
Abnormal Renal or Liver function
1 point EACH
S
Stroke
1 point
B
Bleed History
1 point
L
Labile INR
1 point
E
Elderly (age greater than 65)
1 point
D
Drugs or alcohol
1 point EACH
29
Stroke vs. Bleed Risk
16
CHADS
HAS BLED
Points
Stroke Risk
Points
Bleed Risk
0
1.9%
0
1.13%
1
2.8%
1
1.02%
2
4%
2
1.88%
3
5.9%
3
3.74%
4
8.5%
4
8.7%
5
12.5%
5
12.5%
6
18.2%
30
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 (RELY)Trial
 *Renal clearance
31
Randomized Evaluation of Long-Term Anticoagulation
Therapy (RE-LY)Trial
Connolly et al. 2013
17
32
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)
33
Rocket AF trial (Rivaroxaban)
Patel et al. 2011
18
34
ARISTOTLE (Apixiban)
Granger et al. 2011
19
35
Novel oral anticoagulants
Caveats
 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.
36
Carotid and Intracranial Stenting
37
Carotid Stenting
General Considerations
Who is doing the
procedure?
Why is an
endarterectomy
not being
performed?
Is the patient
symptomatic
?
38
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
20
Gurm et al.
39
SAPPHIRE Trial
Results
 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%.
40
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
21
Brott et al.
41
CREST Trial
8
Rate Percentages
7
6
5
4
Stenting
CEA
3
2
1
0
Stroke/Death/MI
Periprocedural
Stroke
Periprocedural MI
42
Intracranial Atherosclerosis
22
 WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease)
 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
23
Preventing Recurrent Stroke in Intracranial Stenosis)
 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%)
43
Underwriting of Cerebral Aneurysm
and AVM
44
Cerebral Aneurysm
45
Cerebral Aneurysm
Background
24
 Prevalence – 3.2%
 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
46
Zarosky
26
Creative Commons Attribution License 3.0
47
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
29
mm.
48
Risk of Rupture
Size
From UCAS Japan Investigators30 (5720 patients, with 6697 aneurysms
studied for 3 years)
Size
Hazard Ratio
3-4 mm
Reference
5-6 mm
1.13
7-9 mm
3.35
10-24 mm
9.09
>25 mm
76.26
49
Risk of Rupture
Location
Location
Middle Cerebral
Reference
Internal Carotid
0.43
PICA/Vertebral Junction
0.68*
Basilar/Superior Cerebellar Junction
1.49*
Posterior Communicating/Internal
Carotid
1.0
Anterior Communicating Artery
2.0
*Not statistically significant
PICA = Posterior Inferior Cerebellar artery
50
Risk of Rupture
Other Factors
 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
51
How to treat?
Izar et al.
32
Creative Commons Attribution License 3.0
52
Clipping versus Coiling for Aneurysm Management
 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
53
Arteriovenous Malformation
54
Neacsu et al.
34
Creative Commons Attributions License
55
AVM management
ARUBA trial
 Multicenter (39) trial35 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 Scotland36 with 12 years of follow up published in
2014 also supported better outcomes with conservative
management.
56
MARS (Multicenter AVM Research Study)
Kim et al.
37
 Largest natural history cohort analysis to date
57
MARS (Multicenter AVM Research Study)
Predictor
Hazard Ratio
Age at diagnosis
1.10
Female Sex
1.12
Associated Arterial Aneurysm
1.68
Exclusively deep venous drainage
2.14
Hemorrhage at presentation
3.45
58
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