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STROKE-AF

Stroke of Known Cause and Underlying Atrial Fibrillation

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Year of Publication: 2021

Authors: Richard A. Bernstein, Hooman Kamel, Christopher B. Granger, ..., for the STROKE-AF Investigators

Journal: JAMA

Citation: JAMA. 2021;325(21):2169-2177

Link: https://doi.org/10.1001/jama.2021.6470

Clinical Question

Is long-term cardiac monitoring with an insertable cardiac monitor more effective than usual care for detecting atrial fibrillation in patients with ischemic stroke attributed to large- or small-vessel disease?

Bottom Line

In patients with non-cryptogenic ischemic stroke attributed to large- or small-vessel disease, ICM monitoring detected significantly more atrial fibrillation than usual care at 12 months (12.1% vs 1.8%, HR 7.4). The first AF episode was asymptomatic in 26 of 27 ICM patients with detected AF (96.3%). However, the clinical importance of detecting AF in this population remains uncertain.

        Major Points
        At 12 months, AF was detected in 12.1% of ICM patients vs 1.8% of controls (HR 7.4, 95% CI 2.6-21.3, P<0.001)
At 6 months, AF was detected in 7.9% of ICM patients vs 0.8% of controls (HR 9.9, 95% CI 2.3-43.5, P=0.002)
The first AF episode was asymptomatic in 26 of 27 ICM patients with detected AF (96.3%)
Only 6 patients (2.6%) had AF detected in the first 30 days, meaning 78% (21 of 27) of ICM patients with AF at 12 months would have been missed by 30 days of continuous monitoring
AF detection rates were similar in large-vessel (11.7%) vs small-vessel (12.6%) stroke subtypes (P=0.74)
Median duration of longest AF episode was 88 minutes (IQR 10-526 minutes); 55.5% had episodes >1 hour
OAC prescription at 12 months was higher in ICM group: 15.7% vs 5.6% (unadjusted OR 3.1, 95% CI 1.7-6.0, P<0.001)
Recurrent stroke rates were numerically lower in ICM group: 7.2% vs 9.8% (HR 0.7, 95% CI 0.4-1.4, P=0.30), but study was not powered for this endpoint

      

Design

Study Type: Randomized controlled trial, multicenter, parallel-group, open-label

Randomization: 1

Blinding: Open-label; patients, physicians, and clinical events committee were not blinded to randomization assignment due to nature of intervention. However, aggregate efficacy results remained blinded until completion of primary endpoint analysis.

Enrollment Period: April 2016 to July 2019

Follow-up Duration: Primary endpoint at 12 months; planned follow-up up to 36 months

Centers: 33

Countries: United States

Sample Size: 492

Analysis: Intention-to-treat analysis. Kaplan-Meier survival estimates with Cox proportional hazards regression for hazard ratios. Log-rank test for between-group comparisons. Mixed-effects model for site effects. SAS version 9.4 and R version 3.6.0.

Inclusion Criteria

Age ≥60 years, or age 50-59 years with at least 1 additional stroke risk factor (congestive heart failure, hypertension, diabetes, prior ischemic stroke >90 days before index stroke, or other ischemic vascular disease)
Index ischemic stroke attributed to large-artery atherosclerosis (large-vessel disease) or small-vessel occlusion (small-vessel disease) per TOAST criteria
Index stroke within 10 days prior to ICM insertion
TOAST classification assigned by enrolling investigator as used in clinical practice

Exclusion Criteria

Cryptogenic stroke or embolic stroke of undetermined source
Cardioembolic stroke
History of documented atrial fibrillation or atrial flutter
Known indication or contraindication for long-term oral anticoagulation
Untreated hyperthyroidism
Myocardial infarction or cardiac surgery less than 1 month prior to index stroke
Mechanical heart valve or valvular disease requiring immediate surgery

Baseline Characteristics

Characteristic	Control	Active
N	250	242
Age - years (mean ± SD)	67.5 ± 9.5	66.6 ± 9.3
Age <65 years	43.2%	44.2%
Age 65-74 years	30.8%	33.5%
Age ≥75 years	26.0%	21.5%
Sex - Male	64.4%	60.0%
Sex - Female	35.6%	40.0%
CHA2DS2-VASc score (median, IQR)	5.0 (4.0-6.0)	5.0 (4.0-5.0)
Stroke (index event)	100%	100%
Hypertension	80.0%	81.4%
Smoking tobacco	53.2%	53.7%
Diabetes	40.0%	36.0%
Vascular disease	18.8%	18.6%
Congestive heart failure	9.2%	11.6%
TOAST - Large-vessel disease	56.8%	57.9%
TOAST - Small-vessel disease	43.2%	41.3%
Imaging - CT only	4.4%	5.4%
Imaging - MRI only	8.0%	4.5%
Imaging - Both CT and MRI	87.6%	87.2%
Imaging - Neither CT nor MRI	0%	2.9%
NIHSS score (median, IQR)	2.0 (1.0-5.0)	2.0 (1.0-4.0)

Arms

Field	Control	ICM
Intervention	Site-specific usual care consisting of external cardiac monitoring such as 12-lead ECGs, Holter monitoring, telemetry, or event recorders at treating physician discretion. Follow-up visits at 1, 6, and 12 months.	Insertable cardiac monitor (REVEAL LINQ, Medtronic) inserted within 10 days of index stroke and after randomization. Device insertion per site standard procedures. ICMs programmed according to standardized requirements. Follow-up visits at device insertion, 1, 3, 6, 9, and 12 months.
Duration	12 months (primary); up to 36 months planned	12 months (primary); up to 36 months or end of ICM battery life

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first detection of atrial fibrillation (episode of irregular heart rhythm without detectable P waves lasting >30 seconds, adjudicated by clinical events committee) through 12 months	Primary	1.8% (4 patients)	12.1% (27 patients)	7.4	<0.001
AF detection at 6 months	Secondary	0.8% (2 patients)	7.9% (18 patients)		0.002
AF detection in large-vessel disease subgroup at 12 months	Secondary	2.3% (3 patients)	11.7% (15 patients)		0.003
AF detection in small-vessel disease subgroup at 12 months	Secondary	1.0% (1 patient)	12.6% (12 patients)		<0.001
OAC prescription at 12 months	Secondary	5.6% (14 patients)	15.7% (38 patients)		<0.001
OAC prescription among patients with detected AF	Secondary	1.2% (3 patients)	7.4% (18 patients)		<0.001
Recurrent ischemic or hemorrhagic stroke at 12 months	Secondary	9.8% (23 patients)	7.2% (16 patients)		0.30
Recurrent TIA at 12 months	Secondary	0.4% (1 patient)	1.8% (4 patients)		0.21
Asymptomatic first AF episode (ICM group)	Secondary	N/A	96.3% (26/27 patients)
ICM procedure-related adverse events (total)	Adverse	N/A	1.8% (4/221 patients)
Site infection	Adverse	N/A	0.5% (1 patient)
Incision site hemorrhage	Adverse	N/A	0.9% (2 patients)
Implant site pain	Adverse	N/A	0.5% (1 patient)
Death through 12 months	Adverse	12 patients	5 patients

Subgroup Analysis

A Cox model including interaction term between stroke subtype and randomization group showed no significant interaction (P=0.42). The group effect remained significant (P=0.009) while stroke subtype was not significant (P=0.46). AF detection was similar in large-vessel (11.7%) vs small-vessel (12.6%) stroke in the ICM group (HR 0.9, 95% CI 0.4-1.9, P=0.74). Mixed-effects model treating study site as random effect showed site effect was not significant (P=0.10).

Criticisms

Open-label design with no blinding of patients, physicians, or clinical events committee to randomization assignment
Attribution of stroke mechanism is subjective and may have enrolled patients at higher risk of underlying embolism
Cannot determine if AF was related to the stroke, unmasked by it, or coexistent background AF that would be detected without stroke
Study not powered to detect differences in clinical outcomes such as recurrent stroke
Higher frequency of congestive heart failure among patients with incomplete follow-up may have underestimated true AF incidence
ICM detection algorithm requires episodes ≥2 minutes, while primary endpoint defined AF as >30 seconds
ECG monitoring in control group was variable and limited, reflecting real-world practice but reducing AF detection sensitivity
TOAST classifications applied per clinical practice may have greater interrater variation than validated algorithms
No comparator group without stroke to establish background AF incidence
Study cannot make conclusions about clinical value of testing without clinical outcome data

Funding

Medtronic Inc

Based on: STROKE-AF (JAMA, 2021)

Authors: Richard A. Bernstein, Hooman Kamel, Christopher B. Granger, ..., for the STROKE-AF Investigators

Citation: JAMA. 2021;325(21):2169-2177

Content summarized and formatted by NeuroTrials.ai.

STROKE AF

(2023)

Objective

To compare rates of atrial fibrillation (AF) detection through 3 years between an insertable cardiac monitor (ICM) and site-specific usual care in patients with ischemic stroke attributed to large-artery atherosclerotic disease (LAD) or small-vessel occlusive disease (SVD).

Study Summary

• AF detection at 3 years was 21.7% (46 patients) with ICM vs 2.4% (5 patients) with usual care (HR 10.0; 95% CI 4.0-25.2; P<.001)
• AF detection in the ICM group rose steadily: 2.6% at 1 month, 7.9% at 6 months, 12.5% at 12 months, 18.5% at 2 years, 21.7% at 3 years — median time to detection 9.3 months
• 87% of AF cases in the ICM group (40 of 46) would have been missed if monitoring stopped at 30 days
• OAC was prescribed more often in the ICM group (24.4% vs 8.0%; OR 3.7; 95% CI 2.2-6.4; P<.001), but recurrent stroke rates were similar (17.0% vs 14.1%; HR 1.1; 95% CI 0.7-1.8; P=.71)
• One year of negative monitoring should not reassure clinicians that AF will not develop over the next 2 years

Intervention

Insertable cardiac monitor (Reveal LINQ, Medtronic) placed within 10 days of qualifying stroke vs site-specific usual care monitoring.

Inclusion Criteria

Age ≥60 years, or 50-59 years with ≥1 additional stroke risk factor (CHF, hypertension, diabetes, prior ischemic stroke >90 days before index stroke, or other ischemic vascular disease), with index ischemic stroke attributed to LAD or SVD (TOAST criteria) within 10 days prior to ICM insertion.

Study Design

Arms: Insertable cardiac monitor (Reveal LINQ) (n=242) vs site-specific usual care (n=250)

Patients per Arm: ICM: 242; Usual care: 250

Outcome

• AF at 3 years: 21.7% ICM vs 2.4% control (HR 10.0; 95% CI 4.0-25.2; P<.001)
• Median (IQR) time from randomization to AF detection: 9.3 (2.7-18.7) months in ICM group
• OAC prescription: 24.4% ICM vs 8.0% control (OR 3.7; 95% CI 2.2-6.4; P<.001); DOACs were 89% of prescriptions
• Recurrent ischemic and/or hemorrhagic stroke: 17.0% ICM vs 14.1% control (HR 1.1; 95% CI 0.7-1.8; P=.71)

Bottom Line

Patients with ischemic stroke attributed to LAD or SVD face an increasing risk of AF over time (21.7% at 3 years with ICM vs 2.4% with usual care), and most AF is missed by standard monitoring. One year of negative monitoring should not reassure clinicians that AF will not develop over the subsequent 2 years, though AF detection and increased OAC use did not translate into fewer recurrent strokes in this study.

Major Points

AF incidence at 3 years was 21.7% (46 patients) in the ICM group vs 2.4% (5 patients) in the control group (HR 10.0; 95% CI 4.0-25.2; P<.001).
AF detection in the ICM group increased continuously over time: 2.6% at 1 month, 7.9% at 6 months, 12.5% at 12 months, 18.5% at 2 years, and 21.7% at 3 years.
Median (IQR) time from randomization to AF detection was 9.3 (2.7-18.7) months in the ICM group; if monitoring had been censored at 30 days, 87% of AF cases (40 of 46) would have been missed.
OAC was prescribed more often in the ICM group (24.4% vs 8.0%; unadjusted OR 3.7; 95% CI 2.2-6.4; P<.001); direct OACs accounted for 89% of prescriptions (233 of 261).
Recurrent ischemic and/or hemorrhagic stroke was similar between groups (17.0% ICM vs 14.1% control; HR 1.1; 95% CI 0.7-1.8; P=.71).
Of 46 ICM patients with detected AF, 35 (76%) were prescribed OAC; only 2 patients received left atrial appendage occlusion and no AF ablations were performed.
Prior analysis showed patients with heart failure and/or left atrial enlargement were at significantly higher AF risk (23.4% vs 5.0%; HR 5.1; 95% CI 2.0-12.8; P<.001).

Study Design

Study Type: Multicenter, parallel-group randomized clinical trial (prespecified 3-year long-term secondary outcome analysis)
Randomization: Yes
Blinding: Open-label; AF episodes adjudicated by a Clinical Events Committee
Sample Size: 492
Follow-up: Up to 3 years (mean [SD] 29.4 [12.5] months; median observation 35.8 months ICM, 35.2 months control)
Centers: 33
Countries: United States

Primary Outcome

Definition: AF detection through study follow-up (up to 3 years); AF defined as an episode of irregular heart rhythm without detectable P waves lasting more than 30 seconds, adjudicated by a Clinical Events Committee (prespecified long-term outcome)

Control	Intervention	HR/OR	P-value
2.4% (5 patients)	21.7% (46 patients)	10 (4.0-25.2)	<.001

Limitations & Criticisms

Open-label design; AF definition in the ICM group effectively required episodes of at least 2 minutes due to the device's automatic detection algorithms, while the trial definition was >30 seconds
Only 63.8% of patients completed 3-year follow-up, with substantial attrition and 21 crossovers
Increased AF detection and OAC prescription did not translate into a reduction in recurrent stroke (17.0% vs 14.1%; P=.71)
AF burden was device-quantified and not clinically adjudicated
Findings for post hoc endpoints are exploratory given the potential for type I error from multiple comparisons

Citation

JAMA Neurol. 2023;80(12):1277-1283. doi:10.1001/jamaneurol.2023.3931

View Original Publication →

STROKE-AF

Stroke of Known Cause and Underlying Atrial Fibrillation

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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