Timing of procedural stroke and death in asymptomatic patients undergoing carotid endarterectomy: individual patient analysis from four RCTs.

BACKGROUND: The effectiveness of carotid endarterectomy (CEA) for stroke prevention depends on low procedural risks. The aim of this study was to assess the frequency and timing of procedural complications after CEA, which may clarify underlying mechanisms and help inform safe discharge policies. METHODS: Individual-patient data were obtained from four large carotid intervention trials (VACS, ACAS, ACST-1 and GALA; 1983-2007). Patients undergoing CEA for asymptomatic carotid artery stenosis directly after randomization were used for the present analysis. Timing of procedural death and stroke was divided into intraoperative day 0, postoperative day 0, days 1-3 and days 4-30. RESULTS: Some 3694 patients were included in the analysis. A total of 103 patients (2·8 per cent) had serious procedural complications (18 fatal strokes, 68 non-fatal strokes, 11 fatal myocardial infarctions and 6 deaths from other causes) [Correction added on 20 April, after first online publication: the percentage value has been corrected to 2·8]. Of the 86 strokes, 67 (78 per cent) were ipsilateral, 17 (20 per cent) were contralateral and two (2 per cent) were vertebrobasilar. Forty-five strokes (52 per cent) were ischaemic, nine (10 per cent) haemorrhagic, and stroke subtype was not determined in 32 patients (37 per cent). Half of the strokes happened on the day of CEA. Of all serious complications recorded, 44 (42·7 per cent) occurred on day 0 (20 intraoperative, 17 postoperative, 7 with unclear timing), 23 (22·3 per cent) on days 1-3 and 36 (35·0 per cent) on days 4-30. CONCLUSION: At least half of the procedural strokes in this study were ischaemic and ipsilateral to the treated artery. Half of all procedural complications occurred on the day of surgery, but one-third after day 3 when many patients had been discharged.

ANTECEDENTES: La efectividad de la endarterectomía carotídea (carotid endarterectomy, CEA) en la prevención de un accidente cerebrovascular depende de que este procedimiento tenga pocos riesgos. El objetivo de este estudio fue evaluar la frecuencia y el momento de aparición de las complicaciones tras una CEA, lo que podría clarificar los mecanismos subyacentes y ayudar a establecer una política de altas hospitalarias segura. MÉTODOS: Se utilizaron los datos de los pacientes incluidos en cuatro grandes ensayos de intervención carotídea (VACS, ACAS, ACST-1 y GALA; 1983-2007). Para el presente análisis se utilizaron los datos de pacientes sometidos a CEA por estenosis de la arteria carótida asintomática recogidos inmediatamente tras la aleatorización. Se consideraron diferentes intervalos entre el procedimiento, la muerte o el accidente cerebrovascular: intraoperatorio día 0, postoperatorio día 0, postoperatorio días 1-3 y postoperatorio días 4-30. RESULTADOS: En el análisis se incluyeron 3.694 pacientes. Se detectaron complicaciones graves relacionadas con el procedimiento en 103 (2,8%) pacientes (18 accidentes cerebrovasculares fatales, 68 accidentes cerebrovasculares no fatales, 11 infartos de miocardio fatales y 6 muertes por otras causas). De los 86 accidentes cerebrovasculares, 67 (78%) fueron ipsilaterales, 17 (20%) contralaterales y dos (2%) vertebrobasilares. Los accidentes cerebrovasculares fueron isquémicos en 45 (52%) casos, hemorrágicos en 9 (10%) y no se pudo determinar el subtipo de ictus en 32 (37%). La mitad de los accidentes cerebrovasculares ocurrieron el día de la CEA. De todas las complicaciones graves registradas, 44 (43%) ocurrieron en el día 0 (20 intraoperatorias, 17 postoperatorias y 7 en períodos poco definidos), 23 (22%) entre los días 1-3 y 36 (35%) entre los días 4-30. CONCLUSIÓN: En este estudio, al menos la mitad de los accidentes cerebrovasculares relacionados con la CEA fueron isquémicos e ipsilaterales respecto a la arteria tratada. La mitad de todas las complicaciones de la CEA ocurrieron el día de la cirugía, pero un tercio de los casos se presentaron después del día 3, cuando muchos pacientes ya habían sido dados de alta.

Time trends, frequency, characteristics and prognosis of short-duration transient global amnesia.

BACKGROUND AND PURPOSE: Transient global amnesia (TGA) is characterized by a sudden onset of anterograde amnesia lasting up to 24 h. One major differential for TGA is transient epileptic amnesia, which typically lasts < 1 h. However, TGA can also be short in duration and little is known about the time trends, characteristics and prognosis of TGA cases lasting < 1 h. METHODS: We compared the clinical features of TGA ascertained in two independent cohort studies in Oxfordshire, UK [Oxford cohort 1977-1987 versus Oxford Vascular Study (OXVASC) 2002-2018] to determine the time trends of clinical features of TGA. Results were validated in another independent contemporary TGA cohort in Italy [Northern Umbria TGA registry (NU) 2002-2018]. We compared the risk factors, clinical features and long-term prognosis (major cardiovascular events, recurrent TGA and seizure/epilepsy) of patients presenting with episodes lasting < 1 h versus those lasting ≥ 1 h. RESULTS: Overall, 639 patients with TGA were included (114 Oxford cohort, 100 OXVASC, 425 NU). Compared with the original Oxford cohort, there were more cases with TGA lasting < 1 h in OXVASC [32 (32.0%) vs. 9 (8.8%)] and NU (11.8% vs. 8.8% in Oxford cohort). In both OXVASC and NU, patient age, vascular risk factors and clinical features were largely similar between those with TGA lasting < 1 h versus those lasting ≥ 1 h. Moreover, there was no difference in the long-term risk of seizure/epilepsy or major cardiovascular events between TGA lasting < 1 h versus TGA lasting ≥ 1 h. CONCLUSIONS: Short-duration TGA episodes (<1 h) were not uncommon and were more frequent than in earlier studies. The clinical features and long-term prognosis of short-duration TGA did not differ from more typical episodes lasting ≥ 1 h.

Observational, longitudinal study of delirium in consecutive unselected acute medical admissions: age-specific rates and associated factors, mortality and re-admission.

OBJECTIVES: We aimed to determine age-specific rates of delirium and associated factors in acute medicine, and the impact of delirium on mortality and re-admission on long-term follow-up. DESIGN: Observational study. Consecutive patients over two 8-week periods (2010, 2012) were screened for delirium on admission, using the confusion assessment method (CAM), and reviewed daily thereafter. Delirium diagnosis was made using the Diagnostic and Statistical Manual Fourth Edition (DSM IV) criteria. For patients aged ≥65 years, potentially important covariables identified in previous studies were collected with follow-up for death and re-admission until January 2014. PARTICIPANTS: 503 consecutive patients (age median=72, range 16-99 years, 236 (48%) male). SETTING: Acute general medicine. RESULTS: Delirium occurred in 101/503 (20%) (71 on admission, 30 during admission, 17 both), with risk increasing from 3% (6/195) at <65 years to 14% (10/74) for 65-74 years and 36% (85/234) at ≥75 years (p<0.0001). Among 308 patients aged >65 years, after adjustment for age, delirium was associated with previous falls (OR=2.47, 95% CI 1.45 to 4.22, p=0.001), prior dementia (2.08, 1.10 to 3.93, p=0.024), dependency (2.58, 1.48 to 4.48, p=0.001), low cognitive score (5.00, 2.50 to 9.99, p<0.0001), dehydration (3.53, 1.91 to 6.53, p<0.0001), severe illness (1.98, 1.17 to 3.38, p=0.011), pressure sore risk (5.56, 2.60 to 11.88, p<0.0001) and infection (4.88, 2.85 to 8.36, p<0.0001). Patients with delirium were more likely to fall (OR=4.55, 1.47 to 14.05, p=0.008), be incontinent of urine (3.76, 2.15 to 6.58, p<0.0001) or faeces (3.49, 1.81-6.73, p=0.0002) and be catheterised (5.08, 2.44 to 10.54, p<0.0001); and delirium was associated with stay >7 days (2.82, 1.68 to 4.75, p<0.0001), death (4.56, 1.71 to 12.17, p=0.003) and an increase in dependency among survivors (2.56, 1.37 to 4.76, p=0.003) with excess mortality still evident at 2-year follow-up. Patients with delirium had fewer re-admissions within 30-days (OR=0.32, 95% CI 0.09 to 1.1, p=0.07) and in total (median, IQR total re-admissions=0, 0-1 vs 1, 0-2, p=0.01). CONCLUSIONS: Delirium affected a fifth of acute medical admissions and a third of those aged ≥75 years, and was associated with increased mortality, institutionalisation and dependency, but not with increased risk of re-admission on follow-up.

Age-specific incidence, risk factors and outcome of acute abdominal aortic aneurysms in a defined population.

BACKGROUND: Contemporary population-based data on age-specific incidence and outcome from acute abdominal aortic aneurysm (AAA) events are needed to understand the impact of risk factor modification and demographic change, and to inform AAA screening policy. METHODS: In a prospective population-based study (Oxfordshire, UK, 2002-2014), event rates, incidence, early case fatality and long-term outcome from all acute AAA events were determined, both overall and in relation to the four main risk factors: smoking, hypertension, male sex and age. RESULTS: Over the 12-year interval, 103 incident acute AAA events occurred in the study population of 92,728 (men 72·8 per cent; 59·2 per cent 30-day case fatality rate). The incidence per 100,000 population per year was 55 in men aged 65-74 years, but increased to 112 at age 75-84 years and to 298 at age 85 years or above. Some 66·0 per cent of all events occurred in those aged 75 years or more. The incidence at 65-74 years was highest in male smokers (274 per 100,000 population per year); 27 (96 per cent) of 28 events in men aged less than 75 years occurred in ever-smokers. Mean(s.d.) age at event was lowest in current smokers (72·2(7·2) years), compared with that in ex-smokers (81·2(7·0) years) and never-smokers (83·3(7·9) years) (P < 0·001). Hypertension was the predominant risk factor in women (diagnosed in 93 per cent), with 20 (71 per cent) of all 28 events in women occurring in those aged 75 years or above with hypertension. The 30-day case fatality rate increased from 40 per cent at age below 75 years to 69 per cent at age 75 years or more (P = 0·008). CONCLUSION: Two-thirds of acute AAA events occurred at age 75 years or above, and more than 25 per cent of events were in women. Taken with the strong associations with smoking and hypertension, these findings could have implications for AAA screening.

Estimates of benefits and harms of prophylactic use of aspirin in the general population.

BACKGROUND: Accumulating evidence supports an effect of aspirin in reducing overall cancer incidence and mortality in the general population. We reviewed current data and assessed the benefits and harms of prophylactic use of aspirin in the general population. METHODS: The effect of aspirin for site-specific cancer incidence and mortality, cardiovascular events was collated from the most recent systematic reviews. Studies identified through systematic Medline search provided data regarding harmful effects of aspirin and baseline rates of harms like gastrointestinal bleeding and peptic ulcer. RESULTS: The effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, myocardial infarction or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period. CONCLUSIONS: Prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have favourable benefit-harm profile; longer use is likely to have greater benefits. Further research is needed to determine the optimum dose and duration of use, to identify individuals at increased risk of bleeding, and to test effectiveness of Helicobacter pylori screening-eradication before starting aspirin prophylaxis.

Differences in cognitive profile between TIA, stroke and elderly memory research subjects: a comparison of the MMSE and MoCA.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 ('normal' cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. METHODS: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. RESULTS: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. CONCLUSIONS: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic.

Hemodynamic alterations in vertebrobasilar large artery disease assessed by arterial spin-labeling MR imaging.

BACKGROUND AND PURPOSE: VB artery stenosis is associated with a high risk of recurrent ischemic events, and knowledge about the hemodynamic relevance of VB stenosis is important for clinical decision making. In this study, multiple inflow pulsed ASL MR imaging was assessed for its ability to measure CBF and ATT in patients with VB disease. MATERIALS AND METHODS: ASL was performed on a 3T MR imaging scanner in 41 participants. Twenty-one patients had a history of ischemic events in the VB circulation (14 men, 7 women, age 66 ± 11 years). Clinical data and CE-MRA were used to classify VB disease severity. Twenty age-matched adults were controls. Group and within-VB analyses were performed. Mean CBF and ATT values in the ROIs were adjusted by excluding voxels that did not produce a reliable ASL estimate. RESULTS: CBF was reduced (P < .003) in patients compared with controls, which was significant after excluding voxels with a poor fit. Differences in ATT between patients and controls were not significant after voxel correction. There was a strong correlation between CBF and ATT among patients. Finally, ATT was significantly correlated with VB disease severity (P = .026). CONCLUSIONS: Multiple inflow ASL distinguished patients with VB disease from age matched-controls. VB disease rating was associated with prolonged ATT downstream. ASL may have diagnostic potential among patients in whom risk of intervention is high.

Fabry disease in unselected patients with TIA or stroke: population-based study.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. In recent years, the prevalence of FD has been reported to be up to 4% in cryptogenic young stroke patients. However, there have been no population-based studies in unselected patients with transient ischaemic attack (TIA) or stroke across the full range of ages. METHODS: We determined the prevalence of FD mutations in consecutive patients from a population-based study of acute TIA or ischaemic stroke (Oxford Vascular Study). Analysis included amplifying of the α-galactosidase A gene by polymerase chain reaction, denaturing high-performance liquid chromatography (dHPLC) analysis and sequencing using standard automated sequencing protocols [Mutation Surveyor software (Softgenetics)] where the dHPLC indicated a possible mutation. RESULTS: Samples of 1046 consecutive patients (52% women; mean age 73.2 years; 15% age <60 years; 572 stroke; 474 TIA) were tested. No patient had a known gene mutation causing FD, giving an upper 95% confidence interval around the estimated frequency of 0.35% overall and 2.37% in the 154 patients aged under 60 years. However, in 5 (0.48%) samples, a known polymorphism or sequence variation in the gene was identified that can be associated with lower than normal enzyme activity in plasma without causing the full clinical manifestation of FD. CONCLUSIONS: Fabry disease is rare in an unselected group of UK patients with TIA or stroke. Larger studies in unselected younger patients with cryptogenic stroke are required to determine whether routine screening is justified in this group.

Current practice of carotid endarterectomy in the UK.

BACKGROUND: Carotid endarterectomy (CEA) reduces the risk of stroke in patients with internal carotid stenosis of 50-99 per cent. This study assessed national surgical practice through audit of CEA procedures and outcomes. METHODS: This was a prospective cohort study of UK surgeons performing CEA, using clinical audit data collected continuously and reported in two rounds, covering operations from December 2005 to December 2007, and January 2008 to September 2009. RESULTS: Some 352 (92·6 per cent) of 380 eligible surgeons contributed data. Of 19,935 CEAs recorded by Hospital Episode Statistics, 12,496 (62·7 per cent) were submitted to the audit. A total of 10,452 operations (83·6 per cent) were performed for symptomatic carotid stenosis; among these patients, the presenting symptoms were transient ischaemic attack in 4507 (43·1 per cent), stroke in 3572 (34·2 per cent) and amaurosis fugax in 1965 (18·8 per cent). The 30-day mortality rate was 1·0 per cent (48 of 4944) in round 1 and 0·8 per cent (50 of 6151) in round 2; the most common cause of death was stroke, followed by myocardial infarction. The rate of death or stroke within 30 days of surgery was 2·5 per cent (124 of 4918) in round 1 and 1·8 per cent (112 of 6135) in round 2. CONCLUSION: CEA is performed less commonly in the UK than in other European countries and probably remains underutilized in the prevention of stroke. Increasing the number of CEAs done in the UK, together with reducing surgical waiting times, could prevent more strokes.

Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA: a multicenter study.

OBJECTIVES: Stroke risk immediately after TIA defined by time-based criteria is high, and prognostic scores (ABCD2 and ABCD3-I) have been developed to assist management. The American Stroke Association has proposed changing the criteria for the distinction between TIA and stroke from time-based to tissue-based. Research using these definitions is lacking. In a multicenter observational cohort study, we have investigated prognosis and performance of the ABCD2 score in TIA, subcategorized as tissue-positive or tissue-negative on diffusion-weighted imaging (DWI) or CT imaging according to the newly proposed criteria. METHODS: Twelve centers provided data on ABCD2 scores, DWI or CT brain imaging, and follow-up in cohorts of patients with TIA diagnosed by time-based criteria. Stroke rates at 7 and 90 days were studied in relation to tissue-positive or tissue-negative subcategorization, according to the presence or absence of brain infarction. The predictive power of the ABCD2 score was determined using area under receiver operator characteristic curve (AUC) analyses. RESULTS: A total of 4,574 patients were included. Among DWI patients (n = 3,206), recurrent stroke rates at 7 days were 7.1%(95% confidence interval 5.5-9.1) after tissue-positive and 0.4% (0.2-0.7) after tissue-negative events (p diff < 0.0001). Corresponding rates in CT-imaged patients were 12.8% (9.3-17.4) and 3.0% (2.0-4.2), respectively (p diff < 0.0001). The ABCD2 score had predictive value in tissue-positive and tissue-negative events (AUC = 0.68 [95% confidence interval 0.63-0.73] and 0.73 [0.67-0.80], respectively; p sig < 0.0001 for both results, p diff = 0.17). Tissue-positive events with low ABCD2 scores and tissue-negative events with high ABCD2 scores had similar stroke risks, especially after a 90-day follow-up. CONCLUSIONS: Our findings support the concept of a tissue-based definition of TIA and stroke, at least on prognostic grounds.

Reprinted article "Carotid artery disease and stroke during coronary artery bypass: a critical review of the literature".

OBJECTIVES: To determine the role of carotid artery disease in the pathophysiology of stroke after coronary artery bypass (CABG). DESIGN: Systematic review of the literature. RESULTS: The risk of stroke after CABG was 2% and remained unchanged between 1970-2000. Two-thirds occurred after day 1 and 23% died. 91% of screened CABG patients had no significant carotid disease and had a <2% risk of peri-operative stroke. Stroke risk increased to 3% in predominantly asymptomatic patients with a unilateral 50-99% stenosis, 5% in those with bilateral 50-99% stenoses and 7-11% in patients with carotid occlusion. Significant predictive factors for post-CABG stroke included; (i) carotid bruit (OR 3.6, 95% CI 2.8-4.6), (ii) prior stroke/TIA (OR 3.6, 95% CI 2.7-4.9) and (iii) severe carotid stenosis/occlusion (OR 4.3, 95% CI 3.2-5.7). However, the systematic review indicated that 50% of stroke sufferers did not have significant carotid disease and 60% of territorial infarctions on CT scan/autopsy could not be attributed to carotid disease alone. CONCLUSIONS: Carotid disease is an important aetiological factor in the pathophysiology of post-CABG stroke. However, even assuming that prophylactic carotid endarterectomy carried no additional risk, it could only ever prevent about 40-50% of procedural strokes.

Low risk of rebound events after a short course of clopidogrel in acute TIA or minor stroke.

OBJECTIVE: The combination of aspirin and clopidogrel is indicated after acute coronary events and possibly for a short period after TIA or minor ischemic stroke. Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes, but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase. METHODS: A 30-day course of aspirin and clopidogrel (both 75 mg daily) was given to high-risk patients with TIA or minor ischemic stroke seen acutely in the EXPRESS study clinic from April 1, 2002, to March 31, 2009. Clopidogrel was stopped after 30 days and aspirin continued. Recurrent events were ascertained at face-to-face follow-up. RESULTS: A total of 320 patients were prescribed a 30-day course of aspirin and clopidogrel acutely after TIA or minor stroke. There were 5 recurrent ischemic strokes and 7 TIAs during the aspirin and clopidogrel treatment period, but no strokes and 4 TIAs during the 30 days after stopping clopidogrel. A similar temporal trend in stroke risk was seen in the 487 patients prescribed aspirin alone in the acute phase, with 12 and 5 strokes in the equivalent time periods. The upper 95% confidence intervals of the observed 0% risk of stroke during the 30 days after stopping clopidogrel was 1.15% overall. CONCLUSION: Although larger studies are required, our findings suggest there is unlikely to be a large rebound effect after discontinuation of a 30-day course of clopidogrel in acute TIA and minor ischemic stroke. However, planned trials of aspirin and clopidogrel in the acute phase after TIA or stroke should still follow-up beyond the cessation of clopidogrel treatment.

Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review.

BACKGROUND: Treatment of aneurysmal subarachnoid hemorrhage (SAH) has changed substantially over the last 25 years but there is a lack of reliable population-based data on whether case-fatality or functional outcomes have improved. METHODS: We determined changes in the standardized incidence and outcome of SAH in the same population between 1981 and 1986 (Oxford Community Stroke Project) and 2002 and 2008 (Oxford Vascular Study). In a meta-analysis with other population-based studies, we used linear regression to determine time trends in outcome. RESULTS: There were no reductions in incidence of SAH (RR = 0.79, 95% confidence interval [CI] 0.48-1.29, p = 0.34) and in 30-day case-fatality (RR = 0.67, 95% CI 0.39-1.13, p = 0.14) in the Oxford Vascular Study vs Oxford Community Stroke Project, but there was a decrease in overall mortality (RR = 0.47, 0.23-0.97, p = 0.04). Following adjustment for age and baseline SAH severity, patients surviving to hospital had reduced risk of death or dependency (modified Rankin score > 3) at 12 months in the Oxford Vascular Study (RR = 0.51, 0.29-0.88, p = 0.01). Among 32 studies covering 39 study periods from 1980 to 2005, 7 studied time trends within single populations. Unadjusted case-fatality fell by 0.9% per annum (0.3-1.5, p = 0.007) in a meta-analysis of data from all studies, and by 0.9% per annum (0.2-1.6%, p = 0.01) within the 7 population studies. CONCLUSION: Mortality due to subarachnoid hemorrhage fell by about 50% in our study population over the last 2 decades, due mainly to improved outcomes in cases surviving to reach hospital. This improvement is consistent with a significant decrease in case-fatality over the last 25 years in our pooled analysis of other similar population-based studies.

Preliminary evidence of a high risk of bleeding on aspirin plus clopidogrel in aspirin-naïve patients in the acute phase after TIA or minor ischaemic stroke.

BACKGROUND: Aspirin plus clopidogrel (A+C) may be more effective than aspirin only (AO) acutely after TIA and minor stroke, but the risk of bleeding in the acute phase is uncertain. We determined this risk, focusing particularly on aspirin-naïve patients. METHODS: We studied consecutive referrals to the EXPRESS study clinic from 1/4/02 to 31/3/08. A 30- to 90-day course of A+C was given to patients presenting acutely. Bleeding events were identified by face-to-face follow-up, diagnostic coding, and blood transfusion data. Unpublished data from the FASTER pilot trial were also studied. RESULTS: Among 633 EXPRESS patients treated with aspirin (+/- clopidogrel), there were 12 spontaneous bleeds (6 minor, 6 major/life-threatening) within 90 days after assessment, with a higher risk for A+C vs. AO (8/247 vs. 4/386, p = 0.047 overall; 5/247 vs. 1/386, p = 0.03 for major/life-threatening bleeds). The excess of major/life-threatening bleeds on A+C vs. AO was seen in aspirin-naïve patients, (4/137 vs. 0/273, p = 0.01), but not in prior-aspirin patients (1/110 vs. 1/113, p = 0.98). All symptomatic bleeds in the FASTER pilot also occurred in aspirin-naïve patients randomized to A+C (6/104 vs. 0/94, p = 0.03). In a pooled analysis, major/life-threatening bleeding on A+C occurred in 9/241 aspirin-naïve patients (90-day risk = 4.8%, 1.6-8.0) versus 1/204 prior-aspirin patients (p = 0.009). CONCLUSION: Although based on relatively few outcomes, the high risk of major bleeding on A+C acutely after TIA or minor stroke in aspirin-naïve patients is a cause for concern. The potential risk to patients is sufficient to mandate detailed monitoring of bleeding risk in ongoing trials and stratify results by whether patients were aspirin-naïve.

Meta-analysis of small randomized controlled trials in surgery may be unreliable.

BACKGROUND: Meta-analysis of randomized controlled trials (RCTs) should provide reliable evidence about the effects of interventions. This may be less reliable when only small trials are available. METHODS: The sample size was determined for all surgical RCTs included in Cochrane Collaboration systematic reviews. The difficulty in interpreting meta-analysis of small trials is illustrated using two specific reviews. RESULTS: The typical sample size for surgical RCTs was small with a median of only 87 participants. Only 39.8 per cent had adequate prerandomization treatment allocation concealment. In both systematic reviews that were assessed in detail, statistically significant early results from meta-analysis of several small RCTs did not reliably predict the results of subsequent RCTs. CONCLUSION: Surgical RCTs tend to be small and underpowered. Meta-analysis of such trials does not necessarily produce reliable results.

Inconsistent trial assessments by the National Institute for Health and Clinical Excellence and IQWiG: standards for the performance and interpretation of subgroup analyses are needed.

OBJECTIVES: The methodology for the critical assessment of medical interventions is well established. Regulatory agencies and institutions adhere, in principle, to the same standards. This consistency, however, is not always the case in practice. STUDY DESIGN AND SETTING: Using the evaluation of the CAPRIE (Clopidogrel versus Aspirin in Patients at risk of Ischemic Events) trial by the British National Institute for Health and Clinical Excellence (NICE) and the German Institute for Quality and Efficiency in Health Care (IQWiG), we illustrate that there was no consensus for the interpretation of possible heterogeneity in treatment comparisons across subgroups. RESULTS: The NICE concluded that CAPRIE demonstrated clinical benefit for the overall intention-to-treat (ITT) population with sufficient robustness to possible sources of heterogeneity. The IQWiG interpreted the alleged heterogeneity as implying that the clinical benefit only applied to the subgroup of patients with a statistically significant result irrespective of the results of the ITT analysis. CONCLUSION: International standards for the performance and interpretation of subgroup analyses as well as for the assessment of heterogeneity between strata are needed.

The SCAN rule: a clinical rule to reduce CT misdiagnosis of intracerebral haemorrhage in minor stroke.

UNLABELLED: Many patients with minor stroke are referred to outpatient clinics and are not scanned immediately. A clinical rule is needed to identify patients who are likely to have intracerebral haemorrhage (ICH) and require urgent brain imaging and patients who can safely start antiplatelet agents before scanning. METHODS: Clinical factors associated with ICH were determined in 334 consecutive patients with minor stroke (National Institute of Health Stroke Scale score < or = 3), and a predictive model for ICH that was validated in a cohort of 280 patients presenting to a hospital-stroke clinic was derived. Prognostic value was quantified as the area under the ROC curve (c statistics). RESULTS: The proportion of ICH in minor stroke was 5.1% (95% CI 3.2% to 8.0%) in OXVASC, and 5.4% (3.3% to 8.7%) in the clinic cohort. Clinical factors predictive of ICH in OXVASC included blood pressure on initial assessment > or = 180/110 mm Hg (OR 14.5, 95% CI 1.8 to 114, p=0.001), vomiting (OR 15.7, 95% CI 5.4 to 46, p<0.001), confusion (OR 8.2, 95% CI 2.9 to 23, p<0.001) and anticoagulation use (OR 7.8, 95% CI 2.2 to 28, p=0.006), and at least one predictive factor was identified in all 17 patients with ICH and in 35% overall (c statistic 0.92, 95% CI 0.88 to 0.97). Therefore, we derived the SCAN rule to identify ICH if > or = 1 of the following were present: (S) severe hypertension, (C) confusion, (A) anticoagulation, (N) nausea and vomiting. In the clinic validation cohort, > or = 1 predictive factor was identified in 14/15 of patients with ICH and in 24% overall (c statistic 0.87, 95% CI 0.79 to 0.95). CONCLUSION: The SCAN rule appears to be specific and sensitive at identifying ICH in an independent cohort of patients with minor stroke, although further independent validations are needed.

Reproducibility of measures of visit-to-visit variability in blood pressure after transient ischaemic attack or minor stroke.

BACKGROUND: In certain patients in routine practice, blood pressure (BP) measurements differ substantially from week to week or month to month. Although often assumed to be random, such variability could provide information on underlying pathology or prognosis. In order to be informative, however, visit-to-visit BP variability would have to be neither random (i.e. it should be reproducible over time within individuals) nor artefactual (i.e. it should not be an artefact of the method/timing of measurement, for example). METHODS: We quantified visit-to-visit variability in BP and explored potential confounding factors by analysing repeat measurements obtained every few months during follow-up in two large trials in patients with a transient ischaemic attack (TIA) or minor ischaemic stroke: the UK-TIA Aspirin Trial (effect of aspirin, effect of season and day of the week of measurement) and the European Carotid Surgery Trial (ECST - effect of carotid endarterectomy). By comparing different periods of follow-up, we also determined the reproducibilities of mean and several different measures of variability for both systolic (SBP) and diastolic BP (DBP). RESULTS: The mean absolute difference between adjacent SBP readings was 14.7 mm Hg in the UK-TIA Trial and 16.0 mm Hg in ECST. Visit-to-visit variability in both SBP and DBP were independent of the potentially confounding factors studied, but reproducibility of all the variability measures was statistically significantly greater than zero. Reproducibility (intraclass correlation) of standard deviation of SBP was 0.32 (p < 0.0001) in the UK-TIA Trial and 0.18 (p = 0.0007) in ECST. Consequently, classification of patients with high (top quintile) or low (bottom quintile) variability was consistent over time (observed/expected = 2.21, 95% confidence interval 1.71-2.85, p < 0.0001, and 1.65, 1.23-2.21, p = 0.0007, respectively). Reproducibility increased with the number of measurements used to calculate variability, and was independent of any correlation with mean BP. CONCLUSIONS: Visit-to-visit variability in BP in these populations was reproducible, independently of any correlation with mean BP, demonstrating that visit-to-visit intra-individual BP variability is not random.