CRYptogenic STroke and underlying Atria L Fibrillation CRYSTAL
CRYptogenic STroke and underlying Atria. L Fibrillation (CRYSTAL AF): Long-Term Follow-Up Results Rod S. Passman, MD, 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 - 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
Objectives of CRYSTAL-AF • 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 • Determine the proportion of patients with cryptogenic stroke that are subsequently found to have AF • Determine actions taken after patient is diagnosed with AF 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 yield at 24, 30 and 36 months • Proportion of patients who had a maximum one-day AF burden of > 6 minutes • Clinical decisions made by treating physician • Proportion of symptomatic vs asymptomatic AF episodes • Number of tests required to find AF in control arm CRYSTAL AF
Detection of AF at 36 Months 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
Conclusions • AF detection increases over time, with 30% of cryptogenic stroke patients in the ICM arm found to have AF at 36 months versus 3% in the control arm • 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 • Vast majority of AF episodes were asymptomatic • At 36 months, more than 250 tests were required in order to find 5 patients with AF in the control arm • 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 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 Belgium Cliniques Universitaires UCL de Mont-Godinne Blommaert Slovakia Narodny ustav srdcovych a cievnych chorob, a. s. (NUSCH) Urban 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 Bochum. Langendreer - Universitätsklinik Klinikum Coburg Gmb. H 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 g. Gmb. H - 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-August. Universitätsklinikum der Ernst-Moritz-Arndt. Universität Greifswald Asklepios Klinik Altona Canada US US US Germany Asklepios Klinik Barmbek Grönefeld Germany Städtisches Klinikum Karlsruhe Gmb. H Gahn, Schmitt Germany Klinikum Mittelbaden g. Gmb. H Kreiskrankenhaus Rastatt Henry Dunant Hospital Presidio Provinciale Misericordia Keller, Nawrot, Daffertshofen Theodorakis Miracapillo, Brescia Zat Di Lazzaro, Sanna Giudici, Locatelli US US Lankenau Hospital Louisville Cardiology Medical Group, PSC Mid America Heart Institute Northwestern University Margolies Tu Ramza Passman 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 Germany Germany Greece 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
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