Handbook of Practical Medicine Stroke

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 865 16.11 Endarterectomy for symptomatic carotid stenosis 865 endarterectomy, but there are several other clinical and symptomatic event to randomization all modified the angiographic characteristics that might influence the effectiveness of surgery (Fig. 16.42). 466 For patients with risks and benefits of surgery as discussed above. ≥ 50% stenosis, the number needed to operate to prevent NASCET published 11 reports of different univariate one ipsilateral stroke in five years was: subgroup analyses, which are summarized elsewhere. 1 • nine for men vs 36 for women; Although interesting, the results are difficult to interpret • five for age ≥ 75 vs 18 for age < 65 years; because several of the subgroups contained only a few • five for patients randomized within 2 weeks after their tens of patients, with some of the estimates of the effect last ischaemic event vs 125 for patients randomized > of surgery based on only one or two outcome events in 12 weeks. each treatment group, the 95% confidence intervals These observations were consistent across the 50–69% around the absolute risk reductions in each subgroup and ≥ 70% stenosis groups and similar trends were have generally not been given, and there were no formal present in both ECST and NASCET. The fall-off in the tests of the interaction between the subgroup variable absolute benefit of surgery with time since last event and the treatment effect. It is, therefore, impossible to (Fig. 16.43) is particularly important in terms of auditing be certain whether differences in the effect of surgery the performance of stroke prevention services in routine between subgroups were real or due to chance. Sub- clinical practice. group analyses of pooled data from ECST and NASCET Women had a lower risk of ipsilateral ischaemic stroke have greater power to determine subgroup–treatment on medical treatment and a higher operative risk in interactions reliably and there are several clinically comparison to men. For recently symptomatic carotid important interactions: sex, age, and time from the last stenosis, surgery is very clearly beneficial in women with 50–69% stenosis group ≥ 70% stenosis group Events/Patients Events/Patients ARR (%) 95% CI ARR (%) 95% CI Surgical Medical Surgical Medical Sex Male 65/546 89/489 8.0 3.4–12.5 47/467 95/384 15.0 9.8–20.2 Female 36/262 21/205 –2.7 –8.8–3.5 27/199 39/166 9.9 1.8–18.0 Age < 65 years 44/375 33/270 1.3 –4.0–6.7 42/356 60/280 9.8 3.8–15.7 65–74 years 43/329 55/324 5.4 –0.4–11.2 31/272 54/218 13.5 6.5–20.5 >75 years 14/104 22/100 10.7 –0.2–21.6 1/38 20/52 37.2 22.9–51.5 Time since last event < 2 weeks 17/158 34/150 14.8 6.2–23.4 23/167 54/149 23.0 13.6–32.4 2–4 weeks 21/135 20/110 3.3 –6.3–13.0 10/133 24/105 15.9 6.6–25.2 4–12 weeks 36/312 40/280 4.0 –1.7–9.7 27/248 41/218 7.9 1.3–14.4 > 12 weeks 27/203 16/154 –2.9 –10.2–4.3 14/118 15/78 7.4 –3.3–18.1 Primary symptomatic event Ocular only 17/170 17/155 1.5 –5.5–8.4 18/214 22/156 5.5 –1.2–12.1 TIA 40/295 38/238 3.8 –2.6–10.1 25/207 53/199 15.4 7.7–23.1 Stroke 44/343 55/301 7.5 1.6–13.5 31/245 59/195 17.7 9.9–25.5 Diabetes Yes 29/143 32/136 6.2 –4.1–16.5 8/92 24/96 16.7 6.0–27.4 No 72/665 78/558 4.3 0.4–8.2 66/574 110/454 12.9 8.1–17.7 Symptomatic plaque surface Smooth 40/296 35/266 3.3 –2.2–8.9 34/257 44/207 7.8 0.8–14.8 Irreg/ulcerated 71/512 75/428 5.7 0.7–10.6 40/409 90/343 17.1 11.6–22.6 Contralateral carotid occlusion Yes 9/31 5/45 –16.0 –34.8–2.8 5/32 14/37 23.6 3.2–44.0 No 92/777 105/649 5.7 1.9–9.5 69/634 120/513 12.7 8.3–17.1 TOTAL 101/808 110/694 4.7 1.0–8.4 74/666 134/550 13.5 9.1–17.9 –10 0 10 20 30 –10 0 10 20 30 40 50 % Absolute risk reduction (95% CI) % Absolute risk reduction (95% CI) Fig. 16.42 Absolute reduction with surgery in the 5-year risk of proportional to the amount of data represented by each box ipsilateral carotid territory ischaemic stroke and any stroke or and the horizontal lines represent 95% confidence intervals. death within 30 days after surgery according to predefined (Derived from Rothwell et al., 2004. 466 ) CI, confidence interval; subgroup variables in: patients with 50–69% stenosis; patients ARR, absolute risk reduction. with ≥ 70% stenosis. The size of the purple boxes is .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 866 866 Chapter 16 Preventing recurrent stroke and other serious vascular events 40.0 30.2 a way that cannot be described using univariate subgroup analysis, and all of which should be taken into account 30.0 14.8 17.6 to determine the likely balance of risk and benefit ARR (%), 95% CI 20.0 3.3 11.4 4.0 8.9 benefit from surgery in a 78-year-old (increased benefit) 495 For example, what would be the likely from surgery. female (reduced benefit) with 70% stenosis who pre- sented within 2 weeks (increased benefit) of an ocular 10.0 have an ulcerated carotid plaque (increased benefit)? 0.0 ischaemic event (reduced benefit) and who was found to One way to weigh the often-conflicting effects of the –2.9 important characteristics of an individual patient on –10.0 0–2 2–4 4–12 12+ the likely benefit from treatment is to base decisions on Weeks from event to randomization the predicted absolute risks of a poor outcome with each treatment option, using prognostic models. Fig. 16.43 Absolute risk reduction (ARR) with surgery in the 5-year risk of ipsilateral carotid territory ischaemic stroke and One such model for prediction of the risk of stroke any stroke or death within 30 days after surgery in patients on medical treatment in patients with recently symp- with 50–69% stenosis (light purple bars) and ≥ 70% stenosis tomatic carotid stenosis has been derived from the ECST (purple bars) without near-occlusion, stratified by the time (Table 16.14). 1,495 The model was validated using data from last symptomatic event to randomization (Rothwell et al., from the NASCET and showed very good agreement 2004 466 ). The numbers above the bars indicate the actual between predicted and observed medical risk, reliably absolute risk reduction. CI, confidence interval. distinguishing between individuals with a 10% risk of ipsilateral ischaemic stroke after 5 years of follow-up and ≥ 70% stenosis, but not in women with 50–69% sten- those with a risk of over 40% (Fig. 16.44). Importantly, osis (Fig. 16.42). In contrast, surgery reduced the 5-year Fig. 16.44 also shows that the operative risk of stroke absolute risk of stroke by 8.0% in men with 50–69% or death in patients who were randomized to surgery stenosis. These same patterns were also shown in both in NASCET was unrelated to the medical risk. Thus, of the large published trials of endarterectomy for asymptomatic carotid stenosis. 494 50 Benefit from surgery increased with age in the pooled analysis, particularly in patients aged over 75 years (Fig. 16.42). Although patients randomized in trials generally 40 have a good prognosis and there is some evidence of an increased operative mortality in elderly patients in routine clinical practice, as discussed above there is no 30 increase in the operative risk of stroke and death in older Observed risk (%) age groups. There is therefore no justification for with- holding surgery in patients aged over 75 years who are 20 deemed to be medically fit. The evidence suggests that benefit is likely to be greatest in this group because of 10 their high risk of stroke without surgery. Finally, benefit from surgery is probably greatest in patients with stroke, intermediate in those with cerebral 0 TIA and lowest in those with ocular events (Fig. 16.42). 0102030405 0 There was also a trend in the trials towards greater benefit Predicted medical risk (%) in patients with irregular plaque than a smooth plaque. Fig. 16.44 Validation of the ECST model (Table 16.14) for the 5-year risk of stroke on medical treatment in patients with Which individuals benefit most? 50–99% stenosis in NASCET (Rothwell et al., 2005 ). Predicted 1 medical risk is plotted against observed risk of stroke in patients Although there are some clinically useful subgroup randomized to medical treatment in NASCET (squares) and observations in the pooled analysis of the trials, uni- against the observed operative risk of stroke or death in variate subgroup analysis is often of only limited use in patients randomized to surgical treatment (diamonds). Groups clinical practice. Individual patients frequently have are quintiles of predicted risk. Error bars represent 95% several important risk factors, each of which interacts in confidence intervals. .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 867 16.11 Endarterectomy for symptomatic carotid stenosis 867 Table 16.14 A predictive model for the 5-year risk of ipsilateral ischaemic stroke on medical treatment in patients with recently 1 symptomatic carotid stenosis (Rothwell et al., 2005 ). Hazard ratios derived from the model are used for the scoring system. The score for the 5-year risk of stroke is the product of the individual scores for each of the risk factors present. The score is converted into a risk using the graphic in Fig. 16.45. An example is shown. MODEL SCORING SYSTEM EXAMPLE Risk factor Hazard ratio (95%CI) P-value Risk factor Score Stenosis (per 10%) 1.18 (1.10–1.25) <0.0001 Stenosis (%) 50–59 2.4 2.4 60–69 2.8 70–79 3.3 80–89 3.9 90–99 4.6 Near occlusion 0.49 (0.19–1.24) 0.1309 Near occlusion 0.5 No Male sex 1.19 (0.81–1.75) 0.3687 Male sex 1.2 No Age (per 10 years) 1.12 (0.89–1.39) 0.3343 Age (years) 31–40 1.1 41–50 1.2 51–60 1.3 61–70 1.5 1.5 71–80 1.6 81–90 1.8 Time since last event (per 7 days) 0.96 (0.93–0.99) 0.0039 Time since last event (days) 0–13 8.7 8.7 14–28 8.0 29–89 6.3 90–365 2.3 Presenting event 0.0067 Presenting event Ocular 1.000 Ocular 1.0 Single transient 1.41 (0.75–2.66) Single transient ischaemic attack ischaemic attack 1.4 Multiple transient 2.05 (1.16–3.60) Multiple transient ischaemic attacks ischaemic attacks 2.0 Minor stroke 1.82 (0.99–3.34) Minor stroke 1.8 Major stroke 2.54 (1.48–4.35) Major stroke 2.5 2.5 Diabetes 1.35 (0.86–2.11) 0.1881 Diabetes 1.4 1.4 Previous myocardial 1.57 (1.01–2.45) 0.0471 Previous myocardial infarction infarction 1.6 No Peripheral vascular 1.18 (0.78–1.77) 0.4368 Peripheral vascular 1.2 No disease disease Treated hypertension 1.24 (0.88–1.75) 0.2137 Treated hypertension 1.2 1.2 Irregular/ulcerated 2.03 (1.31–3.14) 0.0015 Irregular/ulcerated plaque plaque 2.0 2.0 TOTAL RISK SCORE 263 PREDICTED MEDICAL RISK USING NOMOGRAM (Fig. 16.45) 37% In cases of near-occlusion, enter degree of stenosis as 85%. Presenting event is coded as the most severe ipsilateral symptomatic event in the last 6 months (severity is as ordered above, i.e. ocular events are least severe and major stroke is most severe). Major stroke is defined as stroke with symptoms persisting for at least 7 days. Treated hypertension includes previously treated or newly diagnosed. .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 868 868 Chapter 16 Preventing recurrent stroke and other serious vascular events when the operative risk and the small additional residual have the major advantage that they do not require the risk of stroke following successful endarterectomy were calculation of any score by the clinician or patient. taken into account, benefit from endarterectomy at Figure 16.46 shows a risk table for the 5-year risk of 5 years varied significantly across the quintiles, with no ipsilateral ischaemic stroke in patients with recently benefit in patients in the lower three quintiles of symptomatic carotid stenosis on medical treatment predicted medical risk (absolute risk reduction 0–2%), derived from the ECST model. moderate benefit in the fourth quintile (absolute risk One potential problem with the ECST risk model is reduction 12%), and substantial benefit in the highest that it might overestimate risk in current patients quintile (absolute risk reduction 32%). because of improvements in medical treatment, such as Prediction of risk using models requires a computer, a the increased use of statins. However, this poses more pocket calculator with an exponential function, or inter- problems for generalizability of the overall trial results net access (the ECST model is at www.stroke.ox.ac.uk). than for the risk modelling approach. For example, it As an alternative, a simplified risk score based on the would take only a relatively modest improvement in the hazard ratios derived from the relevant risk model can effectiveness of medical treatment to erode the overall be derived (Table 16.14). As is shown in the example, the benefit of endarterectomy in patients with 50–69% total risk score is the product of the scores for each risk stenosis. In contrast, very major improvements in factor. Figure 16.45 shows a plot of the total risk score medical treatment would be required to significantly against the 5-year predicted risk of ipsilateral carotid ter- reduce the benefit from surgery in patients in the high ritory ischaemic stroke derived from the full model, and predicted-risk quintile in Fig. 16.44. Thus, the likelihood is used as a nomogram for the conversion of the score that ancillary treatments have improved, and are likely into a risk prediction. to continue to improve, is an argument in favour of a Alternatively, risk tables allow a relatively small risk-based approach to targeting treatment. However, it number of important variables to be considered and would be reasonable in a patient on treatment with a statin, for example, to reduce the risks derived from the risk model by 20% in relative terms (Fig 16.45). 75 Other prognostic tools, such as measurements of cere- 70 bral reactivity and emboli load on transcranial Doppler 65 (section 6.8.9) are not widely used in clinical practice 60 and it is unclear to what extent they are likely to add to Per cent predicted medical risk 45 Medical risk if reduced by 20% 16.11.9 Management of patients with other 55 18,496,497 the predictive value of the ECST model. 50 40 potential causes of stroke as well as carotid 35 stenosis 30 An occasional patient with a lacunar ischaemic stroke 25 20 severe carotid stenosis (section 6.4). The question then 15 or transient ischaemic attack (TIA) may have ipsilateral arises whether the stenosis is ‘symptomatic’ (i.e. a small 10 deep lacunar infarct has, unusually, been caused by 5 artery-to-artery embolism or low flow) or ‘asymptomatic’ 0 (i.e. the stenosis is a coincidental bystander and the 0 40 80 120 160 200 240 280 320 360 400 440 480 520 560 600 640 680 infarct was really due to intracranial small vessel disease). The observational studies mostly show that severe stenosis Risk score is about equally rare in the symptomatic and contra- Fig. 16.45 A plot of the total risk score derived from Table lateral carotid arteries of patients with lacunar stroke, 16.14 against the 5-year predicted risk of ipsilateral carotid which rather supports the notion of the stenosis territory ischaemic stroke derived from the full model in the 498 being coincidental, but this doesn’t mean that surgery table in patients in the ECST (thick line). This should be used as wouldn’t still be beneficial. In fact, the published data a nomogram for the conversion of the score into a prediction of 1 the percentage risk (Rothwell et al., 2005 ). The thin line from RCTs show that endarterectomy is beneficial for represents a 20% reduction in risk as might be seen with more patients with severe stenosis ipsilateral to a lacunar intensive medical treatment than was available in the ECST in TIA or stroke, although not for patients with moderate the late 1980s and 1990s. stenosis. 499,500 .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 869 16.11 Endarterectomy for symptomatic carotid stenosis 869 MEN 50–69% stenosis 70–99% stenosis Smooth stenosis Ulcerated/irregular Smooth stenosis Ulcerated/irregular Stroke Age TIA 75+ Ocular Stroke Age TIA 65–74 Ocular % Stroke <10 Age TIA 10–15 <65 Ocular 15–20 >12 4–12 2–4 <2 >12 4–12 2–4 <2 >12 4–12 2–4 <2 >12 4–12 2–4 <2 20–25 Time since last event (weeks) Time since last event (weeks) 25–30 WOMEN 50–69% stenosis 70–99% stenosis 30–35 Smooth stenosis Ulcerated/irregular Smooth stenosis Ulcerated/irregular 35–40 Stroke 40–45 TIA Age 75+ 45–50 Ocular >50 Stroke TIA Age 65–74 Ocular Stroke TIA Age <65 Ocular >12 4–12 2–4 <2 >12 4–12 2–4 <2 >12 4–12 2–4 <2 >12 4–12 2–4 <2 Time since last event (weeks) Time since last event (weeks) Fig. 16.46 A table of the 5-year predicted absolute risk of important patient characteristics. TIA, transient ischaemic ipsilateral carotid territory ischaemic stroke on medical attack. (Figs 16.44–16.46 reprinted from Rothwell et al., Lancet 1 treatment in ECST patients with recently symptomatic carotid © 2005 with permission from Elsevier.) stenosis derived from a Cox model based on six clinically .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 870 870 Chapter 16 Preventing recurrent stroke and other serious vascular events The same arguments probably apply if there is also a 16.12.2 Evidence of benefit major coexisting source of embolism from the heart (such as non-rheumatic atrial fibrillation), in which case Whether the benefits of carotid endarterectomy in the patient may reasonably be offered surgery as well patients with asymptomatic stenosis justify the risks as anticoagulation (section 16.6.2). With the more and cost is still unclear, particularly in an era of widespread use of MR DWI it is, of course, more often improved medical treatments. 501,502 Until relatively possible now to infer the likely aetiology of stroke from recently, guidelines were largely based on the results of the distribution of acute ischaemic lesions (section the Asymptomatic Carotid Atherosclerosis Study (ACAS) 5.5.2). and a few other smaller trials. 502,503 ACAS reported a 47% relative reduction in the risk of ipsilateral stroke or perioperative death in the surgical arm, but a 5-year risk of ipsilateral stroke without the operation of only 11%, even though the patients had moderate or severe steno- 16.12 Endarterectomy for asymptomatic sis. Therefore, even in this optimal trial environment, carotid stenosis the absolute reduction in risk of stroke with endarterec- tomy was only about 1% per year. Of some concern is that the remarkably low operative risks in ACAS may not be matched in routine clinical practice because ACAS 16.12.1 Introduction only accepted surgeons with an excellent safety record, As far as one can tell, less than 20% of ischaemic stroke rejecting 40% of the initial applicants and subsequently patients have had any preceding transient ischaemic barring from further participation some surgeons who attacks (TIAs), even when the stroke is likely to have had adverse operative outcomes during the trial. 504 been due to the embolic or low-flow consequences of Before joining the later, and more pragmatic Asymp- severe carotid stenosis. Until the moment of stroke, any tomatic Carotid Surgery Trial (ACST), the surgeons had stenosis in the other 80% of the patients had been to provide evidence of an operative risk of 6% or less ‘asymptomatic’. It follows that if these asymptomatic for their last 50 patients having an endarterectomy for stenoses could be detected before the stroke, then unher- asymptomatic stenosis, but none were excluded on the alded (by TIA) stroke might be preventable by carotid basis of his/her operative risk during the trial. 505 Selec- endarterectomy, particularly as surgery is beneficial in tion of patients was based on the ‘uncertainty principle’, patients whose stenosis has revealed itself by becoming with very few exclusion criteria. ‘symptomatic’ (section 16.11). Despite the differences in their methods, the absolute Asymptomatic carotid stenosis may be identified reductions in 5-year risk of stroke with surgery were sim- under at least four circumstances: ilar in the two trials: 5.3% (95% CI 3.0–7.8%) in ACST vs • during screening programmes of apparently healthy 5.1% (95% CI 0.9–9.1%) in ACAS. In addition, whereas people when a carotid bruit is heard and/or carotid ACAS had reported only a non-significant 2.7% reduc- ultrasound is being used routinely; tion in the absolute risk of disabling or fatal stroke with • as a result of hearing a carotid bruit or doing an ultra- surgery, ACST reported a significant 2.5% (95% CI 0.8– sound examination during the course of working 4.3%) absolute reduction, although the number-needed- up patients with angina, claudication or non-focal to-operate to prevent one disabling or fatal stroke after neurological symptoms; 5 years remains about 40. The main difference between • when bilateral carotid imaging is done in patients with the trials was in the 30-day operative risks of death of unilateral carotid symptoms (i.e. the patient is symp- 0.14% in ACAS vs 1.11% in ACST, and in the combined tomatic but one carotid artery is asymptomatic); operative risk of stroke and death of 1.5% in ACAS vs • when patients are being worked up for major surgery 3.0% in ACST. below the neck and a carotid bruit is heard or an ultra- sound reveals carotid stenosis. 16.12.3 Selection of patients for carotid When asymptomatic carotid stenosis does come to endarterectomy attention, four questions arise: What is the risk of operat- ing on it? What is the risk (of stroke) if the stenosis is As discussed earlier, the decision to perform carotid left unoperated? Does surgery reduce the risk of stroke? endarterectomy should not be taken lightly, given the What is the balance of immediate surgical risk vs long- inevitable anxiety and risks faced by patients undergoing term benefit? surgery. Applying the same arithmetical approach used .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 871 16.12 Endarterectomy for asymptomatic carotid stenosis 871 for symptomatic stenosis (section 16.11.6), if the surgical 16.12.5 Who benefits most from surgery for risk of stroke is say 4% in routine clinical practice, if the asymptomatic carotid stenosis? unoperated risk of stroke is 10% after 5 years on inten- sive medical treatment, and if successful surgery reduces Given the surgical risk (which to some extent must this risk of stroke to almost zero, then doing about 100 depend on the type of patient under consideration as operations would cause four strokes and avoid up to 10, well as surgical skill), the added risk of any preceding the numbers-needed-to-operate to prevent one stroke catheter angiography unless non-invasive vascular imag- would be 17, about 34 for disabling stroke. Therefore to ing is deemed sufficiently accurate, and what appears to reduce the number-needed-to-operate and increase the be a remarkably low risk of stroke in unoperated patients chance of an individual patient being benefited, it is (even when they have major surgery below the neck), essential that we know who is at highest risk of surgical there is clearly no reason to recommend routine carotid stroke, and who will survive to be at highest risk of endarterectomy for asymptomatic stenosis. It follows ipsilateral ischaemic stroke without surgery. Furthermore, that deliberately screening apparently healthy people given the high cost of surgery even for symptomatic for carotid stenosis is also unwise. What is needed is a carotid stenosis, we need to be aware of the health- prognostic model to pick out those very few patients economic and public health issues related to surgery for whose asymptomatic stenosis is particularly likely to asymptomatic stenosis. 463,464 cause stroke, and then operate only on them. Although carotid endarterectomy may even halve the 16.12.4 Risk of carotid endarterectomy for risk of stroke in patients with asymptomatic severe asymptomatic carotid stenosis stenosis, the absolute unoperated risk of stroke is There are a large number of case series with very different usually so low in these patients that surgery is rarely reported surgical stroke risks for the same reasons as in worthwhile. symptomatic carotid stenosis (section 16.11.3). Although the risk is about half that for symptomatic carotid Which range of stenosis? stenosis, there is still some risk. 428,506 Indeed, the risk may not necessarily be very low in, for example, patients Although the risk of ipsilateral ischaemic stroke on med- with angina whose carotid stenosis was discovered dur- ical treatment increases with degree of carotid stenosis ing preparation for coronary artery surgery, or in patients (Fig. 16.47), in contrast to trials of endarterectomy in who have already had an endarterectomy on one side patients with symptomatic carotid stenosis, neither and are at risk of bilateral vagal or hypoglossal nerve ACST nor ACAS showed increasing benefit from surgery palsies if both sides are operated on (section 16.11.4). with increasing stenosis within the 60–99% range. There As for symptomatic stenosis, the risk of surgery cannot are several possible explanations for this: be generalized from the literature to one’s own institu- • First, ultrasound may be less accurate than catheter tion, that risk should be known locally. Even judging angiography in measuring the degree of stenosis. In from the literature, a systematic review found much ACAS, only patients randomized to surgery underwent higher risks than in ACAS. 506 The overall risk of stroke catheter angiography, and in ACST all imaging was and death was 3.0% in 28 studies published post-ACAS. by ultrasound without any centralized audit. 508 The The risk in 12 studies in which outcome was assessed importance of the precise method used to measure by a neurologist (4.6%) was three times higher than in stenosis was highlighted in a study of patients in the ACAS. Operative mortality (1.1%) was eight times higher no-surgery arm of the ECST which demonstrated that than in ACAS. In studies that reported outcome after angiographic measures of stenosis were most reliable endarterectomy for symptomatic and asymptomatic in predicting recurrent stroke when selective carotid stenosis in the same institution, operative mortality was contrast injections had been given, biplane views were no lower for asymptomatic stenosis (OR 0.80; 95% CI available and when the mean of measurements made 0.6–1.1). Thus, published risks of stroke and death due by two independent observers was used. 509 to surgery for asymptomatic stenosis are considerably • Second, patients with carotid near-occlusion, which higher than in ACAS, particularly if outcome had been is not readily detectable on ultrasound, were not assessed by a neurologist. And even after community- identified in the asymptomatic stenosis trials. In the wide performance measurement and feedback, the ECST, for example, only when near-occlusions were overall risk for stroke or death after endarterectomy for removed was the increased benefit of surgery with asymptomatic stenosis in 10 US states was still 3.8%. 507 increasing stenosis between 70% and 99% clearly .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 872 872 Chapter 16 Preventing recurrent stroke and other serious vascular events 15 40 35 Three-year stroke risk (95% CI) 25 41 Fig. 16.47 Kaplan–Meier 3-year estimates 30 20 (with 95% confidence intervals) of the risk of stroke lasting more than 7 days in the 15 distribution of the asymptomatic carotid 10 Surgery Trial by deciles of diameter 248 103 71 55 artery in patients in the European Carotid carotid stenosis. The number above each 180 5 480 351 439 error bar refers to the number of patients 312 in each stenosis group. (Reprinted from 0 European Carotid Surgery Trialists’ 0–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80–89 90–99 100 Collaborative Group, Lancet 573 Degree of asymptomatic carotid stenosis (%) © 2005 with permission from Elsevier.) apparent. 447 This issue is further complicated by the reported separately. 505 The overall balance of hazard and findings of recent study in which increasing asymp- benefit, which is of most importance to patients and tomatic stenosis on ultrasound was positively associ- clinicians, was not reported, although data could be ated with the risk of ipsilateral hemispheric ischaemic extracted from the web-tables that accompanied the ACST events when stenosis was measured using the ECST report. In a meta-analysis of the effect of endarterectomy criteria, but not when NASCET criteria were used. 510 on the 5-year risk of any stroke and perioperative death • Third, the rate of stenosis progression may determine in ACAS and ACST (Fig. 16.48) the benefit from surgery the risk of stroke in patients with asymptomatic was greater in men than in women, and it was uncertain stenosis, which is potentially important considering the whether there was any worthwhile benefit in women longer time frame over which strokes occur compared at all, although some benefit may emerge with longer with symptomatic stenosis. In the ECST, there was a follow-up which is ongoing in ACST. 494 In patients with strong association between the risk of ipsilateral stroke symptomatic 70–99% stenosis, the surgical complication and the degree of carotid stenosis only for strokes that risk is higher in the presence of contralateral occlusion, occurred during the first year after randomization, and although the evidence still favours endarterectomy in no relationship was seen between initial stenosis and these patients. 466 However, a post-hoc analysis from ACAS strokes occurring more than 2 years later. 445,483 While found that patients with contralateral occlusion derived this could have been partly due to plaque ‘healing’, it no long-term benefit from endarterectomy, largely due is conceivable that in some patients the stenosis had to a lower long-term risk on medical treatment but this progressed and the rate of this progression, rather than analysis was under-powered (163 patients) and there was the degree of stenosis at baseline, was the important no confirmation of this effect in ACST. 505,511 determinant of stroke risk. Which individuals benefit most? Which subgroups benefit most? Given the small absolute reductions in the risk of stroke Although some subgroup analyses were reported in in ACST and ACAS, and the lack of a definite effect in ACAS, the trial had insufficient power to reliably analyse women, there is an urgent need to identify exactly which subgroup–treatment effect interactions. Because of its individual patients are at highest risk of stroke and which larger sample size, ACST had greater power, although individuals are at such low risk that the risks of surgery no analyses were pre-specified in the protocol, and the cannot be justified. At present, it does not seem justifi- reduction in risk of non-perioperative stroke (i.e. the able to operate on patients ‘just because they have asym- benefit) and the perioperative risk (i.e. the harm) were ptomatic severe stenosis’, the number-needed-to-operate .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 873 16.13 Carotid angioplasty and stenting 873 Events/Patients Subgroup Surgical Medical OR 95% CI Fig. 16.48 The effect of endarterectomy Males for asymptomatic carotid stenosis on the ACST 51/1021 97/1023 0.50 0.35–0.72 risk of any stroke or operative death by sex ACAS 18/544 38/547 0.46 0.26–0.81 in the Asymptomatic Carotid Surgery Trial (ACST) and the Asymptomatic TOTAL 69/1565 135/1570 0.49 0.36–0.66 Carotid Atherosclerosis Study (ACAS). Each trial result is represented by a purple Females box whose size is proportional to the ACST 31/539 34/537 0.90 0.55–1.49 statistical weight for that outcome, and ACAS 15/281 14/287 1.10 0.52–1.82 horizontal lines representing 95% confidence intervals. The pooled results TOTAL 46/820 48/824 0.96 0.63–1.45 are represented by diamonds whose widths represent the 95% confidence 0 0.5 1 1.5 intervals. (From Rothwell, 2004 494 ). Odds ratio (95% CI) to prevent one stroke is far too high, and the advantage accurate quantification of fibrous cap thickness. 518 There for any individual patient is far too low. A risk modelling is also good evidence that inflammation has a causal approach similar to that used in symptomatic carotid role in carotid plaque instability. 519,520 MR visualization stenosis is required, perhaps combining patient clinical of plaque macrophages after their uptake of ultra-small features with the results of potentially prognostic invest- particles of iron oxide (USPIO) is now possible. 521,522 igations, such as transcranial Doppler-detected emboli, However, large prospective studies are required to deter- impaired cerebral reactivity, the nature of the stenotic mine whether any of these imaging characteristics plaque on imaging and the rate of plaque progression. predict the risk of stroke well enough to help select Rates of micro-embolic signals detected on transcranial asymptomatic stenosis patients for endarterectomy. Doppler ultrasound scanning might well provide progno- stically useful information but so far the results of studies are mixed. 18,512,513 Further data will soon be available from the ongoing ACES study. 514 Several observational studies have suggested that 16.13 Carotid angioplasty and stenting increased plaque echolucency (a marker of plaque lipid and haemorrhage content) on ultrasound is associated with higher risks of stroke and TIA distal to a carotid Endovascular treatment was first used for the limb arter- stenosis. 515 However, most were in patients with symp- ies in the 1960s, and subsequently in the renal and tomatic stenosis and included TIA in the primary out- coronary arteries, 523 but was introduced more cautiously come. In a recent cohort study of asymptomatic stenosis for treatment of carotid stenosis in the early 1990s because patients, the cumulative stroke rate was 2% per year in of the likely high risk of stroke due to embolization patients with plaques which were uniformly or partly of atheromatous debris during the procedure. However, echolucent and 0.14% per year in the remaining pa- the argument goes that if endarterectomy of a recently tients. 516 However, plaque echolucency on ultrasound symptomatic severe carotid stenosis more-or-less abol- was not associated with benefit from surgery in ACST ishes the risk of ipsilateral ischaemic stroke, then percu- and further research is required to clarify the significance taneous transluminal balloon angioplasty (Fig. 16.49), of plaque lipid content in patients with asymptomatic particularly with stenting (Fig. 16.50) to maintain art- stenosis. 505 erial patency, could do so as well. 524 Indeed, the endo- Other methods of plaque imaging might also turn vascular approach has now become widely used when out to be of prognostic value. In a study of 154 patients carotid pathology makes endarterectomy difficult (e.g. with asymptomatic carotid stenosis imaged with multi- high bifurcation or post-radiation stenosis), although it contrast-weighted MRI, thin or ruptured fibrous cap, is not always feasible because of contrast allergy, difficult intra-plaque haemorrhage, and large lipid core were all vascular anatomy or lumen thrombus. associated with ipsilateral TIA and stroke on follow- Of course, angioplasty and stenting is usually less un- up. 517 With gadolinium enhancement, the fibrous cap pleasant and less invasive than carotid endarterectomy, can be visualized more easily on MRI which may allow and generally more convenient and quicker. Not requiring .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 874 874 Chapter 16 Preventing recurrent stroke and other serious vascular events (a) i ii iii iv Fig. 16.49 Percutaneous transluminal (b) balloon angioplasty of the carotid artery. (a) Diagram to show the principle of angioplasty: (i) the carotid bifurcation with a severe atherothrombotic stenosis; (ii) the guidewire (small short arrow) with the deflated (short thick arrow) balloon catheter (long arrows) is passed across the stenosis; (iii) the balloon is inflated (in some systems the guidewire may be withdrawn prior to inflation, in others it is left in) and the plaque is pushed outwards, so stretching the arterial wall and cracking the plaque; (iv) after the balloon is deflated and removed, the lumen has been widened, the arterial wall remains stretched and the plaque remains. (b) Catheter carotid angiogram to show stenosis: (i) before (arrow) and (ii) after (arrow) angioplasty; the tight stenosis has been converted to a more normal iii (looking) lumen. general anaesthesia, there may be less perioperative • Dilatation of the balloon may cause bradycardia hypertension although cerebral haemorrhage and hyper- or hypotension due to carotid sinus stimulation, or perfusion have been reported. 525,526 It is unlikely to aneurysm formation and even arterial rupture due to cause nerve injuries, wound infection, venous throm- over-distension of the arterial wall. boembolism or myocardial infarction, and hospital stay • Rarely the stent may erode through the arterial wall, may be shorter, but there are potential disadvantages: or fracture. • The angioplasty balloon may dislodge atherothrom- • In the longer-term, restenosis might be more problem- botic debris which then embolizes to the brain or eye, atic after stenting than after endarterectomy. although protection devices might help to reduce the • Haematoma and aneurysm formation may occur at risk of stroke due to periprocedural embolization. the site of arterial cannulation in the groin. • The procedure may cause arterial wall dissection at the Data on the complications after carotid angioplasty/ time or afterwards, and embolization might occur due stenting are available from published case series and to thrombus formation on the damaged plaque. registries, but as for endarterectomy, these studies tend to • The angioplasty balloon may obstruct carotid blood underestimate risks. Formal randomized comparisons of flow for long enough to cause low-flow ischaemic endarterectomy and angioplasty/stenting are therefore stroke. required to reliably determine the overall balance of risks .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 875 16.13 Carotid angioplasty and stenting 875 Fig. 16.50 Selective catheter angiogram before (a) and after (b) stenting; before stenting there is severe stenosis of the internal carotid artery (arrow) and afterwards the mesh of the stainless steel stent can be seen spanning the carotid bifurcation (modern stents are not so easily seen). (Courtesy of Professor Martin Brown, London.) (a) (b) and benefits. Prior to 2006 only five relatively small RCTs carotid Stenosis (EVA-3S) was also of angioplasty/stenting had been reported, the largest of which suggested that vs endarterectomy for 60–99% recently symptomatic the procedural stroke risk was similar to carotid carotid stenosis. 534 The trial stopped early after a high endarterectomy (albeit with wide confidence intervals) 30-day procedural risk was found after angioplasty/ and that there are few strokes in the long-term (with stenting, and there were also more local complications even wider confidence intervals). 527–531 Taken together, after angioplasty/stenting. The results of further follow- the five trials suggested that angioplasty/stenting might up are awaited and two other large trials are currently have a higher procedural risk of stroke or death than ongoing. 535–537 endarterectomy (OR 1.33; 95% CI 0.86–2.04) and a Any advantage for angioplasty/stenting might be higher risk of restenosis. 532 further eroded if the GALA trial (www.galatrial.com) However, improvements in endovascular techniques finds that endarterectomy under regional rather than and cerebral protection might have reduced the proced- general anaestheia is associated with less stroke risk, ural risks, 533 and so several larger trials have been done, because the angioplasty/stenting trials have mainly used two of which reported their initial results in 2006. The the comparison with endarterectomy under general SPACE Trial is the largest trial of carotid stenting vs anaesthetic. endarterectomy to date, doubling the number of ran- Taking all the currently available randomized evidence domized patients. It was intended to study 1900 patients from the trials comparing carotid endarterectomy with with 50–99% recently symptomatic carotid stenosis, but angioplasty/stenting, the endovascular approach appears randomization was stopped early, partly due to a short- to have a higher procedural risk of stroke or death (Fig. age of funding. The procedural 30-day risk of stroke or 16.51), but there is still sufficient uncertainty to justify death was non-significantly higher in the angioplasty/ continuing the remaining ongoing trials. Pending their stenting group with 37 (6.3%) strokes and deaths among results, carotid stenting should be confined to RCTs or to 584 patients randomized to surgery vs 41 (6.8%) in 599 cases in which endarterectomy is technically difficult. patients randomized to stenting. The Endarterectomy Whichever procedure is used, early intervention and versus Angioplasty in Patients With Symptomatic Severe selection of patients based on predicted risk of stroke .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 876 876 Chapter 16 Preventing recurrent stroke and other serious vascular events Study Endovascular Surgical OR (random effects) Weight OR (random effects) or sub-category n/N n/N 95% CI % 95% CI Leicester 1996 5/11 0/12 2.58 21.15 (1.01–445.00) Wallstent1997 13/107 5/112 13.37 2.96 (1.02–8.61) CAVATAS 2001 25/251 25/253 22.69 1.01 (0.56–1.81) Kentucky 2001 0/53 1/51 2.32 0.31 (0.01–7.90) SAPPHIRE 2002 7/156 10/151 14.52 0.66 (0.25–1.79) SPACE 2006 41/599 37/584 25.59 1.09 (0.69–1.72) EVA-3S 2006 25/261 10/259 18.92 2.64 (1.24–5.61) Total (95% CI) 1438 1422 100.00 1.41 (0.85–2.35) Total events: 116 (Endovascular), 88 (Surgical) 2 2 Test for heterogeneity: c = 12.76, df = 6 (P = 0.05), I = 53.0% Test for overall effect: Z = 1.32 (P = 0.19) 0.1 0.2 0.5 1 2 5 10 Favours endovascular Favours surgery Fig. 16. 51 Meta-analysis of the randomized controlled trials of proportional to the statistical weight for that outcome and endovascular treatment vs endarterectomy for carotid stenosis, a horizontal line representing the 95% confidence interval (CI). outcome of stroke or death within 30 days of the procedure. OR, odds ratio (random effects model). (Courtesy of Roland Each trial result is represented by a purple box whose size is Featherstone, London.) without the intervention remain the keys to effective remained unchanged from 1970 to 2000; nine out of stroke prevention. ten screened CABG patients had no significant carotid disease. Stroke risk was about 3% in predominantly At present, there is no evidence to support the routine asymptomatic patients with unilateral 50–99% carotid use of carotid angioplasty stenting outside well- stenosis, 5% in those with bilateral 50–99% stenoses and conducted randomized trials. 7–11% in those with carotid occlusion. Significant pre- dictive factors for post-CABG stroke included carotid bruit, prior stroke/transient ischaemic attack and severe carotid stenosis/occlusion. However, half those who had a perioperative stroke did not have significant 16.14 Carotid endarterectomy before, during carotid disease, and 60% of territorial infarctions on CT or after coronary artery surgery? scan/autopsy could not be attributed to carotid disease alone. 543 Thus, although carotid disease is one important aetiological factor in post-CABG stroke, even assuming If patients with recently symptomatic carotid stenosis that prophylactic carotid endarterectomy carried no also have symptomatic coronary heart disease requiring additional risk, it could only ever prevent about 40% of surgery, it is unclear whether coronary bypass should procedural strokes at most. be done before the carotid endarterectomy (and risk A subsequent systematic review aimed to determine a stroke during the procedure), after the carotid the overall cardiovascular risk for patients with coronary endarterectomy (and risk cardiac complications during and carotid artery disease undergoing simultaneous carotid endarterectomy) or simultaneously under the CABG and carotid endarterectomy, endarterectomy then same general anaesthetic (and risk both stroke and CABG, and CABG then endarterectomy. Mortality was cardiac complications all at once). 538–540 The apparently highest in patients undergoing simultaneous operations high risk of the last option may well be unacceptable, (4.6%), as was the risk of death or stroke (8.7%) and although a very small quasi-randomized trial suggests lowest following endarterectomy then CABG (6.1%). otherwise. 541,542 The risk of death/stroke or myocardial infarction was Although endarterectomy or stenting for carotid 11.5% following simultaneous procedures. 544 stenosis are increasingly recommended before coronary In summary, the available data suggest that only about surgery, there is little evidence to support this practice. A 40% of strokes complicating CABG can be attributable systematic review of published case series found that the to carotid artery disease. The risk of death or stroke risk of stroke during the first few weeks after coronary following staged or simultaneous carotid surgery is high, artery bypass grafting (CABG) was about 2% and had and a large RCT is necessary to determine whether a .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 877 16.15 Extra-to-intracranial bypass surgery 877 policy of prophylactic carotid endarterectomy reduces At present routine extra-to-intracranial bypass surgery the risk of stroke after cardiac surgery. In the meantime, cannot be recommended. the available data do not support a policy of routine intervention for carotid stenosis in patients undergoing CABG. 545 16.16 Surgery and angioplasty for vertebrobasilar ischaemia 16.15 Extra-to-intracranial bypass surgery There is no good evidence that surgery improves the prognosis for patients with vertebrobasilar ischaemia. About 10% of patients with minor carotid ischaemic There is, however, no shortage of ingenious, if technic- events have occlusion of the internal carotid artery ally demanding, techniques which are far from risk-free: (ICA), or stenosis of the ICA well distal to the bifurcation, • Endarterectomy of severe carotid stenosis to improve or middle cerebral artery (MCA) occlusion or stenosis. collateral blood flow, via the circle of Willis, to the All these lesions are inoperable, or out of reach of the basilar artery distal to severe vertebral or basilar artery vascular surgeon, if not of the angioplasty enthusiast’s stenosis or occlusion. balloon. However, these lesions can be bypassed by • Resection and anastomosis, resection and reimplanta- anastomosing a branch of the external carotid artery tion, bypass or endarterectomy of proximal vertebral (usually the superficial temporal) via a skull burr hole to artery stenosis. a cortical branch of the MCA. It was anticipated that • Release of the vertebral artery from compressive this ‘surgical collateral’ would improve the blood supply fibrous bands or osteophytes. in the distal MCA bed and so reduce the risk of stroke, • Various extra-to-intracranial procedures to bypass and reduce the severity of any stroke that did occur. vertebral artery stenosis or occlusion. However, there are several reasons why the procedure There are no RCTs of surgical procedures for posterior might not work: 546–550 circulation disease; data are only available from case • The artery feeding the anastomosis can take months to series. For proximal vertebral reconstruction, perioperat- dilate into an effective collateral channel. ive mortality is 0–4%, and the risk of stroke or death • Many patients have good collateral flow already from 2.5–25%. 555 For distal vertebral reconstruction 2–8% orbital collaterals or via the circle of Willis. mortality has been reported. • Not all strokes distal to ICA/MCA occlusion or inacces- Several case series have described angioplasty and stent- sible stenosis are due to low flow (section 6.3.4). ing of symptomatic vertebral and basilar stenosis. 556 A • The risk of stroke in patients with ICA occlusion is recent review of more than 600 cases published up to not that high compared with severe and recently 2005 provides useful information. 555 In the early studies, symptomatic ICA stenosis (less than 10%/year) and, proximal lesions were treated primarily with angioplasty anyway, not all of these strokes are ipsilateral to the but this was associated with restenosis in 15–31% of occlusion. cases after 15–30 months of follow-up. More recently • Neither resting cerebral blood flow nor cerebral react- stenting has been used for the proximal vertebral system, ivity are necessarily depressed in these patients. especially lesions at the origin. Several series have • The risk of surgery may outweigh the benefit, if any. reported low periprocedural or post-interventional stroke The risk–benefit relationship has been evaluated in risks; pooling data, there was a perioperative stroke risk only one completed randomized trial and this failed to of 1.3% and of death of 0.3%. However, restenosis dur- show any benefit from routine surgery (EC–IC Bypass ing about 14 months of follow-up still occurred in about Study Group 1985). 551 However, it has been argued that one-quarter of the patients, albeit usually asymptomatic. patients with impaired cerebrovascular reactivity, or The complication risk of distal vertebrobasilar lesions with maximal oxygen extraction, were not identified treated with angioplasty and stenting is higher: 7.1% for and perhaps it is these patients who might be benefited by stroke and 3.7% for death after angioplasty, and 10.6% surgery. 552,553 But to show whether stroke is prevented, for stroke and 3.2% for death after stenting, suggesting and not just that pathophysiology is improved, would that complication rates do not differ much between require another RCT in this specific subgroup, not a series angioplasty and stenting in the distal vertebrobasilar of anecdotes, however persuasive. Such a trial is now system. 555 The only RCT of stenting for vertebral artery ongoing. 554 disease was far too small to be informative. 557 Therefore, .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 878 878 Chapter 16 Preventing recurrent stroke and other serious vascular events there are no robust data on the safety and efficacy of Coronary artery bypass surgery (or angioplasty) may of vertebral artery stenting. course be indicated for patients presenting with cere- Subclavian (and innominate) steal (section 6.8.6), brovascular events who also happen to have cardiac although commonly detected with ultrasonography, symptoms. But, because asymptomatic coronary artery very rarely causes neurological symptoms and does not disease is so often associated with symptomatic cere- seem to lead on to ischaemic stroke. However, incapa- brovascular disease (section 6.8.10), would coronary citatingly frequent vertebrobasilar TIAs in the presence intervention also be worthwhile even if there were of demonstrated unilateral or bilateral retrograde verte- no cardiac symptoms or signs? Given the high risk of bral artery flow distal to severe subclavian or innominate cardiac events which might be reduced in the long term disease may sometimes be relieved by: endarterectomy (section 16.2), this is a perfectly reasonable question, but or angioplasty of the subclavian artery; carotid-to- one which could only be answered by an RCT, perhaps subclavian or femoral-to-subclavian bypass; transposition first in patients who are thought to be at particularly of the subclavian artery to the common carotid artery high risk of myocardial infarction on the basis of clinical (CCA); transposition of the vertebral artery to the CCA; features, or non-invasive cardiac investigation. and axillary-to-axillary artery bypass grafting. All these procedures carry a risk and it is not clear which is the most sensible. Irrespective of the neurological situation, some kind of vascular surgical procedure may be needed if the hand and arm become ischaemic distal to sub- 16.18 Putting secondary prevention into clavian or innominate artery disease. practice 16.18.1 Involving patients and carers in treatment decisions 16.17 Other surgical procedures What influences adherence to treatment? Aortic arch atheroma is now increasingly diagnosed by Involving patients (and, where appropriate, their carers) transoesophageal echocardiography in patients with in decisions about their treatment is an important part of transient ischaemic attacks or ischaemic stroke, but so healthcare. Patients need to understand what has hap- far there are no surgical, or indeed medical, treat- pened to them, and why various treatment options are ment options over and above controlling vascular risk being recommended for them. Adherence to medica- factors and antiplatelet drugs. One trial has been started, tion, especially long-term preventive treatments, is the ARCH trial, which is an open-label, multicentre, known to be poor outside the setting of a clinical randomized, controlled trial of warfarin (target INR = trial, 558–560 but seems likely to be improved if patients 2.0–3.0) vs 75–325 mg of aspirin plus 75 mg clopidogrel understand what each treatment is for, and how they per day in patients with an ischaemic stroke within will personally benefit. However, a study of patients who 6 months, and an aortic arch atheromatous plaque that had survived a myocardial infarction and of subjects is either mobile or greater than 4 mm thick. free of cardiovascular disease suggested that patients’ Innominate or proximal common carotid artery stenosis expectations of the absolute benefits of medications are or occlusion is quite often seen on angiograms in usually higher than the actual benefit, so that giving symptomatic patients but, unless very severe, does not accurate information about the likely benefits of a par- influence the decision about endarterectomy for any ticular treatment, although clearly important, may not internal carotid artery stenosis. Although it is possible necessarily increase uptake and long-term adherence. 561 to bypass such lesions it is highly doubtful whether Rates of, and influences on, adherence to long-term this reduces the risk of stroke unless, perhaps, several preventive medication among patients who have had a major neck vessels are involved and the patient has stroke or transient ischaemic attack (TIA) have not been low-flow cerebral or ocular symptoms (section 6.7.5). studied much. 562 Randomized trials of interventions This very rare situation can be due to atheroma, Takayasu’s to improve adherence to long-term medication have disease or aortic dissection. Clearly, close consultation had mixed results, and the most successful methods between physicians and vascular surgeons is needed to have generally been complex and of limited effective- sort out, on an individual patient basis, what to do for ness in terms of improved adherence and clinical out- the best. comes. 558,563 Furthermore, as far as we are aware there .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 879 16.18 Putting secondary prevention into practice 879 have been no randomized trials of interventions to their background knowledge about health-related mat- improve adherence specifically among patients who ters, and a host of social and psychological factors. 566,567 have had a stroke or TIA, and limited numbers of trials (and trial subjects) in the elderly. 16.18.2 Which interventions for which patients? Many preventive interventions have been discussed in Communicating benefits and risks this chapter and an overall summary of which inter- Communicating with patients who have had a stroke ventions should be considered for which patients is or TIA can be particularly challenging. Disability result- given in Fig. 16.52. Clearly, the introduction of each ing from a stroke may directly (e.g. due to dysphasia) or treatment should be considered in terms of both the indirectly (e.g. due to pain, visual field defects, incontin- balance of benefit and risk as well as the individual pre- ence, inattention or neglect, etc.) affect the process of ferences of the particular patient, taking into account communication with the patient, as may the hearing their age, comorbidities, and – for medications – all drugs and visual impairment and other age-related problems already being taken and the possible effects of any that frequently affect elderly patients. It is usually help- medication changes on adherence, drug interactions ful if a relative, friend or carer can also be present during and adverse effects. 568 any discussions with doctors or other health profes- sionals. Information leaflets using simple language are Incremental effectiveness often helpful, and give the patient or carer something to refer to later. Guidance about websites that provide the Another important consideration is the incremental most helpful, accurate and up-to-date information for effectiveness of each of several new treatments added. patients and carers can also be important. Making sure The order in which various treatments are added will that other health professionals involved know what has depend on the mode and timing of the patient’s presen- been said is also crucial, to ensure consistency and avoid tation. For illustrative purposes, let us imagine a 75-year- confusion. old woman presenting to her family doctor 2 days after Because doctors’ treatment recommendations should onset of an acute, non-disabling stroke. She is a non- be based on weighing up the estimated absolute benefits smoker, drinks no more than 5 units of alcohol per week, and harms of any treatment (section 16.1.3), we must and her only past medical history is of a hip replacement also attempt to communicate the same type of informa- and her only medication is occasional paracetamol. tion about treatment options to patients and/or carers. The family doctor assumes the stroke to be ischaemic, We should be aware that we may inappropriately influ- prescribes aspirin 300 mg immediately followed by 75 ence patients’ decisions or behaviour by providing infor- mg daily, takes blood for full blood count, erythrocyte mation about treatment benefits in terms of relative risk sedimentatation rate (ESR), renal function, cholesterol, reductions (e.g. ‘Adding this new tablet dipyridamole and glucose, and refers the patient to a rapid access to your aspirin will reduce your risk of another stroke, stroke specialist outpatient clinic at the local hospital for a heart attack or dying by 20%’) rather than absolute confirmation of the clinical diagnosis and further inves- risk reductions (e.g. ‘If 100 people like you took this new tigation as appropriate. The specialist assesses the patient tablet dipyridamole as well as their aspirin, then each 5 days later, and agrees with the clinical diagnosis, not- year one less of these people would have a stroke, a heart ing that the patient has a regular pulse with a rate of attack or die’). We should always try to tailor our means 80 beats per minute, a blood pressure of 140/83, a clinic- of presenting information on benefits and harms to the ally normal heart, and that the stroke almost certainly level of understanding, needs and wishes of the patient affected the carotid (anterior circulation) territory. or carer. Quoting benefits and risks in terms of natural That day, a 12-lead electrocardiograph confirms sinus frequencies rather than percentages (e.g. ‘one in ten rhythm, a CT brain scan confirms that the stroke was people will develop x’, rather than ‘10% of people will ischaemic and Doppler ultrasound of the carotid arteries develop x’ or ‘the risk of x is 10%’) and using diagrams reveals minor atheroma in both carotid bulbs but no or pictures can make the concepts easier to under- significant stenoses. The results of the blood tests show stand. 561,564,565 Finally, we must be aware that patients’ a normal full blood count, ESR and renal function, and carers’ interpretation of and response to this sort of random blood glucose of 5 mmol/L, and cholesterol of information depends on how much they trust the doctor 5.2 mmol/L. The specialist recommends the addition of or other healthcare professional imparting it, other a statin (simvastatin 40 mg daily), and modified release sources of information they may have access to (other dipyridamole, warning of the possibility of headache with healthcare professionals, friends, the media, and so on), the latter medication, usually settling within 1–2 weeks. .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 880 880 Chapter 16 Preventing recurrent stroke and other serious vascular events Clinically Brain diagnosed stroke imaging as Confirm diagnosis of stroke or TIA or TIA (not SAH) appropriate (Chapter 3) (Chapter 5) Check FBC, ESR, Cr, U&E, Ischaemic lipids, glucose ECG +/– echo. ICH Further treatment for less common causes as indicated (Chapters 6,7,8) Atrial No atrial Drug(s) to reduce BP to fibrillation fibrillation around 120–130/70 mmHg or other or other if persistently raised above high risk high risk Anterior Posterior that level by a week or two cardioembolic cardioembolic circulation circulation post event. source source territory territory Avoid lowering BP below about 140 mmHg systolic Specific in those with >1 severely treatment of Oral anticoagulant stenosed extracranial neck less common (warfarin) Fit enough for artery (Section 16.3) underlying (Section 16.6) and willing to causes (Chapter 7, consider carotid Section 16.10, endarterectomy Statin to reduce Lifestyle modification Anticoagulant cholesterol if baseline Stop smoking Chapter 18) contraindicated total chol ≥ 3.5 mmol/l Avoid excess alcohol or LDL-chol ≥ 2.6 mmol/l Healthy diet (simvastatin 40 mg daily or Encourage atorvastatin 80 mg daily or regular exercise Antiplatelet therapy: aspirin Carotid imaging equivalent) (Section 16.7) 300 mg immediately, then (Section 16.4) 75 mg per day + dipyridamole MR 200 mg bd. Stenosis 50–99% Consider proton-pump (NASCET criteria) inhibitor +/− Helicobacter Diabetes management pylori eradication, especially Optimize glycaemic control in if upper gastrointestinal symptoms. Substitute Refer for urgent carotid patients with previous or newly clopidogrel 75 mg daily endarterectomy if patient willing and diagnosed diabetes if unable to take aspirin estimated benefits outweigh risks (Section 16.9) (Section 16.5) (Section 16.11) Fig. 16.52 Summary of long-term preventive interventions ischaemic attack; SAH, subarachnoid haemorrhage; to be considered after a stroke or transient ischaemic attack. ICH, intracerebral haemorrhage; MR, modified release; NB: Statins to reduce cholesterol, and antithrombotic FBC, full blood count; ESR, erythrocyte sedimentation treatment, may occasionally be appropriate for patients with rate; Cr, creatinine; U&E, urea and electrolytes; ECG, intracerebral haemorrhage at particularly high risk of future electrocardiogram; echo, echocardiogram; NASCET, North ischaemic events (sections 16.4.5, 16.5.2, 16.6.5). TIA, transient American Symptomatic Carotid Endarterectomy Trial. The specialist also asks the family doctor to monitor the Because the risk of a vascular event (mainly recurrent blood pressure regularly and introduce blood-pressure- stroke) is highest early after stroke, the earlier preventive lowering medication if the pressure is persistently above medications are started the greater the absolute benefit 120–130 mmHg systolic/70 mmHg diastolic. A thiazide in the first year. However, as we have seen in earlier diuretic plus an ACE inhibitor if needed are the sug- sections of this chapter, clear evidence for starting pre- gested first-line treatments. Finally, the specialist gives ventive medications immediately after stroke is present some written information about stroke, incorporating for some, but not all, of the various available options. In advice about lifestyle. addition, if several medications are started at the same Table 16.15 shows the order and timing of intro- time and the patient subsequently experiences a sus- duction of medications in this patient’s case, and the pected adverse effect, it can be difficult to sort out which estimated benefits for each during the first year and medication is at fault and should be discontinued. Hence annually thereafter, assuming adherence at the levels a staged introduction of secondary preventive medica- achieved in the randomized trials of these treatments. tions may be best in many circumstances, but with as .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 881 16.18 Putting secondary prevention into practice 881 Table 16.15 Illustration of incremental benefit to an individual patient from reducing the risk of a vascular event by adding, in turn, long-term preventive medications after stroke or transient ischaemic attack (see section 16.18.2 for details of clinical case). Treatment From treatment start to end of first year Annually from end of first year Approx risk Approx risk on RRR ‡ ARR ¶ Approx risk Approx risk on with no all previous with no all previous treatment* treatments † treatment* treatments † RRR ‡ ARR ¶ Aspirin from day 2 18% 18.0% 20% 3.6% 7% 7.0% 20% 1.4% Statin from day 7 § 13% 10.4% 20% 2.1% 7% 5.6% 20% 1.1% MR dipyridamole from day 7 13% 8.3% 20% 1.7% 7% 4.5% 20% 0.9% Thiazide and ACE-inhibitor 11% 5.6% 20% 1.1% 7% 3.6% 20% 0.7% from day 14** All treatments 8.5% †† 4.1% ‡‡ RRR, relative risk reduction; ARR, absolute risk reduction. *Rough estimate of untreated (i.e. no treatment at all) risks from section 16.2 and Table 16.1 (note: in the first few days after the stroke/TIA this risk is falling rapidly from 18% at day 2 to 11% at day 14 until the end of the first year). †Calculated by applying a 20% reduction to completely untreated risk for each treatment already being taken. ‡Assuming that: RRR for vascular events about the same (20%) for all treatments (actual range of point estimates is about 18–22%; see sections 16.3 to 16.5); treatment benefit accrues at a similar rate in the first and subsequent years (may not necessarily be the case – e.g. benefits from cholesterol lowering may not be fully realized until second or third year of treatment – see section 16.4); adherence similar to that in randomized trials. ¶20% of approx risk after earlier treatments started. §Reducing LDL-cholesterol by ~ 1 mmol/L. **Reducing BP by ~ 8 mmHg systolic/4 mmHg diastolic. ††Number-needed-to-treat to prevent or delay one vascular event at 1 year = 100/8.5 = 12, i.e. the patient has a 1 in 12 chance of benefiting from combined drug treatment in the first year. ‡‡Number-needed-to-treat to prevent or delay one vascular event annually after the first year = 100/4.1 = 24, i.e. the patient has a 1 in 24 chance of benefiting from combined drug treatment annually after the first year. little delay as possible between the introduction of cognitively impaired patients. Increased complexity of each additional medication to ensure that they are added medication regimens is unsurprisingly one predictor of as early after the presenting event as is feasible, to max- reduced adherence. 558 Although many patients would imize the benefit to the patient. consider the benefits of each individual drug insufficient to make it worth taking regularly, if they genuinely A staged introduction of secondary preventive understood them, 561 the combined benefit of all of these medications may be best, but with as little delay as drugs is more substantial, making the combined pack- possible between the introduction of each additional age a much better option. This makes the proposal of a medication to ensure that they are added as early after so-called ‘Polypill’, a single combined tablet containing the presenting event as is feasible. all the components proven to reduce risk of vascular events, a potentially highly attractive one. The original Polypill proposal was for a single com- What about a Polypill? bined pill for anyone with a history of vascular disease In the rather straightforward example above, the patient and for anyone over 55 years old, regardless of a history was taking only paracetamol before her stroke, but of vascular disease. However, commentators raised a several weeks later she is also taking aspirin 75 mg daily, range of potential problems and criticisms of such an simvastatin 40 mg daily, modified-release dipyridamole approach. 569 The proposed combined pill contained 200 mg daily, bendrofluazide 2.5 mg daily and perindo- aspirin for antiplatelet effect, folic acid to lower plasma pril 4 mg daily – that is, five additional drugs and six homocysteine, three different drugs in low dose to reduce additional tablets per day. For a cognitively intact, non- blood pressure, and a statin to reduce cholesterol. 570 One disabled patient, this is already quite an undertaking, immediately apparent problem is that this particular and the difficulties will be more substantial for disabled, combination does not reflect the current state of the .. ..

9781405127660_4_016.qxd 10/13/07 10:51 AM Page 882 882 Chapter 16 Preventing recurrent stroke and other serious vascular events evidence (discussed throughout this chapter) for pre- ischaemic stroke: a cohort study. Lancet 2005; ventive interventions in patients with stroke or TIA. For 365(9477):2098–104. example, there is currently no evidence from random- 6 Wiebers DO, Whisnant JP, O’Fallon WM. Reversible ized trials to support routine homocysteine lowering ischemic neurologic deficit (RIND) in a community: with folate supplements to prevent vascular events, Rochester, Minnesota, 1955–1974. Neurology 1982; 32(5):459–65. either in primary prevention or after a stroke or TIA. And 7 Rothwell PM, Buchan A, Johnston SC. Recent advances in even a combined pill whose components reflected the management of transient ischaemic attacks and minor current evidence would surely soon run into practical ischaemic strokes. Lancet Neurol 2006; 5(4):323–31. difficulties, in that the components of the pill would 8 Coull AJ, Rothwell PM. Underestimation of the early risk need to be varied for different patients to ensure toler- of recurrent stroke: evidence of the need for a standard ability and to allow tailoring of treatment to a particular definition. Stroke 2004; 35(8):1925–9. patient’s clinical history and needs. For example, a 9 Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson patient with a recent intracerebral haemorrhage would LW, Schopflocher DP. The high risk of stroke immediately require a very different pill composition from a patient after transient ischemic attack: a population-based study. with a recent ischaemic stroke, and oral anticoagulants Neurology 2004; 62(11):2015–20. would be preferred over antiplatelet treatment for many 10 Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. patients with atrial fibrillation. 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