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Editor's Choice – Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials

  • Urs Fisch
    Affiliations
    Department of Neurology and Stroke Centre, Department of Clinical Research, University Hospital, University of Basel, Basel, Switzerland
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  • Stefanie von Felten
    Affiliations
    Clinical Trial Unit, Department of Clinical Research, University of Basel, Basel, Switzerland

    Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
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  • Andrea Wiencierz
    Affiliations
    Clinical Trial Unit, Department of Clinical Research, University of Basel, Basel, Switzerland
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  • Olav Jansen
    Affiliations
    Clinic for Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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  • George Howard
    Affiliations
    Department of Biostatistics, UAB School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA
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  • Jeroen Hendrikse
    Affiliations
    Department of Radiology, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands
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  • Alison Halliday
    Affiliations
    Nuffield Department of Surgery University of Oxford, Oxford, UK
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  • Gustav Fraedrich
    Affiliations
    Department of Vascular Surgery, Medical University of Innsbruck, Innsbruck, Austria
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  • Hans-Henning Eckstein
    Affiliations
    Department for Vascular and Endovascular Surgery-Vascular Centre, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
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  • David Calvet
    Affiliations
    Department of Neurology, Hôpital Sainte-Anne, Université Paris-Descartes, DHU Neurovasc Sorbonne Paris Cité, INSERM U894, Paris, France
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  • Richard Bulbulia
    Affiliations
    Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK
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  • Jean-Pierre Becquemin
    Affiliations
    Vascular Institute of Paris East, Hôspital Paul D Egine, Champigny-sur-Marne, France
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  • Ale Algra
    Affiliations
    Department of Neurology and Neurosurgery, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands

    Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands
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  • Author Footnotes
    ‡ These authors contributed equally.
    Peter Rothwell
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital and University of Oxford, Oxford, UK
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  • Author Footnotes
    ‡ These authors contributed equally.
    Peter Ringleb
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Department of Neurology, University of Heidelberg Medical School, Heidelberg, Germany
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  • Author Footnotes
    ‡ These authors contributed equally.
    Jean-Louis Mas
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Department of Neurology, Hôpital Sainte-Anne, Université Paris-Descartes, DHU Neurovasc Sorbonne Paris Cité, INSERM U894, Paris, France
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  • Author Footnotes
    ‡ These authors contributed equally.
    Martin M. Brown
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK
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  • Author Footnotes
    ‡ These authors contributed equally.
    Thomas G. Brott
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
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  • Author Footnotes
    ‡ These authors contributed equally.
    Leo H. Bonati
    Correspondence
    Corresponding author. Department of Neurology and Stroke Centre, Department of Clinical Research, University Hospital Basel, Petersgraben 4, Basel, CH-4031, Switzerland.
    Footnotes
    ‡ These authors contributed equally.
    Affiliations
    Department of Neurology and Stroke Centre, Department of Clinical Research, University Hospital, University of Basel, Basel, Switzerland

    Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK
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  • on behalf of theCarotid Stenosis Trialists’ Collaboration
  • Author Footnotes
    ‡ These authors contributed equally.
Open AccessPublished:April 05, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.02.024

      Objective

      Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed.

      Methods

      The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation.

      Results

      A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 – 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 – 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 – 0.88, p = .019).

      Conclusion

      Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.

      Keywords

      Improvements in medical therapy over time may have lowered the risk of stroke in patients with symptomatic carotid stenosis. This study addressed this question by the first comparison of individual patient data from two historical series of large randomised controlled trials with very similar inclusion criteria. Its findings add to the current evidence that stroke risk has decreased over time. Thus, the added benefit of carotid revascularisation to modern medical care needs to be revisited in ongoing and future studies.

      Introduction

      Patients with recently symptomatic carotid artery stenosis are at high risk of stroke.
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      Early risk of recurrence by subtype of ischaemic stroke in population-based incidence studies.
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      Patterns and predictors of early risk of recurrence after transient ischaemic attack with respect to etiologic subtypes.
      Earlier randomised controlled trials (RCTs), conducted in the 1980s and 1990s, demonstrated a reduction in stroke risk by revascularisation by carotid endarterectomy (CEA) when compared with medical therapy alone.
      • Warlow C.
      • Farrell B.
      • Fraser A.
      • Sandercock P.
      • Slattery J.
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
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      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.
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      • et al.
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group.
      Pooled analysis of two of these trials suggested that the benefit of CEA was highest when performed early after the qualifying ischaemic event.
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      • Gutnikov S.
      • Warlow C.
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      Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.
      Current guidelines therefore recommend revascularisation within two weeks of initial symptoms.
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      Guidelines for management of ischaemic stroke and transient ischaemic attack 2008.
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      • et al.
      Guidelines for the prevention of stroke in patients with stroke or transient ischaemic attack.
      Medical therapy for secondary prevention of stroke has evolved since the completion of these trials with widespread use of statins and more aggressive control of vascular risk factors. Thus, the risk of stroke among patients with symptomatic carotid stenosis may have decreased over the years.
      In this study, the risk of early stroke was studied in patients with symptomatic carotid stenosis recruited in four more recent RCTs,
      • Mas J.-L.
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      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      • Eckstein H.H.
      • Ringleb P.
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      • Hacke W.
      • 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.
      • Ederle J.
      • Dobson J.
      • Featherstone R.L.
      • Bonati L.H.
      • van der Worp H.B.
      • de Borst G.J.
      • 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.
      • Brott T.G.
      • Hobson R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      which compared revascularisation by carotid artery stenting (CAS) vs. CEA. The aim was to assess the risk of stroke under medical therapy occurring between randomisation and revascularisation in these recent trials, to identify its predictors, and to compare this risk with the risk of early stroke among medically treated patients in earlier trials, which compared medical therapy vs. CEA.

      Materials and methods

      In the Carotid Stenosis Trialists’ Collaboration (CSTC), the data of individual patients with symptomatic carotid stenosis, who were recruited between 2000 and 2008 into four RCTs comparing CAS vs. CEA were pooled: Endarterectomy vs. Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S), Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs. Endarterectomy (SPACE), International Carotid Stenting Study (ICSS), and Carotid Revascularisation Endarterectomy vs. Stenting Trial (CREST), from here on referred to as recent trials.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • 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.
      • Ederle J.
      • Dobson J.
      • Featherstone R.L.
      • Bonati L.H.
      • van der Worp H.B.
      • de Borst G.J.
      • 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.
      • Brott T.G.
      • Hobson R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      These trials recruited patients with moderate (50% – 69% reduction of the lumen diameter according to the NASCET method
      • Barnett H.J.M.
      • Taylor D.W.
      • Eliasziw M.
      • Fox A.J.
      • Ferguson G.G.
      • Haynes R.B.
      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.
      ) and severe (70% – 99%) stenosis of the internal carotid artery, presenting with recent associated symptoms of retinal ischaemia, hemispheric transient ischaemic attack (TIA), or non-disabling stroke. Patients were thought to require revascularisation by CAS or CEA and were considered suitable for both. In the present analysis, symptomatic patients from CREST were included only if they had received the allocated treatment. Ethics approval for the contributing trials was obtained at the competent institutional review boards, and all patients provided written informed consent.
      In addition, individual patient data were extracted from a pooled analysis
      • Rothwell P.M.
      • Eliasziw M.
      • Gutnikov S.A.
      • Fox A.J.
      • Taylor D.W.
      • Mayberg M.R.
      • et al.
      Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis.
      of three earlier RCTs: European Carotid Surgery Trial (ECST), North American Symptomatic Carotid Endarterectomy Trial (NASCET), and Veterans Affairs Cooperative Studies Program 309 (VA309).
      • Warlow C.
      • Farrell B.
      • Fraser A.
      • Sandercock P.
      • Slattery J.
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      ,
      • Mayberg M.R.
      • Wilson S.E.
      • Yatsu F.
      • Weiss D.G.
      • Messina L.
      • Hershey L.A.
      • et al.
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group.
      ,
      • Barnett H.J.M.
      • Taylor D.W.
      • Haynes R.B.
      • Sackett D.L.
      • Peerless S.J.
      • et al.
      North American Symptomatic Carotid Endarterectomy Trial Collaborators
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      These trials recruited patients from 1981 until 1996 and compared CEA plus medical treatment vs. medical treatment alone. For the study, patients were included with moderate or severe symptomatic carotid stenosis from the medical arms of those earlier trials which served as a historical comparison group (from here on referred to as medical arm of earlier trials). In NASCET, randomisation was delayed until it was clear that surgery could be rapidly delivered if the patient was to be allocated to CEA. For this reason, only patients randomised to the medical arms in the earlier trials were included. Medical treatment in these trials consisted mainly of different doses of aspirin, and antihypertensive and antidiabetic treatment. Statins were not used at the beginning of these trials but were gradually introduced during the recruitment period. Selected inclusion criteria, recommended medical therapy, and medication at baseline of earlier and recent trials are shown in Table S1.
      • Howard V.J.
      • Grizzle J.
      • Diener H.C.
      • Hobson R.W.
      • Mayberg M.R.
      • Toole J.F.
      Comparison of multicenter study designs for investigation of carotid endarterectomy efficacy.
      Definitions of patient baseline characteristics at the time of randomisation, outcome events, subgroup variables, and statistical methods were specified before the data were analysed. Baseline characteristics available for all trials were sex, age, history of hypertension, diabetes, smoking (current or past), coronary heart disease (i.e., angina pectoris or myocardial infarction in the medical arm of earlier trials), degree of ipsilateral carotid stenosis (according to NASCET criteria
      • Barnett H.J.M.
      • Taylor D.W.
      • Eliasziw M.
      • Fox A.J.
      • Ferguson G.G.
      • Haynes R.B.
      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.
      ), contralateral severe carotid stenosis or occlusion, time between qualifying event and randomisation, and type of the qualifying event. Additional baseline characteristics for recent trials were history of hyperlipidaemia or lipid lowering drugs, and modified Rankin scale (mRS). The qualifying event was the most recent (not necessarily the first) ischaemic event before randomisation in the territory of the relevant carotid artery, categorised as retinal ischaemia including amaurosis fugax or retinal infarction, hemispheric TIA, or hemispheric ischaemic stroke.
      The primary outcome event was stroke in any territory occurring within the first 120 days after randomisation and before revascularisation by CEA or CAS. Patients were censored at 120 days after randomisation or at the time of revascularisation, which ever came first. The period of 120 days was chosen because nearly all patients undergoing revascularisation in the recent trials were treated within that period. Stroke was defined as an acute deficit of focal neurological function with symptoms lasting more than 24 hours with ischaemic or haemorrhagic origin. Retinal infarction, defined as visual loss lasting more than 24 hours resulting from retinal ischaemia, was also considered as stroke. Fatal stroke was defined as any stroke leading to death within 30 days after onset, and disabling stroke resulting in new or increased disability with a mRS ≥ 3; all other strokes were classified as non-disabling.

      Statistical analysis

      All analyses were conducted using R (Version 3.4.4, R Core Team, 2017). All data were treated as non-normally distributed. R package mice
      • Buuren S. van
      • Groothuis-Oudshoorn K.
      Mice: multivariate imputation by chained equations in R.
      were used (multiple imputation by chained equations) to create m = 20 imputations per missing value across all covariates (details in the Supplementary material). For the recent trials, the association between baseline characteristics and time to stroke after randomisation or time from qualifying event until randomisation individually was analysed using Cox proportional hazards models. The qualifying event type was analysed both as three single degree of freedom contrast and as a continuous variable for severity (retinal ischaemia < TIA < stroke). The four recent RCTs were fitted as three single degree of freedom contrasts. The models were fitted to each of the imputed data sets. For each combination of model and data set, the Akaike information criterion (AIC), the likelihood ratio χ2, and the corresponding p value were extracted and averaged for each model (across all imputed data sets). The best single predictor was chosen based on the AIC. To select the best model with two predictors a forward variable selection approach was used based on the AIC. The selected models were then applied to all imputed data sets and the results were pooled to one final result using Rubin’s rules.
      • Rubin D.B.
      Multiple Imputation for Nonresponse in Surveys.
      ,
      • Wood A.M.
      • White I.R.
      • Royston P.
      How should variable selection be performed with multiply imputed data?.
      The risk of stroke after randomisation was compared between recent trials and the medical arm of earlier trials using Kaplan–Meier curves and log rank tests for patients with moderate stenosis, patients with severe stenosis, and patients with moderate or severe stenosis combined. Cox proportional hazards models of the original dataset were used with recent trials vs. the medical arm of earlier trials as the explanatory factor. To analyse patients with moderate or severe stenosis, the stenosis degree was used as an additional explanatory factor. Cox proportional hazards models of all imputed data sets were adjusted for time (weeks) from the qualifying event until randomisation, and for other potential confounders: age, carotid stenosis degree (moderate vs. severe), qualifying event severity. The Cox proportional hazards assumption was assessed graphically by plotting the scaled Schoenfeld residuals vs. the transformed survival times and using a χ2 test to detect significant correlations (per variable test and global). A p value < .05 was considered to be statistically significant.

      Results

      In the recent trials comparing CAS vs. CEA, 4 754 patients with symptomatic carotid stenosis were enrolled (CAS 2 393, CEA 2 361). In the earlier trials comparing CEA vs. medical therapy alone, 1 227 patients were assigned to the medical therapy arm.
      Baseline characteristics of patients included in recent trials and the medical arm of earlier trials are listed in Table 1. Recent trials included a larger proportion of patients with severe stenosis than the medical arm of earlier trials. Patients in the recent trials were older, had a more frequent history of cardiovascular risk factors, contralateral carotid stenosis, or occlusion, and presented less frequently with retinal ischaemia. There were 797 patients with an unknown date of the qualifying event in recent trials, most of whom originated from one trial where this information was not systematically collected.
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • 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.
      Time from the qualifying event until randomisation was shorter in recent trials (median 18 days, interquartile range [IQR] 7, 50) than in the medical arm of earlier trials (median 37 days, IQR 14, 75) (Fig. 1).
      Table 1Baseline characteristics of patients included in trials on treatment of symptomatic carotid stenosis
      Baseline characteristicsRecent trials (n = 4 754)Medical arm of earlier trials (n = 1 227)
      Age – y69.3 ± 9.364.8 ± 8.5
      Men3 317 (69.8)881 (71.8)
      History of hypertension3 574 (75.5)558 (49.4)
      History of diabetes1 193 (25.1)242 (19.7)
      History of smoking3 063 (65.0)620 (50.5)
      History of coronary heart disease1 293 (27.8)416 (33.9)
      Ipsilateral carotid stenosis
       Moderate919 (19.3)721 (58.8)
       Severe3 835 (80.7)506 (41.2)
      Contralateral carotid stenosis or occlusion626 (14.7)84 (6.8)
      Qualifying event type
       Retinal ischaemia808 (17.1)396 (32.3)
       Transient ischaemic attack1 741 (36.9)355 (29.0)
       Ischaemic stroke2 173 (46.0)474 (38.7)
      Time qualifying event until randomisation – d18 (7–50)37 (14–75)
      Data of known values are presented as n (%), mean ± standard deviation, or median (interquartile range).
      Figure 1
      Figure 1Cumulative Kaplan–Meier estimate for randomisation after the qualifying event in patients with symptomatic moderate or severe carotid stenosis in recent and the medical arm of earlier trials (n = 5 184 patients). Time between the qualifying event and randomisation for the recent trials was median 18 days (interquartile range [IQR] 7, 50), and for the earlier trials median 37 days (14, 75).
      In the recent trials, the median time from randomisation until revascularisation was six days (IQR 3, 12 days), and from the qualifying event until revascularisation 28 days (IQR 12, 65), with considerable variation between the individual trials (Fig. 2A). A total of 1 133 patients (23.8%) in the recent trials were treated within the recommended 14 days after the qualifying event. A total of 108 patients were censored at 120 days after randomisation because they did not undergo revascularisation until then. Patients randomised to CAS were treated earlier (median 26 days, IQR 11, 61) after the qualifying event than those randomised to CEA (median 29 days, IQR 13, 67) (Fig. 2B).
      Figure 2
      Figure 2Cumulative Kaplan–Meier estimate for revascularisation treatment within 200 days after the qualifying event in recent trials according to (A) individual trials and (B) revascularisation treatment (n = 3 957 patients; 797 with unknown qualifying event date not shown) for symptomatic carotid stenosis. Time between the qualifying event and treatment was a median 24 days (interquartile range [IQR] 12, 47) in EVA-3S, 12 (6, 24) in SPACE, 22 (8, 62) in ICSS, and 15 (5, 47) in CREST. In all recent trials combined, patients randomised to carotid artery stenting (CAS) were treated at a median 26 days (11, 61) and those randomised to carotid endarterectomy (CEA) at 29 (13, 67) after the qualifying event.
      In the recent trials, a total of 23 (15 CEA, 8 CAS) patients suffered a stroke after randomisation while waiting for revascularisation, resulting in a cumulative 120 day risk of 1.97% (95% CI 0.75 – 3.17). Of these 23 patients, 17 were men and 22 had a severe carotid stenosis. The qualifying event was TIA in 13 patients, hemispheric stroke in 9 and retinal ischaemia in one. These patients were randomised between 0 and 133 days after the qualifying event with a median of 10.5 days (IQR 3.75, 42.5, one qualifying event date missing). The mRS at randomisation was 2 or less in 19 patients. Eight patients received treatment as randomised despite their stroke, one patient died from his stroke, and the remaining 14 patients did not receive any revascularisation within 120 days. The severity of the 23 strokes was fatal in one, disabling in 13 and non-disabling in eight patients, with 20 strokes occurring ipsilateral to the symptomatic carotid stenosis. All strokes occurred within the first 31 days after randomisation.
      In the recent trials, the strongest single predictor of stroke was time from the qualifying event until randomisation with a hazard ratio (HR) of 0.88 (95% CI 0.78 – 1.0, χ2 = 6.58, p = .011, AIC = 321.25), indicating that the risk was highest in patients randomised early after the qualifying event. The model with the two strongest predictors included time from qualifying event until randomisation (HR 0.98, 95% CI 0.97 – 1.0) and TIA as the qualifying event (HR 2.72, 95% CI 1.13 – 6.57, χ2 = 11.73, p = .003, average AIC = 318.10). Severity of carotid stenosis as a single predictor was not statistically significant (HR 4.13, 95% CI 0.55 – 30.88, χ2 = 2.99, p = .084, AIC = 324.84).
      In the medical arm of earlier trials, 61 patients had a stroke within 120 days after randomisation with a cumulative risk of 5% (95% CI 3.8 – 6.2). The risk of stroke within 120 days after randomisation in recent trials was not different to the risk in the medical arm of earlier trials in the unadjusted comparison for patients with moderate stenosis (log rank χ2 = 1.68, p = .19; Fig. 3A), severe stenosis (χ2 = 1.43, p = .23; Fig. 3B), and moderate or severe stenosis combined (χ2 = 1.11, p = .29; Fig. 3C, Fig. S1). However, after adjustment for time between the qualifying event and randomisation, age, severity of qualifying event and degree of stenosis, hazards for stroke were significantly lower in the recent trials than in the earlier trials among patients with moderate or severe stenosis combined (HR 0.47, 95% CI 0.25 – 0.88, p = .019).
      Figure 3
      Figure 3Cumulative Kaplan–Meier estimate for stroke within 120 days after randomisation for patients in recent and the medical arm of earlier trials with symptomatic (A) moderate (n = 1 640), (B) severe (n = 4 341), and (C) moderate or severe carotid stenosis combined (n = 5 981 patients). Note the adapted scale for y-axes.

      Discussion

      In this study, the early risk of stroke under medical therapy was analysed in patients with symptomatic carotid stenosis awaiting revascularisation in recent RCTs.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • 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.
      • Ederle J.
      • Dobson J.
      • Featherstone R.L.
      • Bonati L.H.
      • van der Worp H.B.
      • de Borst G.J.
      • 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.
      • Brott T.G.
      • Hobson R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      The cumulative stroke risk was 2% at 120 days and was higher among patients that were randomised shortly after the qualifying event. The risk of stroke was lower in these recent trials than it was among patients treated medically in earlier trials
      • Warlow C.
      • Farrell B.
      • Fraser A.
      • Sandercock P.
      • Slattery J.
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      • Barnett H.J.M.
      • Taylor D.W.
      • Eliasziw M.
      • Fox A.J.
      • Ferguson G.G.
      • Haynes R.B.
      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.
      • Mayberg M.R.
      • Wilson S.E.
      • Yatsu F.
      • Weiss D.G.
      • Messina L.
      • Hershey L.A.
      • et al.
      Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group.
      when the comparison was adjusted for important patient characteristics differing between trials.
      In the recent trials, all strokes occurred within the first 31 days after randomisation. This finding is in line with previous studies showing that the risk of stroke is highest early after an athero-embolic event.
      • Lovett J.K.
      • Coull A.J.
      • Rothwell P.M.
      Early risk of recurrence by subtype of ischaemic stroke in population-based incidence studies.
      ,
      • Purroy F.
      • Montaner J.
      • Molina C.A.
      • Delgado P.
      • Ribo M.
      • Álvarez-Sabín J.
      Patterns and predictors of early risk of recurrence after transient ischaemic attack with respect to etiologic subtypes.
      ,
      • Amarenco P.
      • Lavallée P.C.
      • Labreuche J.
      • Albers G.W.
      • Bornstein N.M.
      • Canhão P.
      • et al.
      One-year risk of stroke after transient ischaemic attack or minor stroke.
      However, observational studies of patients with symptomatic carotid stenosis reported a much higher cumulative risk. A pooled analysis of three prospective cohort studies showed a risk of ipsilateral stroke or retinal infarction of 11.4% at 14 days and 18.9% at 90 days after the qualifying event.
      • Johansson E.
      • Cuadrado-Godia E.
      • Hayden D.
      • Bjellerup J.
      • Ois A.
      • Roquer J.
      • et al.
      Recurrent stroke in symptomatic carotid stenosis awaiting revascularisation.
      Other studies demonstrated similar findings with risks of 7.5% within 30 days,
      • Strömberg S.
      • Nordanstig A.
      • Bentzel T.
      • Österberg K.
      • Bergström G.M.L.
      Risk of early recurrent stroke in symptomatic carotid stenosis.
      3.2% within three days,
      • Mono M.-L.
      • Steiger I.
      • Findling O.
      • Jung S.
      • Reinert M.
      • Galimanis A.
      • et al.
      Risk of very early recurrent cerebrovascular events in symptomatic carotid artery stenosis.
      or 21% at 14 days and 32% at 90 days.
      • Fairhead J.F.
      • Mehta Z.
      • Rothwell P.M.
      Population-based study of delays in carotid imaging and surgery and the risk of recurrent stroke.
      In the study, the majority of patients were randomised more than 14 days after the qualifying event which probably explains the lower stroke risk compared with observational data. In the trials included in the present analysis, the qualifying event was defined as the last ischaemic event before randomisation but the timing of previous events was not uniformly assessed. Therefore, the risk of stroke after the first event could not be estimated. In one study, 11% of patients presenting with ischaemic stroke for CEA reported one or more previous episodes of TIA or amaurosis fugax.
      • Shahidi S.
      • Owen-Falkenberg A.
      • Gottschalksen B.
      • Ellemann K.
      Risk of early recurrent stroke in symptomatic carotid stenosis after best medical therapy and before endarterectomy.
      Furthermore, patients recruited for the RCTs were subjected to a selection bias since patients with significant stroke related disability were not eligible for these trials. In observational studies, patients with any level of disability were included and it is known that higher disability at baseline is associated with greater risk of recurrent events.
      • Johansson E.
      • Cuadrado-Godia E.
      • Hayden D.
      • Bjellerup J.
      • Ois A.
      • Roquer J.
      • et al.
      Recurrent stroke in symptomatic carotid stenosis awaiting revascularisation.
      Thus, the RCTs analysed here included a patient population which was at a lower risk of stroke compared with observational cohorts.
      Guidelines recommend revascularisation of symptomatic carotid stenosis within 14 days after a cerebrovascular event, but the optimal timing is under debate.
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      • Nordanstig A.
      • Rosengren L.
      • Strömberg S.
      • Österberg K.
      • Karlsson L.
      • Bergström G.
      • et al.
      Editor’s Choice – Very urgent carotid endarterectomy is associated with an increased procedural risk: the Carotid Alarm Study.
      In the recent trials, only a quarter of patients were treated within the recommended time. Of note, patients randomised to CAS were treated at median of three days earlier than those randomised to CEA, probably reflecting differences in availability of staff and infrastructure.
      In the second part of the study, the risk of early stroke was compared among patients with symptomatic carotid stenosis waiting for CAS or CEA in recent trials and patients randomised to the medical arms of earlier trials comparing CEA with medical therapy. A lower risk was found in recent trials than in earlier trials, when adjusting the comparison for factors that had been shown to affect the risk of ischaemic events.
      • Rothwell P.
      • Eliasziw M.
      • Gutnikov S.
      • Warlow C.
      • Barnett H.
      Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.
      ,
      • Johansson E.
      • Cuadrado-Godia E.
      • Hayden D.
      • Bjellerup J.
      • Ois A.
      • Roquer J.
      • et al.
      Recurrent stroke in symptomatic carotid stenosis awaiting revascularisation.
      It is possible that improvements in medical therapy and greater awareness for risk factor control and lifestyle modification contributed to this risk reduction. Medical therapy had changed between the completion of the earlier trials and beginning of the recent trials, including the widespread prescription of statins. In an observational study among patients presenting with TIA due to a symptomatic carotid stenosis, the early stroke risk within 90 days was 8.9% among patients with statin pre-treatment and 20.8% among those without statins.
      • Merwick Á Albers G.W.
      • Arsava E.M.
      • Ay H.
      • Calvet D.
      • Coutts S.B.
      • et al.
      Reduction in early stroke risk in carotid stenosis with transient ischemic attack associated with statin treatment.
      Reported statin use at randomisation was notably lower in some of the earlier trials (13% – 16%) than in the recent trials (49% – 63%).
      • Barnett H.J.M.
      • Taylor D.W.
      • Eliasziw M.
      • Fox A.J.
      • Ferguson G.G.
      • Haynes R.B.
      • et al.
      Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis.
      ,
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • 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.
      ,
      • Ederle J.
      • Dobson J.
      • Featherstone R.L.
      • Bonati L.H.
      • van der Worp H.B.
      • de Borst G.J.
      • 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.
      Antithrombotic therapy at randomisation varied greatly among all trials and exact dosages were rarely reported (Table S1). The finding of a lower risk of stroke over time is supported by large prospective observational studies. Prospective registries from 2004 and 2007 reported an approximate 20% risk of recurrent stroke within 90 days after stroke or TIA due to large artery atherosclerosis, whereas a registry published in 2016 reported a mere 6%.
      • Amarenco P.
      • Lavallée P.C.
      • Labreuche J.
      • Albers G.W.
      • Bornstein N.M.
      • Canhão P.
      • et al.
      One-year risk of stroke after transient ischaemic attack or minor stroke.
      The main strength of this analysis is the inclusion of data at individual patient level from two series of clinical trials with very similar inclusion criteria. However, there are also limitations. First, despite the large study population, the number of strokes in recent trials was low, which limited statistical power. However, there are no other comparable data that would allow a similar comparison of two series of large RCTs of patients with symptomatic carotid stenosis. Second, although the comparison of stroke risk between recent and earlier trials was adjusted for important patient characteristics, the trial populations may have differed in factors that were not accounted for. Third, patients enrolled in RCTs are selected and not necessarily representative of the population of all patients with symptomatic carotid stenosis: patients with a persisting major stroke as the presenting event were excluded from both recent and earlier trials; patients with progressive or fluctuating symptoms may have been excluded; and patients perceived to be at very high risk of stroke may have undergone immediate revascularisation outside a trial. Therefore, no statement can be made about stroke risk in these specific patient groups. Fourth, the risk of stroke after the first presenting event could not be estimated. It is likely that some patients suffered from repeated ischaemic events occurring before the qualifying event, as defined in the trials. Therefore, the findings probably underestimate the true risk of early stroke in symptomatic carotid stenosis. Contemporary prospective registries are better suited to provide evidence on early stroke risk in patients with symptomatic carotid stenosis than the more selected population of patients included in clinical trials. Fifth, as far as conservative management is concerned, changes of medical therapy over time, such as the gradual introduction of statins into management during the recruitment period of the early trials, could not be accounted for. In addition, the latest advances in medical treatment such as early dual antiplatelet therapy that were introduced after completion of the recent trials were not considered in this analysis.
      • Johnston S.C.
      • Easton J.D.
      • Farrant M.
      • Barsan W.
      • Convit R.A.
      • Elm J.J.
      • et al.
      Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA.
      Finally, information on behavioural and lifestyle factors was generally lacking. For all these reasons, the applicability of the findings to current carotid disease management is limited and the results should not deflect from the current practice of early treatment of patients considered for revascularisation.
      Despite these limitations, the study adds to the current evidence that the risk of stroke associated with symptomatic carotid stenosis has decreased over time, potentially attributable to improved medical care and risk factor control. The added benefit of carotid revascularisation to modern medical care needs to be revisited in ongoing and future studies. However, at present the data should not deflect from current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment.

      Conflict of interest

      None.

      Funding

      The prospective individual patient data meta-analysis by the Carotid Stenosis Trialists’ Collaboration was funded by a grant from The Stroke Association. Dr Bonati was supported by grants from the Swiss National Science Foundation (PBBSB-116873 and 32003B-156658), the Swiss Heart Foundation, the University of Basel, Switzerland, and The Stroke Association. Dr Brown’s Chair in Stroke Medicine at University College London is supported by the Reta Lila Weston Trust for Medical Research. Dr Halliday’s research is funded by the National Institute for Health Research Oxford Biomedical Research Centre. Dr Howard is funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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