Study of Continuous Cardiac Monitoring to Assess Atrial Fibrillation After Cryptogenic Stroke (CRYSTAL-AF)

CRYptogenic STroke And underLying AF Trial

The 2006 American Heart Association / American Stroke Association Council on Stroke Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic recommended that patients with cryptogenic stroke take antithrombotic drugs (i.e. aspirin) in order to prevent a second stroke. When a stroke patient is found to have atrial fibrillation (AF), the guidelines recommend oral anticoagulation due to its superior efficacy over aspirin for stroke prevention. Physicians can best optimize the use of medicines only if they can precisely and correctly diagnose a patient's AF. The purpose of this study is to evaluate the time to first AF by 6 months' continuous rhythm monitoring versus control treatment in subjects with a recent cryptogenic stroke or Transient Ischemic Attack (TIA) without history of AF.

Study Overview

• Status: Completed
• Conditions: Cryptogenic Symptomatic Transient Ischemic Attack; Cryptogenic Ischemic Stroke
• Intervention / Treatment: Device: Reveal® XT Insertable Cardiac Monitor

• Study Type: Interventional
• Enrollment (Actual): 447
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • LKH Universitätsklinikum Graz
  • Linz, Austria
    • AKH Linz
  • Tulln, Austria
    • Landesklinikum Donauregion Tulln
• Belgium
  • Antwerp, Belgium
    • UZ Antwerpen
  • Brussels, Belgium
    • Brussels Heart Center (St. Lean - St. Pierre)
  • Leuven, Belgium
    • UZ Leuven
  • Mont Godinne, Belgium
    • Cliniques Universitaires UCL Mont-Godinne
• Canada
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences / Hamilton General Hospital
  • Quebec
    • Sherbrooke, Quebec, Canada
      • CHUS / Hopital Fleurimont
• Denmark
  • Aarhus, Denmark
    • Skejby Hospital
• Finland
  • Turku, Finland
    • Neurology clinic, Turku University Central Hospital
• France
  • Bordeaux, France
    • Hôpital Saint André -CHU de Bordeaux
  • Le Chesnay, France
    • Clinique Parly II - Centre Hospitalier de Versailles
  • Marseille, France
    • Hopital de la Timone
• Germany
  • Bochum, Germany
    • Knappschaftskrankenhaus Bochum
  • Dortmund, Germany
    • Klinikum Dortmund
  • Essen, Germany
    • Universitätsklinikum Essen
  • Goettingen, Germany
    • UMG, Goettingen
  • Greifswald, Germany
    • Universitätsklinikum der Ernst-Moritz-Arndt-Universität Greifswald
  • Hamburg, Germany
    • Asklepios Altona
  • Hamburg, Germany
    • Asklepios Barmbek
  • Karlsruhe, Germany
    • Städtisches Klinikum Karlsruhe GmbH
  • Rastatt, Germany
    • Kreiskrankenhaus Rastatt
  • Bayern
    • Coburg, Bayern, Germany
      • Klinikum Coburg GmbH
• Greece
  • Athens, Greece
    • Henry Dunant General Hospital
• Italy
  • Grosseto, Italy
    • Ospedale Misericordia di Grosseto
  • Imperia, Italy
    • Ospedale di Imperia
  • Rome, Italy
    • Policlinico Universitario Agostino Gemelli
  • Seriate, Italy
    • Ospedale Bolognini
• Netherlands
  • Heerlen, Netherlands
    • Atrium medisch centrum
  • Nieuwegein, Netherlands
    • St. Antonius Ziekenhuis
  • Utrecht, Netherlands
    • UMC Utrecht
• Slovakia
  • Bratislava, Slovakia
    • NUSCH, a.s. Bratislava
  • Kosice, Slovakia
    • VUSCH Kosice
• Spain
  • Majadahonda, Spain
    • Hospital Puerta de Hierro Majadahonda
• Sweden
  • Lund, Sweden
    • University Hospital Lund
• United States
  • California
    • Mountain View, California, United States
      • El Camino Hospital
  • Colorado
    • Denver, Colorado, United States
      • South Denver Cardiology / Swedish Medical Center
  • Illinois
    • Chicago, Illinois, United States
      • Northwestern Memorial Hospital
  • Iowa
    • Des Moines, Iowa, United States
      • Iowa Heart / Ruan Neurology
  • Kentucky
    • Louisville, Kentucky, United States
      • Louisville Cardiology
  • Mississippi
    • Tupelo, Mississippi, United States
      • Cardiology Associates Research, LLC
  • Missouri
    • Kansas City, Missouri, United States
      • Mid America Heart Institute / St. Lukes Hospital
    • St. Louis, Missouri, United States
      • Washington University Medical School
  • New Jersey
    • Hackensack, New Jersey, United States
      • Hackensack University Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States
      • Forsyth Medical Center
  • Ohio
    • Columbus, Ohio, United States
      • Ohio Health Research
  • Oregon
    • Eugene, Oregon, United States
      • Sacred Heart Medical Center
  • Pennsylvania
    • Doylestown, Pennsylvania, United States
      • Central Bucks Specialists / Doylestown Hospital
    • Philadelphia, Pennsylvania, United States
      • Thomas Jefferson University
    • Wynnewood, Pennsylvania, United States
      • Lankenau
  • South Carolina
    • Greenville, South Carolina, United States
      • Greenville Hospital System Cardiology/Cardiovascular Research
  • Tennessee
    • Nashville, Tennessee, United States
      • St. Thomas Research Institute
  • Texas
    • Dallas, Texas, United States
      • Baylor Research Institute
    • Dallas, Texas, United States
      • University of Texas - Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Recent cryptogenic symptomatic transient ischemic attack (TIA) or cryptogenic ischemic stroke.

Exclusion Criteria:

1. Known etiology of TIA or stroke.
2. Untreated hyperthyroidism.
3. Myocardial infarction less than 1 month prior to stroke or TIA.
4. Coronary bypass grafting less than 1 month prior to stroke or TIA.
5. Valvular disease requiring immediate surgical intervention.
6. History of AF or atrial flutter.
7. Patent Foramen Ovale (PFO) and PFO is or was an indication to start oral anticoagulation (OAC).
8. Permanent indication for OAC at enrollment.
9. Permanent contra-indication for OAC.
10. Included in another clinical trial.
11. Life expectancy less than 1 year.
12. Pregnant.
13. Indicated for Implantable Pulse Generator (IPG), Implantable Cardioverter-Defibrillator (ICD), Cardiac Resynchronization Therapy (CRT) or an implantable hemodynamic monitoring system.
14. Not fit, unable or unwilling to follow the required procedures of the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continuous Monitoring; Continuous cardiac monitoring by the Reveal® XT Insertable Cardiac Monitor	Device: Reveal® XT Insertable Cardiac Monitor; The Insertable Cardiac Monitor is implanted under the skin in the region of the thorax. It continuously monitors the heart's electrical activity for up to three years. ECG data are stored when the device detects a cardiac arrhythmia.; Other Names: Reveal® XT
No Intervention: Control Arm; Follow-up at the same frequency, but with no Insertable Cardiac Monitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AF Detection Rate Within 6 Months	Percentage of subjects with AF detected within 6 months of follow-up	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AF Detection Rate Within 12 Months	Percentage of subjects with AF detected within 12 months of follow-up	12 months
Incidence of Recurrent Stroke or TIA (Transient Ischemic Attack)	Percentage of subjects with recurrent stroke or TIA within 12 months of follow-up	12 months
Use of Oral Anticoagulation (OAC) Drugs	Percentage of subjects who were using OAC drugs at the 12 months follow-up visit	12 months
Use of Antiarrhythmic Drugs	Percentage of subjects who were using antiarrhythmic drugs at the 12 months follow-up visit	12 months
Health Outcome as Evaluated by EQ-5D Questionnaire	EQ-5D VAS (visual analog scale) quality of life score, which is a continuous measure of quality of life ranging from 0 (worst) to 100 (perfect health).	12 months
Clinical Disease Burden and Care Pathway	Incidence of cardiovascular (CV) or stroke/TIA related hospitalizations within 12 months	12 months
Impact of Patient Assistant Use on AF Diagnosis	AF detection lag (days from AF occurrence to AF diagnosis) characterized by patient assistant (PA) use frequency	Follow-up closure

Collaborators and Investigators

• Sponsor: Medtronic Cardiac Rhythm and Heart Failure
• Collaborators: Medtronic Bakken Research Center
• Investigators: Principal Investigator: Johannes Brachmann, MD, Klinikum Coburg, Germany; Principal Investigator: Tommaso Sanna, MD, Catholic University, Italy; Principal Investigator: Hans Christoph Diener, MD, Klinik für Neurologie, Essen, Germany; Principal Investigator: Carlos Morillo, MD, McMaster Clinic, Hamilton, Ontario, Canada; Principal Investigator: Richard Bernstein, MD, PhD, Davee Department of Neurology, Chicago, IL USA; Principal Investigator: Vincenzo Di Lazzaro, MD, Catholic University Rome, Rome Italy; Principal Investigator: Rod Passman, MD, Northwestern Memorial Hospital, Chicago, IL USA; Principal Investigator: Marilyn Rymer, MD, St. Lukes Hospital of Kansas City, Kansas City, MI USA

Publications and helpful links

General Publications

• Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T; American Heart Association; American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006 Feb;37(2):577-617. doi: 10.1161/01.STR.0000199147.30016.74.
• Sinha AM, Diener HC, Morillo CA, Sanna T, Bernstein RA, Di Lazzaro V, Passman R, Beckers F, Brachmann J. Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL AF): design and rationale. Am Heart J. 2010 Jul;160(1):36-41.e1. doi: 10.1016/j.ahj.2010.03.032.
• Kaffenberger T, Bernhardt J, Koehler JL, Ziegler PD, Thijs VN. Ambulatory activity in stroke survivors associated with functional outcome and quality of life: An observational cohort study. Ann Phys Rehabil Med. 2022 Mar;65(2):101540. doi: 10.1016/j.rehab.2021.101540. Epub 2021 Nov 13.
• Witte KK, Tsivgoulis G, Reynolds MR, Tsintzos SI, Eggington S, Ismyrloglou E, Lyon J, Huynh M, Egea M, de Brouwer B, Ziegler PD, Franco N, Joglekar R, Rosemas SC, Liu S, Thijs V. Burden of oral anticoagulation in embolic stroke of undetermined source without atrial fibrillation. BMC Cardiovasc Disord. 2021 Mar 31;21(1):160. doi: 10.1186/s12872-021-01967-x.
• Verma N, Ziegler PD, Liu S, Passman RS. Incidence of atrial fibrillation among patients with an embolic stroke of undetermined source: Insights from insertable cardiac monitors. Int J Stroke. 2019 Feb;14(2):146-153. doi: 10.1177/1747493018798554. Epub 2018 Sep 10.
• Brachmann J, Morillo CA, Sanna T, Di Lazzaro V, Diener HC, Bernstein RA, Rymer M, Ziegler PD, Liu S, Passman RS. Uncovering Atrial Fibrillation Beyond Short-Term Monitoring in Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke and Underlying Atrial Fibrillation Trial. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003333. doi: 10.1161/CIRCEP.115.003333.
• Bernstein RA, Di Lazzaro V, Rymer MM, Passman RS, Brachmann J, Morillo CA, Sanna T, Thijs V, Rogers T, Liu S, Ziegler PD, Diener HC. Infarct Topography and Detection of Atrial Fibrillation in Cryptogenic Stroke: Results from CRYSTAL AF. Cerebrovasc Dis. 2015;40(1-2):91-6. doi: 10.1159/000437018. Epub 2015 Jul 11.
• Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014 Jun 26;370(26):2478-86. doi: 10.1056/NEJMoa1313600.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: June 17, 2009
• First Submitted That Met QC Criteria: June 18, 2009
• First Posted (Estimate): June 19, 2009

Study Record Updates

• Last Update Posted (Estimate): July 28, 2014
• Last Update Submitted That Met QC Criteria: June 26, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: atrial fibrillation; continuous monitoring; implantable loop recorder; cryptogenic stroke; insertable cardiac monitor
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Stroke; Ischemic Stroke; Ischemia; Ischemic Attack, Transient
• Other Study ID Numbers: CRYSTAL-AF