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Articles

Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of

P M Rothwell, M Eliasziw, S A Gutnikov, C P Warlow, H J M Barnett, for the Trialists Collaboration

Summary Introduction Carotid endarterectomy is one of the most common Background Carotid endarterectomy reduces the risk of vascular surgical procedures,1–3 and it reduced the risk of in patients with recently symptomatic stenosis. ischaemic stroke in patients with recently symptomatic Benefit depends on the degree of stenosis, and we aimed to carotid stenosis in two large randomised controlled see whether it might also depend on other clinical and trials.4,5 A smaller trial, the Veterans Affairs trial (VA309)6 angiographic characteristics, and on the timing of surgery. was stopped early when investigators in the European Carotid Surgery Trial (ECST) and the North American Methods We analysed pooled data from the European Symptomatic Carotid Endarterectomy Trial (NASCET) Carotid Surgery Trial and North American Symptomatic reported their initial findings.7,8 In 1998, the final results Carotid Endarterectomy Trial. The risk of ipsilateral ischaemic of the ECST and NASCET were reported, and the stroke for patients on medical treatment, the perioperative investigators made different recommendations about the risk of stroke and death, and the overall benefit from surgery degree of stenosis above which surgery was effective.1,2 were determined in relation to seven predefined and seven However, there were important differences between the post hoc subgroups. trials in the method of measurement of carotid stenosis on the prerandomisation angiograms and in the definitions of Results 5893 patients with 33 000 patient-years of follow-up outcome events.9–11 Subsequent analysis after remeasure- were analysed. Sex (p=0·003), age (p=0·03), and time from ment of the ECST angiograms by the method used in the last symptomatic event to randomisation (p=0·009) NASCET, and use of the definition of stroke as any modified the effectiveness of surgery. Benefit from surgery cerebral or retinal event with symptoms lasting longer was greatest in men, patients aged 75 years or older, and than 24 h, yielded results that were highly consistent with those randomised within 2 weeks after their last ischaemic NASCET.12 event, and fell rapidly with increasing delay. For patients with A recent meta-analysis of individual patients’ data from 50% or higher stenosis, the number of patients needed to the ECST, NASCET, and VA309, using the same undergo surgery (ie, number needed to treat) to prevent one method of measurement of stenosis and definitions of ipsilateral stroke in 5 years was nine for men versus 36 for outcome events, showed that surgery was harmful in women, five for age 75 years or older versus 18 for younger patients with less than 30% stenosis, of no benefit in those than 65 years, and five for those randomised within 2 weeks with 30–49% stenosis, of some benefit for 50–69% after their last ischaemic event, versus 125 for patients stenosis, and highly beneficial for those with 70% or more randomised after more than 12 weeks. These results were stenosis without near-occlusion.13 However, there are consistent across the individual trials. several other factors that might affect the risks and benefits of surgery, including the delay between presen- Interpretation: Benefit from endarterectomy depends not tation of symptoms and surgery, and specific clinical and only on the degree of carotid stenosis, but also on several angiographic characteristics,14–21 but neither ECST nor other clinical characteristics such as delay to surgery after NASCET had high enough statistical power to determine the presenting event. Ideally, the procedure should be done the effect of surgery in subgroups. We therefore analysed within 2 weeks of the patient’s last symptoms. pooled individual patients’ data from these two trials to determine the effect of surgery in relation to seven Lancet 2004; 363: 915–24 predefined and seven post hoc clinical and angiographical subgroups. Methods Eligibility criteria Criteria for inclusion of trials, and methods of data pooling and analysis have been reported previously.13 Two small early trials were excluded because the Stroke Prevention Research Unit, University Department of Clinical methods were not consistent with current clinical Neurology, Radcliffe Infirmary, Oxford OX2 6HE, UK practice.22,23 VA309 was not included in the present study (P M Rothwell FRCP, S A Gutnikov DPhil); Departments of Community because the trial was confined to men, and several other Health Sciences and Clinical Neurosciences, University of Calgary, subgroup variables were unavailable for analysis. The Calgary, Alberta, Canada (M Eliasziw PhD); Department of Clinical remaining large trials ECST and NASCET included Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK 95% of patients ever randomised to endarterectomy (Prof C P Warlow FRCP); and The John P Robarts Research Institute, versus medical treatment for symptomatic carotid London, Ontario, Canada (Prof H J M Barnett MD) stenosis. The methods of the two trials were very similar, Correspondence to: Dr P M Rothwell and have been reported and compared in detail (e-mail: [email protected]) previously.13,24,25

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ECST NASCET Total N Mean (SD)% p stenosis Patients 3008 2885 5893 Predefined patient subgroups Predefined patient subgroups Sex Sex Male 4175 40·2 (34·1)0·02 Male 2163 (71·9%) 2012 (69·7%) 4175 (70·8%) Female 1718 42·5 (32·2) Female 845 (28·1%) 873 (30·3%) 1718 (29·2%) Age (years) Age (years) <65 2900 37·1 (37·3)<0·0001 <65 1739 (57·8%) 1161 (40·2%) 2900 (49·2%) 65–74 2408 44·1 (29·7) 65–74 1093 (36·3%) 1315 (45·6%) 2408 (40·9%) у75 585 45·9 (25·6) у75 176 (5·9%) 409 (14·2%) 585 (9·9%) Time since last event (weeks) Time since last symptoms <2 1183 46·8 (32·5)<0·0001 (weeks) 2–4 1054 38·6 (36·5) <2 437 (14·5%) 746 (25·9%) 1183 (20·1%) 4–12 2312 40·7 (33·7) 2–4 574 (19·1%) 480 (16·6%) 1054 (17·9%) >12 1344 37·5 (31·2) 4–12 1214 (40·4%) 1098 (38·1%) 2312 (39·2%) Primary symptomatic event >12 783 (26·0%) 561 (19·4%) 1344 (22·8%) Ocular only 1165 48·4 (32·6) <0·0001 Primary symptomatic event Cerebral TIA 2112 40·2 (33·0) Ocular only 619 (20·6%) 546 (18·9%) 1165 (19·8%) Stroke 2616 38·0 (34·0) Cerebral TIA 1079 (35·9%) 1033 (35·8%) 2112 (35·8%) Diabetes Stroke 1310 (43·5%) 1306 (45·3%) 2616 (44·4%) Yes 974 45·2 (28·0)<0·0001 Diabetes 352 (11·7%) 622 (21·6%) 974 (16·5%) No 4919 40·0 (34·5) Irregular or ulcerated plaque* 1934 (64·6%) 1440 (49·9%) 3374 (57·3%) Plaque surface† Contralateral ICA occlusion 97 (3·2%) 155 (5·4%) 252 (4·3%) Smooth 2503 37·1 (36·5) <0·0001 Post hoc patient subgroups Irregular or ulcerated 3374 43·8 (31·0) Duration of cerebral TIA Contralateral ICA occlusion TIA р1 h 788 (26·2%) 776 (26·9%) 1564 (26·5%) Yes 252 52·3 (24·9) <0·0001 TIA >1 h 291 (9·7%) 257 (8·9%) 548 (9·3%) No 5641 40·3 (33·8) Previous TIA or stroke 821 (27·3%) 987 (34·2%) 1808 (30·7%) Post hoc patient subgroups Myocardial infarction 361 (12·0%) 571 (19·8%) 932 (15·8%) Duration of cerebral TIA 505 (16·8%) 775 (26·9%) 1280 (21·7%) TIA р1 h 1564 42·0 (32·9) <0·0001 Treated hypertension 1164(38·7%) 1577 (54·7%) 2741 (46·5%) TIA >1 h 548 35·1 (32·6) Treated hyperlipidaemia 257 (8·5%) 991 (34·4%) 1248 (21·2%) Previous TIA or stroke Smoking 1393 (46·3%) 1218 (42·4%) 2611 (44·3%) Yes 1808 43·7 (32·2) <0·0001 Data are number (%) unless otherwise indicated. TIA=transient ischaemic No 4085 39·6 (34·1) attack. ICA=internal carotid . *Plaque surface not adequately visible in Myocardial infarction one patient in NASCET and 15 patients in ECST. Yes 932 45·4 (28·4) <0·0001 Table 1: Baseline clinical and angiographic subgroup variable No 4961 40·0 (34·4) frequencies by source trial Angina Yes 1280 46·7 (27·3) <0·0001 Patients were recruited if they had had a recent carotid No 4613 39·2 (34·9) Treated hypertension distribution transient ischaemic attack, non-disabling Yes 2741 43·7 (31·2) <0·0001 ischaemic stroke, or a retinal infarction, in the territory of No 3152 38·4 (35·3) a stenosed carotid artery. Before randomisation, patients Treated hyperlipidaemia were seen by a neurologist or stroke physician to confirm Yes 1248 47·3 (27·1) <0·0001 their eligibility, and that the symptomatic carotid artery No 4645 39·1 (34·9) Smoking was imaged by selective catheter . Yes 2611 40·9 (36·4) 0·88 Participants were assigned by central telephone No 3282 40·8 (31·1) randomisation to immediate carotid endarterectomy plus *Based on available data from 5893 patients, unless otherwise indicated. best medical treatment versus best medical treatment †Data available for 5877 (99·7%) patients. alone. Follow-up was done at prespecified intervals by a Table 2: Degree of symptomatic carotid stenosis stratified neurologist or stroke physician. according to subgroup variables* Methods of pooling of individual patients’ data have been reported previously.13 Data for presenting events; sation, which was defined in a hierarchical manner as clinical, brain imaging, and angiographic characteristics at hemispheric stroke versus hemispheric transient ischaemic baseline; surgical and anaesthetic technique; and follow- attack but no stroke versus retinal event only; (5) diabetes up were merged into one database. Consideration was versus no diabetes; (6) irregular or ulcerated symptomatic given to the definitions of variables used in the original carotid plaque versus smooth plaque on the prerandomi- trials, and similar data were merged. sation angiogram (details of the assessment have been published previously);26,27 and (7) contralateral carotid Selection of subgroups occlusion versus no occlusion. To reduce the risk of chance findings, a restricted number To identify any important but unexpected treatment of subgroups was predefined on the basis of potential effect modifiers, seven post hoc subgroup variables were clinical importance and availability in both trials at a identified on the basis that comparable baseline data were meeting of collaborators in 1999 before the pooling of available from the two trials: (1) duration of cerebral data. These subgroups were derived from the risk factors transient ischaemic attack (р1 h vs >1 h); (2) previous that had been predefined at the beginning of NASCET.8 transient ischaemic attack or stroke (ie, events before the The following subgroup analyses were specified: (1) men 6-month eligibility period as well as recent events); versus women (2) age younger than 65 versus 65–74 (3) previous myocardial infarction; (4) previous angina; versus 75 years or older; (3) time from most recent (5) treated hypertension (defined as that needing a blood- symptomatic ischaemic event to randomisation less than pressure-lowering drug); (6) treated hyperlipidaemia 2 weeks, 2–4 weeks, 4–12 weeks, and more than 12 weeks; (defined as that needing a dietary change or cholesterol- (4) primary ischaemic event in the territory of the lowering drug); and (7) regular smoking during the stenosed artery during the 6 months before randomi- previous year.

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Ipsilateral p Perioperative p the two treatment groups. The risk of stroke and death is ischaemic stroke or high immediately after carotid endarterectomy in patients stroke death randomised to surgery, but is low thereafter, whereas the Predefined patient subgroups cumulative risk increases gradually with time in those Sex randomised to medical treatment. Consequently, surgery Women vs 0·79 (0·64–0·97) 0·03 1·50 (1·14–1·97) 0·004 is harmful during early follow-up, but might be beneficial Men with longer follow-up. The qualitative change in the effect Age (years) <65 1·00 0·001 1·00 0·78 of treatment over time means that standard meta- 65–74 1·23 (1·00–1·51) 0·99 (0·76–1·32) analytical techniques are not appropriate for derivation of у75 1·70 (1·28–2·56) 0·83 (0·49–1·41) estimates of overall treatment effects. Time since last An alternative, if hazard rates and treatment effects are event (weeks) similar across the trials, is to pool the individual patients’ <2 1·00 0·003 1·00 0·69 2–4 0·80 (0·61–1·06) 1·22 (0·78–1·90) data and to undertake Kaplan-Meier analyses of event-free 4–12 0·69 (0·55–0·88) 1·14 (0·77–1·68) survival for the pooled data. We showed previously that >12 0·61 (0·46–0·82) 1·28 (0·84–1·95) trials did not differ significantly in either the risks of the Primary study outcomes during follow-up in the medical or surgical symptomatic groups, or in the effects of surgery.13 We also showed that event Ocular only 1·00 <0·0001 1·00 <0·0001 no imbalances in baseline characteristics between the Cerebral TIA 1·88 (1·38–2·55) 2·62 (1·68–4·09) surgery and medical groups were introduced by pooling Stroke 2·33 (1·74–3·13) 1·91 (1·22–3·01) the trial data.13 Analyses of the effect of subgroup variables Diabetes 1·31 (1·05–1·65) 0·02 1·45 (1·05–2·02) 0·03 on the benefit from surgery were therefore done on the Irregular or 1·35 (1·11–1·64) 0·003 1·37 (1·03–1·82) 0·03 pooled data. Any significant treatment effect modifiers ulcerated plaque Contralateral ICA 1·30 (0·90–1·88) 0·16 2·21 (1·33–3·67) 0·002 were then assessed separately in the ECST and NASCET occlusion to measure consistency. Determination of the significance of treatment effect Post hoc patient subgroups Duration of modification by subgroup is confounded by the differential cerebral TIA changes in event rate with time in the two treatment TIA р1 h 1·00 1·00 groups. Nevertheless, we initially analysed data in a TIA >1 h 1·45 (1·03–2·04) 0·03 1·24 (0·81–1·92) 0·33 Cox proportional hazards model with treatment Previous TIA or 1·20 (0·99–1·46) 0·07 1·59 (1·21–2·09) 0·001 allocation, a source study term, degree of stenosis, a stroke ϫ Myocardial 1·40 (1·11–1·77) 0·004 0·87 (0·59–1·27) 0·46 subgroup treatment allocation interaction term, and a infarction stenosisϫtreatment allocation interaction term. An Angina 1·26 (1·02–1·56) 0·03 0·67 (0·47–0·97) 0·03 additional test for trend was also done for the analysis of the Treated 1·39 (1·15–1·68) 0·001 1·33 (1·02–1·74) 0·04 effects of age and time from last event to randomisation. To hypertension obtain maximum statistical power to detect treatment effect Treated 0·78 (0·62–0·98) 0·03 1·06 (0·74–1·51) 0·75 modification by subgroup, these analyses of subgroup by hyperlipidaemia Smoking 0·96 (0·80–1·16) 0·70 0·97 (0·74–1·27) 0·81 treatment interaction were done for all degrees of stenosis. We believed that the direction of any treatment effect Data are hazard ratio (95% CIs) unless otherwise indicated. Hazard ratios were derived from a Cox proportional hazards model including the subgroup variable, modification by subgroup was unlikely to differ qualitatively source study, and the degree of symptomatic carotid stenosis. with degree of stenosis. However, we did a further Cox Table 3: Relation between subgroup variables and risk of each model to test the significance of the three-way interaction main element of the primary outcome measure between stenosis, subgroup, and treatment allocation. In view of the non-proportionality of the event rate in Data analysis the two treatment groups, we also tested heterogeneity of All patients included in the final analysis of the original the relative risk reduction at 5 years follow-up based on trials were included in the pooled analyses, and all analyses risk estimates obtained from life table analysis. The were done on an intention-to-treat basis according to the absolute reductions in 5-year risk of stroke were also randomised treatment allocation. Stroke was defined as determined for each subgroup by life tables for patients any cerebral or retinal event with symptoms lasting longer with 50–69% stenosis, those with 70% or more stenosis than 24 h. As in the original trials, the primary outcome for (based on the method of measurement of stenosis used in analyses of the effect of surgery was time to first ipsilateral the NASCET trial),5 and for all patients. The significance ischaemic stroke in the territory of the symptomatic carotid of the difference between subgroups in the 5-year absolute artery, and any stroke or death that occurred within risk reduction with carotid endarterectomy was 30 days after trial surgery. The symptomatic carotid artery determined from life table analysis. Predefined subgroup was defined as in the original trials.4–6 Trial surgery was treatment effect modifiers were regarded as significant at defined as the first carotid endarterectomy in patients who p<0·05 and post hoc subgroup treatment effect modifiers were randomised to surgery. at p<0·01. Effect modifiers were judged robust if they were We first assessed the relation between every subgroup significant according to all three tests. There were too few variable and: (1) risk of ipsilateral carotid territory patients with carotid near-occlusions to allow ischaemic stroke in patients randomised to medical treat- subclassification by subgroups. For this investigation, these ment (medical risk); (2) any stroke or death that occurred patients were analysed together with the group that had within 30 days after trial surgery (perioperative risk). The 70% or more stenosis. All analyses were done with SPSS 5-year cumulative risks of ipsilateral ischaemic stroke were for Windows (version 10.0). determined in relation to every subgroup variable. The associations were also determined in a Cox proportional Role of funding source hazards model with adjustment for source trial and degree None of the funding organisations had any input into the of carotid stenosis. design of the collaborative study, data collection, analysis In randomised controlled trials of carotid endarterec- of data, data interpretation, or preparation of the manu- tomy, the cumulative risk of outcome events is different in script.

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Medical risk Surgical risk Events/patientsRisk (%) 95% CI Events/patients Risk (%) 95% CI

Predefined subgroups

Sex Men184/873 23·0 20·0–25·967/997 6·8 5·3–8·4 Women60/371 17·1 13·2–21·139/453 8·7 6·1–11·3

Age (years) <6593/550 18·0 14·6–21·356/719 7·9 5·9–9·8 65–74109/542 22·0 18·3–25·741/594 7·1 5·0–9·1 у7542/152 30·5 22·5–38·59/137 6·7 2·5–11·0

Time since last event (weeks) <288/299 31·5 26·0–37·022/322 6·9 4·1–9·7 2–444/215 21·7 16·0–27·422/264 8·4 5·0–11·8 4–12 weeks81/498 17·6 14·1–21·138/548 7·1 4·9–9·2 >1231/232 15·6 10·6–20·624/316 7·7 4·8–10·7

Primary symptomatic event Ocular only 39 /311 13·1 9·3–17·016/382 4·2 2·2–6·2 TIA91/437 22·6 18·4–26·748/495 9·9 7·2–12·5 Stroke114/496 25·4 21·3–29·542/573 7·5 5·3–9·7

Diabetes Yes56/232 27·5 21·2–33·822/232 9·7 5·8–13·5 No188/1012 19·9 17·3–22·484/1218 7·0 5·5–8·5

Symptomatic plaque surface Smooth79/473 17·5 14·0–21·135/544 6·5 4·4–8·6 Irregular or ulcerated165/771 23·5 20·3–26·771/906 8·0 6·2–9·7

Contralateral carotid occlusion Yes19/82 25·8 15·5–36·011/62 18·0 8·4–27·7 No225/1162 20·9 18·4–23·395/1388 7·0 5·6–8·3

Post hoc subgroups

Duration of cerebral TIA TIA р1 65/338 20·5 16·0–25·038/388 9·9 6·9–12·9 TIA >1 h26/99 29·7 19·9–39·510/107 9·7 4·0–15·4

Previous TIA or stroke Yes92/392 25·0 20·6–29·541/491 8·5 6·0–11·0 No152/852 19·4 16·6–22·265/959 6·9 5·3–8·5

Myocardial infarction Yes52/211 27·4 20·9–33·819/241 8·2 4·6–11·7 No192/1033 20·0 17·4–22·587/1209 7·3 5·8–8·8

Angina Yes64/294 24·0 18·8–29·217/329 5·3 2·9–7·8 No180/950 20·4 17·7–23·089/1121 8·0 6·4–9·6

Treated hypertension Yes141/610 25·0 21·4–28·657/712 8·2 6·1–10·2 No103/634 17·6 14·5–20·649/738 6·7 4·9–8·5

Treated hyperlipidaemia Yes62/317 21·4 16·6–26·223/304 7·7 4·7–10·8 No182/927 21·1 18·4–23·983/1146 7·4 5·8–8·9

Smoking Yes112/593 20·0 16·7–23·449/671 7·4 5·4–9·4 No132/651 22·3 18·9–25·857/779 7·4 5·6–9·3

Total244/1244 21·2 18·8–23·6106/1450 7·4 6·1–8·8

0 10 20 30 40 0 10 20 30 % risk (95% CI) % risk (95% CI)

Figure 1: Relation, in patients with у50% carotid stenosis, between predefined subgroup variables and 5-year cumulative risk of ipsilateral carotid ischaemic stroke in the medical group (medical risk) and risk of any stroke or death within 30 days after trial surgery (surgical risk) TIA=transient ischaemic attack.

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Results Effect of surgery on the risk of the Data for individual patients were available for all 5903 primary outcome patients included in the final analysis of the ECST and Relative risk reduction Absolute NASCET. Of these, nine ECST patients had an occlusion Cox model 5-year reduction in of the symptomatic carotid artery on the prerandomisation actuarial risk 5-year angiogram, and the degree of stenosis was unknown in one actuarial risk ECST patient. These cases were excluded from our Predefined patient subgroups analyses, leaving 5893 (99·8%) patients. Mean follow-up Sex 0·007 0·008 0·003 was 66 months (SD 34, range 1 day to 166 months), giving Age groups 0·09 0·04 0·03 a total of 33 000 patient-years of follow-up. 0·05 (trend) Time since last event groups 0·04 0·05 0·009 Table 1 shows data for subgroup variables. There were 0·006 (trend) significant differences in the degree of stenosis between all Primary symptomatic event 0·21 0·30 0·16 of the subgroup variables except smoking (table 2). Diabetes 0·51 0·85 0·63 Analyses of risk in relation to subgroup variables were Irregular or ulcerated plaque 0·58 0·23 0·10 therefore adjusted for degree of stenosis as well as the Contralateral ICA occlusion 0·30 0·34 0·25 source trial. Post hoc subgroups The risk of ipsilateral stroke in the medical group was Duration of cerebral TIA 0·44 0·47 0·42 significantly related to all subgroup variables apart from Previous TIA or stroke 0·08 0·23 0·50 Myocardial infarction 0·06 0·02 0·01 occlusion of contralateral internal carotid artery and Angina 0·08 0·11 0·06 smoking (table 3). In predefined subgroups, the risk of Treated hypertension 0·19 0·29 0·09 ipsilateral ischaemic stroke fell with time since last event, Treated hyperlipidaemia 0·63 0·85 0·85 rose with age, and was higher in men than in women, Smoking 0·40 0·40 0·38 higher in patients presenting with hemispheric events than Table 4: Significance of treatment-effect modifiers for relative retinal events, in diabetics, and in patients with irregular and absolute treatment effect for subgroup variables or ulcerated plaques. Figure 1 shows the effect of every subgroup variable on the 5-year absolute risk of ipsilateral than a smooth plaque in both stenosis groups. However, ischaemic stroke for patients with greater than 50% these treatment effectsϫsubgroup interactions were still stenosis. The subgroup trends in this clinically relevant not significant when the analysis was restricted to patients range of stenosis are the same as those shown in table 3. with 50% or more stenosis: p=0·06 for irregular plaque Of the 3157 patients who underwent trial surgery, there and p=0·1 for primary symptomatic event. were 222 operative or deaths (7·0%, 95% CI No subgroup-treatment effect interaction term was 6·2–8·0). In the predefined subgroups, the perioperative significant at the p<0·01 threshold for the post hoc risk of stroke or death was higher in women than in men, subgroups. There was a trend towards increased benefit in in patients with hemispheric events, diabetes, contralateral patients with a previous myocardial infarction (table 4). carotid occlusion and irregular or ulcerated plaques The effect of surgery on the 5-year absolute risk reduction (table 3). In the post hoc subgroups, perioperative risk was of ipsilateral ischaemic stroke and any perioperative stroke reduced in patients with angina and increased in those with or death is shown for all posthoc subgroups for all patients hypertension and with a previous transient ischaemic and those with 50–69% and 70% or more stenosis in attack or stroke. The same patterns were evident in the figure 3. unadjusted analysis of only patients with greater than 50% To assess the consistency of the effects of sex, age, and stenosis (figure 1). time since last event on the benefit from carotid Table 4 shows the significance of the tests of subgroup endarterectomy, the ECST and NASCET were analysed treatment effect modification in relative and absolute separately for patients with 50% or more stenosis. Both reductions in the risk of the primary outcome with trials showed the same patterns (figure 4). For patients surgery. In the predefined subgroups there was significant with 50% or more stenosis, estimates of the number of heterogeneity of risk reduction by each of the different patients needed to undergo surgery (NNT) to prevent one tests in relation to sex, age, and time since last event ipsilateral stroke in 5 years from the pooled data were nine (table 4). The effect of surgery on the 5-year absolute risk for men versus 36 for women, five for age 75 years or of ipsilateral ischaemic stroke is shown in figure 2 by older versus 18 for age younger than 65 years, and five for subgroup for all patients, and those with 50–69% and patients randomised within 2 weeks versus 125 for those 70% or more stenosis. Overall patterns in treatment effect randomised after more than 12 weeks. were consistent across the stenosis categories. For The absolute risk reduction with surgery in the 70% or example, benefit from carotid endarterectomy in patients more stenosis group is reduced by inclusion of patients with 50–69% stenosis was significantly less in women with near-occlusion, in whom surgery is less effective.13 By (p=0·04), fell significantly with increasing time since last exclusion of such individuals, figure 5 shows what could event (p=0·009), and tended to increase with age potentially be achieved by timely surgery in patients with (p=0·23). 70% or more (but not near-occluded) stenosis. The The three-way interaction terms in the Cox model did 30·2% reduction in absolute risk of stroke with carotid not identify significant relations between treatment effect endarterectomy in patients randomised within 2 weeks of by subgroup interaction and degree of stenosis for any their last event was reduced to nearly a third in patients subgroup, although there were non-significant trends for randomised more than 4 weeks after their last event. For the effect of irregular plaque (p=0·09) and primary patients with 50–69% stenosis, clinically important symptomatic event (p=0·08) on treatment effect to be benefit was only seen for those patients randomised within greater at higher degrees of stenosis. Figure 2 shows that 2 weeks of their last event. benefit tended to be greatest in patients with stroke and to progressively decline in individuals with cerebral transient Discussion ischaemic attack and retinal events in both the 50–69% We found three significant and clinically important and 70% or more stenosis groups, and also shows a trend subgroup treatment effect modifiers in the predefined towards greater benefit in patients with irregular plaque subgroup variables. Benefit from surgery was greater in

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For personal use. Only reproduce with permission from The Lancet publishing Group. ARTICLES 50 40 30 20 % ARR 95% CI) 10 0 –10 ARR (%) 95% CI 30 days after trial surgery according to predefined 70% stenosis у Events/patients 30 20 10 % ARR (95% CI) 0 –10 70% stenosis. ARR (%) 95% CI у 50–69% stenosis Events/patients 20 % ARR (95% CI) –10 0 10 ARR (%) 95% CI All patients Events/patients Surgical Medical Surgical Medical Surgical Medical 253/2307 Absolute reduction with surgery in 5-year actuarial risk of ipsilateral carotid ischaemic stroke and any or death within 75 32/288 65/297 11·9 5·7–18·1 14/104 22/100 10·7 –0·2–21·6 1/38 20/52 37·2 22·9–51·5 12 92/750 66/594 –0·7 –4·3–3·0 27/203 16/154 –2·9 –10·2–4·3 14/118 15/78 7·4 –3·3–18·1 Sex Men 301/1868 6·0 3·8–8·2 65/546 89/489 8·0 3·4–12·5 47/467 95/384 15·0 9·8–20·2 Women 134/929 107/789 –0·4 –3·8–3·0 36/262 21/205 –2·7 –8·8–3·5 27/199 39/166 9·9 1·8–18·0 Age (years) <65 186/1645 163/1255 2·2 –0·3–4·7 44/375 33/270 1·3 –4·0–6·7 42/356 60/280 9·8 3·8–15·7 65–74 169/1303 180/1105 4·1 1·2–7·1 43/329 55/324 5·4 –0·4–11·2 31/272 54/218 13·5 6·5–20·5 у Time since last event (weeks) <2 85/627 122/556 9·2 4·7–13·7 17/158 34/150 14·8 6·2–23·4 23/167 54/149 23·0 13·6–32·4 2–4 63/602 72/452 6·4 2·1–10·7 21/135 20/110 3·3 –6·3–13·0 10/133 24/105 15·9 6·6–25·2 4–12 147/1257 148/1055 2·9 0·0–5·8 36/312 40/280 4·0 –1·7–9·7 27/248 41/218 7·9 1·3–14·4 у Primary symptomatic event Ocular only 48/647 52/518 2·8 –0·6–6·2 17/170 17/155 1·5 –5·5–8·4 18/214 22/156 5·5 –1·2–12·1 TIA only 157/1160 144/952 2·3 –0·8–5·4 40/295 38/238 3·8 –2·6–10·1 25/207 53/199 15·4 7·7–23·1 Stroke 182/1429 212/1187 6·3 3·4–9·3 44/343 55/301 7·5 1·6–13·5 31/245 59/195 17·7 9·9–25·5 Diabetes Yes 86/518 92/456 5·4 0·2–10·6 29/143 32/136 6·2 –4·1–16·5 8/92 24/96 16·7 6·0–27·4 No 301/2718 316/2201 3·8 1·9–5·8 72/665 78/558 4·3 0·4–8·2 66/574 110/454 12·9 8·1–17·7 Symptomatic plaque surface Smooth 152/1379 150/1124 2·3 –0·4–4·9 40/296 35/266 3·3 –2·2–8·9 34/257 44/207 7·8 0·8–14·8 Irregular or ulcerated 235/1850 258/1524 5·5 3·0–8·0 71/512 75/428 5·7 0·7–10·6 40/409 90/343 17·1 11·6–22·6 Contralateral carotid occlusion Yes 23/112 26/140 –0·2 –10·5–10·1 9/31 5/45 –16·0 –34·8–2·8 5/32 14/37 23·6 3·2–44·0 No 364/3124 382/2517 4·2 2·3–6·1 92/777 105/649 5·7 1·9–9·5 69/634 120/513 12·7 8·3–17·1 Total 387/3236 408/2657 4·1 2·3–6·0 101/808 110/694 4·7 1·0–8·4 74/666 134/550 13·5 9·1–17·9 subgroup variables in all patients; individuals with 50–69% stenosis; and those Figure 2: ARR=absolute risk reduction. Size of squares representing point estimates is reduced by 75% in A.

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For personal use. Only reproduce with permission from The Lancet publishing Group. ARTICLES 4 30 20 10 0 –10 ARR (%) 95% CI 70% stenosis у n 30 days after trial surgery according to the post hoc 30 20 10 0 –10 ARR (%) 95% CI 70% stenosis у 50–69% stenosis 20 10 0 % ARR (95% CI) % ARR (95% CI) % ARR (95% CI) –10 ARR (%) 95% CI All patients Events/patients Events/patients Events/patients Surgical Medical Surgical Medical Surgical Medical Absolute reduction with surgery in 5-year cumulative risk of ipsilateral carotid ischaemic stroke and any or death withi 1 h 115/872 97/692 1·2 –2·3–4·8 32/228 23/175 –0·4 –7·4–6·6 20/166 42/163 14·4 6·0–22·8 р Duration of cerebral TIA TIA TIA >1 h 42/288 47/260 4·7 –1·7–11·2 8/67 15/63 15·6 2·0–29·2 5/41 11/36 19·9 1·3–38·5 Previous TIA or Stroke Yes 150/979 148/829 3·1 –0·5–6·6 40/266 32/202 1·9 –5·0–8·8 26/233 60/190 21·0 13·2–28·8 No 237/2257 260/1828 4·6 2·4–6·7 61/542 78/492 6·1 1·7–10·5 48/433 74/360 9·5 4·3–14·7 Myocardial infarction Yes 61/515 86/417 10·7 5·6–15·8 22/138 30/127 8·3 –1·9–18·4 12/109 22/84 16·2 4·9–27·5 No 326/2721 322/2240 3·0 1·0–4·9 79/670 80/567 3·6 –0·4–7·5 62/557 112/466 13·0 8·3–17·7 Angina Yes 84/705 111/575 8·0 3·7–12·2 25/191 32/166 6·9 –1·2–15·1 15/145 32/128 14·8 5·6–24·0 No 303/2531 297/2082 3·0 1·0–5·1 76/617 78/528 4·0 –0·2–8·1 59/521 102/422 13·1 8·1–18·1 Treated hypertension Yes 303/1501 231/1240 6·0 3·1–8·9 58/410 63/331 6·5 0·8–12·1 36/316 78/279 16·6 10·2–23·0 No 184/1735 177/1417 2·5 0·2–4·9 43/398 47/363 3·4 –1·5–8·2 38/350 56/271 10·1 4·2–16·0 Treated hyperlipidaemia Yes 72/615 94/633 3·8 –0·2–7·7 21/183 29/181 4·9 –2·6–12·4 22/124 33/136 6·6 –3·3–16·6 No 315/2621 314/2024 4·2 2·1–6·3 80/625 81/513 4·5 0·2–8·8 52/542 101/414 15·1 10·2–20·0 Smoking Yes 178/1436 180/1175 3·3 0·6–6·1 41/332 39/302 1·4 –4·0–6·8 43/351 73/291 12·9 6·8–19·0 No 209/1800 228/1482 5·0 2·5–7·4 60/476 71/392 7·5 2·4–12·6 31/315 61/259 14·1 7·9–20·3 Total 387/3236 408/2657 4·1 2·3–6·0 101/808 110/694 4·7 1·0–8·4 74/666 134/550 13·5 9·1–17·9 Figure 3: Size of squares representing point estimates is reduced by 75% in all patients. subgroup variables in all patients; individuals with 50–69% stenosis; and those with subgroup variables in all patients; individuals with 50–69%

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ECST Events / Patients ARR (%) 95% CI NASCET Surgical Medical Total Subgroup Sex Men 47/504 60/333 9·8 4·9–14·8 65/509 124/540 10·7 5·9–15·5 112/1013 184/873 11·0 7·6–14·4

Women 32/211 22/152 –0·4 –7·9–7·1 31/250 38/219 5·2 –1·5–11·9 63/461 60/371 2·8 –2·2–7·8

Age (years) <65 40/385 45/274 6·6 1·1–12·0 46/346 48/276 4·3 –1·6–10·1 86/731 93/550 5·6 1·6–9·6

65–74 33/283 28/180 4·8 –1·8–11·5 41/318 81/362 9·7 3·8–15·7 74/601 109/542 8·6 4·2–13·0

у75 years 6/47 9/31 19·1 0·1–38·1 9/95 33/121 19·2 8·9–29·5 15/142 42/152 19·2 10·2–28·2

Time since last event (weeks) <2 13/112 26/75 24·7 12·3–37·1 27/213 62/224 15·9 8·3–23·5 40/325 88/299 18·5 12·1–24·9

2–4 17/136 13/81 4·4 –5·5–14·2 14/132 31/134 13·1 4·0–22·2 31/268 44/215 9·8 3·0–16·5

4–12 29/271 31/216 4·1 –2·0–10·2 34/289 50/282 6·4 0·4–12·5 63/560 81/498 5·5 1·2–9·8

>12 20/196 12/113 0·7 –6·5–8·0 21/125 19/119 –3·1 –13·3–7·2 41/321 31/232 0·8 –5·2–6·8

Total 175/1474 244/1244 8·5 5·6–11·3

–10 0 10 20 30 % ARR (95% CI) Figure 4: Absolute reduction with surgery in the 5-year cumulative risk of ipsilateral carotid ischaemic stroke and any stroke or death within 30 days after trial surgery according to three variables in patients with у50% carotid stenosis in ECST and NASCET men than in women, and in the elderly, and benefit reports about leucoariosis on brain imaging,28 ipsilateral decreased with time since last symptoms. These intracranial stenosis of the internal carotid artery,29 and observations were consistent across the 50–69% and 70% angiographic collateral flow towards the symptomatic or more stenosis groups and across the two trials. Taken hemisphere.30 with other evidence discussed later, we feel that these In most trials of treatments for vascular disease, such as subgroup observations are sufficiently robust to be used to trials of blood-pressure lowering or lipid lowering, the guide the use of carotid endarterectomy in routine clinical effects of risk factors on the main outcome events are practice. Several other variables could not be studied in qualitatively similar in treatment and control groups. The the pooled data because they were not obtained in the analysis of subgroup effects in carotid endarterectomy is ECST. However, NASCET have published separate more difficult because the overall effect of surgery is

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40 30·2 70–99% stenosis possibly because of the healing of the unstable 50–69% stenosis atheromatous plaque or an increase in collateral blood flow to the symptomatic hemisphere, but there have been no 30 17·6 reliable data for the extent to which the effectiveness of 14·8 carotid endarterectomy also falls with time. There has been 20 11·4 8·9 concern that the operative risk might be increased if surgery is done early, especially in patients with major cerebral 3·3 38–40 4·0 infarction or stroke-in-evolution. For neurologically- ARR (%) 10 stable individuals, such as those enrolled in the trials, benefit from the operation was greatest in patients randomised within 2 weeks of their last event and fell 0 rapidly with increasing delay. However, most patients who undergo carotid endarterectomy for symptomatic stenosis –2·9 –10 in Europe and North America are being operated on more 0–2 2–4 4–12 >12 than 2 weeks after their presenting event, and many are Time from event to randomisation (weeks) operated on more than 12 weeks after the event, when benefit is considerably reduced in individuals with 70% or Figure 5: Absolute reduction with surgery in the 5-year more stenosis and absent in those with 50–69% stenosis. cumulative risk of ipsilateral carotid ischaemic stroke and any Clinical guidelines merely state that patients should be stroke or death within 30 days after trial surgery in patients operated on within 6 months of their presenting event,41–43 with 50–69% stenosis and у70% stenosis without near- and should now be revised on the basis of these results. We occlusion stratified by the time from last symptomatic event need to establish whether the reduction in benefit from to randomisation carotid endarterectomy with time from the presenting event Numbers above bars indicate actual absolute risk reduction. Vertical bars is dependent on the type of presenting event or other are 95% CIs. factors, but our overall findings have major implications for the urgency with which health services should assess and determined by the balance of two different outcomes investigate patients with transient ischaemic attack and (ipsilateral carotid territory ischaemic stroke on medical stroke. treatment versus the perioperative risk of stroke or death The drawbacks of subgroup analysis, particularly the within 30 days of carotid endarterectomy), which have very selective reporting of multiple post hoc analyses, are well different mechanisms. Specific risk factors might therefore documented.44,45 However, we believe that our results are have qualitatively different effects on the two outcomes, reliable. Our predefined analyses were chosen before which was the case in our analysis for sex, increasing age, pooling trial data, and we have reported all of the analyses and decreasing time from last event to randomisation. that were done. We reported the significance of only the Women had a lower risk of ipsilateral ischaemic stroke on overall interaction of the subgroup variable with the medical treatment and a higher operative risk than did men. treatment effect, rather than the significance of the The same patterns were also shown in a large trial of carotid treatment effect within each subgroup category. Statistical endarterectomy for asymptomatic stenosis.31 Consequently, tests of subgroup-treatment effect interaction terms are this procedure for asymptomatic stenosis was beneficial in conservative and a p value less than 0·1 is generally regarded men but not in women. We have shown that carotid as significant. However, to reduce the risk of chance endarterectomy is clearly beneficial in women with 70% or findings we specified significance as p<0·05 for predefined more symptomatic stenosis, but not in those with 50–69% subgroups and p<0·01 for post hoc subgroups. We were stenosis. Whether surgery is still indicated in individual also fortunate to have two major trials with very similar women will depend on the balance of their other risk methods and were therefore able to assess the consistency of factors.14,32 observations in two independent studies. Indeed, the Arguably, the increased benefit from surgery in patients consistency in the subgroup effects between the trials is older than 75 years might not be generalisable to routine more convincing than the significance of the overall effects. clinical practice because participants in trials generally have The degree of symptomatic carotid stenosis is the most a good outlook,33 and elderly patients might have a greater important determinant of benefit from carotid operative risk in clinical practice. There is some evidence of endarterectomy, but other factors, particularly the a higher operative risk in administrative database studies, timeliness of surgery, are also important. The procedure especially for patients older than 85 years,34 but in a recent should ideally be done within 2 weeks of the patient’s last systematic review of published surgical case-series, symptoms. The results of our analyses should be useful in researchers reported pooled odds of stroke and death of 1·2 identification of patients who are most likely to benefit from (95% CI 1·0–1·4, p=0·08, 19 studies) for patients older carotid endarterectomy, especially those with 50–69% than 75 years versus younger people, and 1·2 (0·9–1·5, stenosis, but the effects of combinations of these variables in p=0·19, 11 studies) for patients older than 80 years versus individual patients is yet to be established. younger individuals (Rothwell, unpublished data). There is therefore no justification for withholding carotid Contributors endarterectomy for patients older than 75 years who are P M Rothwell worked on the ECST trial from 1992, remeasured the ECST deemed medically fit to undergo surgery. Our analysis angiograms by the method used in the NASCET study, restructured indicates that benefit is likely to be greatest in this group baseline variables and outcomes in the individual trials to achieve because of their high risk of stroke on medical treatment, comparability, pooled the data, did the analyses, and wrote the manuscript. S A Gutnikov did the computer programming necessary to prepare and pool although it is noteworthy that the trials included very few the data from the individual trials, and analysed the data. M Eliasziw worked patients older than 80 years. on the NASCET trial, advised on pooling of the data, and commented on The urgency with which carotid endarterectomy should analyses and successive drafts of the manuscript. C P Warlow was the be done has been much debated.35,36 The risk of stroke on principal investigator on the ECST, and commented on analyses and successive drafts of the manuscript. H J M Barnett was the principal medical treatment after a transient ischaemic attack or investigator in the NASCET trial, and commented on analyses and minor stroke falls rapidly over the subsequent year,4,5,37 successive drafts of the manuscript.

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Conflict of interest statement risk of stroke in patients with severe carotid artery stenosis. Stroke 2000; None declared. 31: 128–32. 20 Alamowitch S, Eliasziw M, Algra A, Meldrum H, Barnett HJM, for the Acknowledgments NASCET trial. Risk, causes, and prevention of ischaemic stroke in We thank the collaborators in the original trials. Their names are listed in elderly patients with symptomatic internal carotid artery stenosis. Lancet the relevant final results reports.4,5 S A Gutnikov is funded by a grant from 2001; 357: 1154–60. the UK Stroke Association (grant 8/99). P M Rothwell is funded by the UK 21 Rothwell PM, Slattery J, Warlow CP. A systematic review of clinical and Medical Research Council (G116/112). M Eliasziw was funded by grant angiographic predictors of stroke and death due to carotid R01-NS-24456 from the National Institute of Neurological Disorders and endarterectomy. BMJ 1997; 315: 1571–77. Stroke, and by a senior health scholarship from the Alberta Heritage 22 Fields WS, Maslenikov V, Meyer JS, Hass WK, Remington RD, Foundation for Medical Research. ECST was funded by the UK Medical MacDonald M. Joint study of extracranial arterial occlusion: progress Research Council. NASCET was funded by the National Institute of report on prognosis following surgery or non-surgical treatment for Neurological Disorders and Stroke (grant R01-NS-24456). Salary support transient cerebral ischaemic attacks and cervical carotid artery lesions. for some of the researchers involved in this study was provided by the UK JAMA 1970; 211: 1993–03. Medical Research Council, which also funded the ECST; the UK Stroke 23 Shaw DA, Venables GS, Cartilidge NEF, Bates D, Dickinson PH. Association; and the National Institute of Neurological Disorders and Carotid endarterectomy in patients with transient cerebral ischaemia. Stroke, which also funded NASCET. J Neurol Sci 1984; 64: 45–53. 24 Cina CS, Clase CM, Haynes RB. Carotid endarterectomy for symptomatic carotid stenosis (Cochrane Review). In: References The Cochrane Library, Issue 3, 1999. Oxford: Update Software. 1 Tu JV, Hannan EL, Anderson GM, et al. The fall and rise of carotid 25 Howard VJ, Grizzle J, Diener HC, Hobson RW II, Mayberg MR, endarterectomy in the United States and Canada. N Engl J Med 1998; Toole JF. Comparison of multicenter study designs for investigation of 339: 1441–47. carotid endarterectomy efficacy. Stroke 1992; 23: 583–93. 2 Hsia DC, Moscoe LM, Krushat M. Epidemiology of carotid 26 Rothwell PM, Gibson R, Warlow CP. The interrelation between endarterectomy among medicare beneficiaries. Stroke 1998; 29: 346–50. plaque surface morphology, degree of stenosis and the risk of ischaemic 3 Masuhr F, Busch M, Einhaupl KM. Differences in medical and surgical stroke in patients with symptomatic carotid stenosis. Stroke 2000; 31: therapy for stroke prevention between leading experts in North America 615–21. and Western Europe. Stroke 1998; 29: 339–45. 27 Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, 4 European Carotid Surgery Trialists’ Collaborative Group. Randomised Barnett HJM. Significance of plaque ulceration in symptomatic patients trial of endarterectomy for recently symptomatic carotid stenosis: final with high-grade carotid stenosis: North American Symptomatic Carotid results of the MRC European Carotid Surgery Trial (ECST). Lancet Endarterectomy Trial. Stroke 1994; 25: 304–08. 1998; 351: 1379–87. 28 Streifler JY, Eliasziw M, Benavente OR, et al, for the NASCET trial. 5 North American Symptomatic Carotid Endarterectomy Trialists’ Prognostic importance of leukoaraiosis in patients with symptomatic Collaborative Group. The final results of the NASCET trial. internal carotid artery stenosis. Stroke 2002; 33: 1651–55. 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Carotid Lancet 1991; 337: 1235–43. endarterectomy for patients with asymptomatic internal carotid artery 8 North American Symptomatic Carotid Endarterectomy Trial stenosis. JAMA 1995; 273: 1421–28. Collaborators. Beneficial effect of carotid endarterectomy in 32 Barnett HJM, Meldrum HE, Eliasziw M. The appropriate use of carotid symptomatic patients with high-grade carotid stenosis. N Engl J Med endarterectomy. CMAJ 2002; 166: 1169–79. 1991; 325: 445–53. 33 Stiller CA. Centralised treatment, entry to trials and survival. 9 Barnett HJM, Warlow CP. Carotid endarterectomy and the Br J Cancer 1994; 70: 352–62. measurement of stenosis. Stroke 1993; 24: 1281–84. 34 Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES. 10 Rothwell PM, Gibson RJ, Slattery J, Sellar RJ, Warlow CP. 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Urgent carotid endarterectomy for monocular blindness associated with carotid artery stenosis. stroke in evolution. Vasa 2001; 30: 115–21. N Engl J Med 2001; 345: 1084–90. 41 The Intercollegiate Working Party for Stroke. National clinical 16 Eliasziw M, Streifler JY, Fox AJ, Hacjinski VC, Ferguson GG, guidelines for stroke. London: Royal College of Physicians, 2000. Barnett HJM, for the NASCET trial. Significance of plaque ulceration in 42 Moore WS, Barnett HJM, Beebe HG, et al. Guidelines for carotid symptomatic patients with high grade stenosis. Stroke 1994; 25: 304–08. endarterectomy: a multidisciplinary consensus statement from the ad 17 Morgenstern LB, Fox AJ, Sharpe BL, Eliasziw M, Barnett HJM, hoc committee, American Heart Association. Stroke 1995; 26: 188–201. Grotta JC, for the NASCET trial. The risks and benefits of carotid 43 Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy in patients with near occlusion of the carotid artery. endarterectomy: a statement for healthcare professionals from a special Neurology 1997; 48: 911–15. writing group of the Stroke Council, American Heart Association. 18 Kappelle LJ, Eliasziw M, Fox AJ, Sharpe BL, Barnett HJM, for the Circulation 1998; 97: 501–09. NASCET trial. Importance of intracranial atherosclerotic disease in 44 Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. patients with symptomatic stenosis of the internal carotid artery. Stroke Ann Intern Med 1992; 116: 78–84. 1999; 30: 282–86. 45 Peto R, Collins R, Gray R. Large-scale randomized evidence: large, 19 Henderson RD, Eliasziw M, Fox AJ, Rothwell PM, Barnett HJM, for simple trials and overviews of trials. J Clin Epidemiol 1995; 48: the NASCET trial. Angiographically defined collateral circulation and 23–40.

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