Antithrombotic Treatment for Cervical Artery Dissection: A Systematic Review and Individual Patient Data Meta-Analysis

Josefin E Kaufmann; Eric L Harshfield; Henrik Gensicke; Susanne Wegener; Patrik Michel; Georg Kägi; Krassen Nedeltchev; Lars Kellert; Sverre Rosenbaum; Christian H Nolte; Hanne Christensen; Marcel Arnold; Philippe Lyrer; Christopher Levi; Philip M Bath; Stefan T Engelter; Christopher Traenka; Hugh S Markus

doi:10.1001/jamaneurol.2024.1141

. 2024 May 13;81(6):630–637. doi: 10.1001/jamaneurol.2024.1141

Antithrombotic Treatment for Cervical Artery Dissection

A Systematic Review and Individual Patient Data Meta-Analysis

Josefin E Kaufmann ^1,², Eric L Harshfield ³, Henrik Gensicke ^1,², Susanne Wegener ⁴, Patrik Michel ⁵, Georg Kägi ^6,⁷, Krassen Nedeltchev ⁸, Lars Kellert ^9,¹⁰, Sverre Rosenbaum ¹¹, Christian H Nolte ^12,¹³, Hanne Christensen ¹¹, Marcel Arnold ⁶, Philippe Lyrer ¹, Christopher Levi ¹⁴, Philip M Bath ¹⁵, Stefan T Engelter ^1,^2,^✉, Christopher Traenka ^1,², Hugh S Markus ^3,^✉, for the CADISS and TREAT-CAD Investigators

¹Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Switzerland

²Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel, Switzerland

³Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom

⁴Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich, and University of Zurich, Switzerland

⁵Stroke Center and Neurology Service, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

⁶Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland

⁷Department of Neurology and Stroke Center, Cantonal Hospital St Gallen, St Gallen, Switzerland

⁸Department of Neurology and Stroke Center, Cantonal Hospital Aarau, Aarau, Switzerland

⁹Department of Neurology, Ludwig Maximilian University, Munich, Germany

¹⁰Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany

¹¹Department of Neurology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark

¹²Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin, Charite-Universitätsmedizin Berlin, Berlin, Germany

¹³Berlin Institute of Healths at Charite, Charite-Universitätsmedizin Berlin, Berlin, Germany

¹⁴Faculty of Health and Medicine, University of Newcastle, and John Hunter Hospital, Newcastle, Australia

¹⁵Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, United Kingdom

Group Information: The CADISS and TREAT-CAD investigators appear in Supplement 2.

Accepted for Publication: February 15, 2024.

Published Online: May 13, 2024. doi:10.1001/jamaneurol.2024.1141

^✉

Corresponding Authors: Hugh S. Markus, MD, Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (hsm32@medschl.cam.ac.uk); Stefan T. Engelter, MD, Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Switzerland; Neurology and Neurorehabilitation, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel Switzerland (stefan.engelter@felixplatter.ch).

Author Contributions: Drs Engelter and Markus had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Kaufmann and Dr Harshfield contributed equally to this study. Drs Engelter, Traenka, and Markus are joint senior authors.

Concept and design: Kaufmann, Harshfield, Arnold, Lyrer, Levi, Bath, Engelter, Traenka, Markus.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kaufmann, Harshfield, Rosenbaum, Traenka.

Critical review of the manuscript for important intellectual content: Harshfield, Gensicke, Wegener, Michel, Kägi, Nedeltchev, Kellert, Rosenbaum, Nolte, Christensen, Arnold, Lyrer, Levi, Bath, Engelter, Traenka, Markus.

Statistical analysis: Kaufmann, Harshfield, Bath.

Obtained funding: Kaufmann, Harshfield, Michel, Arnold, Levi, Engelter, Markus.

Administrative, technical, or material support: Gensicke, Nolte, Arnold, Levi.

Supervision: Michel, Kägi, Nedeltchev, Kellert, Nolte, Arnold, Lyrer, Levi, Engelter, Traenka, Markus.

Conflict of Interest Disclosures: Dr Kaufmann reported receiving grants from the Goldschmidt-Jacobson Foundation during the conduct of the study; and grants from the Internal Pool of the University Hospital of Basel outside the submitted work. Dr Harshfield reported receiving grants from the Alzheimer's Society, BHF program grant, and Cambridge NIHR Biomedical Research Centre during the conduct of the study; and grants from Cambridge BHF Centre of Research Excellence outside the submitted work. Dr Michel reported receiving grants from the Swiss National Science Foundation, Swiss Heart Foundation, and Faculty of Biology and Medicine of Lausanne University outside the submitted work. Dr Kellert reported receiving funding for travel or speaker honoraria from Alexion, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol-Meyer-Squibb, Daiichi Sankyo, and Pfizer outside the submitted work. Dr Nolte reported receiving speaker honoraria from Abbott, Alexion, AstraZeneca, BMS, Daiichi Sankyo, Novartis, Pfizer, Portola, and Takeda. Dr Arnold reported receiving grants from the Swiss National Science Foundation for Treat-CAD during the conduct of the study; and scientific advisory board fees from Amgen; lecture fees from AstraZeneca; lecture and scientific advisory board fees from Bayer; scientific advisory board fees from BMS; scientific advisory board fees from Boehringer Ingelheim; lecture fees from Covidien; scientific advisory board fees from Daiichi Sankyo; lecture and scientific advisory board fees from Medtronic; and scientific advisory board fees from Novartis, Novo Nordisk, Pfizer, and Sanofi outside the submitted work. Dr Bath reported receiving advisory board fees from CoMind, DiaMedica, Phagenesis, and Roche outside the submitted work. Dr Engelter reported receiving grants from the Swiss National Science Foundation, Swiss Heart Foundation, Freiwillige Akademische Gesellschaft Basel, University of Basel, and University Hospital Basel during the conduct of the study. Dr Traenka reported receiving grants from University Hospital Basel, Novartis Foundation for Biological and Medical Research, Swiss Heart Foundation, Bangerter Foundation Basel, and FAG Basel outside the submitted work. Dr Markus reported receiving grants from Stroke Association funded CADISS study during the conduct of the study. No other disclosures were reported.

Funding/Support: This research project as a doctoral thesis was funded by the Goldschmidt-Jacobson Foundation. The CADISS study was supported by a project grant from the Stroke Association, and recruitment was supported by the English National Institute for Health Research Stroke Research Network. The TREAT-CAD trial was funded by Swiss National Science Foundation grant 140340, Swiss Heart Foundation, Stroke Funds Basel, University Hospital Basel, University of Basel, and Academic Society Basel, and we gratefully acknowledge the work of the data safety monitoring board and the clinical event adjudicators. The Stroke Research Group at the University of Cambridge has received funding from the Cambridge British Heart Foundation Centre of Research Excellence (RE/18/1/34212) and a British Heart Foundation program grant (RG/F/22/110052), and infrastructural support was provided by the Cambridge University Hospitals National Institute for Health and Care Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20014). Dr Harshfield is funded by the Alzheimer’s Society (AS-RF-21-017).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The CADISS and TREAT-CAD Investigators are presented in Supplement 2.

Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the NIHR, National Health Service, or UK Department of Health and Social Care.

Data Sharing Statement: See Supplement 3.

^✉

Corresponding author.

PMCID: PMC11091821 PMID: 38739383

Key Points

Question

In patients with cervical artery dissection, should anticoagulation or antiplatelet therapy be used to prevent the risk of ischemic stroke, major bleeding, or death?

Findings

In this systematic review and individual patient data meta-analysis, 444 patients from 2 randomized clinical trials, Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection trial, were evaluated. There were fewer primary end points in those randomized to anticoagulation (1%) vs antiplatelets (4%) but the finding was not statistically significant.

Meaning

The findings of this meta-analysis found no significant difference between anticoagulants and antiplatelets in preventing early recurrent events.

Abstract

Importance

Cervical artery dissection is the most common cause of stroke in younger adults. To date, there is no conclusive evidence on which antithrombotic therapy should be used to treat patients.

Objective

To perform an individual patient data meta-analysis of randomized clinical trials comparing anticoagulants and antiplatelets in prevention of stroke after cervical artery dissection.

Data Sources

PubMed.gov, Cochrane database, Embase, and ClinicalTrials.gov were searched from inception to August 1, 2023.

Study Selection

Randomized clinical trials that investigated the effectiveness and safety of antithrombotic treatment (antiplatelets vs anticoagulation) in patients with cervical artery dissection were included in the meta-analysis. The primary end point was required to include a composite of (1) any stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up.

Data Extraction/Synthesis

Two independent investigators performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and inconsistencies were resolved by a principal investigator.

Main Outcomes and Measures

The primary outcome was a composite of (1) ischemic stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. The components of the composite outcome were also secondary outcomes. Subgroup analyses based on baseline characteristics with a putative association with the outcome were performed. Logistic regression was performed using the maximum penalized likelihood method including interaction in the subgroup analyses.

Results

Two randomized clinical trials, Cervical Artery Dissection in Stroke Study and Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection, were identified, of which all participants were eligible. A total of 444 patients were included in the intention-to-treat population and 370 patients were included in the per-protocol population. Baseline characteristics were balanced. There were fewer primary end points in those randomized to anticoagulation vs antiplatelet therapy (3 of 218 [1.4%] vs 10 of 226 [4.4%]; odds ratio [OR], 0.33 [95% CI, 0.08-1.05]; P = .06), but the finding was not statistically significant. In comparison with aspirin, anticoagulation was associated with fewer strokes (1 of 218 [0.5%] vs 10 of 226 [4.0%]; OR, 0.14 [95% CI, 0.02-0.61]; P = .01) and more bleeding events (2 vs 0).

Conclusions and Relevance

This individual patient data meta-analysis of 2 currently available randomized clinical trial data found no significant difference between anticoagulants and antiplatelets in preventing early recurrent events.

The meta-analysis examines the use of anticoagulation vs antiplatelet therapy reported in randomized clinical trials on patients with cervical artery dissection.

Introduction

Cervical artery dissection (CAD) is the most common cause of stroke in the younger population.¹ It has been associated with an increased risk of early recurrent stroke,² and most clinicians give either antiplatelets or anticoagulants to reduce this risk,³ but the optimal choice of antithrombotic treatment in patients with CAD is unresolved.⁴

Two randomized clinical trials (RCTs), Cervical Artery Dissection in Stroke Study (CADISS)^5,6,7 and Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection (TREAT-CAD),^8,9 compared antiplatelet with anticoagulation therapy in CAD. Both trials, as well as a meta-analysis published in the European Stroke Organisation guidelines in 2021,⁴ showed neither regimen was superior. Both antithrombotic therapy options are recommended in the European Stroke Organisation guidelines, with the treatment choice being left to the treating physician’s discretion.

Cervical artery dissection can present with a variety of symptoms, including both local symptoms, such as headache, cervical pain, and Horner syndrome, and central symptoms of cerebral ischemic events, such as ischemic strokes, transient ischemic attacks, or retinal infarction.^1,10 It has been suggested that different presentations are associated with different risks of recurrent stroke; for example, central symptoms have been associated with a higher risk.¹¹ This raises the issue of whether individualized antithrombotic therapy is needed for different risk groups.^11,12,13

To better understand the use of antiplatelets and anticoagulants in preventing early recurrent stroke in CAD, we performed a systematic review and individual patient data meta-analysis on the existing RCTs. We further examined whether different subgroups of patients with CAD responded differently to these regimens and would benefit from individualized regimens.

Methods

We first conducted a systematic search of PubMed.gov, Cochrane database, Embase, and ClinicalTrials.gov for studies published from inception to August 1, 2023, to identify all randomized clinical trials examining the efficacy of antithrombotic regimens in CAD. We then obtained data from the RCTs and performed an individual patient data meta-analysis to examine antithrombotic treatment options in patients with CAD. We performed the systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline.¹⁴ We identified 2 RCTs comparing antiplatelet agents with anticoagulants (CADISS^5,6,7 and TREAT-CAD^8,9) and obtained individual patient data for each. Two independent investigators (J.E.K. and C.T.) performed a systematic review, and inconsistencies were resolved by a principal investigator (S.T.E.). Details of the systematic review, such as eligibility criteria, search strategy and selection process, and assessment of the risk of bias, can be found in eTable 3, eFigure 1, eFigure 4, and the eMethods in Supplement 1.

The CADISS RCT

CADISS was constructed as a phase 3 feasibility trial comparing the efficacy of antiplatelet drugs with anticoagulation drugs for the prevention of recurrent stroke. Between February 2006 and June 2013, 250 patients were recruited at hospitals with specialized stroke or neurology services in Australia (n = 7) and the UK (n = 39). In the per-protocol (PP) population, there were 3 strokes in the antiplatelet group (n = 96) and 1 in the anticoagulation group (n = 101), resulting in a nonsignificant difference between the 2 antithrombotic treatment groups after 90 days (odds ratio [OR], 0.35 [95% CI, 0.01-4.39]; P = .66). None of the participants died in the initial 90-day follow-up. There was 1 major bleeding event (subarachnoid bleeding) in the anticoagulation group.^5,6,7

The TREAT-CAD RCT

TREAT-CAD was a multicenter, randomized, noninferiority trial recruiting participants between September 11, 2013, and December 21, 2018, in specialized stroke services in Denmark (n = 1), Germany (n = 2), and Switzerland (n = 7). The primary outcome was a composite of clinical (ischemic stroke, major extracranial or intracranial hemorrhage, and death assessed at a mean [SD] of 90 [30] days) and magnetic resonance imaging outcomes (new ischemic or hemorrhagic brain lesions assessed at 14 [10] days after commencing treatment).^8,9 In the PP analyses, the primary outcome occurred in 21 of 91 participants (23.1%) in the aspirin group and 12 of 82 participants (14.6%) in the anticoagulation group. The absolute difference was 8.4% (95% CI, −4.3% to 21.2%), with a noninferiority margin of 12%, indicating that the noninferiority of aspirin over anticoagulation was not shown.

Further details of each trial have been published.^5,6,7,8,9 The baseline and outcome data of the 2 trials can be found in eTable 1 and eTable 2 in Supplement 1.

Data Collection and Transfer

We pooled data on the study design and methods, participants’ demographic characteristics, risk factors, symptoms at baseline, details of the CAD, diagnostic imaging, antithrombotic treatment, time from symptom onset to start of treatment, acute recanalization therapy, and the primary end points. Data were securely transferred between the research teams via password-protected OwnCloud and SharePoint sites.

Defined Outcome for the Meta-Analysis

For the meta-analysis, we defined the primary outcome as a clinical composite of (1) any stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up, as defined in each trial.^5,6,7,8,9 Stroke was defined as a focal neurologic event lasting more than 24 hours according to the World Health Organization definition.¹⁵ We also analyzed each component of the composite primary outcome (ie, any stroke, death, or major bleeding [extracranial or intracranial]) separately as secondary outcomes.

Patient Population

We conducted analyses on 2 different populations: the intention-to-treat (ITT) population and the PP population. All randomized participants of the eligible trials qualified for the full analysis dataset. The PP dataset consists of participants (1) in whom CAD was verified on central adjudication, (2) who received allocated treatment (excluding crossovers) according to the PP definition used by each trial, and (3) who had complete 90 days of follow-up data regarding the primary and secondary outcomes or met the primary outcome resulting in termination of follow-up.

Statistical Analysis

We examined the distribution of relevant baseline characteristics between the antiplatelet and anticoagulant groups in both the combined dataset and separately in each trial for both the ITT and PP populations. We then assessed the primary outcome (a clinical composite of [1] ischemic stroke, [2] death, or [3] major bleeding [extracranial or intracranial] at 90 days of follow-up) and secondary outcomes (every component of the composite primary outcome) in logistic models using the maximum penalized likelihood method in both the ITT and PP populations.

Post hoc analyses were performed with additional subgroups (time from randomization to treatment ≤24 vs >24 hours and single-vessel vs multivessel dissection) and a cumulative frequency curve for ischemic strokes was generated.

We identified relevant baseline characteristics that had been suggested to alter the risk of recurrent stroke through a literature search. Each baseline characteristic was dichotomized into subgroups as follows: younger vs older age (divided by the median at ≤48 vs >48 years),¹⁶ male vs female sex assigned at birth,¹⁷ presenting with clinical cerebral ischemia vs local symptoms only,^11,13 favorable vs unfavorable outcome on the modified Rankin scale (<3 favorable vs ≥3 unfavorable),¹⁸ acute recanalization therapy including intravenous thrombolysis and/or endovascular therapy vs no acute recanalization therapy,^19,20 complete occlusion of the dissected artery vs nonocclusion,^11,12,21 type of dissected artery (internal carotid artery vs vertebral artery),¹¹ dissecting aneurysm at baseline vs absence of a dissecting aneurysm,^22,23 time from symptom onset to start of treatment (divided by the median at <5 vs ≥5 days),^13,24 and dual therapy vs monotherapy antiplatelet treatment.⁴

We then performed subgroup analyses based on the baseline characteristics. Each subgroup was assessed in a separate logistic interaction model.

All results are provided as relative effect estimates (ORs with 95% CIs), always with anticoagulation reported first and with a P value for interaction as appropriate. Statistical significance was indicated as a 2-sided P < .05 or 95% CI that does not cross 1. The analyses were replicated independently at the University of Cambridge and University of Basel, using Stata, version 16.1 (StataCorp LLC), and R, version 4.3.1 (R Foundation for Statistical Computing). The results were compared, and any discrepancies were resolved in online meetings.

Sensitivity analyses were performed with a best-case and a worst-case scenario for missing data. Thereby, the missing baseline data were replaced by the absence or presence of the baseline characteristics (eFigure 2 and eFigure 3 in Supplement 1).

Results

Individual Patient Data Meta-Analysis

The ITT population of the CADISS and TREAT-CAD combined dataset included 444 participants (Figure 1) with a median age of 48 (range, 48-88) years. A total of 67% were men (n = 297) and 33% were women (n = 147), the internal carotid artery was affected in 55.9% of the patients (n = 248), and 87.6% (n = 389) of the participants presented with an ischemic cerebral event at baseline. A total of 50.9% of the participants (n = 226) received antiplatelet therapy, of whom 24.3% (n = 55) received dual antiplatelet therapy and 49.1% (n = 218) received anticoagulation. Baseline characteristics (Table 1) were balanced between the patients with antiplatelet therapy and anticoagulation therapy.

Table 1. Baseline Characteristics by Treatment Group.

Characteristic	No. (%)
	Intention-to-treat population		Per-protocol population
	Antiplatelet group (n = 226)^a	Anticoagulant group (n = 218)	Antiplatelet group (n = 192)^b	Anticoagulant group (n = 178)
Age, mean (SD), y	48.6 (11.4)	48.2 (11.9)	48.2 (11.0)	47.5 (11.5)
Sex
Women	77 (34.1)	70 (32.1)	67 (34.9)	58 (32.6)
Men	149 (65.9)	148 (67.9)	125 (65.1)	120 (67.4)
Site of dissection
Internal carotid artery^c	130 (57.5)	118 (54.1)	116 (60.4)	97 (54.5)
Vertebral artery^c	97 (42.9)	102 (46.8)	77 (40.1)	83 (46.6)
Presenting signs and symptoms
Amaurosis fugax	6 (2.7)	12 (5.5)	6 (3.1)	9 (5.1)
Retinal infarction	3 (1.3)	2 (0.9)	3 (1.6)	2 (1.1)
Transient ischemic attack	41 (18.1)	30 (13.8)	32 (16.7)	25 (14.0)
Ischemic stroke	145 (64.2)	150 (68.8)	121 (63.0)	120 (67.4)
Headache	156 (69.0)	147 (67.4)	133 (69.3)	122 (68.5)
Neck pain	108 (47.8)	110 (50.7)	87 (45.3)	92 (52.0)
Horner syndrome	62 (27.4)	68 (31.2)	56 (29.2)	57 (32.0)
Time between symptoms and randomization, mean (SD), d	5.4 (3.8)	4.8 (3.4)	5.5 (4.0)	4.7 (3.5)
Modified Rankin score, mean (SD)	1.79 (1.38)	1.80 (1.42)	1.78 (1.38)	1.80 (1.42)
Acute recanalization therapy (received stroke thrombolysis)	28 (12.4)	21 (9.6)	25 (13.1)	16 (9.0)
Risk factors
Treated hypertension	61 (27.0)	54 (24.8)	51 (26.6)	44 (24.7)
Diabetes	6 (2.7)	8 (3.7)	4 (2.1)	6 (3.4)
Treated hyperlipidemia	35 (15.5)	39 (17.9)	30 (15.6)	29 (16.3)
Ever smoked	109 (48.2)	113 (51.8)	95 (49.5)	93 (52.3)
Migraine	51 (22.6)	44 (20.3)	45 (23.4)	39 (22.0)
Diagnostic imaging
Dissecting aneurysm	18 (8.4)	9 (4.5)	16 (8.7)	8 (4.8)
CT	176 (77.9)	163 (74.8)	148 (77.1)	134 (75.3)
MRI	203 (89.8)	187 (85.8)	171 (89.1)	152 (85.4)
Angiography
Any	214 (94.7)	205 (94.0)	182 (94.8)	169 (94.9)
Magnetic resonance angiography	175 (77.4)	152 (69.7)	147 (76.6)	127 (71.4)
CT angiography	116 (51.3)	112 (51.4)	103 (53.7)	95 (53.4)
Digital subtraction angiography	7 (3.1)	8 (3.7)	7 (3.7)	7 (4.0)

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Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging.

^{^a}

Three patients experienced both vertebral and internal carotid artery dissection.

^{^b}

55 Participants in the antiplatelet group were treated with dual antiplatelets.

^{^c}

50 Participants in the antiplatelet group were treated with dual antiplatelets.

There were 34 participants allocated to antiplatelets and 40 participants allocated to anticoagulants who did not meet the study inclusion criteria (Figure 1). Therefore, we also conducted an analysis of the PP population (n = 370), which consisted of 192 participants allocated to antiplatelets and 178 participants allocated to anticoagulants.

Primary Outcome

The primary outcomes (composite of ischemic stroke, death, or major bleeding (extracranial or intracranial) occurred in 10 patients in the antiplatelet group (4.4% ITT vs 5.2% PP) and 3 patients in the anticoagulation group (1.4% ITT vs 1.7% PP) (Table 2). There was no significant difference in the primary end point on the ITT analysis (OR, 0.33 [95% CI, 0.08-1.05]; P = .06 in favor of anticoagulants). A similar finding was observed in the PP population (OR, 0.35 [95% CI, 0.09-1.09]; P = .07) (Figure 2, Table 2).

Table 2. Outcomes Within 90 Days by Treatment Group^a.

Outcome	Intention-to-treat population				Per-protocol population
Outcome	Antiplatelet group (n = 226), No. (%)	Anticoagulant group (n = 218), No. (%)	OR (95% CI)	P value	Antiplatelet group (n = 192), No. (%)	Anticoagulant group (n = 178), No. (%)	OR (95% CI)	P value
Primary end point
Ischemic stroke, death, or major bleeding	10 (4.4)	3 (1.4)	0.33 (0.08-1.05)	.06	10 (5.2)	3 (1.7)	0.35 (0.09-1.09)	.07
Secondary end point
Ischemic stroke	10 (4.0)	1 (0.5)	0.14 (0.02-0.61)	.01	9 (4.7)	1 (0.6)	0.15 (0.02-0.63)	.01
Death^b	0	0			0	0
Major bleeding	0	2 (0.9)	5.23 (4.22-723.08)	.22	0	2 (1.1)	5.49 (0.44-758.85)	.20

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Abbreviation: OR, odds ratio.

^{^a}

Regression estimates were obtained using penalized maximum likelihood regression.

^{^b}

As there were no deaths, ORs with 95% CIs were not calculated.

Figure 2. — ^aAmaurosis fugax, 1 (information not available [NA]).

^bInitial thrombolysis, 1 (information NA).

^cOcclusion, 26 (information NA).

^dPatients with a dissection of the carotid artery and the vertebral artery were removed in the subgroup site of dissection (n = 3).

^eDissecting aneurysm, 21 (information NA).

Secondary Outcome

Nine of 10 ischemic strokes occurred in the antiplatelet group and 1 ischemic stroke occurred in the anticoagulation group. Two cases of major bleeding occurred, both in the anticoagulation group. Treatment with anticoagulants was associated with a reduced risk of ischemic stroke (OR, 0.14 [95% CI, 0.02-0.61]; P = .01). There was no significant difference between groups for major bleeding (anticoagulation, 2 vs antiplatelet, 0; OR, 5.23 [95% CI, 4.22-723.08]; P = .22) and there were no deaths in either group (Table 2).

Subgroup Analyses

The subgroup analyses showed that the antithrombotic treatment effect depended on whether the patients had a dissecting aneurysm at baseline (P = .03 for interaction). Patients without a dissecting aneurysm at baseline had a significantly reduced likelihood of the primary outcome when treated with anticoagulants rather than with antiplatelets (OR, 0.16 [95% CI, 0.02-0.71]). In patients with a dissecting aneurysm at baseline, there was no significant difference. However, for this variable, we had a high number of missing data (n = 21). For other subgroups, there was no significant benefit for either therapy and no evidence of interaction (Figure 2; eFigure 5 in Supplement 1). Results from post hoc analyses regarding additional subgroups (time from randomization to treatment ≤24 vs 24 hours and single-vessel vs multivessel dissection) and a cumulative frequency curve for ischemic stroke can be found in eFigure 6 and eFigure 7 in Supplement 1).

Discussion

In this individual patient data meta-analysis using pooled data from the 2 RCTs comparing anticoagulants with antiplatelets in secondary prevention of stroke after CAD, we found no significant difference in favor of either therapy on the predefined primary end point of ischemic stroke, major bleeding, or death. However, in participants treated with anticoagulants, there was a nonsignificant decrease in the odds of primary end points occurring, and this was significant for the secondary end point of ischemic stroke alone.

In the RCTs, particularly CADISS, a proportion of participants did not have CAD confirmed on central review of imaging.^5,6 For this reason we also performed a PP analysis, which resulted in very similar findings. Several markers at baseline have been associated with an increased risk of further stroke after presentation, particularly central vs local symptoms.¹¹ We hypothesized that different subgroups might respond differently to the 2 therapies, and therefore examined efficacy within the subgroups. We found that no regimen was better in any particular subgroup, except for anticoagulants being significantly more effective in participants without a dissecting aneurysm at baseline. However, this finding needs to be treated as hypothesis generating, particularly given the number of subgroups in which comparisons between the 2 regimens were made.

Our analysis provides data comparing anticoagulants with antiplatelet agents in the secondary prevention of stroke after CAD. Furthermore, in both trials, the primary end point assessment was blinded and independently adjudicated, which increases the validity of the datasets used in this analysis.

Limitations

Despite using all available RCT data, our analysis has limitations. We only had data on 444 participants, which provided insufficient power to detect smaller, but still clinically meaningful, differences. The study was also underpowered to examine for interactions within subgroups. Second, we did not adjust for multiple testing. Therefore, the results of the secondary analyses should be interpreted with caution and primarily used for hypothesis generation, for example, to adjust future study protocols accordingly or to plan patient selection for further studies more precisely. In addition, the use of magnetic resonance imaging techniques may have overestimated the presence of occlusion in the transected artery. There was also heterogeneity in the antiplatelet group with participants treated with either monotherapy (most) or dual antiplatelet therapy.

Our analysis showed no significant difference in the primary end point between the 2 regimens, although the finding with anticoagulants on the secondary end point of stroke alone was statistically significant. This suggests that further larger RCTs are required. These need to consider advances in both anticoagulant and antiplatelet treatments made since CADISS and TREAT-CAD were performed. Both trials used vitamin K antagonists (with or without lead-in heparin or low-molecular-weight heparin) as anticoagulants. Future RCTs should examine the efficacy of direct oral anticoagulants. These medications have a better benefit-risk profile in atrial fibrillation–related stroke,²⁵ but whether they might in CAD remains to be determined. They would have an advantage in cases presenting with local symptoms or minor cerebral symptoms in allowing rapid initiation of therapy and early discharge. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to be more effective than aspirin alone in both reducing embolization in symptomatic carotid stenosis²⁶ and preventing early recurrent stroke in patients with minor stroke and transient ischemic attack.^27,28 Most patients in the CADISS and TREAT-CAD trials had only single antiplatelet agents and it is possible that dual antiplatelet therapy may also be more effective in CAD. Future trials of CAD should therefore include this regimen. Another possible treatment would be a combined strategy of antiplatelet agents and low-dose anticoagulants, similar to that tested in the COMPASS study.²⁹ A large observational study (STOP-CAD) is currently under way to compare outcomes with different antithrombotic treatment options, including dual antiplatelet agents and direct oral anticoagulants, in a large CAD cohort of approximately more than 3600 participants, and will provide important results.³⁰ However definitive data on the optimal regimen for secondary prevention will only be provided by large, well-powered RCTs.

Conclusions

The findings of this individual patient data meta-analysis using all available RCT-based data showed no significant difference between anticoagulants and antiplatelets in early secondary prevention after CAD. Our results suggest further large RCTs in with regard to anticoagulant use are required.

Supplement 1.

eMethods. Details of the Systematic Review

eReferences

eFigure 1. PRISMA Flowchart

eFigure 2. Best Case Scenario

eFigure 3. Worst Case Scenario

eFigure 4. Risk of Bias Assessment (RoB2)

eFigure 5. Mono Versus Dual Antiplatelet Therapy

eFigure 6. Post-Hoc Subgroup Analyses

eFigure 7. Cumulative Frequency Curve for Ischemic Stroke

eTable 1. Baseline Characteristics by Trial and Treatment Group

eTable 2. Outcomes Within 90 Days by Trial and Treatment Group

eTable 3. Risk of Bias Assessment Details (RoB2)

jamaneurol-e241141-s001.pdf^{(603.5KB, pdf)}

Supplement 2.

Nonauthor Collaborators. The CADISS and TREAT-CAD Investigators

jamaneurol-e241141-s002.pdf^{(182KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaneurol-e241141-s003.pdf^{(14.6KB, pdf)}

References

1.Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol. 2009;8(7):668-678. doi: 10.1016/S1474-4422(09)70084-5 [DOI] [PubMed] [Google Scholar]
2.Biousse V, D’Anglejan-Chatillon J, Touboul PJ, Amarenco P, Bousser MG. Time course of symptoms in extracranial carotid artery dissections: a series of 80 patients. Stroke. 1995;26(2):235-239. doi: 10.1161/01.STR.26.2.235 [DOI] [PubMed] [Google Scholar]
3.Menon RK, Markus HS, Norris JW. Results of a UK questionnaire of diagnosis and treatment in cervical artery dissection. J Neurol Neurosurg Psychiatry. 2008;79(5):612. doi: 10.1136/jnnp.2007.127639 [DOI] [PubMed] [Google Scholar]
4.Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J. 2021;6(3):XXXIX-LXXXVIII. doi: 10.1177/23969873211046475 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Markus HS, Hayter E, Levi C, Feldman A, Venables G, Norris J; CADISS trial investigators . Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14(4):361-367. doi: 10.1016/S1474-4422(15)70018-9 [DOI] [PubMed] [Google Scholar]
6.Markus HS, Levi C, King A, Madigan J, Norris J; Cervical Artery Dissection in Stroke Study (CADISS) Investigators . Antiplatelet therapy vs anticoagulation therapy in cervical artery dissection: the Cervical Artery Dissection in Stroke Study (CADISS) randomized clinical trial final results. JAMA Neurol. 2019;76(6):657-664. doi: 10.1001/jamaneurol.2019.0072 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Markus H; Cervical Artery Dissection in Stroke Study Trial Investigators . Antiplatelet therapy vs anticoagulation in cervical artery dissection: rationale and design of the Cervical Artery Dissection in Stroke Study (CADISS). Int J Stroke. 2007;2(4):292-296. doi: 10.1111/j.1747-4949.2007.00165.x [DOI] [PubMed] [Google Scholar]
8.Engelter ST, Traenka C, Gensicke H, et al. ; TREAT-CAD investigators . Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol. 2021;20(5):341-350. doi: 10.1016/S1474-4422(21)00044-2 [DOI] [PubMed] [Google Scholar]
9.Traenka C, Gensicke H, Schaedelin S, et al. ; TREAT-CAD investigators . Biomarkers and antithrombotic treatment in cervical artery dissection—design of the TREAT-CAD randomised trial. Eur Stroke J. 2020;5(3):309-319. doi: 10.1177/2396987320921151 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Engelter ST, Traenka C, Von Hessling A, Lyrer PA. Diagnosis and treatment of cervical artery dissection. Neurol Clin. 2015;33(2):421-441. doi: 10.1016/j.ncl.2014.12.002 [DOI] [PubMed] [Google Scholar]
11.Lichy C, Metso A, Pezzini A, et al. ; Cervical Artery Dissection and Ischemic Stroke Patients-Study Group . Predictors of delayed stroke in patients with cervical artery dissection. Int J Stroke. 2015;10(3):360-363. doi: 10.1111/j.1747-4949.2012.00954.x [DOI] [PubMed] [Google Scholar]
12.Traenka C, Grond-Ginsbach C, Goeggel Simonetti B, et al. ; CADISP-Plus Study Group . Artery occlusion independently predicts unfavorable outcome in cervical artery dissection. Neurology. 2020;94(2):e170-e180. doi: 10.1212/WNL.0000000000008654 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Weimar C, Kraywinkel K, Hagemeister C, et al. ; German Stroke Study Collaboration . Recurrent stroke after cervical artery dissection. J Neurol Neurosurg Psychiatry. 2010;81(8):869-873. doi: 10.1136/jnnp.2009.192153 [DOI] [PubMed] [Google Scholar]
14.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372(71):n71. doi: 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. Cerebrovascular disease in the community: results of a WHO collaborative study. Bull World Health Organ. 1980;58(1):113-130. [PMC free article] [PubMed] [Google Scholar]
16.Traenka C, Dougoud D, Simonetti BG, et al. ; CADISP-Plus Study Group . Cervical artery dissection in patients ≥60 years: often painless, few mechanical triggers. Neurology. 2017;88(14):1313-1320. doi: 10.1212/WNL.0000000000003788 [DOI] [PubMed] [Google Scholar]
17.Metso AJ, Metso TM, Debette S, et al. ; CADISP Group . Gender and cervical artery dissection. Eur J Neurol. 2012;19(4):594-602. doi: 10.1111/j.1468-1331.2011.03586.x [DOI] [PubMed] [Google Scholar]
18.Lyrer PA, Brandt T, Metso TM, et al. ; Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) Study Group . Clinical import of Horner syndrome in internal carotid and vertebral artery dissection. Neurology. 2014;82(18):1653-1659. doi: 10.1212/WNL.0000000000000381 [DOI] [PubMed] [Google Scholar]
19.Traenka C, Jung S, Gralla J, et al. Endovascular therapy versus intravenous thrombolysis in cervical artery dissection ischemic stroke—results from the SWISS registry. Eur Stroke J. 2018;3(1):47-56. doi: 10.1177/2396987317748545 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke. 2009;40(12):3772-3776. doi: 10.1161/STROKEAHA.109.555953 [DOI] [PubMed] [Google Scholar]
21.Gensicke H, Ahlhelm F, Jung S, et al. New ischaemic brain lesions in cervical artery dissection stratified to antiplatelets or anticoagulants. Eur J Neurol. 2015;22(5):859-865, e61. doi: 10.1111/ene.12682 [DOI] [PubMed] [Google Scholar]
22.Daou B, Hammer C, Chalouhi N, et al. Dissecting pseudoaneurysms: predictors of symptom occurrence, enlargement, clinical outcome, and treatment. J Neurosurg. 2016;125(4):936-942. doi: 10.3171/2015.10.JNS151846 [DOI] [PubMed] [Google Scholar]
23.Larsson SC, King A, Madigan J, Levi C, Norris JW, Markus HS. Prognosis of carotid dissecting aneurysms: results from CADISS and a systematic review. Neurology. 2017;88(7):646-652. doi: 10.1212/WNL.0000000000003617 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Morris NA, Merkler AE, Gialdini G, Kamel H. Timing of incident stroke risk after cervical artery dissection presenting without ischemia. Stroke. 2017;48(3):551-555. doi: 10.1161/STROKEAHA.116.015185 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi: 10.1016/S0140-6736(13)62343-0 [DOI] [PubMed] [Google Scholar]
26.Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005;111(17):2233-2240. doi: 10.1161/01.CIR.0000163561.90680.1C [DOI] [PubMed] [Google Scholar]
27.Wang Y, Wang Y, Zhao X, et al. ; CHANCE Investigators . Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19. doi: 10.1056/NEJMoa1215340 [DOI] [PubMed] [Google Scholar]
28.Johnston SC, Easton JD, Farrant M, et al. ; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators . Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225. doi: 10.1056/NEJMoa1800410 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Eikelboom JW, Connolly SJ, Bosch J, et al. ; COMPASS Investigators . Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. doi: 10.1056/NEJMoa1709118 [DOI] [PubMed] [Google Scholar]
30.Shu L, Mandel D, Yaghi S. Abstract number-56: anti-thrombotic therapy for stroke prevention in cervical artery dissection: protocol of a multicenter international study. Stroke Vasc Intervent Neurol. 2023;3(S1):e12678. doi: 10.1161/SVIN.03.suppl_1.256 [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods. Details of the Systematic Review

eReferences

eFigure 1. PRISMA Flowchart

eFigure 2. Best Case Scenario

eFigure 3. Worst Case Scenario

eFigure 4. Risk of Bias Assessment (RoB2)

eFigure 5. Mono Versus Dual Antiplatelet Therapy

eFigure 6. Post-Hoc Subgroup Analyses

eFigure 7. Cumulative Frequency Curve for Ischemic Stroke

eTable 1. Baseline Characteristics by Trial and Treatment Group

eTable 2. Outcomes Within 90 Days by Trial and Treatment Group

eTable 3. Risk of Bias Assessment Details (RoB2)

jamaneurol-e241141-s001.pdf^{(603.5KB, pdf)}

Supplement 2.

Nonauthor Collaborators. The CADISS and TREAT-CAD Investigators

jamaneurol-e241141-s002.pdf^{(182KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaneurol-e241141-s003.pdf^{(14.6KB, pdf)}

[noi240023r1] 1.Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol. 2009;8(7):668-678. doi: 10.1016/S1474-4422(09)70084-5 [DOI] [PubMed] [Google Scholar]

[noi240023r2] 2.Biousse V, D’Anglejan-Chatillon J, Touboul PJ, Amarenco P, Bousser MG. Time course of symptoms in extracranial carotid artery dissections: a series of 80 patients. Stroke. 1995;26(2):235-239. doi: 10.1161/01.STR.26.2.235 [DOI] [PubMed] [Google Scholar]

[noi240023r3] 3.Menon RK, Markus HS, Norris JW. Results of a UK questionnaire of diagnosis and treatment in cervical artery dissection. J Neurol Neurosurg Psychiatry. 2008;79(5):612. doi: 10.1136/jnnp.2007.127639 [DOI] [PubMed] [Google Scholar]

[noi240023r4] 4.Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J. 2021;6(3):XXXIX-LXXXVIII. doi: 10.1177/23969873211046475 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r5] 5.Markus HS, Hayter E, Levi C, Feldman A, Venables G, Norris J; CADISS trial investigators . Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14(4):361-367. doi: 10.1016/S1474-4422(15)70018-9 [DOI] [PubMed] [Google Scholar]

[noi240023r6] 6.Markus HS, Levi C, King A, Madigan J, Norris J; Cervical Artery Dissection in Stroke Study (CADISS) Investigators . Antiplatelet therapy vs anticoagulation therapy in cervical artery dissection: the Cervical Artery Dissection in Stroke Study (CADISS) randomized clinical trial final results. JAMA Neurol. 2019;76(6):657-664. doi: 10.1001/jamaneurol.2019.0072 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r7] 7.Markus H; Cervical Artery Dissection in Stroke Study Trial Investigators . Antiplatelet therapy vs anticoagulation in cervical artery dissection: rationale and design of the Cervical Artery Dissection in Stroke Study (CADISS). Int J Stroke. 2007;2(4):292-296. doi: 10.1111/j.1747-4949.2007.00165.x [DOI] [PubMed] [Google Scholar]

[noi240023r8] 8.Engelter ST, Traenka C, Gensicke H, et al. ; TREAT-CAD investigators . Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol. 2021;20(5):341-350. doi: 10.1016/S1474-4422(21)00044-2 [DOI] [PubMed] [Google Scholar]

[noi240023r9] 9.Traenka C, Gensicke H, Schaedelin S, et al. ; TREAT-CAD investigators . Biomarkers and antithrombotic treatment in cervical artery dissection—design of the TREAT-CAD randomised trial. Eur Stroke J. 2020;5(3):309-319. doi: 10.1177/2396987320921151 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r10] 10.Engelter ST, Traenka C, Von Hessling A, Lyrer PA. Diagnosis and treatment of cervical artery dissection. Neurol Clin. 2015;33(2):421-441. doi: 10.1016/j.ncl.2014.12.002 [DOI] [PubMed] [Google Scholar]

[noi240023r11] 11.Lichy C, Metso A, Pezzini A, et al. ; Cervical Artery Dissection and Ischemic Stroke Patients-Study Group . Predictors of delayed stroke in patients with cervical artery dissection. Int J Stroke. 2015;10(3):360-363. doi: 10.1111/j.1747-4949.2012.00954.x [DOI] [PubMed] [Google Scholar]

[noi240023r12] 12.Traenka C, Grond-Ginsbach C, Goeggel Simonetti B, et al. ; CADISP-Plus Study Group . Artery occlusion independently predicts unfavorable outcome in cervical artery dissection. Neurology. 2020;94(2):e170-e180. doi: 10.1212/WNL.0000000000008654 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r13] 13.Weimar C, Kraywinkel K, Hagemeister C, et al. ; German Stroke Study Collaboration . Recurrent stroke after cervical artery dissection. J Neurol Neurosurg Psychiatry. 2010;81(8):869-873. doi: 10.1136/jnnp.2009.192153 [DOI] [PubMed] [Google Scholar]

[noi240023r14] 14.Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372(71):n71. doi: 10.1136/bmj.n71 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r15] 15.Aho K, Harmsen P, Hatano S, Marquardsen J, Smirnov VE, Strasser T. Cerebrovascular disease in the community: results of a WHO collaborative study. Bull World Health Organ. 1980;58(1):113-130. [PMC free article] [PubMed] [Google Scholar]

[noi240023r16] 16.Traenka C, Dougoud D, Simonetti BG, et al. ; CADISP-Plus Study Group . Cervical artery dissection in patients ≥60 years: often painless, few mechanical triggers. Neurology. 2017;88(14):1313-1320. doi: 10.1212/WNL.0000000000003788 [DOI] [PubMed] [Google Scholar]

[noi240023r17] 17.Metso AJ, Metso TM, Debette S, et al. ; CADISP Group . Gender and cervical artery dissection. Eur J Neurol. 2012;19(4):594-602. doi: 10.1111/j.1468-1331.2011.03586.x [DOI] [PubMed] [Google Scholar]

[noi240023r18] 18.Lyrer PA, Brandt T, Metso TM, et al. ; Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) Study Group . Clinical import of Horner syndrome in internal carotid and vertebral artery dissection. Neurology. 2014;82(18):1653-1659. doi: 10.1212/WNL.0000000000000381 [DOI] [PubMed] [Google Scholar]

[noi240023r19] 19.Traenka C, Jung S, Gralla J, et al. Endovascular therapy versus intravenous thrombolysis in cervical artery dissection ischemic stroke—results from the SWISS registry. Eur Stroke J. 2018;3(1):47-56. doi: 10.1177/2396987317748545 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r20] 20.Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke. 2009;40(12):3772-3776. doi: 10.1161/STROKEAHA.109.555953 [DOI] [PubMed] [Google Scholar]

[noi240023r21] 21.Gensicke H, Ahlhelm F, Jung S, et al. New ischaemic brain lesions in cervical artery dissection stratified to antiplatelets or anticoagulants. Eur J Neurol. 2015;22(5):859-865, e61. doi: 10.1111/ene.12682 [DOI] [PubMed] [Google Scholar]

[noi240023r22] 22.Daou B, Hammer C, Chalouhi N, et al. Dissecting pseudoaneurysms: predictors of symptom occurrence, enlargement, clinical outcome, and treatment. J Neurosurg. 2016;125(4):936-942. doi: 10.3171/2015.10.JNS151846 [DOI] [PubMed] [Google Scholar]

[noi240023r23] 23.Larsson SC, King A, Madigan J, Levi C, Norris JW, Markus HS. Prognosis of carotid dissecting aneurysms: results from CADISS and a systematic review. Neurology. 2017;88(7):646-652. doi: 10.1212/WNL.0000000000003617 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r24] 24.Morris NA, Merkler AE, Gialdini G, Kamel H. Timing of incident stroke risk after cervical artery dissection presenting without ischemia. Stroke. 2017;48(3):551-555. doi: 10.1161/STROKEAHA.116.015185 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r25] 25.Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi: 10.1016/S0140-6736(13)62343-0 [DOI] [PubMed] [Google Scholar]

[noi240023r26] 26.Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005;111(17):2233-2240. doi: 10.1161/01.CIR.0000163561.90680.1C [DOI] [PubMed] [Google Scholar]

[noi240023r27] 27.Wang Y, Wang Y, Zhao X, et al. ; CHANCE Investigators . Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19. doi: 10.1056/NEJMoa1215340 [DOI] [PubMed] [Google Scholar]

[noi240023r28] 28.Johnston SC, Easton JD, Farrant M, et al. ; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators . Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225. doi: 10.1056/NEJMoa1800410 [DOI] [PMC free article] [PubMed] [Google Scholar]

[noi240023r29] 29.Eikelboom JW, Connolly SJ, Bosch J, et al. ; COMPASS Investigators . Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330. doi: 10.1056/NEJMoa1709118 [DOI] [PubMed] [Google Scholar]

[noi240023r30] 30.Shu L, Mandel D, Yaghi S. Abstract number-56: anti-thrombotic therapy for stroke prevention in cervical artery dissection: protocol of a multicenter international study. Stroke Vasc Intervent Neurol. 2023;3(S1):e12678. doi: 10.1161/SVIN.03.suppl_1.256 [DOI] [Google Scholar]

PERMALINK

Antithrombotic Treatment for Cervical Artery Dissection

Josefin E Kaufmann, MMed

Eric L Harshfield, PhD

Henrik Gensicke, MD

Susanne Wegener, MD

Patrik Michel, MD

Georg Kägi, MD

Krassen Nedeltchev, MD

Lars Kellert, MD

Sverre Rosenbaum, MD

Christian H Nolte, MD

Hanne Christensen, MD

Marcel Arnold, MD

Philippe Lyrer, MD

Christopher Levi, MD

Philip M Bath, MD

Stefan T Engelter, MD

Christopher Traenka, MD

Hugh S Markus, DM

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction/Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

The CADISS RCT

The TREAT-CAD RCT

Data Collection and Transfer

Defined Outcome for the Meta-Analysis

Patient Population

Statistical Analysis

Results

Individual Patient Data Meta-Analysis

Figure 1. Patient Flowchart.

Table 1. Baseline Characteristics by Treatment Group.

Primary Outcome

Table 2. Outcomes Within 90 Days by Treatment Groupa.

Figure 2. Primary End Point and Subgroup Analyses.

Secondary Outcome

Subgroup Analyses

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 2. Outcomes Within 90 Days by Treatment Group^a.