Atrial Fibrillation T. Jared Bunch, MD, FACC

Transcription

1 Atrial Fibrillation T. Jared Bunch, MD, FACC Director of Heart Rhythm Services, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Intermountain Healthcare; Salt Lake City, UT Objectives: Identify Stroke Rates in Atrial Fibrillation Patients Explain predictive rules for atrial fibrillation Define the role if implantable cardiac devices in patients with and without atrial fibrillation Indicate therapeutic options (pharmacologic and nonpharmacologic)

2 Atrial Fibrillation and Stroke Mechanisms, Detection, and Treatment T. Jared Bunch MD Medical Director of Heart Rhythm Services for Intermountain Healthcare Director of Heart Rhythm Research for Intermountain Medical Center Heart Institute Associated Clinical Professor (Affiliated) Stanford University

3 Disclosures: None

4 AF population (x1,000) Age Distribution of People with AF Compared with U.S. General Population 30, ,000 10,000 U.S. population Population with atrial fibrillation Median age U.S. population (x1,000) 0 0 < >95 Age (yr) Arch Int Med 155:471, 1995; Updated in AF Guidelines, 2006 CP

5 Trends in Age-Adjusted Incidence of AFib Olmsted County, MN Men Incidnece/1,000 person-years Women Overall (12.6% relative ) Miyasaka: Circ, 2006 Year CP

6 Projected Prevalence of AFib in U.S. Projected number of persons with AF (millions) Impact of Olmsted County Incidence Data % Proportion Aged 80 Yr Year Go: JAMA, 2001; Miyasaka: Circ 2006 Year CP

7 The Epidemiology of AF in the USA and Other Countries 50 yr, USA (CHS), single ECG yr, UK, single ECG yr, Netherlands, single ECG & medical record yr, UK, single ECG yr, Netherlands, single ECG yr, USA, medical record yr, UK, single ECG review results 60 yr, Australia, triennial survey % 40 yr, Japan, single ECG yr, Hong Kong, single ECG yr, main land, China, single ECG yr, Denmark, singles ECG yr, West Germany, single ECG yr, India, single ECG 0.1 Hu, HRS 06 CP

8 Significant Heterogeneity of AF Prevalence Chugh SS, et al. Circulation 2014;129:Online

9 Rising Incidence of AF Approx. 5 million/yr 77.5 (28% ) 59.5 (35% ) Chugh SS, et al. Circulation 2014;129:Online

10 Age-Adjusted Prevalence Rates in Developed vs. Developing Nations (2010) Men Women Per 100,000 Population Developed Countries Developing Countries Chugh SS, et al. Circulation 2014;129:Online

11 Higher Mortality in Women Driven by AF-Associated Mortality in Developing Nations Chugh SS, et al. Circulation 2014;129:Online

12 Atrial Fibrillation in the USA Approx million people affected* Increases with age Marked age-independent increase Incidence Prevalence Lifetime risk 25% approx Independent predictor of mortality Risk of stroke 3-7%/year Increases with age Approx 45% of embolic strokes Approx 100,000 strokes/year *Miyasaka, Circ 2007 A growing epidemic *Approx 15 million by

13 Are Today s Elderly a Sicker Patient Population? Ramses II died age 91 yr % Prevalence of Comorbid Conditions in Olmsted County Controls (Non-Stroke Patients) * * Michelangelo 0 died age 89 yr Cardiac VHD CHF MI CAD HTN surgery Comorbid conditions *Statistically significant John Day Tsang T 100+ yr? * * *

14 Trends of AF Outcomes Survival (%) Mortality Trends of AF Age- and genderadjusted P= Years after first AF diagnosis Cumulative incidence of CHF (%) Heart Failure Incidence Trends from First AF Age- and genderadjusted P= Years after first AF diagnosis Cumulative incidence of stroke (%) Time Trends of Ischemic Stroke After First AF Age- and genderadjusted P= Years after first AF diagnosis Miyasaka et al: JACC 49:986, 2007 Miyasaka et al: EHJ 27:936, 2006 Miyasaka et al: Stroke 36:2362, 2005 CP

15 Advocated Stroke Paradigm with Atrial Fibrillation 48 Hours

16 Not That Simple AF is often a symptom of a system disease 86 yo Female Acute Stroke with AF when Anticoagulation Held for Surgery

17 SPAF III Adjusted Warfarin (INR 2-3) vs. Low Dose Warfarin (0.5-3 mg/inr ) + ASA (325 mg) Event rate (%/yr) Intracranial hemorrhage Disabling ischemic stroke Non-disabling ischemic stroke P=0.007 P= Adjusted-dose warfarin Combination therapy Adjusted-dose warfarin Combination therapy Lancet, 1996 No previous thromboembolism Previous thromboembolism CP

18 Annualized Rates of Intracranial Bleeds on Warfarin/Coumadin Anticoagulation Charidimou, Front Neurol, 2012

19 Persistent Ischemic Events/Bleeds on Warfarin and NOACS Stroke and Non-CNS Embolism Event Rate/100 Pt-Yrs Stroke or Systemic Embolism Death from Any Cause ISTH Major Bleeding Intracranial Bleeding Net Clinical Outcomes* Event Rate/100 Pt-Yrs Patel MR, et a. N Engl J Med Granger CB, et al. N Engl J Med. 2011

20 Risks Factors for AF Risks also Drive AF Incidence

21 Risk of MACE (death, MI, stroke) with AF by CHADS(2) Score 4 Hazard Ratio Crandall, Bunch PACE 2009 P= CHADS(2) Score

22 CRP and CHADS2 Scores in patients 7 with and without AF AF Present AF Absent CRP (mg/l) Crandall, Bunch PACE CHADS(2) Score

23 Shared Risks Factors for Atrial Fibrillation and Stroke Advancing Age Diabetes Mellitus Chronic kidney Disease Vascular Disease Stroke Heart Failure Inactivity/Low Activity Genetics/Inherited Sleep Apnea Hypertension Alcohol Consumption Atrial Fibrillation

24 If Atrial Fibrillation Increases Risk Will Early Detection and Treatment Reduce Stroke Risk?

25 Challenges in Correlating Atrial Fibrillation and Stroke 30% of strokes are cryptogenic - Cryptogenic at the time of stroke diagnosis - Suspicious echocardiograms left atrial enlargement, diastolic dysfunction, valvular heart disease, left ventricular hypertrophy, left ventricular dysfunction Atrial fibrillation is often paroxysmal Nearly 1/3 of patients are asymptomatic or have subclinical symptoms during atrial fibrillation

26 Results of Odds Ratio by Risk Factor and Study Heart Failure Valvular Disease Coronary Artery Disease Age (per 10 year) Benjamin, 1994 Benjamin, 1994 Krahn, 1995 Tsang, 2002 Aviles, 2003 Gami, 2007 Gammage, 2007 Schnabel, 2009 de Vos, 2010 Marcus, 2010 Marcus, 2010 Chamberlin, [ 3.07, 6.60 ] 5.90 [ 4.14, 8.40 ] 3.37 [ 2.29, 4.96 ] 3.75 [ 2.20, 6.40 ] 1.88 [ 1.44, 2.45 ] [ 7.60, ] 3.75 [ 2.16, 6.52 ] 3.20 [ 1.98, 5.16 ] 2.20 [ 1.50, 3.22 ] 3.04 [ 2.43, 3.81 ] 2.93 [ 2.39, 3.59 ] 3.03 [ 2.32, 3.95 ] Benjamin, 1994 Benjamin, 1994 Krahn, 1995 Psaty, 1997 Thomas, [ 1.30, 2.50 ] 3.40 [ 2.57, 4.50 ] 3.15 [ 1.98, 5.00 ] 2.16 [ 1.34, 3.48 ] 1.56 [ 0.84, 2.91 ] Benjamin, 1994 Benjamin, 1994 Krahn, 1995 Psaty, 1997 Tsang, 2002 Gami, 2007 Thomas, 2008 Schnabel, 2009 Marcus, 2010 Marcus, 2010 Chamberlin, [ 0.98, 2.00 ] 1.20 [ 0.80, 1.80 ] 3.62 [ 2.58, 5.07 ] 1.38 [ 1.02, 1.87 ] 2.78 [ 1.71, 4.51 ] 5.15 [ 3.56, 7.44 ] 1.37 [ 0.92, 2.03 ] 1.44 [ 1.02, 2.03 ] 2.22 [ 1.89, 2.61 ] 3.56 [ 2.91, 4.36 ] 2.21 [ 1.72, 2.84 ] Benjamin, 1994 Benjamin, 1994 Psaty, 1997 Tsang, 2002 Aviles, 2003 Gami, 2007 Schnabel, 2009 de Vos, 2010 Marcus, 2010 Marcus, [ 1.76, 2.50 ] 2.20 [ 1.86, 2.60 ] 1.97 [ 1.50, 2.59 ] 1.34 [ 0.91, 1.97 ] 1.85 [ 1.63, 2.10 ] 2.11 [ 1.85, 2.41 ] 2.28 [ 2.09, 2.49 ] 1.57 [ 1.07, 2.30 ] 2.16 [ 1.97, 2.37 ] 3.11 [ 2.85, 3.39 ] RE Model 3.58 [2.74, 4.68] RE Model 2.38 [1.76, 3.23] RE Model 2.14 [1.60, 2.86] RE Model 2.11 [1.86, 2.39] Hypertension Diabetes Gender Benjamin, 1994 Benjamin, 1994 Krahn, 1995 Psaty, 1997 Tsang, 2002 Aviles, 2003 Gami, 2007 Gammage, 2007 Thomas, 2008 Schnabel, 2009 Rosengren, 2009 Conen, 2009 de Vos, 2010 Marcus, 2010 Marcus, 2010 Chamberlin, [ 1.12, 2.00 ] 1.40 [ 1.09, 1.80 ] 1.42 [ 1.10, 1.84 ] 1.12 [ 1.05, 1.19 ] 1.59 [ 0.99, 2.56 ] 1.28 [ 1.09, 1.51 ] 2.85 [ 2.02, 4.02 ] 1.39 [ 1.07, 1.80 ] 1.23 [ 0.96, 1.58 ] 1.21 [ 1.10, 1.33 ] 1.73 [ 1.47, 2.03 ] 3.32 [ 2.18, 5.06 ] 1.52 [ 1.05, 2.20 ] 1.50 [ 1.32, 1.70 ] 2.11 [ 1.87, 2.38 ] 2.63 [ 1.83, 3.78 ] Benjamin, 1994 Benjamin, 1994 Tsang, 2002 Verdecchia, 2003 Aviles, 2003 Gami, 2007 Gammage, 2007 Thomas, 2008 Schnabel, 2009 Rosengren, 2009 Marcus, 2010 Marcus, 2010 Chamberlin, [ 0.98, 2.00 ] 1.60 [ 1.16, 2.20 ] 1.90 [ 1.02, 3.54 ] 1.43 [ 0.61, 3.36 ] 1.18 [ 1.02, 1.36 ] 2.50 [ 1.65, 3.78 ] 2.02 [ 1.44, 2.84 ] 1.28 [ 0.94, 1.74 ] 1.10 [ 0.88, 1.38 ] 1.49 [ 0.92, 2.41 ] 1.53 [ 1.32, 1.78 ] 2.09 [ 1.78, 2.45 ] 1.87 [ 1.51, 2.32 ] Benjamin, 1994 Furberg, 1994 Tsang, 2002 Verdecchia, 2003 Aviles, 2003 Gami, 2007 Gammage, 2007 Thomas, 2008 Schnabel, 2009 Marcus, 2010 Marcus, 2010 Chamberlin, [ 1.25, 1.80 ] 0.97 [ 0.65, 1.45 ] 0.90 [ 0.56, 1.45 ] 0.97 [ 0.58, 1.61 ] 1.71 [ 1.49, 1.96 ] 1.86 [ 1.44, 2.41 ] 2.42 [ 1.86, 3.15 ] 0.65 [ 0.52, 0.81 ] 1.90 [ 1.58, 2.29 ] 1.59 [ 1.42, 1.78 ] 1.73 [ 1.53, 1.96 ] 1.92 [ 1.60, 2.30 ] RE Model 1.60 [1.38, 1.86] RE Model 1.58 [1.37, 1.83] RE Model 1.45 [1.17, 1.81] Brunner KJ, Bunch TJ, Mahapatra MCP 2014

27 Monitoring for Atrial Fibrillation by Symptoms AF is Frequently Asymptomatic and Symptoms Correlate Poorly with AF Strickbergeret al followed 48 patients for 12 months and found that, Almost 95% of documented AT episodes were asymptomatic, and symptoms attributed to atrial fibrillation were associated with AT only approximately 15% of the time. 1 Page et al studied a group of patients with symptomatic paroxysmal AF and showed that sustained asymptomatic AF occurred 12.1 fold as often as sustained symptomatic AF. 2 Symptoms Reported: No significant differences in the specific symptoms that correlated with or without a documented atrial tachyarrhythmia were observed Strickberger A. et al. Relationship between atrial tachyarrhythmias and symptoms. Heart Rhythm 2005;2: Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation. 1994;89:

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29 Extending Monitoring and Using Automated Detection Increases AF Diagnosis X2

30 Atrial Fibrillation Limitations of Intermittent, External Monitoring Data from 574 pacemaker patients were analyzed retrospectively over 1 year, with intermittent monitoring simulated by analyzing data from randomly selected days Intermittent and symptom based monitoring is highly inaccurate for identifying patients with any or longduration AT/AF and for assessing AT/AF burden. Ziegler P. Comparison of continuous versus intermittent monitoring of atrial arrhythmias. Heart Rhythm 2006;3: ).

31 Comparison of Monitoring Strategies Continuous Monitoring Arm: Insertion of REVEAL XT Standard Monitoring Arm Minimally invasive outpatient procedure Local anesthetic and no leads or fluoroscopy minute procedure Device can be followed remotely MRI conditional 3 year device longevity Automatic AF detection algorithm Cardiac monitoring performed according to local standards, after mandated testing completed Symptoms consistent with AF were evaluated by study physicians

32 CRYptogenic STroke and underlying AtriaL Fibrillation (CRYSTAL AF): Long Term Follow Up Results Rod Passman, MD, MSCE, Johannes Brachmann, MD, Ph.D. Carlos Morillo, MD, Tommaso Sanna, MD, Richard Bernstein, MD, Ph.D., Vincenzo Di Lazzaro, MD, Hans-Christoph Diener, MD, Ph.D., Marilyn Rymer, MD, Frank Beckers, Ph.D, Tyson Rogers, M.S., Paul Ziegler, M.S. for the Crystal AF Investigators

33 Crystal AF Trial

34 Baseline Characteristics ICM Control Age 61.6 ± 11.4 years 61.4 ± 11.3 years Gender - Male 142 (64.3%) 138 (62.7%) Index Event Stroke 200 (90.5%) 201 (91.4%) Index Event TIA 21 (9.5%) 19 (8.6%) Time between index event 36.6 ± 28.2 days 39.6 ± 26.9 days and randomization Time between randomization and device insertion 8.7 ± 27.6 days n/a

35 Detection Rates: Primary & Secondary Endpoints Primary Endpoint: Detection of AF at 6 months Hazard Ratio: 6.43 (1.90, 21.74) p = Secondary Endpoint: Detection of AF at 12 months Hazard Ratio: 7.32 (2.57, 20.81) p < Presented at ISC 2/14/14, San Diego CA

36 Long-term Analysis AF detection rate at 24, 30 and 36 months Proportion of patients who had a maximum one-day AF burden of > 6 minutes Clinical decisions made in response to AF Proportion of symptomatic vs asymptomatic first AF episodes Number of tests required to find AF in control arm Time to first AF detection

37 Detection of AF at 36 Months Estimated rate of detection in ICM arm was 30.0% vs 3.0% in control arm

38 Proportion of AF episodes > 6 minutes 100% 90% 97.3% 94.7% 94.9% 80% 70% 60% 50% 40% AF > 6 Minutes 30% 20% 10% 0% 24 Months 30 Months 36 Months 95% of patients with AF had a day with > 6 minutes of AF

39 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% Clinical Decisions OAC Usage in AF Patients: Both Arms 0% 90.9% 89.1% 89.4% 24 Months 30 Months 36 Months Pa ents Prescribed OAC Approximately 90% of patients with AF were prescribed OAC

40 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Asymptomatic AF Episodes: Both Arms 75.0% 76.1% 76.6% 24 Months 30 Months 36 Months Percentage of Asymptoma c AF Episodes Approximately 75% of first episodes of AF were asymptomatic

41 Tests Required to Find AF in Control Arm Follow-up Period ECGs Holter Monitors Event Recorders Incremental Patients Found with AF 0-6 months months months months months months Total

42 Time to First AF Detection ICM (N=42) Control (N=5) Median Time from Randomization to AF Detection Median: 8.4 months IQR: months Median: 2.4 months IQR: months

43 Stroke Prevention in Atrial Fibrillation Patients Stroke Risks Age Hypertension Heart Failure Diabetes Stroke/TIA Peripheral Vascular Disease Gender Shared Risks Major Bleeding Risks Age Hypertension Labile INR Stroke Prior Bleed Abnormal Liver Function Abnormal Renal Function Aging with Atrial Fibrillation Related Variance in Risk Increase in Traditional/Nontraditional Risks Hypertension Heart failure Diastolic Dysfunction Left Atrial Enlargement Diabetes Stroke/TIA Peripheral Vascular Disease Atrial Fibrillation Burden Increase in Traditional/Nontraditional Risks Hypertension Renal Failure Stroke/TIA Dementia/Cognitive Decline/Frailty Renal Dysfunction Microbleeds Coexistent CV disease Polypharmacy Whisenant B, Bunch TJ, Circulation 2014

44 Can Implantable Devices (Pacemakers, ICDs, Loop Recorders) Guide Anticoagulation Use?

45 If So This Likes Needs to Be True Most of the Time 48 Hours

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48 The median time from the previous TE to enrollment in the study was 39 (12 73) months.

49 Burden and Duration Longer In Patients with Prior TE/Stroke Majority of patients with prior TE had AF/AT on one day >6 hours

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51 (hazard ratio AHRE versus no AHRE and 95% confidence intervals 2.48 [1.25, 4.91]; P0.0092), In patients with sinus node dysfunction, pacemaker-detected AHRE, lasting at least 5 minutes, identify patients that are more than twice as likely to die or have a stroke, and are nearly 6 times as likely to develop atrial fibrillation as similar patients without AHRE.

52 A Look into the Future? The Rhythm Evaluation for AntiCoagulaTion with COntinuous Monitoring (REACT.COM) pilot study (ClinicalTrials.gov NCT ) is designed to assess the feasibility of "pill-in-thepocket" anticoagulation using daily remote transmissions from an ICM. Major inclusion criteria include a CHADS2 score of 1 or 2, non- permanent AF, no documented AF lasting over a one hour on two consecutive months on a previously implanted ICM, and compliance with a NOAC for 30 consecutive days prior to enrollment. Enrolled patients are maintained on aspirin therapy (81 mg) and transmit daily from their ICM. Daily transmissions allow for AF detection within 24 hours of an episode. Any AF episode lasting one hour results in re-initiation of a patient's prescribed NOAC for 30 days. A patient with an episode of AF every month, for example, may never be able to discontinue anticoagulation.

53 Treatment of Atrial Fibrillation Matters (catheter ablation) 37,908 Intermountain Healthcare patients - 4,212 consecutive AF ablation patients - 16,848 age/gender matched controls with AF - 16,848 age/gender matched controls w/o AF 3 years follow-up Mean age: 65.0±13 years Bunch TJ, et al. JCE 2011

54 Baseline Demographics Characteristic No AF (n=16,848) AF, no ablation (n=16,848) AF, ablation (n=4,212) p-value Age (years) 64.1± ± ±12.7 < Sex (male) 60.8% 60.8% 60.8% 1.00 Diabetes 19.0% 21.1% 16.3% < Hypertension 41.2% 45.3% 47.8% < Hyperlipidemia 58.4% 37.3% 44.0% < CHF 14.5% 23.6% 29.5% < Renal Failure 5.6% 7.8% 7.5% < TIA History 4.0% 4.2% 4.6% 0.16 CVA History 4.4% 6.3% 4.5% < MI History 10.0% 6.4% 6.4% < Valve History 11.6% 15.3% 27.7% <0.0001

55 Ablation Results (n=4,212) 3 Year Success Rate (no antiarrhythmics, no AF recurrences): 64.4% Repeat procedure: 1,162 (27.6%) Complications: -Pericardiocentesis: 25 (0.6%) -AV fistula: 7 (0.2%) -TIA 16 (0.4%) -Esophageal perforations: 2 (0.05%) -Pulmonary vein stenosis: 4 (0.1%) -Death: 2 (0.05%)

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57 Age Groups AF ablation vs AF, no ablation Increased risk with AF, no Ablation

58 Age Groups AF ablation vs No Known AF Increased risk with AF, Ablation

59 Survival Free of AF Bunch, Day JCE 2009 AF Ablation Outcomes (AC treatment) n=690 0 Strokes Aspirin Total Warfarin Aspirin Warfarin Days

60 Should Patients with a CHADS Score of 2 or 3 Continue to Take Warfarin Long- Term After a Successful Atrial Fibrillation Ablation? John D.. Day, MD, Brian G. Crandall, MD, Jeffrey S. Osborn, MD, J. Peter. Weiss, MD, Donald L. Lappe, MD, Tami Bair, MS, Heidi T. May, PhD, Jeffrey L. Anderson, MD, Brent Muhlestein, MD, Jennifer Nelson, RN, T. Jared Bunch, MD. Intermountain Medical Center, Salt Lake City, UT

61 Study Methods 158 patients, CHADS 2-3 who had a successful AF ablation (AF cure off antiarrhythmics) Unable to take warfarin due to significant bleeding or had discontinued warfarin against the advice of their physician 2 years follow-up Stroke rate compared to 16,848 patients in Intermountain Healthcare with no history of AF

62 Patients Ablation (n=158) Control, no AF (n=16,848) Heart Failure 63.9% 14.5% Hypertension 96.8% 41.2% Age 68.0± ±13.0 Diabetes 46.2% 19.0% CVA/TIA 6.3% 4.0% CHADS

63 Results at 2 Years (597±440 days) AF Ablation (n=158) No AF (n=16,848) CHADS Score Stroke %

64 Athena Trial 4628 patients with AF (additional risk factors for death) Cumulative Incidence (%) CV Hospitalization and Morality P< Months Placebo Dronedarone Cumulative Incidence (%) Total Mortality 25 Placebo P=0.18 Dronedarone Months Cumulative Incidence (%) CV Mortality P=0.03 Placebo Dronedarone Months Cumulative Incidence (%) First Hospitalization for CV P< Months Placebo Dronedarone Hohnloser et al: NEJM 360: , 2009

65 Long Term CVA Outcomes In AF Patients ATHENA Trial (4628 patients randomized to dronedarone vs placebo) Connolly SJ, Circulation 2009

66 Direct Oral Anticoagulant Distribution Propensity-Matched with a Warfarin Population (n=2,627) Apixaban (n=590) 1 Long-term Dementia Rivaroxaba n (n=1454) Dabigatran (n=590) % DOAC Warfarin 2.5 % Stroke/Tia Dementia Long-Term Total Events Follow-up for Dabigatran >1 yr Longer than other DOACs

67 Conclusions Atrial Fibrillation is the increasing worldwide and is associated with significant morbidities and mortality Atrial fibrillation is the most common identified cause of disabling strokes Nearly 30% of acute strokes are labeled cryptogenic Long-term monitoring discloses high rates of atrial fibrillation in patients previously diagnosed with a cryptogenic stroke Implantable devices can be used to enhance detection and have provided new understanding regarding the temporal relationship between atrial fibrillation and stroke Anti-coagulation guided by implantable devices will required an improved understanding of the temporal relationship Rhythm control strategies that reduce burden and frequency of arrhythmia may lower stroke risk

68 Thank You

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