Elsevier

The Lancet Neurology

Volume 10, Issue 6, June 2011, Pages 530-537
The Lancet Neurology

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Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)

https://doi.org/10.1016/S1474-4422(11)70080-1Get rights and content

Summary

Background

In the randomised Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the primary endpoint did not differ between carotid artery stenting and carotid endarterectomy in patients with symptomatic and asymptomatic stenosis. A prespecified secondary aim was to examine differences by sex.

Methods

Patients who were asymptomatic or had had a stroke or transient ischaemic attack within 180 days before random allocation were enrolled in CREST at 117 clinical centres in the USA and Canada. The primary outcome was the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years. We used standard survival methods including Kaplan-Meier survival curves and sex-by-treatment interaction term to assess the relation between patient factors and risk of reaching the primary outcome. Analyses were by intention to treat. CREST is registered with ClinicalTrials.gov, NCT00004732.

Findings

Between Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262), 872 (34·9%) of whom were women. Rates of the primary endpoint for carotid artery stenting compared with carotid endarterectomy were 6·2% versus 6·8% in men (hazard ratio [HR] 0·99, 95% CI 0·66–1·46) and 8·9% versus 6·7% in women (1·35, 0·82–2·23). There was no significant interaction in the primary endpoint between sexes (interaction p=0·34). Periprocedural events occurred in 35 (4·3%) of 807 men assigned to carotid artery stenting compared with 40 (4·9%) of 823 assigned to carotid endarterectomy (HR 0·90, 95% CI 0·57–1·41) and 31 (6·8%) of 455 women assigned to carotid artery stenting compared with 16 (3·8%) of 417 assigned to carotid endarterectomy (1·84, 1·01–3·37; interaction p=0·064).

Interpretation

Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.

Funding

National Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions (formerly Guidant).

Introduction

The 2010 US guidelines for management of symptomatic carotid atherosclerosis recommend carotid endarterectomy under class I, level A evidence.1 The guidelines take into account patient-specific factors such as age, sex, comorbidities, and severity of symptoms.1 For asymptomatic disease, guidelines also recommend carotid endarterectomy under class I, level A evidence for highly selected patients, on the basis of assessment of comorbid conditions, life expectancy, and individual factors, and take sex into account.2 Both guidelines suggest that higher perioperative event rates in women than in men might result in smaller gains from carotid endarterectomy for women.1, 2 These guidelines support the use of carotid artery stenting as an alternative to carotid endarterectomy for patients for whom surgery is contraindicated with class IIb, level B evidence, but no recommendations are made about potential sex differences. By contrast, the 2008 guidelines of the European Stroke Organisation do not recommend carotid endarterectomy or carotid artery stenting for asymptomatic individuals and suggest no benefit from carotid endarterectomy for women.3 For symptomatic patients, the European recommendations for carotid endarterectomy are similar to the US guidelines and take into account sex differences, but angioplasty, carotid artery stenting, or both are only recommended for selected subgroups of patients with severe stenosis with class I, level A evidence.

The statement in the US guidelines that women have a higher perioperative rate of stroke or death than men was based on a post-hoc finding from the multicentre US Asymptomatic Carotid Atherosclerosis Study (ACAS).4, 5 Similar results were reported in a prespecified secondary analysis of the multicentre European Asymptomatic Carotid Surgery Trial (ACST),6 but the results regarding sex were not statistically significant for either trial. Potential sex differences were assessed post hoc in multicentre symptomatic carotid endarterectomy trials;7, 8 however, only the European Carotid Surgery Trial (ECST)8 detected a significant increase in perioperative stroke and death in women compared with men.

Although women bear the greater burden from stroke mortality,9 they have been under-represented in revascularisation trials. Women made up 34% of participants in ACAS,4 34% in ACST,6 30% in the North American Symptomatic Carotid Endarterectomy Trial (NASCET),10, 11 30% in ECST,8 and 30% in the Aspirin and Carotid Endarterectomy (ACE) trial.12 Similar under-representation of women also occurred in randomised trials of carotid artery stenting versus carotid endarterectomy: the percentage of women enrolled in the Stent-Protected Angioplasty versus Carotid Endarterectomy in Symptomatic Patients (SPACE) trial13 was 28% of 1186 participants and in the International Carotid Stenting Study (ICSS)14 it was 30% of 1710. Other trials enrolled less than 100 women.15 Thus, there is a paucity of information available to guide the use of carotid revascularisation in women—the group with the largest absolute burden from stroke.9

In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the risk of the primary endpoint (the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years) did not differ between carotid artery stenting and carotid endarterectomy in patients with asymptomatic and symptomatic carotid artery stenosis.16 When CREST was designed in the late 1990s, prespecified plans for sex-specific subgroup analyses were included, as were recruitment strategies targeted for women.17 A recruitment goal of 40% women was set to provide reasonable power to detect potential treatment differences between sexes—ie, to assess whether the overall difference in risk between carotid artery stenting and carotid endarterectomy is shared equally by men and women. We present the results of this a-priori plan.

Section snippets

Study design

Details of the design and primary results of CREST have been reported previously.16, 17 Patients were enrolled at 117 clinical centres in the USA and Canada. Patients who had had a stroke or transient ischaemic attack within 180 days before random allocation were deemed to have a symptomatic artery and were eligible if they had ipsilateral stenosis of at least 50% by angiography, at least 70% by ultrasound, or at least 70% by computed tomographic angiography or magnetic resonance angiography if

Results

Between Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262),16 872 (34·9%) of whom were women. Fewer women than men were white, and women had higher prevalence of hypertension, higher mean systolic blood pressure, lower mean diastolic blood pressure, and shorter lesion length than men (table 1). 466 women and 855 men had symptomatic stenosis and 406 women and 775 men had asymptomatic stenosis.

As reported in

Discussion

No difference between carotid artery stenting and carotid endarterectomy was detected for women or men in the primary endpoint of CREST. However, we did identify a sex difference in the periprocedural rates of stroke, myocardial infarction, or death after carotid artery stenting and carotid endarterectomy. This sex difference was driven by a higher risk of periprocedural stroke after carotid artery stenting in women; the risk of periprocedural stroke did not differ by procedure for men. These

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