Randomized Trial of Anticoagulation Guided by Remote Rhythm Monitoring In Patients with Implanted...

Randomized Trial of Anticoagulation Randomized Trial of Anticoagulation Guided by Remote Rhythm Guided by Remote Rhythm

MonitoringMonitoringIn Patients with ImplantedIn Patients with Implanted

Cardioverter-Defibrillator and Cardioverter-Defibrillator and Resynchronization DevicesResynchronization Devices

David T Martin, MD FACCDavid T Martin, MD FACCLahey Hospital and Medical CenterLahey Hospital and Medical Center

On Behalf of the On Behalf of the IMPACT InvestigatorsIMPACT Investigators

Funded by BIOTRONIK, Inc.Funded by BIOTRONIK, Inc.

ClinicalTrials.gov: NCT00559988ClinicalTrials.gov: NCT00559988

BackgroundBackground

Episodes of atrial fibrillation (AF) are often asymptomaticEpisodes of atrial fibrillation (AF) are often asymptomatic

Atrial fibrillation can be detected by implanted cardiac rhythm Atrial fibrillation can be detected by implanted cardiac rhythm management devicesmanagement devices

Up to 65% of patients with pacemakers exhibit atrial Up to 65% of patients with pacemakers exhibit atrial tachyarrhythmias (AT)tachyarrhythmias (AT)

Thromboembolism (TE) risk appears to be related to Thromboembolism (TE) risk appears to be related to duration/burden of device-detected atrial tachyarrhythmiasduration/burden of device-detected atrial tachyarrhythmias

BackgroundBackground

From Glotzer TV, Daoud EG, Wyse DG, et al. Circ Arrhythm Electrophysiol 2009;2:474-80.

Study OverviewStudy Overview

Hypothesis:Hypothesis: Initiation of oral anticoagulation (OAC) early after Initiation of oral anticoagulation (OAC) early after detection of AT and withdrawing OAC when AT abates detection of AT and withdrawing OAC when AT abates might reduce thromboembolism and hemorrhage in might reduce thromboembolism and hemorrhage in patients with ICD and CRT-D devicespatients with ICD and CRT-D devices

Design:Design: Multicenter, single-blinded, randomization stratified by Multicenter, single-blinded, randomization stratified by CHADSCHADS22 category and device type category and device type

Treatment Groups:Treatment Groups: Intervention: Remote monitoring for AT with pre-defined Intervention: Remote monitoring for AT with pre-defined anticoagulation plan based on AT burden and CHADSanticoagulation plan based on AT burden and CHADS22

Control: In-office identification of AT with OAC directed by Control: In-office identification of AT with OAC directed by treating physiciantreating physician

Primary Endpoint:Primary Endpoint: First stroke, systemic embolism, or major bleedFirst stroke, systemic embolism, or major bleed

Secondary Endpoints:Secondary Endpoints: All-cause mortality, stroke rate, AT burdenAll-cause mortality, stroke rate, AT burden

Number of Patients:Number of Patients: 2,718 from 104 sites (North America, Europe, & Australia)2,718 from 104 sites (North America, Europe, & Australia)

Scheduled Visits:Scheduled Visits: At least every 6 months until last subject completes 3 At least every 6 months until last subject completes 3 year visityear visit

Anticoagulation ProtocolAnticoagulation ProtocolIntervention GroupIntervention Group

Continuous remote Continuous remote monitoring for ATmonitoring for AT(36 of 48 atrial beats (36 of 48 atrial beats

≥200 bpm)≥200 bpm)

Stop OACStop OACCHADSCHADS22 1 & 2 1 & 2

AT for ≥48hAT for ≥48h

Start OACStart OAC

No AT for 30dNo AT for 30d

Any ATAny AT

Stop OACStop OACCHADSCHADS22 3 & 4 3 & 4

AT for ≥24h in 2dAT for ≥24h in 2d

Start OACStart OAC

No AT for 90dNo AT for 90d

Any ATAny AT

Any ATAny AT

CHADSCHADS22 5 & 6 5 & 6(or prior TE)(or prior TE)

Start and maintain OACStart and maintain OAC

Eligibility CriteriaEligibility Criteria

Key Inclusion CriteriaKey Inclusion Criteria CHADSCHADS22 risk score ≥ 1 risk score ≥ 1 Implanted ICD or CRT-D with Home MonitoringImplanted ICD or CRT-D with Home Monitoring®® technology technology Able and willing to begin anticoagulation therapy, if neededAble and willing to begin anticoagulation therapy, if needed Acceptable P-wave amplitude documented (≥ 1.0 mV sinus rhythm, ≥ Acceptable P-wave amplitude documented (≥ 1.0 mV sinus rhythm, ≥

0.5 mV AF) 0.5 mV AF) Age ≥ 18 years and able to provide informed consentAge ≥ 18 years and able to provide informed consent

Key Exclusion CriteriaKey Exclusion Criteria Permanent AFPermanent AF History of stroke, TIA, or systemic embolism and documented AF or History of stroke, TIA, or systemic embolism and documented AF or

atrial flutteratrial flutter Currently requiring OAC or known contraindication to OACCurrently requiring OAC or known contraindication to OAC < 3 months of OAC therapy after successful AF ablation < 3 months of OAC therapy after successful AF ablation

Recruitment and Follow-UpRecruitment and Follow-Up

Full planned cohort of 2,718 patients enrolled between February 28, Full planned cohort of 2,718 patients enrolled between February 28, 2008 and May 17, 20132008 and May 17, 2013

Data Monitoring Committee determined futility when 75% of expected Data Monitoring Committee determined futility when 75% of expected events accrued events accrued No concerns about safetyNo concerns about safety

Steering Committee stopped the study on June 12, 2013Steering Committee stopped the study on June 12, 2013 Database locked September 30, 2013Database locked September 30, 2013

Follow-up completedFollow-up completed Median exposure = 701 daysMedian exposure = 701 days Cumulative follow-up = 5,430 patient-yearsCumulative follow-up = 5,430 patient-years

Baseline CharacteristicsBaseline Characteristics

Control GroupControl GroupN = 1,361N = 1,361

Intervention GroupIntervention GroupN = 1,357N = 1,357 pp

Age, yAge, y 6464 6565 0.2360.236

Gender, % maleGender, % male 73.073.0 74.474.4 0.4080.408

Median CHADSMedian CHADS22 22 22 0.5440.544

CHF or LV dysfunction, %CHF or LV dysfunction, % 89.589.5 90.590.5 0.3720.372

Hypertension, %Hypertension, % 84.184.1 83.583.5 0.7160.716

Coronary artery disease, %Coronary artery disease, % 71.271.2 71.971.9 0.6710.671

Diabetes, %Diabetes, % 40.240.2 41.441.4 0.5320.532

Previous stroke or TIA, %Previous stroke or TIA, % 9.79.7 8.28.2 0.1790.179

Device type, % ICDDevice type, % ICD 64.464.4 63.663.6 0.6600.660

Aspirin, %Aspirin, % 77.177.1 74.874.8 0.1640.164

Other antiplatelet, %Other antiplatelet, % 30.730.7 34.534.5 0.0370.037

Mean follow-up, yMean follow-up, y 2.012.01 1.991.99 0.6850.685

Atrial Tachyarrhythmias Atrial Tachyarrhythmias During the TrialDuring the Trial

pp = 0.0908 = 0.0908

AT Meeting AT Meeting Anticoagulation CriteriaAnticoagulation Criteria


Intervention GroupIntervention GroupN = 1,357N = 1,357

Adjudication Adjudication ResultsResults

115 126

326

Adjudication Adjudication ResultsResults

126

355

138

False PositiveFalse PositiveAny ATAny AT AT Meeting CriteriaAT Meeting CriteriaConfirmed AFConfirmed AF

452452493493

OAC Options and UtilizationOAC Options and Utilization

0%

2%

4%

6%

8%

10%

12%

14%

Per

cent

age

of A

ctiv

e S

ubje

cts

Any OAC VKA Dabigatran Rivaroxaban Apixaban

Anticoagulation TherapyAnticoagulation Therapy

Control GroupControl Group Intervention GroupIntervention Group

All patientsAll patients N = 1,361N = 1,361 N = 1,357N = 1,357

Started OACStarted OAC 158 (11.6%)158 (11.6%) 182 (13.4%)182 (13.4%)

Stopped OACStopped OAC 71 (5.2%)71 (5.2%) 97 (7.1%)97 (7.1%)

Mean days on OACMean days on OAC 396396 374374

Time in therapeutic range (VKA)Time in therapeutic range (VKA) 58.5%58.5% 59.2%59.2%

Patients meeting OAC criteriaPatients meeting OAC criteria N = 115N = 115 N = 126N = 126

Started OACStarted OAC 69 (60.0%)69 (60.0%) 91 (72.2%)91 (72.2%)

Stopped OACStopped OAC 29 (25.2%)29 (25.2%) 46 (36.5%)46 (36.5%)

Mean days on OACMean days on OAC 450450 409409

Median time to start (days)Median time to start (days) 5454 33

Compliance with OAC protocolCompliance with OAC protocol N = 126N = 126

Started in specified timeframeStarted in specified timeframe 45.2%45.2%

Time in therapeutic range (VKA)Time in therapeutic range (VKA) 61.2%61.2%

N, EventsN, Events

ControlControl 1361, 01361, 0 928, 27928, 27 543, 43543, 43 228, 57228, 57 75, 6075, 60 2, 612, 61

InterventionIntervention 1357, 01357, 0 906, 28906, 28 538, 49538, 49 214, 59214, 59 66, 6266, 62 3, 633, 63

Primary Outcome EventsPrimary Outcome Events

Time (years)Time (years)

00

8080

8585

9090

9595

100100E

vent

-fre

e S

urvi

val (

%)

Eve

nt-f

ree

Sur

viva

l (%

)

00 11 22 33 44 55

pp = 0.777 = 0.777

InterventionInterventionControlControl


Ischemic Stroke or Systemic EmbolismIschemic Stroke or Systemic EmbolismHemorrhagic Stroke or Other Major BleedHemorrhagic Stroke or Other Major Bleed

Primary Outcome EventsPrimary Outcome Events

Clinical OutcomesClinical Outcomes


Intervention GroupIntervention GroupN = 1,357N = 1,357

Hazard Hazard RatioRatio pp

NN raterate NN raterate

Primary endpointPrimary endpoint 6161 2.32.3 6363 2.42.4 1.061.06 0.7320.732

MortalityMortality 140140 5.15.1 147147 5.45.4 1.071.07 0.6620.662

ThromboembolismThromboembolism 3737 1.41.4 3232 1.21.2 0.880.88 0.5860.586

Ischemic strokeIschemic stroke 2828 1.01.0 2222 0.80.8 0.790.79 0.4170.417

Systemic embolismSystemic embolism 22 00 -- 0.9690.969

TIATIA 88 1010 1.271.27 0.6190.619

Hemorrhagic strokeHemorrhagic stroke 33 0.10.1 33 0.10.1 1.031.03 0.9730.973

Other major bleedOther major bleed 3232 1.21.2 4343 1.61.6 1.391.39 0.1450.145

Rates are expressed as the number of events per 100 patient-years.Rates are expressed as the number of events per 100 patient-years.

VKA Therapy at Time of EventVKA Therapy at Time of Event


No VKA/ No VKA/ INR <2INR <2

INR INR 2 - 32 - 3

INR INR >3>3

No VKA/ No VKA/ INR <2INR <2

INR INR 2 - 32 - 3

INR INR >3>3

Ischemic strokeIschemic stroke 27/2827/2896.4%96.4%

1/281/283.6%3.6%

21/2221/2295.5%95.5%

1/221/224.5%4.5%

Systemic embolismSystemic embolism 1/21/250.0%50.0%

1/21/250.0%50.0%

TIATIA 7/87/887.5%87.5%

1/81/812.5%12.5%

9/109/1090.0%90.0%

1/101/1010.0%10.0%

Hemorrhagic strokeHemorrhagic stroke 3/33/3100%100%

2/32/366.7%66.7%

1/31/333.3%33.3%

Other major bleedsOther major bleeds 26/32*26/32*81.2%81.2%

3/323/329.4%9.4%

3/323/329.4%9.4%

30/4330/43††

69.8%69.8%6/436/43

13.9%13.9%7/437/43

16.3%16.3%

*Two control subjects with other major bleed were on a novel OAC at time of event.*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. Three intervention subjects with other major bleed were on a novel OAC at time of event.

AF

Bur

den

(0 t

o 10

0%,

log

sca

le)

AF

Bur

den

(0 t

o 10

0%,

log

sca

le)

00 66 36361818 2424 30301212 4242 4848 5454-54-54 -48-48 -42-42 -36-36 -30-30 -24-24 -18-18 -12-12 -6-6Months Months from TEfrom TE

Temporal Relationship of Atrial Temporal Relationship of Atrial Fibrillation & ThromboembolismFibrillation & Thromboembolism

Temporal Relationship of Atrial Temporal Relationship of Atrial Fibrillation & ThromboembolismFibrillation & Thromboembolism

ControlControlGroupGroup

Intervention Intervention GroupGroup

Patients with TEPatients with TE 3737 3232

AF anytime during studyAF anytime during study 1717 1212

AF prior to TEAF prior to TE 1212 88

AF after TEAF after TE 55 44

No AF during studyNo AF during study 2020 2020

Thromboembolism in Relation to Thromboembolism in Relation to Atrial Tachyarrhythmia DurationAtrial Tachyarrhythmia Duration

AT Duration CategoriesAT Duration Categories

Control Control pp-trend = 0.173, Intervention -trend = 0.173, Intervention pp-trend = 1.000 -trend = 1.000 Interaction Interaction pp = 0.470 = 0.470

LimitationsLimitations

Suboptimal compliance with OAC protocol in the intervention Suboptimal compliance with OAC protocol in the intervention groupgroup

Greater use of antiplatelet therapy in the intervention groupGreater use of antiplatelet therapy in the intervention group

Low event rate limited power to detect differences in outcomes Low event rate limited power to detect differences in outcomes between groupsbetween groups

Conclusions

Starting and stopping OAC based on device-detected AF did not Starting and stopping OAC based on device-detected AF did not improve clinical outcomes in this studyimprove clinical outcomes in this study

Temporal dissociation of device-detected AF and thromboembolic Temporal dissociation of device-detected AF and thromboembolic events suggests that an accelerated anticoagulation strategy events suggests that an accelerated anticoagulation strategy provides no added benefit for TE preventionprovides no added benefit for TE prevention

The decision to start OAC for device-detected AF should be based The decision to start OAC for device-detected AF should be based upon comprehensive clinical assessment of risk and benefitupon comprehensive clinical assessment of risk and benefit

Once started for AF, the absence of device-detected AF should not Once started for AF, the absence of device-detected AF should not lead to discontinuation of OAClead to discontinuation of OAC

IMPACT StudyStudy GroupInvestigators: 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;

Investigators (con’t): 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.

IMPACT StudyStudy 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.

IMPACT StudyStudy Group

Relationship of CHADSRelationship of CHADS22 & AF & AF

The CHADSThe CHADS22 score provides clinical guidance for defining stroke risk for score provides clinical guidance for defining stroke risk for patients with AFpatients with AF

The relationship between CHADSThe relationship between CHADS22 score and the incidence of AF is not well score and the incidence of AF is not well defineddefined

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

0%

10%

20%

30%

40%

50%

1 2 3 4 5 6

AF

Burden

Pat

ient

s (%

)

CHADS2 Score

% with AF Mean AF Burden

Randomized Trial of Anticoagulation Guided by Remote Rhythm Monitoring In Patients with Implanted...

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