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 30-day continuous EKG monitoring compared with 24 hour holter monitoring improve detection of atrial fibrillation in patients with cryptogenic strokes and affect treatment decisions regarding anti-coagulation))?

Bottom Line

((Ambulatory 30 day EKG monitoring improved the detection of 30 sec episodes of paroxysmal atrial fibrillation by a factor of 5 compared to 24 hour EKG monitoring and nearly doubled rate of anti-coagulation treatment at 90 days.))

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=572
    • Extended, up to 30 day monitoring (n=287, analyzed 286, 1 withdrew from study immediately after randomization with no baseline data recorded)
    • 24 hour monitoring (n=285,analyzed 285)
  • Setting: 16 centers in Canada
  • Enrollment: June 2009 through March 2012
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcome:Detection of atrial fibrillation episode lasting longer than 30 seconds
  • Monitoring device used for extended EKG monitoring: ER910AF Cardiac Event Monitor, Braemar

Population

Inclusion Criteria

  • Age>55
  • Cryptogenic embolic ischemic stroke or TIA within the last 6 months
  • No history of atrial fibrillation and EKG at time of stroke/TIA presentation showed no AF or atrial flutter
  • No atrial fibrillation or flutter >30 seconds on prior holter monitoring obtained as part of the routine clinical post-stroke/TIA work-up
  • Clinician suspicion for paroxysmal atrial fibrillation as source of stroke at time of patient enrollment
  • Prior to enrollment, patient has received brain imaging in the form of a CT or MRI, vessel imaging (CTA, MRA or US doppler is anterior circulation), and trans-thoracic or trans-esophageal echocardiogram
  • Patient gave informed consent
  • Patient likely to have life expectancy >6 months at time of enrollment
  • Patient had a valid provincial health number at time of enrollment

Exclusion Criteria

  • Previous documented episode of AF or atrial fibrillation
  • Exclusive retinal TIA or stroke
  • Patient in whom the likely stroke etiology has already been identified
  • Patients with planned carotid endarterectomy within 90 days.
  • Patient participating already in another trial
  • Patients with another evidence-based indication for long-term anticoagulation
  • Patients with endocarditis
  • Patients with pacemakers or ICDS
  • Patients with known skin reactions to synthetic polymers or to silver.

Baseline Characteristics

(Intervention n=286 vs. control n=285)

  • Mean age (years): 72.8 vs. 73.2
  • Female Gender (%): 46.2 vs. 43.9
  • Race (%):
    • White: 89.9 vs. 91.2
    • Asian: 5.2 vs. 4.9
    • Black: 2.1 vs. 0.7
    • Other: 2.8 vs. 3.2
  • Modified Rankin score <2 (No.): 274 vs. 263
  • Medical history:
    • Hypertension: 204 vs. 191
    • Diabetes: 55 vs. 55
    • Hyperlipidemia: 191 vs. 177
    • Smoking Status:
      • Current smoker: 19 vs. 24
      • Previous smoker: 141 vs. 121
    • Previous TIA: 42 vs. 46
    • Congestive heart failure: 5 vs. 7
    • Myocardial Infarction: 48 vs. 42
    • Coronary angioplasty or stenting: 24 v. 23
    • Coronary bypass surgery: 29 vs. 19
    • Cardiac-valve surgery: 6 vs. 1
  • Type of index event:
    • Ischemic stroke: 188 vs. 172
    • TIA: 98 vs. 113
  • Oxfordshire classification of index event:
    • Total anterior circulation syndrome: 7 vs. 5
    • Partial anterior circulation syndrome: 201 vs. 216
    • Posterior circulation syndrome: 63 vs. 56
    • Lacunar syndrome: 15 vs. 7
  • Number of days from index event until randomization: 76.6 vs. 73.7

Interventions

  • Randomized to 30 days EKG monitoring or 24 hour EKG monitoring
  • Intervention group told to wear the monitor as much as possible for 30 days. If AF detected prior to end of 30 days, patient was able to stop wearing the monitor earlier.
  • All abnormal rhythms were adjudicated by a cardiologist and an internist blinded to the patient’s demographic and clinical characteristics. Disagreements were resolved by consultation with another cardiologist.

Outcomes

Comparisons are 30 days vs. 24 hours.

Primary Outcomes

Detection of atrial fibrillation with duration

≥30 sec within 90 day:

16.1% vs. 3.2% (number needed to screen 8; 95% CI 5.7-12.5; P<0.001)

Secondary Outcomes

Detection of atrial fibrillation with duration ≥2.5 min
9.9% vs. 2.5% (number needed to screen 14; 95% CI 8.8-29.4; P<0.001)
Detection of atrial fibrillation of any duration
19.7% vs. 4.7% (number needed to screen 7; 95% CI 4.9-10.2; P<0.001)
Anticoagulant therapy at 90 days
52/280 (18.6%) vs. 31/279 (11.1), Absolute difference 7.5% (95% CI: 1.6 to 13.3), P=0.01
Antiplatelet therapy only at 90 days
223/280 (79.6%) vs. 246/279 (88.2%), Absolute difference −8.6% (95% CI: −14.6 to −2.5), P=0.006
Therapy at randomization changed by 90 days from antiplatelet therapy to anticoagulant therapy
38/280 (13.6%) vs. 13/279 (4.7%), Absolute difference 8.9%, (95% CI: 4.2 to 13.6), P <0.001
Therapy at randomization changed by 90 days from anticoagulant therapy to antiplatelet therapy
3/280 (1.1%) vs. 2/279 (0.7%), Absolute difference 0.4%, (95% CI: −1.2 to 1.9), P= 0.66

Subgroup Analysis

AF detection rate was higher among patients who underwent randomization within 3 months after the index stroke or TIA compared with those who underwent randomization 3-6 months after index event (36 of 195 patients [18.5%] vs. 8 of 89 [9.0%]; P=0.049 for linear association).

Adverse Events

  • One patient in the 30 days EKG monitoring group had an adverse skin reaction.

Criticisms

  • Authors conceded that cutoff of 30 seconds for duration of atrial fibrillation used in this study was arbitrary. Duration of 2.5 minutes was chosen as a secondary endpoint because it was the maximum time of recording available on the device chosen for the study. 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.
  • Patients with high stroke burden which is more likely due to a cardioembolism embolism were underrepresented in this study compared to the population
  • New arrhythmias have been reported after right sided insular infarcts.[4] There is a possibility that the AF detected is a reaction and not the etiology of such a stroke. The authors disclosed in a correspondence that insular infarcts accounted for 5% of strokes within the trial.
  • Compared with CRYSTAL-AF, which had an average delay from index event to recording of 38 days, the delay from index event to recording was 75 days in EMBRACE. This may limit the applicability of the EMBRACE trial to patients for whom extended EKG monitoring is pursued immediately following the ischemic event.

Funding

Canadian Stroke Network

Further Reading

  1. Higgins P, MacFarlane PW, Dawson J, McInnes GT, Langhorne P, Lees KR. Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke 2013;44:2525-31.
  2. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012;366:120-129
  3. Glotzer TV, Hellkamp AS, Zimmerman J, 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;107:1614-1619
  4. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006;59:691-699