CRYSTAL-AF

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Sanna T, et al. "Cryptogenic Stroke and Underlying Atrial Fibrillation". The New England Journal of Medicine. 2014. 370(26):2478-2486.
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Clinical Question

Does an implantable long term cardiac monitor compared with conventional follow up for atrial fibrillation improve detection of atrial fibrillation in patients with cryptogenic strokes?

Bottom Line

Implantable long term cardiac monitors improved the detection of 30 sec episodes of paroxysmal atrial fibrillation by a factor of 6.4 compared to conventional follow up at 6 months and by a factor of 7.3 at 12 months.

Major Points

Currently, approximately 1 in 4 ischemic strokes and half of TIAs have an etiology that is not identified readily after the routine work up (i.e. 24-48 hour holter, echo cardiogram, vessel imaging) and are labelled as cryptogenic. Many have an appearance on neurological imaging consistent with embolism (i.e. larger size, wedge shaped) and have been referred to in recent literature as embolic strokes of unknown source (ESUS). It has long been suspected that a significant portion of these patients have subclinical atrial fibrillation that is not identified during the conventional holter monitoring period.

The sensitivity of a single 24 or 48 hour holter for atrial fibrillation is poor. In a population of patients with implantable pacemakers which where interrogated, it was found that the average time to detection for a subclinical prolonged tachyarrhythmia (>190 bpm for >6 min) was 35 days. Prior to CRYSTAL-AF, an earlier RCT demonstrated benefit of extended EKG monitoring of up to 1 week for the increased detection of AF following ischemic stroke. [1] The CRYSTAL-AF trial, showed using an implanted device that among patients with cryptogenic strokes, detection of AF increased further with longer duration of monitoring up to 3 years. AF detection rate in CRYSTAL AF were 8.9% at 6 months, 12.4% at 12 months, and 30% at 3 years in those with cryptogenic stroke. A contemporary trial published in the same issues of the NEJM, EMBRACE, corroborated this conclusion by demonstrating an increased detection of AF with prolonged 30 day wearable EKG monitoring after cryogenic strokes compared to conventional management.

Guidelines

  • AHA/ASA 2014 Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: For patients who have experienced an acute ischemic stroke or TIA with no other apparent cause, prolonged rhythm monitoring (≈30 days) for AF is reasonable within 6 months of the index event.
  • Canadian Stroke Best Practice Recommendations-secondary prevention of stroke guidelines 2014: In cases where the ECG or initial cardiac rhythm (e.g. 24 or 48 h ECG monitoring) does not show atrial fibrillation but a cardioembolic mechanism is suspected, prolonged ECG monitoring is recommended in selected patients for the detection of paroxysmal atrial fibrillation (i.e. older patients with recent embolic stroke of undetermined source who are potential candidates for anticoagulant therapy).

Design

  • Open-label, multicenter, randomized control trial
  • N=441
    • Implanted cardiac monitor (n=221 randomized, 208 received implanted cardiac monitor)
    • Control (n=220)
  • Setting: 55 centers in Europe, Canada and US
  • Enrollment: June 2009 through April 2012
  • Follow-up: 6 months for primary endpoint, 12 month for secondary end points
  • Analysis: Intention-to-treat
  • Primary outcome:Percentage of subjects with AF detected within 6 months of follow-up
  • Monitoring device used: REVEAL XT, Medtronic

Population

Inclusion Criteria

  • Age >40
  • Recent (within last 90 days) diagnosis of cryptogenic symptomatic transient ischemic attack (TIA) with speech, weakness or hemianopsia OR cryptogenic ischemic stroke. Cryptogenic is defined as having no clear etiology identified after standard working including 12 lead EKG, 24 hours holter, echocardiography, screening for thrombophilic state for patients <55 years of age and large vessel imaging (doppler US, MRA, TCA).

Exclusion Criteria

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

Baseline Characteristics

(Intervention n=221 vs. control n=220)

  • Age — yr: 61.6±11.4 vs. 61.4±11.3
  • Sex — no (%)
    • Male: 142 (64.3) vs. 138 (62.7)
    • Female: 79 (35.7) vs. 82 (37.3)
  • Race or ethnic group — no. (%)
    • Asian: 3 (1.4) vs. 2 (0.9)
    • Black: 7 (3.2) vs. 10 (4.5)
    • Hispanic or Latino: 2 (0.9) vs. 2 (0.9)
    • White: 194 (87.8) vs. 191 (86.8)
    • Other: 0 vs. 3 (1.4)
    • Not available: 15 (6.8) vs. 12 (5.5)
  • Geographic region — no. (%)
    • North America: 83 (37.6) vs. 72 (32.7)
    • Europe: 138 (62.4) vs. 148 (67.3)
  • Patent foramen ovale — no. (%): 52 (23.5) vs. 46 (20.9) 0.57
  • Index event — no. (%)
    • Stroke: 200 (90.5) vs. 201 (91.4)
    • TIA: 21 (9.5) vs. 19 (8.6)
  • Prior stroke or TIA — no. (%)
    • Stroke: 37 (16.7) vs. 28 (12.7)
    • TIA: 22 (10.0) vs. 27 (12.3)
  • Score on modified Rankin scale — no. (%)
    • 0–2: 184 (83.3) vs. 186 (84.5)
    • >2: 36 (16.3) vs. 34 (15.5)
  • Score on NIH Stroke Scale: 1.6±2.7 vs. 1.9±3.8
  • Hypertension — no. (%): 144 (65.2) vs. 127 (57.7)
  • Diabetes — no. (%) 34 (15.4) vs. 38 (17.3)
  • CHADS2 score — no. (%):
    • 2: 69 (31.2) vs. 81 (36.8)
    • 3: 92 (41.6) vs. 91 (41.4)
    • 4: 50 (22.6) vs. 34 (15.5)
    • 5: 9 (4.1) vs. 14 (6.4)
    • 6: 1 (0.5) vs. 0
  • Hypercholesterolemia — no. (%): 125 (56.6) vs. 128 (58.2)
  • Current smoker — no. (%): 43 (19.5) vs. 44 (20.0)
  • Coronary artery disease — no. (%): 16 (7.2) vs. 9 (4.1)
  • Use of antiplatelet agent — no. (%): 212 (95.9) vs. 212 (96.4)

Interventions

  • Implantable cardiac monitor is placed subcutaneously in the thoracic region. It works for up to three years. ECG data is stored a cardiac arrhythmia is detected.

Outcomes

Comparisons are Implantable Cardiac Monitors vs. Control.

Primary Outcomes

Detection of atrial fibrillation at 6 months
19 (8.6%, asymptomatic 14/19) vs. 3 (1.4%, asymptomatic 1/3), HR=6.4 (95% CI, 1.9–21.7), P<0.001
  • Atrial fibrillation defined as an episode of irregular heart rhythm, without detectable P waves, lasting more than 30 seconds.

Secondary Outcomes

AF Detection Rate Within 12 Months
29 (12.4%) vs. 4 (2.0%), HR=7.3 (95% CI, 2.6 to 20.8), P<0.001
Incidence of Recurrent Stroke or TIA (Transient Ischemic Attack) at 12 months
15 (7.1%) vs. 19 (9.1%), HR and P not given by author
Use of Oral Anticoagulation (OAC) Drugs at 12 months
32 (14.7%) vs. 13 (6.0%), P=0.007

Subgroup Analysis

AF detection rate using the two methods did not have an interaction with age, sex, race, index event (stroke vs TIA), CHADS2 score or presence of of a patent foramen ovale on subgroup analysis.

Adverse Events

  • 5 (2.4%) of implanted cardiac monitors were removed owing to infection at the insertion site or pocket erosion.
  • 3 (1.4%) of patients with implanted cardiac monitors had infections, 3 (1.4%) had pain and 4 (1.9%) had irritation or inflammation at the insertion site.

Criticisms

  • Like the contemporary EMBRACE study, the CRYSTAL AF authors chose a relatively short cut off of 30 seconds for duration of atrial fibrillation used in the primary end point. Previous trials such as the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) [2] as well as the Mode Selection Trial (MOST) [3] showed atrial tachyarrhythmia lasting longer than 6 minutes and 5 minutes respectively as associated with clinical atrial fibrillation, increased risk of stroke and mortality. It is unclear if the systemic embolism risks of short runs of subclinical AF is similar to clinical AF and if patients wwould benefit in the same way from anti-coagulation.
  • New arrhythmias have been reported after right sided insular infarcts.[4] While 14.7% of patients had strokes as their index event, the CRYSTAL-AF authors did not disclosed the percentage of patients with insular infarcts.
  • The device used was a Medtronic Reveal® XT Insertable Cardiac Monitor and algorithm used for AF detection has a reported acuracy of 98.5%.[5] The results of this study may not be translatable to other implantable monitors.
  • White and male patients made up the majority of study participants limiting the generalizability of results

Funding

Medtronic Cardiac Rhythm and Heart Failure Medtronic Bakken Research Center

Further Reading

  1. Higgins P et al. Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke 2013. 44:2525-31.
  2. Healey JS et al. Subclinical atrial fibrillation and the risk of stroke. N. Engl. J. Med. 2012. 366:120-9.
  3. Glotzer TV et al. Atrial high rate episodes detected by pacemaker diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde Selection Trial (MOST). Circulation 2003. 107:1614-9.
  4. Abboud H et al. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann. Neurol. 2006. 59:691-9.
  5. Hindricks G et al. Performance of a new leadless implantable cardiac monitor in detecting and quantifying atrial fibrillation: Results of the XPECT trial. Circ Arrhythm Electrophysiol 2010. 3:141-7.