Randomized Trial of Anticoagulation Guided by Remote Rhythm Monitoring In Patients with Implanted Cardioverter-Defibrillator and Resynchronization Devices

1
Randomized Trial of Anticoagulation Guided by
Remote Rhythm MonitoringIn Patients with
ImplantedCardioverter-Defibrillator and
Resynchronization Devices

• David T Martin, MD FACC
• Lahey Hospital and Medical Center
• On Behalf of the IMPACT Investigators

Funded by BIOTRONIK, Inc. ClinicalTrials.gov
NCT00559988
2
Background

• Episodes of atrial fibrillation (AF) are often
  asymptomatic
• Atrial fibrillation can be detected by implanted
  cardiac rhythm management devices
• Up to 65 of patients with pacemakers exhibit
  atrial tachyarrhythmias (AT)
• Thromboembolism (TE) risk appears to be related
  to duration/burden of device-detected atrial
  tachyarrhythmias

3
Background
From Glotzer TV, Daoud EG, Wyse DG, et al. Circ
Arrhythm Electrophysiol 20092474-80.
4
Study Overview
Hypothesis Initiation of oral anticoagulation (OAC) early after detection of AT and withdrawing OAC when AT abates might reduce thromboembolism and hemorrhage in patients with ICD and CRT-D devices
Design Multicenter, single-blinded, randomization stratified by CHADS2 category and device type
Treatment Groups Intervention Remote monitoring for AT with pre-defined anticoagulation plan based on AT burden and CHADS2 Control In-office identification of AT with OAC directed by treating physician
Primary Endpoint First stroke, systemic embolism, or major bleed
Secondary Endpoints All-cause mortality, stroke rate, AT burden
Number of Patients 2,718 from 104 sites (North America, Europe, Australia)
Scheduled Visits At least every 6 months until last subject completes 3 year visit
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Anticoagulation ProtocolIntervention Group
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Eligibility Criteria

• Key Inclusion Criteria
• CHADS2 risk score 1
• Implanted ICD or CRT-D with Home Monitoring
  technology
• Able and willing to begin anticoagulation
  therapy, if needed
• Acceptable P-wave amplitude documented ( 1.0 mV
  sinus rhythm, 0.5 mV AF)
• Age 18 years and able to provide informed
  consent
• Key Exclusion Criteria
• Permanent AF
• History of stroke, TIA, or systemic embolism and
  documented AF or atrial flutter
• Currently requiring OAC or known contraindication
  to OAC
• lt 3 months of OAC therapy after successful AF
  ablation

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Recruitment and Follow-Up

• Full planned cohort of 2,718 patients enrolled
  between February 28, 2008 and May 17, 2013
• Data Monitoring Committee determined futility
  when 75 of expected events accrued
• No concerns about safety
• Steering Committee stopped the study on June 12,
  2013
• Database locked September 30, 2013
• Follow-up completed
• Median exposure 701 days
• Cumulative follow-up 5,430 patient-years

8
Baseline Characteristics
Control GroupN 1,361 Intervention GroupN 1,357 p
Age, y 64 65 0.236
Gender, male 73.0 74.4 0.408
Median CHADS2 2 2 0.544
CHF or LV dysfunction, 89.5 90.5 0.372
Hypertension, 84.1 83.5 0.716
Coronary artery disease, 71.2 71.9 0.671
Diabetes, 40.2 41.4 0.532
Previous stroke or TIA, 9.7 8.2 0.179
Device type, ICD 64.4 63.6 0.660
Aspirin, 77.1 74.8 0.164
Other antiplatelet, 30.7 34.5 0.037
Mean follow-up, y 2.01 1.99 0.685
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Atrial Tachyarrhythmias During the Trial
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AT Meeting Anticoagulation Criteria
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OAC Options and Utilization
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Anticoagulation Therapy
Control Group Intervention Group
All patients N 1,361 N 1,357
Started OAC 158 (11.6) 182 (13.4)
Stopped OAC 71 (5.2) 97 (7.1)
Mean days on OAC 396 374
Time in therapeutic range (VKA) 58.5 59.2
Patients meeting OAC criteria N 115 N 126
Started OAC 69 (60.0) 91 (72.2)
Stopped OAC 29 (25.2) 46 (36.5)
Mean days on OAC 450 409
Median time to start (days) 54 3
Compliance with OAC protocol N 126
Started in specified timeframe 45.2
Time in therapeutic range (VKA) 61.2
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Primary Outcome Events
Time (years)
N, Events
Control 1361, 0 928, 27 543, 43 228, 57 75, 60 2, 61
Intervention 1357, 0 906, 28 538, 49 214, 59 66, 62 3, 63
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Primary Outcome Events
Hemorrhagic Stroke or Other Major Bleed
Ischemic Stroke or Systemic Embolism
Control Group
Intervention Group
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Clinical Outcomes
Control Group N 1,361 Control Group N 1,361 Intervention GroupN 1,357 Intervention GroupN 1,357 Hazard Ratio p
N rate N rate Hazard Ratio p
Primary endpoint 61 2.3 63 2.4 1.06 0.732
Mortality 140 5.1 147 5.4 1.07 0.662
Thromboembolism 37 1.4 32 1.2 0.88 0.586
Ischemic stroke 28 1.0 22 0.8 0.79 0.417
Systemic embolism 2 0 - 0.969
TIA 8 10 1.27 0.619
Hemorrhagic stroke 3 0.1 3 0.1 1.03 0.973
Other major bleed 32 1.2 43 1.6 1.39 0.145
Rates are expressed as the number of events per
100 patient-years.
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VKA Therapy at Time of Event
Control Group Control Group Control Group Intervention Group Intervention Group Intervention Group
No VKA/ INR lt2 INR 2 - 3 INR gt3 No VKA/ INR lt2 INR 2 - 3 INR gt3
Ischemic stroke 27/28 96.4 1/283.6 21/2295.5 1/224.5
Systemic embolism 1/250.0 1/250.0
TIA 7/887.5 1/812.5 9/1090.0 1/1010.0
Hemorrhagic stroke 3/3100 2/366.7 1/333.3
Other major bleeds 26/3281.2 3/329.4 3/329.4 30/4369.8 6/4313.9 7/4316.3
Two control subjects with other major bleed were
on a novel OAC at time of event.Three
intervention subjects with other major bleed were
on a novel OAC at time of event.
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Temporal Relationship of Atrial Fibrillation
Thromboembolism
AF Burden (0 to 100, log scale)
Months from TE
0
6
36
18
24
30
12
42
48
54
-54
-48
-42
-36
-30
-24
-18
-12
-6
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Temporal Relationship of Atrial Fibrillation
Thromboembolism
AF Burden (0 to 100, log scale)
Months from TE
0
6
36
18
24
30
12
42
48
54
-54
-48
-42
-36
-30
-24
-18
-12
-6
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Temporal Relationship of Atrial Fibrillation
Thromboembolism
ControlGroup Intervention Group
Patients with TE 37 32
AF anytime during study 17 12
AF prior to TE 12 8
AF after TE 5 4
No AF during study 20 20
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Thromboembolism in Relation to Atrial
Tachyarrhythmia Duration
Control p-trend 0.173, Intervention p-trend
1.000 Interaction p 0.470
AT Duration Categories
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Limitations

• Suboptimal compliance with OAC protocol in the
  intervention group
• Greater use of antiplatelet therapy in the
  intervention group
• Low event rate limited power to detect
  differences in outcomes between groups

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Conclusions

• Starting and stopping OAC based on
  device-detected AF did not improve clinical
  outcomes in this study
• Temporal dissociation of device-detected AF and
  thromboembolic events suggests that an
  accelerated anticoagulation strategy provides no
  added benefit for TE prevention
• The decision to start OAC for device-detected AF
  should be based upon comprehensive clinical
  assessment of risk and benefit
• Once started for AF, the absence of
  device-detected AF should not lead to
  discontinuation of OAC

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IMPACT Study Group

• Investigators John Ip, Sparrow Clinical Research
  Institute, Lansing, MI Anand Irimpen, Tulane
  University Medical Center, New Orleans, LA Craig
  McCotter, Upstate Cardiology, Greenville, SC
  Sandeep Gupta, Middletown Cardiovascular
  Associates, Middletown, OH Harvey Serota, St.
  Louis Heart Vascular, St. Louis, MO Jerome
  Dwyer, St. Louis Cardiology Center, St. Louis,
  MO Felix Ayala-Paredes, Centre hospitalier
  universitaire de Sherbrooke, Sherbrooke, QC
  Sushil Singhi, Carolina Cardiology Associates,
  Rock Hill, SC Ira Lieber, Texas Cardiology
  Research Center, Kingwood, TX Scott Kaufman,
  Northwest Indiana Cardiovascular Physicians,
  Valparaiso, IN Abdul Alawwa, Cardiology
  Consultants of East Michigan, Lapeer, MI Marcio
  Sturmer, Hopital du Sacre-Coeur de Montreal,
  Montreal, QC William Bailey, Louisiana Heart
  Rhythm Specialists, Lafayette, LA Benoit Coutu,
  Centre hospitalier de l'Universite de Montreal,
  Montreal, QC Werner Jung, Schwarzwald-Baar
  Klinikum, Villingen-Schwennigen, Germany Bernard
  Thibault, Montreal Heart Institute, Montreal, QC
  Asim Yunus, Michigan Cardiovascular Institute,
  Saginaw, MI Nizar Assi, Gateway Cardiology, St.
  Louis, MO Timothy Shinn, Michigan Heart,
  Ypsilanti, MI Romesh Japra, Pacific Cardiology
  Associates, Fremont, CA Hanscy Seide, Cardiology
  Consultants, Daytona Beach, FL Shanker
  Chandiramani, Blue Grass Cardiology, Louisville,
  KY Eric Good, University of Michigan, Ann Arbor,
  MI Miguel Castellanos, Orange, TX Mark
  Richards, Northwest Ohio Cardiology Consultants,
  Toledo, OH Spyridon Akrivakis, Northeast
  Cardiology Associates, Bangor, ME Usman
  Siddiqui, Florida Cardiology, Davenport, FL
  David Martin, Lahey Clinic, Burlington, MA Kent
  Gleed, Alegent Creighton Health Research Center,
  Omaha, NE Michael Rozengarten, Arrhythmia
  Institute of Penn Cardiac Care, Newtown, PA
  Joseph Pennington, Christiana Care Health
  Services, Newark, DE Wilber Su, Heart Rhythm
  Specialists of Arizona, Phoenix, AZ Saurabh
  Shah, Advocate Medical Group, Chicago, IL Luke
  Kusmirek, Drexel University College of Medicine ,
  Philadelphia, PA Matthew Sevensma, Metro Health
  Hospital, Wyoming, MI Juergen Schreieck,
  Universitatsklinikum Tubingen, Tubingen, Germany
  Lon Castle, Cleveland Clinic, Westlake, OH
  Mehran Attari, University of Cincinnati,
  Cincinnati, OH Sandeep Garg, Pacific Heart
  Associates, Tualatin, OR Kishor Vora, Owensboro
  Heart and Vascular, Owensboro, KY Ivan Cakulev,
  University Hospitals Case Medical Center,
  Cleveland, OH Vijendra Swarup, Arizona
  Arrhythmia Research Center, Scottsdale, AZ James
  Stone, Cardiology Associates Research, Tupelo,
  MS Zoltan Toth, Cardiology Associates of Corpus
  Christi, Corpus Christi, TX Lameh Fananapazir,
  Cumberland, MD Nadim Khan, Florida Medical
  Clinic, Zephyrhills, FL Venkat Pasnoori, Liberty
  Cardiovascular Specialists, Liberty, MO David
  McManus, University of Massachusetts Medical
  School, Worcester, MA Dan Blendea, Massachusetts
  General Hospital, Boston, MA Jayakumar
  Sahadevan, Cleveland VA Medical Center,
  Cleveland, OH Richard Schultz, Piedmont
  Cardiology, Hickory, NC

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IMPACT Study Group

• Investigators (cont) Sameer Oza, Rocky Mountain
  Cardiology, Boulder, CO Huijian Wang, Complete
  Cardiology Care, Edgewater, FL Brett Atwater,
  Durham VA Medical Center, Durham, NC Muthu
  Krishnan, Lake Cardiovascular Institute, Osage
  Beach, MO Gery Tomassoni, Lexington Cardiology
  Consultants, Lexington, KY William Barrington,
  University of Pittsburgh Medical Center,
  Pittsburgh, PA Claudio Bonometti, Santa Barbara,
  CA Madaiah Revana, Humble Cardiology Associates,
  Humble, TX Brian Schwartz, Kettering Medical
  Center, Kettering, OH Ravi Ranjan, University of
  Utah, Salt Lake City, UT Jeffrey Hastings,
  Dallas VA Medical Center, Dallas, TX Michael
  Orlov, Steward St. Elizabeth's Medical Center,
  Boston, MA Mark Wathen, Tennessee Heart,
  Cookeville, TN John Beshai, University of
  Chicago Medical Center, Chicago, IL John Lee,
  Kansas City Heart Foundation, Kansas City ,MO
  Kathleen Magness, PMA Medical Specialists,
  Phoenixville, PA Doug Mendoza, Southern Medical
  Research, Hammond, LA Lawrence Gering,
  Kentuckiana Heart and Vascular, Owensboro, KY
  Thomas Swain, Melbourne Internal Medicine
  Associates, Melbourne, FL Richard Otten,
  Parkview Research Center, Fort Wayne, IN Peter
  Illes, Sydney Adventist Hospital, Sydney, AU
  Bryan Lucenta, Tulsa, OK Naushad Shaik,
  Cardiovascular Associates, Kissimmee, FL Chad
  Bonhomme, Community Heart Vascular,
  Indianapolis, IN Ruth Ann Greenfield, Duke
  University Medical Center, Durham, NC Eric
  Stecker, Oregon Health Science University,
  Portland, OR Alaa Shalaby, VA Pittsburgh
  Healthcare System, Pittsburgh, PA Suneet Mittal,
  Valley Hospital, Ridgewood, NJ Richard Borge,
  Abington Medical Specialists, Abington, PA Rehan
  Mahmud, Bay Regional Medical Center, Bay City,
  MI Daniel Soroff, Central Maine Heart Vascular
  Institute, Lewiston, ME Jens Nielsen, Aarhus
  University Hospital, Aarhus, Denmark Robert
  Sheppard, Heart Vascular Institute of Florida,
  St. Petersburg, FL Richard Kehoe, Cardiac
  Arrhythmia Consultants, Chicago, IL Harinder
  Gogia, Cardiology Consultants of Orange County,
  Anaheim, CA Anil Ranginani, Mercy Hospital,
  Chicago, IL Michael Yerkey, Rockwood Clinic,
  Spokane, WA Andrew Cohen, Aurora Denver
  Cardiology Associates, Aurora, CO Ishu Rao,
  Cardiology Associates Medical Group, Ventura, CA
  Niranjan Seshadri, Heart Care Research, Sarasota,
  FL Aldino Cellini, Sebastian Cardiology,
  Sebastian, FL William Frumkin, Lenox Hill
  Hospital, New York City, NY Nicholas Skipitaris,
  Mt. Sinai Heart, New York City, NY Christina
  Murray, University of Oklahoma Health Sciences
  Center, Oklahoma City, OK Heiko Schmitt,
  University of Connecticut Health Center,
  Farmington, CT Bharat Kantharia, University of
  Texas Medical School, Houston, TX Gregory Lip,
  Birmingham City Hospital, Birmingham, UK John
  Kall, Cardiovascular Associates, Elk Grove
  Village, IL Kousik Krishnan, Rush University
  Medical Center, Chicago, IL Nayereh Pezeshkian,
  UC Davis Medical Center, Sacramento, CA Wayne
  Adkisson, University of Minnesota, Minneapolis,
  MN George Mark, Cardiovascular Associates of
  Delaware Valley, Haddon Heights, NJ Pablo
  Saavedra, Vanderbilt Heart Institute, Nashville,
  TN.

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IMPACT Study Group

• Data Monitoring Committee D. George Wyse
  (Chair), University of Calgary, Calgary, Canada
  Robert G. Hart, McMaster University, Hamilton,
  Ontario, Canada David DeMets, University of
  Wisconsin, Madison, WI.
• Clinical Events Committee Howard S. Kirshner
  (Chair), Vanderbilt University Medical Center,
  Nashville, TN Salvador Cruz-Flores,Texas Tech
  University Health Sciences Center, El Paso, TX
  Joshua Beckman, Brigham and Women's Hospital,
  Boston, MA Jerome Cohen, Saint Louis University
  School of Medicine, St Louis, MO.
• Steering Committee Jonathan L. Halperin
  (Co-chair), Icahn School of Medicine at Mount
  Sinai, New York, NY John Ip (Co-chair), Sparrow
  Research Foundation, Lansing, MI David T.
  Martin, Lahey Hospital and Medical Center,
  Burlington, MA Malcolm M. Bersohn, Veterans
  Administration and University of California Los
  Angeles School of Medicine, Los Angeles, CA
  Albert L. Waldo, Case Western Reserve University
  School of Medicine, Cleveland, OH Mark S.
  Wathen, Tennessee Heart, Nashville, TN Wassim K.
  Choucair, Cardiology Associates of Corpus
  Christi, Corpus Christi, TX Gregory Y. H. Lip,
  University of Birmingham Centre for
  Cardiovascular Sciences, City Hospital,
  Birmingham, United Kingdom Joseph G. Akar, Yale
  University School of Medicine, New Haven, CT.

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Relationship of CHADS2 AF

• The CHADS2 score provides clinical guidance for
  defining stroke risk for patients with AF
• The relationship between CHADS2 score and the
  incidence of AF is not well defined