Transcript IMPACT Presentation Slides (ACC.14)

Randomized Trial of Anticoagulation
Guided by Remote Rhythm Monitoring
In Patients with Implanted
Cardioverter-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
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
Background
From Glotzer TV, Daoud EG, Wyse DG, et al. Circ Arrhythm Electrophysiol 2009;2:474-80.
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
Anticoagulation Protocol
Intervention Group
Any AT
CHADS2 1 & 2
Start OAC
AT for ≥48h
Stop OAC
No AT for 30d
Any AT
Continuous remote
monitoring for AT
(36 of 48 atrial beats
≥200 bpm)
CHADS2 3 & 4
Start OAC
AT for ≥24h in 2d
CHADS2 5 & 6
(or prior TE)
Stop OAC
No AT for 90d
Start and maintain OAC
Any AT
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
 < 3 months of OAC therapy after successful AF ablation
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
Baseline Characteristics
Control Group
N = 1,361
Intervention Group
N = 1,357
p
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
Age, y
Atrial Tachyarrhythmias
During the Trial
2,718
Patients Enrolled
1,361
Control
452 (33.2%)
had AT
909 (66.8%)
had no AT
1,357
Intervention
p = 0.0908
493 (36.3%)
had AT
864 (63.7%)
had no AT
AT Meeting
Anticoagulation Criteria
Any AT
Confirmed AF
AT Meeting Criteria
False Positive
493
452
355
326
Adjudication
Results
Adjudication
Results
126
115
Control Group
N = 1,361
138
126
Intervention Group
N = 1,357
OAC Options and Utilization
14%
Percentage of Active Subjects
12%
10%
8%
6%
4%
2%
0%
Any OAC
VKA
Dabigatran
Rivaroxaban
Apixaban
Anticoagulation Therapy
Control Group
Intervention Group
N = 1,361
N = 1,357
Started OAC
158 (11.6%)
182 (13.4%)
Stopped OAC
71 (5.2%)
97 (7.1%)
396
374
58.5%
59.2%
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
All patients
Mean days on OAC
Time in therapeutic range (VKA)
Patients meeting OAC criteria
Compliance with OAC protocol
N = 126
Started in specified timeframe
45.2%
Time in therapeutic range (VKA)
61.2%
Primary Outcome Events
Event-free Survival (%)
100
95
90
85
Control
80
Intervention
p = 0.777
0
0
1
2
3
4
5
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
Primary Outcome Events
Hemorrhagic Stroke or Other Major Bleed
Ischemic Stroke or Systemic Embolism
Control Group
Intervention Group
Clinical Outcomes
Control Group
N = 1,361
Intervention Group
N = 1,357
Hazard
N
rate
Ratio
N
rate
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.
VKA Therapy at Time of Event
Control Group
No VKA/
INR <2
INR
2-3
Ischemic stroke
27/28
96.4%
1/28
3.6%
Systemic embolism
1/2
50.0%
1/2
50.0%
TIA
7/8
87.5%
1/8
12.5%
Hemorrhagic stroke
3/3
100%
Other major bleeds
26/32*
81.2%
3/32
9.4%
Intervention Group
INR
>3
3/32
9.4%
No VKA/
INR <2
INR
2-3
21/22
95.5%
1/22
4.5%
9/10
90.0%
1/10
10.0%
2/3
66.7%
1/3
33.3%
30/43†
69.8%
6/43
13.9%
INR
>3
7/43
16.3%
*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.
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
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
Temporal Relationship of Atrial
Fibrillation & Thromboembolism
Control
Group
Intervention
Group
Patients with TE
37
32
AF anytime during study
17
12
AF prior to TE
12
8
AF after TE
5
4
20
20
No AF during study
Thromboembolism in Relation to
Atrial Tachyarrhythmia Duration
Control p-trend = 0.173, Intervention p-trend = 1.000
Interaction p = 0.470
AT Duration Categories
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
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
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;
IMPACT Study Group
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 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.
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
Mean AF Burden
50%
5.0%
40%
4.0%
30%
3.0%
20%
2.0%
10%
1.0%
0%
0.0%
1
2
3
4
CHADS2 Score
5
6
AF Burden
Patients (%)
% with AF