update on cryptogenic stroke evaluation and treatment · •hypercoagulable state in setting of...
TRANSCRIPT
Fadi Nahab MD Associate Professor of Neurology and Pediatrics
Emory University Medical Director, Stroke Program
Emory University Hospital, Emory University Hospital Midtown
Update on Cryptogenic Stroke Evaluation and Treatment
emoryhealthcare.org
Disclosures
• Consultant: Imedex, Medtronic, Expert witness
• Speaker’s bureau: Medtronic
emoryhealthcare.org
Objectives
• Be familiar with the risk of recurrent cryptogenic stroke and potential causes
• Recognize that biomarkers may help to identify causes of cryptogenic stroke
• Consider unrecognized paroxysmal atrial fibrillation as an important contributor to cryptogenic stroke and the benefits of prolonged cardiac monitoring
• Understand the risks and potential benefits of various treatment strategies, including ongoing studies
3
emoryhealthcare.org
Cryptogenic Stroke: Causes
Bang OY et al. Stroke. 2014;45:1186-1194.
emoryhealthcare.org
Cryptogenic Stroke: Causes
• Cardiac etiologies: – Paroxysmal AFib, SBE (culture negative), papillary fibroelastoma
• Subtle arterial dissections • CNS vasculitis • Hypercoagulable state in setting of cancer • Metabolic disorders: Hyper-homocysteine, Fabry’s disease • Plaque in aortic arch • HIV, CNS infection • Drug abuse • Genetic etiologies (CADASIL, MELAS, etc.)
emoryhealthcare.org
Definitions of Cryptogenic Stroke
1. Adams HP et al. Stroke. 1993;24:35-41; 2. Causative Classification System for Ischemic Stroke (CCS). Available at:
https://ccs.mgh.harvard.edu/ccs_intro.php. Accessed April 15, 2015; 3. Hart RG et al. Lancet Neurol. 2014;13:429-438; 4. Amarenco
P et al. Cerebrovasc Dis. 2013;36:1-5.
emoryhealthcare.org
Cardiac Testing
Manning WJ. Available at:
http://www.uptodate.com/contents/echocardiography-in-detection-of-
cardiac-and-aortic-sources-of-systemic-embolism.
Accessed December 15, 2015.
emoryhealthcare.org
TTE vs TEE
17
39
0
20
40
60
80
100
Identified onBoth TTE and
TEE
Identified onTEE Only
Potential Cardioembolic Source Identified
de Bruijn SF et al. Stroke. 2006;37:2531-2534.
Patients
(%
)
emoryhealthcare.org
MRV Pelvis & Cryptogenic Stroke
• N=46 – 18-60 yrs
– Ischemic stroke <72 hrs
– Deficit >3 hours
• MRV pelvis time of flight (TOF, PC)
• Low interrater agreement, K=0.23
Stroke 2004;35:46-50
emoryhealthcare.org
CE-MRV Pelvis & Cryptogenic Stroke
• Contrast-enhanced Pelvic MRV
• Excellent interrater agreement, K=1.0
Stroke 2014;45:2324-2329
emoryhealthcare.org
Cryptogenic Stroke & D-dimer
• Case-control study (n=140) – D-dimer obtained >10
days from stroke
– Mean D-dimer levels were significantly higher in the UCA vs CSA group
• UCA 615 vs CSE 139, p<0.001
CSA=Definite stroke association; UCA=Unidentified/cancer-associated stroke
Stroke 2012;43:3029-3034.
emoryhealthcare.org
Cryptogenic Stroke & D-dimer
• 348 consecutive cryptogenic stroke patients
• 71 (20%) with active cancer at time of stroke
• D-dimer obtained within 24 hours of admission
• Mean D-dimer level was significantly higher in cancer-associated stroke patients vs those without cancer (p<0.001)
PLoS One 2012;7:e44959
emoryhealthcare.org
Atrial Fibrillation Burden and Short-Term Risk of
Stroke: Case-Crossover Analysis of Continuously
Recorded Heart Rhythm From Cardiac Electronic
Implanted Devices • 187 acute ischemic stroke patients
with CIEDs monitored for at least 4 months prior to index event.
• 28 patients had ≥5.5 hours of AF burden within 30 days prior to stroke.
• AF burden of >5.5 hr increased the
risk for ischemic stroke 4-5 fold.
• The risk for stroke was transient and reduced rapidly after 10d post AF event.
Turakhia, Circ Arrhythm Electrophysiol; 2015
emoryhealthcare.org
Cardiac Monitoring Strategies
1. Vasamreddy CR et al. J Cardiovasc Electrophysiol. 2006;17:134-139; 2. Gladstone DJ et al. N Engl J Med. 2014;370:2467-2477; 3. Rosenberg MA et al. Pacing Clin Electrophysiol.
2013;36:328-333; 4. Kamel H et al. Stroke. 2013;44:528-530. 5. Shinbane JS et al. Heart Rhythm Society 2013 34th Annual Scientific Sessions, Volume 10, Issue 5S, 2013.
emoryhealthcare.org
Studies of Outpatient Monitoring in Cryptogenic Stroke Patients
Glotzer TV, Ziegler PD. Heart Rhythm. 2015;12:234-241.
Kasshout O, et al. J Stroke Cerebrovasc 2015 (in review)
Emory (2015) 132 30 seconds MCOT 30 days 13%
Three-year longevity for long-term monitoring2
MR Conditional at 1.5 and the only ICM
at 3.0 Tesla with no post-insertion
waiting required‡
Proven AF algorithm accurately detects AF
in 98.5% of patients1
Reveal LINQ ™ ICM The Smallest ICM to Provide Continuous and Wireless Data Collection and
Trending
† Reveal LINQ ICM has been demonstrated to pose no known hazards in a specified MR environment with specified conditions of use. Please see Reveal LINQ
ICM clinician manual or MRI Technical Manual for more details.
1. Hindricks G, Pokushalov E, Urban L, et al. Performance of a new leadless implantable cardiac monitor in detecting and quantifying atrial fibrillation: Results of
the XPECT Trial. Circ Arrhythm Electrophysiol. April 2010;3(2):141-147.
2. See the Reveal LINQ ICM clinician manual for usage parameters
Reveal LINQ ICM is 1/3
the width of an AAA battery
No wires or leads
CRYSTAL AF
CRYSTAL AF: Study Design and End Points
End Point
Primary • Time to first detection of AF at 6 months of follow-up
Secondary • Time to first detection of AF at 12 months • Recurrent stroke or TIA • Change in use of oral anticoagulant drugs
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
• Randomized, controlled clinical trial with 441 patients
• Compared continuous, long-term monitoring with Reveal ICM vs.
conventional follow-up
• Assessment at scheduled and unscheduled visits
• ECG monitoring performed at the discretion of the site investigator
CRYSTAL AF: Patients
• Age ≥40 years
• Diagnosis of stroke or TIA occurring within previous 90 days
• Stroke was classified as cryptogenic after extensive testing: – 12-lead ECG
– ≥24 hours of ECG monitoring
– TEE
– Screening for thrombophilic states (in patients <55 years of age)
– Magnetic resonance angiography, computerized tomography angiography, or catheter angiography of head and neck
– Ultrasonography of cervical arteries or transcranial Doppler ultrasonography of intracranial arteries allowed in place of MRA or CTA for patients aged ≥55 years
Patients were only categorized with cryptogenic stroke after extensive diagnostic testing
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
CRYSTAL AF: Study Population
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
447 patients were enrolled
6 were excluded • 4 did not meet eligibility criteria
• 2 withdrew consent
441 underwent randomization
221 were assigned to ICM • 208 had ICM inserted
• 13 did not have ICM inserted
220 were assigned to control • 220 received standard of care
12 crossed over to control
12 exited the study • 3 died
• 1 was lost to follow-up
• 5 withdrew
• 3 were withdrawn by investigator
6 crossed over to ICM
13 exited the study • 2 died
• 1 was lost to follow-up
• 7 withdrew
• 3 were withdrawn by investigator
221 were included in intention-to-treat analysis 220 were included in intention-to-treat analysis
CRYSTAL AF: AFib at 6 months
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
CRYSTAL AF: AFib at 12 months
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
12 Month Endpoints
ICM Control
Median Time from Randomization to AF Detection
84 days
52.5 days
Patients found to have AF 29 4
% Asymptomatic Episodes 79% 50%
Oral Anticoagulation Usage, overall 14.7% 6.0%
OAC use in AF patients 96.6% 100%
Tests required to find AF Automatic AF detection
121 ECGs 32 24-hour Holters 1 Event Recorder
Complications 5 (2.4%) ICMs removed due to insertion site infection or pocket erosion
None
CRYSTAL AF: Detection of AF at 36 Months
Sanna T et al. N Engl J Med. 2014;370:2478-2486.
emoryhealthcare.org
Predictors for Atrial Fibrillation Detection after
Cryptogenic Stroke:
Results from CRYSTAL AF
Assessed whether these parameters
predicted ICM detected AF:
• Age, sex, race
• Body Mass Index,
• Type and severity of index event
• CHADS2 score
• PR-interval
• Diabetes, hypertension
• Congestive heart failure
• Patent foramen ovale
• Premature atrial contractions
Increasing age and a prolonged PR-
interval were independently
associated with AF, but the
predictive ability was only moderate.
Thijs et al. Neurology 2015 (in press)
emoryhealthcare.org
MRI FLAIR Lesions & PAF
• Cortical lesions (vs other) were significantly associated with detection of PAF:
– OR 5.5 (95% CI: 1.4 - 20.9)
MRI Lesion 30-day PAF
Cortical lesion 21.2 %
High subcortical 4.1%
None 5.9%
P-value: 0.01
Kasshout O, et al. J Stroke Cerebrovasc 2015 (under review)
emoryhealthcare.org
Echocardiography Variables & PAF Variable Area under the
Curve (AUC) Value Sensitivity Specificity
LA Diameter .67 (48-87) 3.75 83% 52%
A .49 (.25-.74) 82.5 67% 49%
a’ septal .93 (.80-.99) 8.5 99% 85%
a’ lateral .52 (.29-.76) 13.5 71% 32%
LAVI .7 (.52-.88) 31.5 83% 68%
LAVI/A .61 (.37-.86) 0.33 83% 45%
LAVI/a’(lateral) .67 (.45-.9) 2.3 83% 59%
LAVI/a’(septal) .98 (.92-.99) 4.6 99% 96% LA=Left atrium; a’=Tissue Doppler velocity; A=Late diastolic Doppler velocity ; LAVI=Left atrial volume index
Kasshout O, et al. J Stroke Cerebrovasc 2015 (under review)
emoryhealthcare.org
Real World Experience
Methods: • Inclusion Criteria: Received ICM after CS as
defined by physician, follow-up censored at 182 days of monitoring
• Data transmitted via CareLink Remote Monitoring
• AF episodes (≥2 minutes) were adjudicated • AF detection rates were computed using
Kaplan Meier survival estimates Results: • 1247 patients included, 53% male, mean age
of 65 years • 1521 AF episodes detected in 147 patients,
yield of 12.2% at 6 months • Median time to detection: 58 [IQR 11-101]
Days • Median duration of longest AF episode: 3.4
[IQR 0.4-11.8] hours
emoryhealthcare.org
Emory Experience • A random sampling of ILR tracings identified as atrial fibrillation by
the Medtronic algorithm was adjudicated by a board certified electrophysiologist for accuracy.
• Among 166 rhythm strips identified as atrial fibrillation by the Medtronic algorithm in 52 consecutive patients:
– 140 (84%) were incorrectly identified as atrial fibrillation
• 57% as premature atrial complexes(PACs) • 22% as T wave over-sensing, • 10% due to noise • 5.0% due to premature ventricular complexes (PVCs) • 2.9% due to under-sensing • 2.9% due to sinus arrhythmia.
• Of the 38 (73%) patients with cryptogenic stroke, 4 (11%) were identified as having true atrial fibrillation over 413 patient-months of monitoring – Mean time to atrial fibrillation detection was 93 days after ILR.
International Stroke Conference 2016
emoryhealthcare.org
30
(ESUS)
Lancet Neurol 2014;13:429-438.
emoryhealthcare.org
ESUS Studies
Anticipated completion: 1November 2017 (n=6000), 2January 2018 (n=7060)
1. ClinicalTrials.gov. NCT02239120. Accessed Dec 15, 2015
2. ClinicalTrials.gov. NCT02313909. Accessed Dec 15, 2015.
emoryhealthcare.org
Risks of ESUS Treatment Paradigm
• Assumption #1 – A significant % of these strokes are due to either:
• 1. AFib • 2. Another mechanism that is responsive to anticoagulation
therapy
• Assumption #2 – Treatment with an anticoagulant will be safe for these
other causes
• Assumption #3 – Enough patients will survive long enough to show overall
benefit
32
emoryhealthcare.org
Cryptogenic Stroke: Recurrent Stroke Risk
33
Age +PFO 2-yr stroke or death rate
-PFO 2-yr stroke or death rate
P-value
<55 yrs 2.0% 9.3% 0.15
55-64 yrs 10.0% 13.9% 0.70
≥65 yrs 37.9% 14.5% 0.01
Stroke 2004;35:2145-2149.
emoryhealthcare.org
Cryptogenic Stroke Treatment Options
• Preferred therapy = single antiplatelet agent unless: – Heart rhythm monitoring shows atrial fibrillation
• Anticoagulation
– TTE with large left atrium and no prior valvular disease • Cardiac monitor; consider aspirin/clopidogrel vs anticoagulation
– D-dimer >1000 beyond 10 days from stroke onset • Routine cancer screening; consider whole body imaging. Consider anticoagulation if
cancer identified.
– PFO • Monitor cardiac rhythm; consider leg ultrasound, contrast-enhanced MRV pelvis if D-
dimer elevated. Single antiplatelet therapy. No clear benefit from PFO closure.
– Migraine w/ aura • Headache prophylaxis for frequent HA
– Recurrent stroke on antiplatelet agent • Assess medication adherence, drug-drug interactions (e.g. NSAID use) and opportunity
to optimize risk factors before considering anticoagulation
emoryhealthcare.org
Diet & Stroke
• REGARDS Study – Southern Diet (added fats, fried food, eggs, organ and
processed meats, and sugar-sweetened beverages) • 56% higher risk of acute CHD (comparing highest vs lowest
quartile); p=0.003
– Participants eating ≥2 weekly servings of fried fish (vs <1 serving/month)
• 63% higher hazard of ischemic stroke or MI
• Adjusted for socio-demographic variables, health behaviors, and cardiovascular disease risk factors.
Shikany JM, et al. Circulation 2015;132:804-814. Nahab F, et al. AJCN 2015 (under review)
emoryhealthcare.org
Summary
• The risk of recurrent cryptogenic stroke depends on the underlying (and unknown) cause
• Biomarkers may be important predictors of cancer-related cryptogenic stroke
• Unrecognized paroxysmal atrial fibrillation is a significant contributor to cryptogenic stroke and prolonged cardiac monitoring is important; age and left atrial parameters on echocardiography may refine those at highest risk.
• The success of any therapy will likely depend on the treated population and the efficacy and safety of the chosen treatment