Transcript Document

CRYptogenic STroke and underlying
AtriaL Fibrillation (CRYSTAL AF):
Long-Term Follow-Up Results
Rod S. 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
CRYSTAL AF
Disclosures
Medtronic
- Study funded by Medtronic, Inc.
- Speakers bureau, consultant, research support
Pfizer
- Speakers bureau
Bristol Myers Squibb
- Speakers bureau
Boehringer Ingelheim
- Speakers bureau
Janssen Pharmaceuticals
- Speakers bureau
CRYSTAL AF
Background
• 30% of ischemic strokes are of unknown mechanism
(cryptogenic stroke)
• Atrial fibrillation (AF) is a known cause of ischemic stroke
• Detection of AF should prompt long-term anticoagulation
instead of antiplatelet therapy in a patient with prior
ischemic stroke
• Optimal monitoring duration to detect AF is currently
undetermined
• AF may be paroxysmal, occur rarely, and be
asymptomatic, making detection with routine methods
difficult
CRYSTAL AF
CRYSTAL-AF: Primary Objective
• Assess whether a long-term cardiac monitoring strategy with an
insertable cardiac monitor (ICM) is superior to standard
monitoring for the detection of AF in patients with cryptogenic
stroke
CRYSTAL AF
Key Inclusion/Exclusion Criteria
Inclusion:
• ≥40 years of age
•Cryptogenic stroke (or clinical TIA), with infarct seen on MRI or CT,
within the previous 90 days; and no mechanism (including AF)
determined after:
• 12-lead ECG
• Minimum of 24-hour ECG monitoring (e.g. Telemetry, Holter)
• Transesophageal echocardiography (TEE)
• CTA or MRA of head and neck to rule out arterial source
• Screening for hypercoagulable states in patients <55 years old
Exclusion:
•History of AF or Atrial Flutter
•Permanent indication or contraindication for anticoagulation
•Indication for pacemaker or implantable cardioverter defibrillator
CRYSTAL AF
Comparison of Monitoring Strategies
Continuous Monitoring Arm:
Insertion of REVEAL® XT
Minimally invasive outpatient procedure
Local anesthetic and no leads or
fluoroscopy
15-30 minute procedure
Device can be followed remotely
Standard Monitoring Arm
Cardiac monitoring performed according
to local standards, after mandated
testing completed
Symptoms consistent with AF were
evaluated by study physicians
MRI conditional
3 year device longevity
Automatic AF detection algorithm
CRYSTAL AF
Methods
• Patients in both arms received scheduled follow-up visits at:
– 1 month
– 6 months
– 12 months
– Every 6 months thereafter until study closure
• AF defined as an episode of irregular heart rhythm, without
detectable p waves, greater than 30 seconds
• AF episodes were identified by patient’s physician and
adjudicated by an independent committee
CRYSTAL AF
Study Endpoints
• Primary:
– AF Detection Rates at 6 Months
• Secondary:
– AF Detection Rates at 12 Months
– Change in Use of Oral Anticoagulant (OAC) Drugs
CRYSTAL AF
Patient Flow
CRYSTAL AF
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
and randomization
36.6 ± 28.2 days
39.6 ± 26.9 days
Time between randomization 8.7 ± 27.6 days
and device insertion
n/a
CRYSTAL AF
Detection Rates: Primary & Secondary Endpoints
Primary Endpoint:
Detection of AF at
6 months
Hazard Ratio: 6.43
(1.90, 21.74)
p = 0.0006
Secondary Endpoint:
Detection of AF at
12 months
Hazard Ratio: 7.32
(2.57, 20.81)
p < 0.0001
Presented at ISC 2/14/14, San Diego CA
CRYSTAL AF
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
CRYSTAL AF
Detection of AF at 36 Months
Estimated rate of detection in ICM arm was 30.0% vs 3.0% in control arm
CRYSTAL AF
Proportion of AF episodes > 6 minutes
95% of patients with AF had a day with > 6 minutes of AF
CRYSTAL AF
Clinical Decisions
OAC Usage in AF Patients: Both Arms
Approximately 90% of patients with AF were prescribed OAC
CRYSTAL AF
Asymptomatic AF Episodes: Both Arms
Approximately 75% of first episodes of AF were asymptomatic
CRYSTAL AF
Tests Required to Find AF in Control Arm
Follow-up Period ECGs
Holter
Monitors
Event
Recorders
Incremental
Patients Found
with AF
0-6 months
88
20
1
3
6-12 months
33
12
0
1
12-18 months
42
9
0
0
18-24 months
20
5
0
1
24-30 months
16
4
0
0
30-36 months
3
2
0
0
Total
202
52
1
5
CRYSTAL AF
Time to First AF Detection
Median Time from
Randomization to AF
Detection
ICM (N=42)
Control (N=5)
Median: 8.4 months
IQR: 1.4-14.9 months
Median: 2.4 months
IQR: 1.1-11.5 months
CRYSTAL AF
Conclusions
• AF detection in cryptogenic stroke patients increases over time
with monitoring, with an estimated rate of AF detection of 30%
in the ICM versus 3% in the control arm at 36 months
• For those patients with detected AF in the ICM arm, the duration
was more than 6 minutes on one or more days in > 94% of
patients
• Physicians took action when AF was found with 89% of patients
being prescribed OAC
• Majority of first AF episodes (75%) were asymptomatic
• At 36 months, more than 250 tests were required in order to find
5 patients with AF in the control arm
• The time to first AF detection was beyond the time-frame of
typical external monitors
• Long-term continuous monitoring should be performed in
patients with cryptogenic stroke
CRYSTAL AF
Steering Committee Members
•
Tommaso Sanna, M.D., Catholic University of the Sacred Heart, Institute of Cardiology, Rome, IT
• Hans-Christoph Diener, M.D., Ph.D., FAHA, FAAN: University Hospital Essen, Department of
Neurology and Stroke Center, Essen, DE
• Rod S. Passman, M.D., MSCE: Northwestern University Feinberg School of Medicine, Chicago, IL
USA
• Vincenzo Di Lazzaro, M.D.: Campus Bio-Medico School of Medicine, Rome, IT 00128
• Richard A. Bernstein, M.D., Ph.D.: Davee Department of Neurology Northwestern University,
Chicago, IL USA
• Carlos Morillo, M.D., FRCPC, FACC, FHRS, FESC.: Population Health Research Institute, Hamilton,
ON, CAN
• Marilyn Rymer, M.D.: Kansas University Medical Center, Kansas City, KS, USA
• Johannes Brachmann, M.D. PH.D.: FHRS Hospital Klinikum Coburg, Teaching Hospital of the
University of Würzburg, Coburg, DE
CRYSTAL AF
Study Investigators
Austria
LKH - Universitätsklinikum Graz
Netherlands
Atrium Medisch Centrum Parkstad - Atrium
Heerlen
Schreuder
Allgemeines Krankenhaus der Stadt Linz
Landesklinikum Donauregion Tulln
Universitair Ziekenhuis Antwerpen
Niederkorn,
Pieske
Gruber
Brainin, Frank
Cras
Austria
Austria
Belgium
Netherlands
St. Antonius Ziekenhuis - Locatie Nieuwegein
Hilkens
Belgium
Clinique Saint-Jean ASBL
Goethals
Netherlands
Universitair Medisch Centrum Utrecht
Tuinenburg
Belgium
UZ Leuven - Campus Gasthuisberg
Thijs, Heidbüchel
Slovakia
Cliniques Universitaires UCL de Mont-Godinne
Blommaert
Narodny ustav srdcovych a cievnych chorob,
a.s. (NUSCH)
Urban
Belgium
Denmark
Århus Universitetshospital Skejby
Gerdes
Slovakia
Turun Yliopistollinen keskussairaala
Hôpital Saint André -Centre Hospitalier
Universitaire de Bordeaux
Clinique Parly II - Centre Hospitalier de
Versailles
Hôpital de la Timone - Centre Hospitalier
Universitaire de Marseille
Knappschaftskrankenhaus BochumLangendreer - Universitätsklinik
Klinikum Coburg GmbH
Roine
Papaioannou,
Sibon
Bertrand, Dechy
Vychodoslovensky ustav srdcovych a
cievnych chorob,a.s.
Stancak
Finland
France
Spain
Sweden
Canada
Hospital Puerta de Hierro Majadahonda
Universitetssjukhuset i Lund
Centre Hospitalier Universitaire de Sherbrooke
(CHUS)
Fernández Lozano
Platonov
Ayala-Paredes
Klinikum Dortmund gGmbH - Akademisches
Lehrkrankenhaus der Universität Münster
Universitätsklinikum Essen
Rudel
Wachter
Hamilton General Hospital
Baylor Research Institute
Cardiology Associates Research, LLC
Doylestown Hospital
El Camino Hospital
Endovascular Research- Sacred Heart Med. Ctr
Forsyth Medical Center
Greenville Hospital System
Hackensack University Medical Center
Iowa Heart Center, P.C. (West Des Moines)
Morillo
Assar
Kyker
Harding
Fung
Reddy
Chase
Rubenstein
Shukla
Jacoby
Germany
Universitätsmedizin Göttingen Georg-AugustUniversität
Universitätsklinikum der Ernst-Moritz-ArndtUniversität Greifswald
Asklepios Klinik Altona
Canada
US
US
US
US
US
US
US
US
US
Germany
Asklepios Klinik Barmbek
Grönefeld
Germany
Städtisches Klinikum Karlsruhe GmbH
Gahn, Schmitt
Germany
Klinikum Mittelbaden gGmbH Kreiskrankenhaus Rastatt
Henry Dunant Hospital
Presidio Provinciale Misericordia
Keller, Nawrot,
Daffertshofen
Theodorakis
Miracapillo,
Brescia
Zat
Di Lazzaro, Sanna
Giudici, Locatelli
US
US
US
US
Lankenau Hospital
Louisville Cardiology Medical Group, PSC
Mid America Heart Institute
Northwestern University
Margolies
Tu
Ramza
Passman
US
US
US
US
US
US
Ohio Health Corporation
Saint Thomas Research Institute, LLC
Swedish Medical/South Denver Cardiology
Thomas Jefferson University
Univ of Texas Southwestern Medical Center
Washington University School of Medicine
Nichols
Pickett
Choe
Ho
Daniels
Chen
France
France
Germany
Germany
Germany
Germany
Germany
Germany
Greece
Italy
Italy
Italy
Italy
Ospedale di Imperia
Policlinico Universitario Agostino Gemelli
Azienda Ospedaliera Bolognini Seriate Ospedale Bolognini
Deharo, Nicoli
Schlegel
Brachmann
Diener, Erbel
Khaw, Kessler,
Felix
Röther
CRYSTAL AF
CRYSTAL AF