Greater Manchester Stroke Operational Delivery Network Cryptogenic Stroke

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

Cryptogenic strokes Greater Manchester Stroke Operational Delivery Network ‘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 etiologies 1 Classification Diagnostic evaluation TOAST criteria 1 Not specified Causative Classification of Stroke (CCS)2 Brain CT/MR, 12 -lead ECG, precordial echocardiogram, extra/intravascular imaging Embolic strokes of undetermined Brain CT/MR, 12 -lead ECG, precordial echocardiogram, source 3 extra/intravascular imaging, cardiac monitoring for ≥ 24 hours ASCO(D) phenotyping 4 Does not include a cryptogenic stroke category 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 1.

Cumulative probability of survival (A), stroke recurrence (B), and composite cardiovascular event (C) by stroke type. Greater Manchester Stroke Operational Delivery Network • ESUS 10% • 20% recurrent stroke risk at 2 years 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 Greater Manchester Stroke Operational Delivery Network

PAF Greater Manchester Stroke Operational Delivery Network • 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.

Greater Manchester Stroke Operational Delivery Network

Greater Manchester Stroke Operational Delivery Network

Greater Manchester Stroke I/P telemetry (95% CI) 24 h Holter (95% CI) Operational Delivery Network >24 h monitoring Pooled Proportion (95% CI) 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 Greater Manchester Stroke Operational Delivery Network Gladstone DJ et al. N Engl J Med 2014; 370: 2467 -2477

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

Cost effectiveness Greater Manchester Stroke Operational Delivery Network • Invasive monitoring: CS patients for three years using an ICM is cost-effective for the prevention of recurrent stroke, compared to So. C. 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 lifeyears 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 Greater Manchester Stroke Operational Delivery Network • • • Brain Imaging 12 -lead ECG Lipid/Hba 1 c Carotid Dopplers Arrhythmia monitoring- 5 -7 day cardiac monitoring +/-TTE

Greater Manchester Stroke Operational Delivery Network

Greater Manchester Stroke Operational Delivery Network ? 10 %

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

Conclusion Greater Manchester Stroke Operational Delivery Network • 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.