CRYSTAL AF
Cryptogenic Stroke and Underlying Atrial Fibrillation
Clinical Question
In patients with cryptogenic stroke or TIA, is long-term ECG monitoring with an insertable cardiac monitor (ICM) more effective than conventional follow-up for detecting atrial fibrillation?
Bottom Line
Among patients with recent cryptogenic stroke, continuous ICM monitoring detected AF in 8.9% vs 1.4% with conventional follow-up at 6 months (HR 6.4; P<0.001), 12.4% vs 2.0% at 12 months (HR 7.3; P<0.001), and 30.0% vs 3.0% at 36 months (HR 8.8; P<0.001). Most AF episodes were asymptomatic (74-79%). Oral anticoagulant use was doubled in the ICM group (14.7% vs 6.0% at 12 months; P=0.007). NNT to detect one AF: 14 at 6 months, 10 at 12 months, 4 at 36 months.
Major Points
- ICM detected 6x more AF at 6 months: 8.9% (19/221) vs 1.4% (3/220); HR 6.4 (95% CI 1.9-21.7; P<0.001).
- Superiority increased over time: 12 months 12.4% vs 2.0% (HR 7.3); 36 months 30.0% vs 3.0% (HR 8.8) — all P<0.001.
- Most AF was asymptomatic: 74% at 6 months, 79% at 12 months — explaining why conventional monitoring fails.
- Conventional monitoring was inadequate: control group had only 88 ECGs in 65 patients and 20 Holters in 17 patients over 6 months.
- ICM led to more anticoagulation: 10.1% vs 4.6% at 6 months (P=0.04); 14.7% vs 6.0% at 12 months (P=0.007). 97% with detected AF received anticoagulants.
- NNT to detect one AF: 14 at 6 months, 10 at 12 months, 4 at 36 months.
- Trend toward fewer recurrent ischemic stroke or TIA: 5.2% vs 8.6% at 6 months, 7.1% vs 9.1% at 12 months — not powered for this endpoint.
- AF burden substantial when detected: median max single-day AF 11.2 hours; 46% had episodes >12 hours.
- ICM safe: only 2.4% removed for infection/erosion. Retained in 98.1% at 6 months.
- Consistent across all subgroups: no interaction by age, sex, PFO, CHADS2, or index event type.
Design
Study Type: Randomized, controlled, parallel-group, open-label trial
Randomization: 1
Blinding: Open-label (ICM insertion precludes blinding). Permuted blocks, stratified by index event type (stroke/TIA) and PFO status.
Enrollment Period: June 2009 to April 2012
Follow-up Duration: Primary at 6 months; secondary at 12 months; long-term up to 36 months. Total 815.5 patient-years.
Centers: 55
Countries: United States, Canada, Germany, Italy, Belgium
Sample Size: 441
Analysis: Intention-to-treat. Kaplan-Meier for AF detection. Log-rank test. Cox proportional hazards. O'Brien-Fleming stopping boundaries for interim analysis. SAS 9.2.
Inclusion Criteria
- Age ≥40 years.
- Stroke or TIA within previous 90 days (extended from 60 days by protocol amendment).
- Stroke supported by consistency between symptoms and brain MRI/CT findings.
- Classified as cryptogenic after extensive testing: 12-lead ECG, ≥24h ECG monitoring, TEE, thrombophilia screening (<55yr), MRA/CTA/catheter angiography of head and neck, carotid ultrasound + transcranial Doppler (allowed in lieu of MRA/CTA for >55yr).
- For TIA: symptoms must include speech problems, limb weakness, or hemianopsia.
Exclusion Criteria
- History of atrial fibrillation or atrial flutter.
- Indication or contraindication for permanent oral anticoagulant therapy at enrollment.
- Indication for pacemaker or implantable cardioverter-defibrillator.
- Evidence of AF during ≥24 hours of ECG monitoring before randomization.
Arms
| Field | Insertable Cardiac Monitor (ICM) | Control |
|---|---|---|
| Intervention | Reveal XT (Medtronic) insertable cardiac monitor. Automatically detects and records AF irrespective of heart rate or symptoms. Insertion within 10 days of randomization (208/221 received device; 88.5% within 10 days). Standardized programming. Remote data transmission via Medtronic CareLink Network. AF defined as irregular rhythm without P waves >30 seconds, adjudicated by independent committee. | Standard of care follow-up. ECG monitoring at discretion of site investigator. Actual monitoring received at 6 months: 88 conventional ECGs in 65 patients, 20 Holter monitors in 17 patients, 1 event recorder in 1 patient. Follow-up visits at 1, 6, 12 months, then every 6 months. |
| Duration | Continuous monitoring up to 36 months | Up to 36 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first detection of AF (>30 seconds) at 6 months | Primary | 3/220 (1.4%) | 19/221 (8.9%) | 6.4 | <0.001 |
| AF detection at 12 months | 95% CI: 2.6-20.8 | Secondary | 4/220 (2.0%) | 29/221 (12.4%) | HR 7.3 | <0.001 |
| AF detection at 36 months | 95% CI: 3.5-22.2 | Secondary | 5/220 (3.0%) | 42/221 (30.0%) | HR 8.8 | <0.001 |
| Oral anticoagulant use at 6 months | Secondary | 4.6% | 10.1% | 0.04 | |
| Oral anticoagulant use at 12 months | Secondary | 6.0% | 14.7% | 0.007 | |
| Recurrent ischemic stroke/TIA at 6 months (not powered) | Secondary | 18 (8.6%) | 11 (5.2%) | ||
| Recurrent ischemic stroke/TIA at 12 months (not powered) | Secondary | 19 (9.1%) | 15 (7.1%) | ||
| Asymptomatic AF (of first episodes at 6mo) | Secondary | 1/3 (33%) | 14/19 (74%) | ||
| Asymptomatic AF (of first episodes at 12mo) | Secondary | 2/4 (50%) | 23/29 (79%) | ||
| Median max single-day AF duration (12mo) | Secondary | 11.2 hours (IQR 0.7-19.6) | |||
| AF >12h in single day (12mo) | Secondary | 46% of patients with AF | |||
| ICM removed (infection/erosion) | Adverse | 5/208 (2.4%) | |||
| Insertion site infection | Adverse | 3/208 (1.4%) | |||
| Insertion site pain | Adverse | 3/208 (1.4%) | |||
| Insertion site irritation/inflammation | Adverse | 4/208 (1.9%) | |||
| ICM retained at 6 months | Adverse | 98.1% | |||
| ICM retained at 12 months | Adverse | 96.6% | |||
| Deaths at 6 months | Adverse | 2 | 3 | ||
| Crossovers at 6 months | Adverse | 6 (crossed to ICM) | 12 (crossed to control) |
Subgroup Analysis
No significant interactions across any subgroup (all P>0.7). Age >65: ICM 17.0% vs control 2.5%. Age ≤65: 4.4% vs 0.8%. PFO present: 11.8% vs 0%. No PFO: 8.0% vs 1.8%. CHADS2 score 4: 15.4% vs 3.2%; score 5: 33.3% vs 0.0%; score 6: 0.0% vs NA; score 3: 7.8% vs 2.2%; score 2: 3.0% vs 0%. TIA: 15.0% vs 0%. Stroke: 8.3% vs 1.6%.
Criticisms
- Causality uncertain — newly discovered AF may not be causally related to the index stroke.
- Clinical significance of brief AF episodes unknown.
- Device memory limitation — once full, oldest episodes overwritten.
- AF detection algorithm not infallible; reported 98.5% accuracy applies to duration of AF (not detection sensitivity/specificity).
- Open-label design — could influence monitoring intensity in control group.
- Underpowered for stroke recurrence endpoint.
- Low detection in control (1.4%) reflects inadequate conventional monitoring (only 88 ECGs, 20 Holters).
- Predominantly white (87%) — limited diversity.
- No mandate for anticoagulation upon AF detection — physician discretion.
- Small number of control AF events (n=3 at 6mo) yields wide confidence intervals.
Funding
Medtronic. Sponsor had non-voting steering committee membership, assisted design, data collection, analysis, and manuscript review. No role in submission decision.
Based on: CRYSTAL AF (The New England Journal of Medicine, 2014)
Authors: Tommaso Sanna, Hans-Christoph Diener, Rod S. Passman, ..., for the CRYSTAL AF Investigators
Citation: N Engl J Med 2014;370:2478-86.
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