Cryptogenic Stroke and AF Amit Kishore Consultant and Honorary Senior Lecturer in Stroke Medicine , SRFT Amit.Kishore@srft.nhs.uk January 2017

Cryptogenic strokes ‘Brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a standard vascular, cardiac, and serologic evaluation’. Amount to 30% -35% of all stroke etiologies1 Classification Diagnostic evaluation TOAST criteria1 Not specified Causative Classification of Stroke (CCS)2 Brain CT/MR, 12-lead ECG, precordial echocardiogram, extra/intravascular imaging Embolic strokes of undetermined source3 Brain CT/MR, 12-lead ECG, precordial echocardiogram, extra/intravascular imaging, cardiac monitoring for ≥24 hours ASCO(D) phenotyping4 Does not include a cryptogenic stroke category 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; 3. Hart RG et al. Lancet Neurol. 2014;13:429-438; 4. Amarenco P et al. Cerebrovasc Dis. 2013;36:1-5

20% recurrent stroke risk at 2 years Cumulative probability of survival (A), stroke recurrence (B), and composite cardiovascular event (C) by stroke type. ESUS 10% 20% recurrent stroke risk at 2 years Cumulative probability of survival (A), stroke recurrence (B), and composite cardiovascular event (C) by stroke type. ESUS indicates embolic stroke of undetermined source. George Ntaios et al. Stroke. 2015;46:2087-2093 Copyright © American Heart Association, Inc. All rights reserved.

Potential aetiologies Occult Paroxysmal Atrial Fibrillation Patent Foramen Ovale (PFO) Aortic Arch Atheroma Others

PAF Ischaemic stroke is as common in PAF as in permanent AF 5,6 Earlier studies -The type of AF and the length of time the patient was in AF had no effect on the stroke rate 5,7 Difficult- >90% are asymptomatic, > 30% are intermittent Change in management once AF diagnosed How hard do we look to find PAF??? 5 Atrial fibrillation investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154: 1449-57 , 6 Friberg L, et al. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study). Eur Heart J. 2006; 27:1954-1964. 7 Hart RG,, et al. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol. 2000; 35: 183–7 .

Unselected Selected I/P telemetry (95% CI) 24h Holter >24h monitoring Pooled Proportion Unselected 5.5 (4.2-6.9) 5.0(2.0-9.0) 14.1(1.5-36.4) 6.2(4.4-8.3) Selected 15.0(7.0-25.0) 10.7(3.4-21.5) 14.7(10.7-19.3) 13.4(9.0-18.4)

Incremental Yield of Prolonged ECG Monitoring Figure 2 Incremental Yield of Prolonged ECG Monitoring for the Detection of Atrial Fibrillation in Patients with Cryptogenic Stroke or TIA. The proportion of patients in whom atrial fibrillation was detected increased with increasing duration of ECG monitoring. The data reflect the timing of the first detected episode of atrial fibrillation; data for 2 patients are not shown because the exact date of the detection of atrial fibrillation was unknown. Atrial fibrillation was detected in 6 of 277 patients who underwent monitoring with a 24-hour Holter monitor (the control group). In the group of 284 patients who underwent 30-day monitoring, atrial fibrillation was detected in 21 patients within the first week of monitoring, in 33 within the first 2 weeks of monitoring, in 35 within the first 3 weeks of monitoring, and in 42 within 4 weeks of monitoring (including 1 patient with atrial fibrillation that was first detected on day 34). Gladstone DJ et al. N Engl J Med 2014;370:2467-2477

Time to First Detection of Atrial Fibrillation 30% new AF detection rates v 3%control at 3 yrs Figure 2 Time to First Detection of Atrial Fibrillation. Sanna T et al. N Engl J Med 2014;370:2478-2486

Cost effectiveness Invasive monitoring: CS patients for three years using an ICM is cost-effective for the prevention of recurrent stroke, compared to SoC. An ICER of £17,175 per QALY gained was < £20,000 and £30,000 threshold considered as acceptable for government funding, according to the UK NICE 8 Non-Invasive monitoring: With 7 days additional monitoring, the cost-utility ratio of outpatient cardiac monitoring would be $13,000 per quality-adjusted life-years gained based on 6% new AF detection rates 9 Diamantopoulos A et al. Cost-effectiveness of an insertable cardiac monitor to detect atrial fibrillation in patients with cryptogenic stroke International Journal of Stroke 2016, Vol. 11(3) 302–312. Kamel H et al Stroke. 2010 Jul;41(7):1514-20

Standard AIS Work-Up Brain Imaging 12-lead ECG Lipid/Hba1c Carotid Dopplers Arrhythmia monitoring- 5-7 day cardiac monitoring +/-TTE

? 10 %

Clinical and economic outcomes Stroke Patients   Stroke Burden Number of patients with ischaemic stroke admitted in 2013/2014 3952 Percentage of strokes with undetermined cause (ESUS-Cryptogenic) 10% Number of ESUS- Cryptogenic Stroke Patients 395 AF detection and stroke risk reduction Clinical Outcomes AF detection rate of Reveal at 3 years 30% AF detection rate of Standard of Care at 3 years 3% Additional patients detected with AF with Reveal 107 Recurrence risk of stroke at 10 years 39% Stroke risk reduction through treating AF with OAC 73% Costs of Recurrent Stroke Costs of stroke NHS costs per stroke per patient over 5 years £22,000 NHS costs per stroke per patient over lifetime: minor - major event £28,000- £84,000 Total costs per stroke over 10 years £60,000 Results - Using Reveal in Secondary stroke prevention: Without Reveal With Reveal Recurrent Strokes Number of recurrent ischaemic strokes over lifetime 176 158 Clinical and economic outcomes Estimated number of strokes avoided with Reveal 18 Quality adjusted life years gained with Reveal 47 Incremental Cost Effectiveness Ratio (DOACs) £17,184

Conclusion Diagnostic evaluation of IS important for targeted secondary prevention strategies Occult AF is ‘tip of iceberg’ as cause of cryptogenic strokes Initial cardiac monitoring strategies currently insufficient to pick up PAF: 9-fold increase in AF detection with ICM Prolonged cardiac monitoring is cost-effective A cryptogenic stroke registry and ‘real-life’ data may be vital for QI.