Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials

Virginia J Howard¹, Ale Algra², George Howard³, Leo H Bonati^{4

5

6}, Gert J de Borst⁷, Richard Bulbulia^{8

9}, David Calvet¹⁰, Hans-Henning Eckstein¹¹, Gustav Fraedrich¹², Jacoba P Greving¹³, Alison Halliday¹⁴, Jeroen Hendrikse¹⁵, Olav Jansen¹⁶, Martin M Brown⁴, Jean-Louis Mas¹⁰, Peter A Ringleb¹⁷, Thomas G Brott¹⁸; Carotid Stenosis Trialists’ Collaboration

Affiliations

¹ Department of Epidemiology (V.J.H.), School of Public Health, University of Alabama at Birmingham.
² Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus and Julius Center for Health Sciences and Primary Care (A.A.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
³ Department of Biostatistics (G.H.), School of Public Health, University of Alabama at Birmingham.
⁴ Department of Brain Repair and Rehabilitation, Stroke Research Centre, University College of London Queen Square Institute of Neurology, University College London, United Kingdom (L.H.B., M.M.B.).
⁵ Department of Neurology, Stroke Center (L.H.B.), University Hospital Basel, University of Basel, Switzerland.
⁶ Department of Clinical Research (L.H.B.), University Hospital Basel, University of Basel, Switzerland.
⁷ Department of Vascular Surgery (G.J.d.B.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
⁸ Clinical Trial Service Unit and Epidemiological Studies Unit (R.B.), Nuffield Department of Population Health, University of Oxford, United Kingdom.
⁹ Medical Research Council Population Health Research Unit (R.B.), Nuffield Department of Population Health, University of Oxford, United Kingdom.
¹⁰ Department of Neurology, Hopital Sainte-Anne, Universite Paris-Descartes, DHU Neurovasc Sorbonne Paris Cite, INSERM U894, France (D.C., J.-L.M.).
¹¹ Department of Vascular and Endovascular Surgery/Vascular Center, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany (H.-H.E.).
¹² Department of Vascular Surgery, Medical University of Innsbruck, Austria (G.F.).
¹³ Department of Epidemiology (J.P.G.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
¹⁴ Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, United Kingdom (A.H.).
¹⁵ Department of Radiology, University Medical Center Utrecht, the Netherlands (J.H.).
¹⁶ Department of Radiology and Neuroradiology, UKSH Campus Kiel, Germany (O.J.).
¹⁷ Department of Neurology, University of Heidelberg Medical School, Germany (P.A.R.).
¹⁸ Department of Neurology, Mayo Clinic, Jacksonville, FL (T.G.B.).

PMID: 33493046
PMCID: PMC9136999
DOI: 10.1161/STROKEAHA.120.030184

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials

Virginia J Howard et al. Stroke. 2021 Jan.

. 2021 Jan;52(2):416-423.

doi: 10.1161/STROKEAHA.120.030184. Epub 2021 Jan 25.

Authors

Affiliations

¹ Department of Epidemiology (V.J.H.), School of Public Health, University of Alabama at Birmingham.
² Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus and Julius Center for Health Sciences and Primary Care (A.A.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
³ Department of Biostatistics (G.H.), School of Public Health, University of Alabama at Birmingham.
⁴ Department of Brain Repair and Rehabilitation, Stroke Research Centre, University College of London Queen Square Institute of Neurology, University College London, United Kingdom (L.H.B., M.M.B.).
⁵ Department of Neurology, Stroke Center (L.H.B.), University Hospital Basel, University of Basel, Switzerland.
⁶ Department of Clinical Research (L.H.B.), University Hospital Basel, University of Basel, Switzerland.
⁷ Department of Vascular Surgery (G.J.d.B.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
⁸ Clinical Trial Service Unit and Epidemiological Studies Unit (R.B.), Nuffield Department of Population Health, University of Oxford, United Kingdom.
⁹ Medical Research Council Population Health Research Unit (R.B.), Nuffield Department of Population Health, University of Oxford, United Kingdom.
¹⁰ Department of Neurology, Hopital Sainte-Anne, Universite Paris-Descartes, DHU Neurovasc Sorbonne Paris Cite, INSERM U894, France (D.C., J.-L.M.).
¹¹ Department of Vascular and Endovascular Surgery/Vascular Center, Klinikum rechts der Isar der Technischen Universitat Munchen, Munich, Germany (H.-H.E.).
¹² Department of Vascular Surgery, Medical University of Innsbruck, Austria (G.F.).
¹³ Department of Epidemiology (J.P.G.), and Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.
¹⁴ Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, United Kingdom (A.H.).
¹⁵ Department of Radiology, University Medical Center Utrecht, the Netherlands (J.H.).
¹⁶ Department of Radiology and Neuroradiology, UKSH Campus Kiel, Germany (O.J.).
¹⁷ Department of Neurology, University of Heidelberg Medical School, Germany (P.A.R.).
¹⁸ Department of Neurology, Mayo Clinic, Jacksonville, FL (T.G.B.).

PMID: 33493046
PMCID: PMC9136999
DOI: 10.1161/STROKEAHA.120.030184

Abstract

Background and purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter.

Methods: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P≤0.10.

Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (P=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period.

Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).

Keywords: carotid stenosis; endarterectomy; sex characteristics; stents; women.

PubMed Disclaimer

Figures

**Figure 2:**
Event rates estimated via Kaplan-Meier techniques for the pooled trials, shown by treatment and sex

See this image and copyright information in PMC

References

1. Howard VJ, Lutsep HL, Mackey A, Demaerschalk BM, Sam AD 2nd, Gonzales NR, Sheffet AJ, Voeks JH, Meschia JF, Brott TG, et al. Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Lancet Neurol. 2011;10:530–537 - PMC - PubMed
1. International Carotid Stenting Study Investigators,Ederle J, Dobson J, Featherstone RL, Bonati LH, van der Worp HB, de Borst GJ, Lo TH, Gaines P, Dorman PJ, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet. 2010;375:985–997 - PMC - PubMed
1. Bonati LH, Dobson J, Featherstone RL, Ederle J, van der Worp HB, de Borst GJ, Mali WP, Beard JD, Cleveland T, Engelter ST, et al. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet. 2015;385:529–538 - PMC - PubMed
1. Stingele R, Berger J, Alfke K, Eckstein HH, Fraedrich G, Allenberg J, Hartmann M, Ringleb PA, Fiehler J, investigators S, et al. Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent-protected angioplasty: a subanalysis of the SPACE study. Lancet Neurol. 2008;7:216–222 - PubMed
1. Eckstein HH, Ringleb P, Allenberg JR, Berger J, Fraedrich G, Hacke W, Hennerici M, Stingele R, Fiehler J, Zeumer H, et al. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol. 2008;7:893–902 - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials

Affiliations

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical