Subclinical AF: Implications of device based episodes

Subclinical AF: Implications of device based episodes Michael R Gold, MD, PhD Medical University of South Carolina Charleston, SC Disclosures: Clinical Trials and Consulting: Medtronic, Boston Scientific

Introduction Atrial Fibrillation is common in patients with pacemakers and ICDs (CIEDs) SSS is the most frequent indication for PPM in US with most having Afib ICD patients have LV dysfunction and CHF, two conditions with a high incidence of AF Devices also allow for the detection of AF, which is often asymptomatic. The prognostic importance and therapeutic implications of such episodes is not fully understood

Stroke Risk in Pacemaker Patients: By History of AF Hx. Of AF Healey JS Circulation 2006 No Hx of AF 5 years

What is Atrial Fibrillation?

Atrial Tachyarrhythmia Detected by Pacemakers Modern pacemakers can precisely document brief, asymptomatic AT

Stored Electrograms moment of AT detection Ventricular far-field oversensing memory data require confirmation by stored electrograms before any conclusions can be made!

Intermittent AF Undersensing AT onset criteria fulfilled high-degree AT undersensing Stored AF episode, duration only 25 s due to intermittent AF undersensing. True AF duration was >6 months (permanent).

Are all AHRE real? AWARE Trial (N=1642) Appropriate: 73% AF 42% Aflutter 27% Atrial Tachycardia 4% Inappropriate: 37% RNRVAS 17% Noise 5% Farfield R-wave oversensing 3% Sinus tachycardia 2%

Potential Clinical Impact of AHRE AT with EGM documentation AT with ECG documentation AT >48 h without symptoms or ECG documentation In 110 patients with a history of AT AT recurred during 19 mo FU in 46% (ECG) versus 88% (device) AT >24 h in 50 patients 19/50 patients with AT >24 h asymptomatic and in SR at FU Israel et al, JACC 2004;43:47-52

Monitored AF Embolic Risk Capucci et al J Am Coll Cardiol 2005;46:1913

MOST Study Death or Stroke Glotzer et al Circulation 2003

Retrospective Composite Limitations of MOST No adjudication of EGMs One-third of patients with AHRE had previously documented Atrial Fibrillation

Prospective TRENDS Study n=2486, no adjudication of AHRE Variable Value Age 70.9 ± 11.1 yrs Male 66% (n=1650) CHADS 2 2.2 ± 1.2 CHF 60% (n=1479) Hypertension 76% (n=1887) Diabetes 32% (n=783) Prior Stroke/TIA 13 % (n=333) Systolic BP 133.3 ± 22.5 mmhg

Baseline Clinical Features Variable Value Pacemaker ICD CRT Warfarin Aspirin Documented AT/AF History 50% (n=1234) 31% (n=781) 19% (n=471) 21% (n=517) 62% (n=1547) 20% (n=498)

Results The median value for maximum daily burden in all 30-day windows with nonzero AT/AF was 5.5h All 30 day Windows (100%) Zero AT/AF Burden Windows (76%) Any AT/AF Burden Windows (24%) Low AT/AF Burden Windows: < Median Burden Value (12%) High AT/AF Burden Windows: Median Burden Value (12%) < 5.5h > 5.5h

TE Rate per 100 Patient-years TRENDS Prospective Registry (n=2486) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Zero AT Low AT (<5.5h) High AT (5.5 h) Glotzer et al. Circ Arrhythm Electrophysiol 2009;2:474-80.

ASymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing Trial

Patient Eligibility ASSERT Enrolled after new dual-chamber pacemaker Age 65 years History of hypertension Excluded if any history of AF Excluded if on Vitamin K antagonist Pre-specified primary analysis: Monitor from enrolment to 3 month visit for atrial tachyarrhythmia defined as >6 minutes and an atrial rate of >190 bpm Prospective follow up for ischemic stroke or systemic embolism from 3 month visit onwards Adjudication of all available AHRE

Study Design Prospective Cohort Design To determine if device-detected atrial tachyarrhythmias are associated with an increased risk of stroke or embolism? Mininum Follow up Maxmum Follow Up Mean Follow Up 1.75 yrs 5 yrs 2.8 yrs Enrolled 0-8 wks post implant Arrhythmia Detection Follow Up Period Primary Outcome: Ischemic Stroke or Systemic Embolism Visits -3 0 3 9 15 21 27 33 39 45 51 57 Months

NEJM 2012;366:120-9 ASSERT: Patient Baseline Characteristics Device-Detected Atrial Tachyarrhythmia before 3 Month Visit No N = 2319 Yes N = 261 P-Value Age (years) (mean ± SD) 76.3 ± 6.7 77.0 ± 6.8 0.13 Male 58.7% 54.9% 0.27 History of Prior Stroke 7.2% 6.9% 0.84 History of Heart Failure 14.4% 14.9% 0.83 History of Diabetes Mellitus 29.1% 22.6% 0.03 History of Myocardial Infarction 18.4% 12.3% 0.01 CHADS 2 score (mean ± SD) 2.26 ± 1.02 2.21 ± 1.11 0.47 Sinus Node Disease 42% 50% 0.01 Heart Rate 70.0 ± 11.6 67.7 ± 11.7 0.001 Systolic BP (mm Hg) 136.5 ± 20 137.2 ± 20 0.60 Baseline use of ASA 61.7% 61.3% 0.91 Baseline use of Clopidogrel 10.7% 9.6% 0.56

Cumulative Hazard Rates Time to First Device-Detected Atrial Tachyarrhythmia > 6 min, >190 bpm ASSERT : Time to Adjudicated AHRE(>6 minutes,>190/minute) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 # at Risk Year 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 2580 2059 1842 1663 1371 1008 706 446 243 3 month Visit 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Years of Follow-up

Cumulative Hazard Rates Ischemic Stroke or Systemic Embolism 0.0 0.02 0.04 0.06 0.08 0.10 # at Risk Year 0.5 1.0 1.5 2.0 2.5 + _ 261 249 238 218 178 122 2319 2145 2070 1922 1556 1197 RR=2.49 95%CI 1.28-4.85 P=0.007 Device-Detected Atrial Tachyarrhythmia Detected 0-3 months No Asymptomatic Atrial Tachycardia Detected 0-3 months 0 0.5 1.0 1.5 2.0 2.5 T 0 at 3-month visit Years of Follow-up

Stroke Etiologies Hemorrhagic (15%) Ischemic (85%) Types of Ischemic Stroke Cryptogenic (25-40%) Atherothrombotic (25-30%) Cardioembolic (20%) Lacunar/Small Vessel (15-20%) Other/Uncommon (5-10%)

Association of AF and Stroke 5-fold in risk of stroke 1,2 Stroke severity (and mortality) is worse with AF than without AF 3 Incidence of all-cause stroke in patients with AF: 5% 1 Stroke risk persists even in asymptomatic AF 4 1. Fuster V, et al. J Am Coll Cardiol. 2001;38(4):1231-1266. 2. Benjamin EJ, et al. Circulation. 1998;98(10):946-952. 3. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123. 4. Page RL, et al. Circulation. 2003;107:1141-1145. 25

Should all Patients with stroke or TIA and known clinical AF or documented AF at the time of stroke be anticoagulated if possible? 26

Comparison of Stroke Risk Stratification Schemes Annual Stroke Rate (%) Risk Factor CHADS 2 CHA 2 DS 2 - VASc Renal Insuff (CrCl<60 ml/min) R 2 - CHADS 2 --- --- 2 CHF 1 1 1 Hypertension 1 1 1 Age >75 years 1 2 1 Diabetes 1 1 1 Stroke/TIA 2 2 2 Vascular Disease --- 1 --- Age >65-74 Years --- 1 --- Sex (Female) --- 1 --- Score CHADS 2 CHA 2 DS 2 - VASc R 2 - CHADS 2 0 1.9 0 0.4 1 2.8 1.3 1.3 2 4.0 2.2 2.2 3 5.9 3.2 2.6 4 8.5 4.0 3.6 5 12.5 6.7 5.3 6 18.2 9.8 5.9 7 9.6 2.8 8 6.7 7.4 Lip GY, Halperin JL. Am J Med 2010;123(6):84-488; Olesen JB, et al. Br Med J 2011;342:d124; Piccini JP, et al.circulartion 2013;127:224-232.

Should all Patients with Embolic or Cryptogenic strokes and no known AF (ESUS) be anticoagulated? 28

Comparison of Warfarin versus Aspirin for the Prevention of Recurrent Stroke or Death: Subgroup Analyses from the Warfarin-Aspirin Recurrent Stroke Study Cerebrovasc Dis 2006;22:4 12 - DOI:10.1159/000092331 2006 S. Karger AG, Basel

Comparison of Warfarin versus Aspirin for the Prevention of Recurrent Stroke or Death: Subgroup Analyses from the Warfarin-Aspirin Recurrent Stroke Study Cerebrovasc Dis 2006;22:4 12 - DOI:10.1159/000092331 2006 S. Karger AG, Basel

N Engl J Med, 2014

AF Burden (0 to 100%, log scale) Temporal Relationship of Atrial Fibrillation & Thromboembolism Months from TE -54-48 -42-36 -30-24 -18-12 -6 0 6 12 18 24 30 36 42 48 54

ASSERT: Temporal Relationship Between AF and Stroke Of 51 pts experiencing S/SE during follow-up, 26 (51%) had SCAF. 18 pts (35%) had SCAF before S/SE. 4 pts (8%) had SCAF detected within 30 days before S/SE. 1 of these 4 patients experienced SCAF at the time of the stroke. 8 pts (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days before their event. Brambatti M, et al. Circulation 2014;129:2094

Cumulative event rates ASSERT: AF duration & stroke incidence longest single SCAF episode > 6 min 6 hours: 462 pts (18.8%) longest single SCAF episode > 6 hours 24 hours: 169 pts (6.9%) longest single SCAF episode > 24 hours: 262 pts (10.7%) 0.0 0.05 0.10 0.15 0.20 No SCAF 6mins~6hrs 6hrs~24hrs >24hrs No. at Risk No SCAF 6mins~6hrs 6hrs~24hrs >24hrs 0 0.5 1 1.5 2 2.5 3 3.5 Years of Follow-up 2455 1926 1708 1528 1251 900 624 390 0 226 302 347 322 281 218 155 0 88 104 103 108 93 80 52 0 91 124 144 140 126 116 85 Van Gelder I, et al. Europ Heart J 2017;doi:10.1093/eurhert/ehx042

ASSERT II = SCAF by ILR Age 65 a d O e of : -CHA 2 DS 2 -VASc 2 -Obstructive s eep ap ea -BMI >30 a d O e of : -Left atrial volume 58ml or LA diameter 4.4cm -Serum NT-ProBNP 290 pg/ml Hea ey et a #4

Incidence of SCAF Rate per year (95% CI) 34.4% (27.7% 42.3%) 21.8% (16.7% 27.8%) 7.1% (4.5% 10.6%) 2.7% (1.2% 5.0%) #7

Intermittent AF Screening

The STROKE-STOP Study Population-based Patients aged 75 and 76 No prior AF Screened with twice-daily, handheld ECG for 2 weeks 3% previously unrecognized AF 2% previously diagnosed but untreated AF

Patients with: - SCAF (at least 1 episode 6 min but none > 24 hrs) - CHA 2 DS 2 -VASc score 3 Doubleblind, doubledummy design Active aspirin 81mg OD + Placebo apixaban bid CONSENT and RANDOMIZE Placebo aspirin OD + Active apixaban 5mg or 2.5mg* bid Follow-up Visits at 1 month and every 6 months until 248 primary efficacy outcomes (est. avg 3 yrs) Primary Efficacy Outcomes: Outcomes: Stroke (including TIA with imaging) Systemic Embolism Primary Safety Major Bleeding (ISTH) * 2.5 mg if either of the following: - At least 2 of 3 of: - Age 80 - Weight 65 kg - Serum Creatinine 133 µmol/l (1.5 mg/dl) - Ongoing need for inhibitor of both CYP3A4 and P- glycoprotein

Conclusions Clear association between SCAF and stroke in PPM and ICD patients Risk of stroke lower than for clinical AF but higher than no AF on monitor Very few strokes occur during or soon after an AF episode The risk of stroke increases with increased duration of AF Ongoing studies will help determine who should be anticoagulated