Blood pressure and risk of dementia and its subtypes: a historical cohort study with long-term follow-up in 2.6 million people.

BACKGROUND AND PURPOSE: Elevated blood pressure (BP) is prevalent and modifiable and has been hypothesized to lead to increased risk of dementia. DATA: Data on 2 593 629 people from the UK Clinical Practice Research Database aged ≥40 years with a BP measurement between 1992 and 2011 and no prior record of dementia were collected. METHODS: Poisson regression models were used to study the association between BP and physician-diagnosed dementia. BP is believed to fall during the prodromal phase of dementia development, so associations were investigated by categories of time since BP measurement (<5, 5-10, >10 years) and by subtypes of dementia. RESULTS: During a median follow-up of 8.2 years, 65 618 cases of dementia were observed: 49 161 Alzheimer's, 13 816 vascular dementia and 2541 other subtypes. For each 10 mmHg higher systolic BP, the future dementia risk was 9.2% (95% confidence interval 8.4%-10.0%) lower, but this association varied markedly by time since BP measurement. Short-term associations with dementia were inverse with a 15.8% (15.5%-17.0%) lower risk 0-5 years after BP measurement and a 5.8% (7.7%-4.4%) lower risk 5-10 years after BP measurement. During the period >10 years after BP measurement, dementia risk was only 1.6% (0.1%-3.0%) lower, with a 4.3% (2.5%-6.0%) lower risk of Alzheimer's disease and a 7.0% (3.8%-10.2%) higher risk of vascular dementia. CONCLUSIONS: Elevated BP is associated with decreased risk of dementia in the short term, possibly due to reverse causation. Long-term associations of BP with dementia are less marked and differ by dementia subtype.

WITHDRAWN: Tacrine for Alzheimer's disease.

BACKGROUND: Tacrine is one of the first drugs to be widely marketed for the loss of memory and intellectual decline in Alzheimer's disease, often accompanied by abnormal behaviour and physical decline. The alleged success of tacrine in the treatment of these symptoms has been heralded as confirmation of the cholinergic theory of Alzheimer's disease. The efficacy of tacrine for symptoms of dementia remains controversial. This is reflected by the low rate of prescription of tacrine in countries where it is approved and the lack of approval by several regulatory authorities in Europe and elsewhere. The uncertainty about the efficacy of tacrine is due to the difficulties in interpretation of the results from the clinical trials. The reasons for this are the small effects of tacrine compared to placebo for all outcomes; the high incidence of adverse events; the lack of benefit observed in several trials; the use of cross-over designs and their associated methodological problems in a disease like dementia; the use of different measurement scales to assess outcome in different trials; and the problem of high dropout rates. OBJECTIVES: To determine the clinical efficacy of tacrine for the symptoms of Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'tacrine', 'tetrahydroaminoacridine' and 'THA' (see the Group's search strategy for full details). SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with tacrine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: This review produced no clear results. The results were compatible with tacrine producing improvement, no change or even harm for those with Alzheimer's disease. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analyses failed to detect any difference between tacrine and placebo (OR 0.87; 95%CI 0.61 - 1.23). Behavioural disturbance, as measured by the Alzheimer's Disease Assessment Scale-noncognitive, failed to detect any difference between tacrine and placebo (SMD -0.04; 95%CI -0.52 - 0.43). For cognition function, the effect of tacrine was not statistically significantly different from placebo for the MiniMental State Examination score (0-30; high =good) (SMD 0.14; 95%CI -0.02 - 0.30) and was barely statistically significantly in favour of treatment for the Alzheimer's Disease Assessment Scale-cognitive scale (SMD -0.22; 95%CI -0.32 - -0.13). Adverse events were not reported in a systematic way in the different trials, making formal comparison difficult. Raised serum liver enzymes was the major reason for withdrawal. The odds ratio for withdrawal due to an adverse event was significantly different from one, the control group experienced fewer events (OR 5.7; 95%CI 4.1-7.9). Gastrointestinal side effects (diarrhoea, anorexia, dyspepsia and abdominal pain) were the other major cause of adverse events and for withdrawal, and the odds ratio for withdrawal was also significantly different from one in favour of the control group (OR 3.8; 95%CI 2.8-5.1). No deaths were reported in any of the studies during the trial period, up to six months. AUTHORS' CONCLUSIONS: This review provides no convincing evidence that tacrine is a useful treatment for the symptoms of Alzheimer's disease. However, as so few trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. An independent meta-analysis of the individual-patient data is required. The results and conclusions of this update are unaltered by further searching as the additional studies do not add any further valid/eligible data.

A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

Apolipoproteins as predictors of ischaemic stroke in patients with a previous transient ischaemic attack.

BACKGROUND: Weak associations between total and LDL cholesterol and ischaemic stroke compared with coronary heart disease (CHD) are at odds with the similar effectiveness of statin drugs in preventing ischaemic stroke and CHD, suggesting that other lipid sub-fractions that are affected by statins might be better predictors of ischaemic stroke. Apolipoprotein B levels are reduced by statins and are a stronger predictor of CHD than total and LDL cholesterol in patients both on and off statins. However, there are very few published data on apolipoproteins and stroke risk and no studies in patients with previous transient ischaemic attack (TIA). METHODS: We performed a prospective cohort study of the associations of baseline total cholesterol, LDL, HDL, apolipoproteins A1 and B (apo A1; apo B) and risk of ischaemic stroke in 261 patients with previous TIA. Cox proportional hazards models were used to determine crude and multivariate-adjusted hazard ratios (HR) above versus below median values at 10-years follow-up. RESULTS: The apo B/apo A1 ratio was the strongest independent predictor of ischaemic stroke (HR=2.94, 95% CI 1.43-5.88, p=0.003) followed by apo B (HR=2.26, 95% CI 1.16-4.38, p=0.02). The associations between total cholesterol, LDL, HDL, LDL/HDL ratio and apo A1 and ischaemic stroke risk did not reach statistical significance. CONCLUSIONS: Apo B and the apo B/apo A1 ratio are predictive of ischaemic stroke in patients with previous TIA. Further studies are required to determine whether the prognostic value of apolipoprotein levels is maintained in patients on statins.

Corticosteroids for acute ischaemic stroke.

BACKGROUND: Much of the brain swelling in ischaemic stroke is due to cytotoxic oedema, which is related to cell membrane dysfunction. Early treatment with corticosteroids may help reduce the swelling and improve the outcomes after a stroke. OBJECTIVES: The objective of this review was to assess the effect of corticosteroids in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched: 10 April 2001) and contacted investigators in the field. SELECTION CRITERIA: Published randomised trials comparing corticosteroids with placebo or control in people with acute (presumed or definite) ischaemic stroke. Trials were included if treatment began within 48 hours of stroke onset and if clinical outcome was assessed. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted the data. MAIN RESULTS: Seven trials involving 453 people were included. Details of trial quality that may relate to bias were not available from most trials. No difference was shown in the odds of death within one year (odds ratio 1.08, 95% confidence interval 0.68 to 1.72). Treatment did not appear to improve functional outcome in survivors. Six trials reported neurological impairment but pooling the data was impossible because no common scale or time interval was used. The results were inconsistent between individual trials. The only adverse effects reported were small numbers of gastrointestinal bleeds, infections and deterioration of hyperglycaemia across both groups. Results unchanged since last update. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate corticosteroid treatment for people with acute presumed ischaemic stroke. Conclusions unchanged since last update.

Thiamine for Alzheimer's disease.

BACKGROUND: Vitamin B1 (thiamine) plays an important role in Wernicke-Korsakoff syndrome (a form of amnesia caused by brain damage occurring in long-term alcoholics who rely mainly on alcohol for nutrition). The acute syndrome is normally reversible but may proceed to profound dementia, although its progress can be stopped by a timely injection of a large dose of thiamine. There have been suggestions that thiamine may have a beneficial effect in Alzheimer's disease. OBJECTIVES: The objective of this systematic review is to evaluate the efficacy of thiamine for people with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Issue 3:2000), the CDCIG Trials Register and other sources were searched for this update in July 2000 using the terms 'alzheimer*', thiamin* and vitamin B1'. In addition bibliographies of published reviews, and conference proceedings were searched and pharmaceutical companies and trials investigators were contacted. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with thiamine was administered for more than a day and compared with placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers and the odds ratios (95% CI) or the average differences (95% CI) were estimated. MAIN RESULTS: There are three included studies, but few results were reported that could be included. The cross-over studies did not report results from the first phase. It was not possible to pool any results for a meta-analysis. Nolan 1991 reports results that show no evidence of an effect on MMSE at 3, 6, 9 and 12 months for thiamine compared with placebo for those who completed the trial. Meador 1993a noted that 3/8 on thiamine compared with 6/9 on placebo were worse as measured on the ADAS-Cog at 3 months compared with baseline, but the difference is not statistically significant. Blass 1988 and Nolan 1991 reported that no significant side-effects were noted during the study, and Meador 1993a did not mention side-effects. Blass 1988 noted that 5/16 and Nolan 1991 that 5/15 did not complete the study, but neither mentioned the groups to which these people belonged. REVIEWER'S CONCLUSIONS: It is not possible to draw any conclusions from this review. The number of people included in the studies if less than 50 and the reported results are inadequate.

Experimental approaches and drugs in development for the treatment of dementia.

Treatment of dementia can be divided as symptomatic treatment of cognitive or non-cognitive symptoms and the treatment of underlying pathology. In the last decade the thrust of symptomatic treatment of Alzheimer's disease (AD) has been enhancement of cholinergic transmission. Besides the acetycholinesterase inhibitors (AChE-I) currently in use, cholinergic agonists and enhancers are in development. Other therapeutic approaches directed towards neurotransmitter substitution or modulation include serotoninergic, noradrenergic substances, neuropeptides and those acting via excitatory amino acid receptors, such as ampakines or NMDA antagonists. Introduction of atypical neuroleptics represents the most recent development in the treatment of behavioural symptoms. Efforts to treat the underlying pathology are based on modulation of APP processing in order to decrease the accumulation of beta-amyloid, those to decrease tau hyperphosphorylation, use of nerve growth factors and those based on Apo-E modulation. Potential use of oestrogens and NSAIDs are also under investigation. Recently, vaccination with amyloid-beta peptide has been reported to be effective in an animal model of AD, this putative vaccine is now in clinical trials. Likewise, recent studies suggest that some statins may have a prophylactic effect.

Economic evaluation alongside n-of-1 trials: getting closer to the margin.

The n-of-1 trial is a particularly flexible form of randomized controlled trial that involves a single patient receiving multiple episodes of alternative therapies. Although n-of-1 trials are only applicable in certain treatment areas, the collection of economic data within such trials may provide unique advantages. This paper illustrates the issues around the use of economic n-of-1 trials with a hypothetical example, and discusses their potential for the estimation of individualized cost-effectiveness.

Tacrine for Alzheimer's disease.

OBJECTIVES: To determine the clinical efficacy of tacrine for the symptoms of Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'tacrine', 'tetrahydroaminoacridine' and 'THA' (see the Group's search strategy for full details). SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with tacrine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: This review produced no clear results. The results were compatible with tacrine producing improvement, no change or even harm for those with Alzheimer's disease. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analyses failed to detect any difference between tacrine and placebo (OR 0.87; 95%CI 0. 61 - 1.23). Behavioural disturbance, as measured by the Alzheimer's Disease Assessment Scale-noncognitive, failed to detect any difference between tacrine and placebo (SMD -0.04; 95%CI -0.52 - 0. 43). For cognition function, the effect of tacrine was not statistically significantly different from placebo for the MiniMental State Examination score (0-30; high =good) (SMD 0.14; 95%CI -0.02 - 0.30) and was barely statistically significantly in favour of treatment for the Alzheimer's Disease Assessment Scale-cognitive scale (SMD -0.22; 95%CI -0.32 - -0.13). Adverse events were not reported in a systematic way in the different trials, making formal comparison difficult. Raised serum liver enzymes was the major reason for withdrawal. The odds ratio for withdrawal due to an adverse event was significantly different from one, the control group experienced fewer events (OR 5.7; 95%CI 4.1-7.9). Gastrointestinal side effects (diarrhoea, anorexia, dyspepsia and abdominal pain) were the other major cause of adverse events and for withdrawal, and the odds ratio for withdrawal was also significantly different from one in favour of the control group (OR 3.8; 95%CI 2. 8-5.1). No deaths were reported in any of the studies during the trial period, up to six months. REVIEWER'S CONCLUSIONS: This review provides no convincing evidence that tacrine is a useful treatment for the symptoms of Alzheimer's disease. However, as so few trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. An independent meta-analysis of the individual-patient data is required. The results and conclusions of this update are unaltered by further searching as the additional studies do not add any further valid/eligible data.

Corticosteroids for acute ischaemic stroke.

BACKGROUND: Much of the brain swelling in ischaemic stroke is due to cytotoxic oedema, which is related to cell membrane dysfunction. Early treatment with corticosteroids may help reduce the swelling and improve the outcomes after a stroke. OBJECTIVES: The objective of this review was to assess the effect of corticosteroids in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register and contacted investigators in the field. SELECTION CRITERIA: Published randomised trials comparing corticosteroids with placebo or control in people with acute (presumed or definite) ischaemic stroke. Trials were included if treatment began within 48 hours of stroke onset and if clinical outcome was assessed. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted the data. MAIN RESULTS: Seven trials involving 453 people were included. Details of trial quality that may relate to bias were not available from most trials. No difference was shown in the odds of death within one year (odds ratio 1.08, 95% confidence interval 0.68 to 1.72). Treatment did not appear to improve functional outcome in survivors. Six trials reported neurological impairment but pooling the data was impossible because no common scale or time interval was used. The results were inconsistent between individual trials. The only adverse effects reported were small numbers of gastrointestinal bleeds, infections and deterioration of hyperglycaemia across both groups. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate corticosteroid treatment for people with acute presumed ischaemic stroke.

Tacrine for Alzheimer's disease.

BACKGROUND: Tacrine is one of the first drugs to be widely marketed for the loss of memory and intellectual decline in Alzheimer's disease. The alleged success of tacrine in the treatment of these symptoms has been heralded as confirmation of the cholinergic theory of Alzheimer's disease. However, the efficacy of tacrine for symptoms of dementia remains controversial. This is reflected by the low rate of prescription of tacrine in countries where it is approved and the lack of approval by several regulatory authorities in Europe and elsewhere. The uncertainty about the efficacy of tacrine is due to the difficulties in interpretation of the results from the clinical trials. The reasons for this are the small effects of tacrine compared to placebo for all outcomes; the high incidence of adverse events; the lack of benefit observed in several trials; the use of cross-over designs and their associated methodological problems in a disease like dementia; the use of different measurement scales to assess outcome in different trials; and the problem of high dropout rates. OBJECTIVES: To determine the clinical efficacy of tacrine for the symptoms of Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched using the terms 'tacrine', 'tetrahydroaminoacridine' and 'THA' (see the Group's search strategy for full details). SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with tacrine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. MAIN RESULTS: This review produced no clear results. The results were compatible with tacrine producing improvement, no change or even harm for those with Alzheimer's disease. It was not possible to use many of the published results in a combined analysis. For measures of overall clinical improvement, the intention-to-treat analyses failed to detect any difference between tacrine and placebo (OR 0.87; 95%CI 0.61 - 1.23). Behavioural disturbance, as measured by the Alzheimer's Disease Assessment Scale-noncognitive, failed to detect any difference between tacrine and placebo (SMD -0.04; 95%CI -0.52 - 0.43). For cognition function, the effect of tacrine was not statistically significantly different from placebo for the MiniMental State Examination score (0-30; high =good) (SMD 0.14; 95%CI -0.02 - 0.30) and was barely statistically significantly in favour of treatment for the Alzheimer's Disease Assessment Scale-cognitive scale (SMD -0.22; 95%CI -0.32 - -0.13). Adverse events were not reported in a systematic way in the different trials, making formal comparison difficult. Raised serum liver enzymes was the major reason for withdrawal. The odds ratio for withdrawal due to an adverse event was significantly different from one, the control group experienced fewer events (OR 5.7; 95%CI 4.1-7.9). Gastrointestinal side effects (diarrhoea, anorexia, dyspepsia and abdominal pain) were the other major cause of adverse events and for withdrawal, and the odds ratio for withdrawal was also significantly different from one in favour of the control group (OR 3.8; 95%CI 2.8-5.1). No deaths were reported in any of the studies during the trial period, up to six months. REVIEWER'S CONCLUSIONS: This review provides no convincing evidence that tacrine is a useful treatment for the symptoms of Alzheimer's disease. However, as so few trials presented data in a format suitable for pooling, the results of this review may be modified when further data from all relevant trials are included. There is an urgent need for the independent evaluation of the data already existing in the trials but not accessible through published or grouped data. A

Thiamine for Alzheimer's disease.

BACKGROUND: Vitamin B1 (thiamine) plays an important role in Wernicke-Korsakoff syndrome (a form of amnesia caused by brain damage occurring in long-term alcoholics who rely mainly on alcohol for nutrition). The acute syndrome is normally reversible but may proceed to profound dementia, although its progress can be stopped by a timely injection of a large dose of thiamine. There have been suggestions that thiamine may have a beneficial effect in Alzheimer's disease. OBJECTIVES: The objective of this systematic review is to evaluate evidence of the effect of thiamine for Alzheimer's disease. SEARCH STRATEGY: The Cochrane Controlled Trials Register and the CDCIG Register were searched using the terms 'thiamine*, alzheimer* and vitamin* B1'. Other sources were also searched. SELECTION CRITERIA: All unconfounded, double-blind, randomized trials in which treatment with thiamine was administered for more than a day and compared to placebo in patients with dementia of the Alzheimer's type. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers, pooled if appropriate and possible, and the pooled odds ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available to be used. MAIN RESULTS: Few data were available for review. The data were compatible with thiamine producing harm, no change or improvement. For measures of cognition, the effect of thiamine was non-significantly worse than placebo on the Mini Mental State Examination score (0-30; high=good) at 12 months: WMD -4.3 (95% CI: -14.4 - +5.8) and at time points 3, 6 and 9 months. Change from baseline analyses showed placebo to be significantly better than thiamine at all time points beyond three months; WMD -4.8 (95% CI: -6.0 to -3.6) at 12 months. There was no statistically significant difference in the test of Verbal Fluency and the Boston Naming Test. These analyses were based only on those who completed the study and not on intention-to-treat analyses. There were no results presented for withdrawal by treatment group. Data on measures of functional autonomy, behaviour, quality of life, dependency, or effect on carer were not available. REVIEWER'S CONCLUSIONS: This review finds no evidence that thiamine is a useful treatment for the symptoms of Alzheimer's disease. The data are so poor and sparse that it is difficult to state almost anything of its effect in Alzheimer's disease. Thiamine cannot be recommended for patients with Alzheimer's disease.

Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration.

OBJECTIVES: To determine the effects of cholinesterase inhibition with tacrine hydrochloride for the symptoms of Alzheimer disease in terms of cognitive performance, clinical global impression, behavior, and functional autonomy. DATA SOURCES: The Cochrane Dementia Group registry of trials. STUDY SELECTION: Unconfounded, randomized, double-blind, placebo-controlled trials in which tacrine had been given for more than 1 day and that were completed before January 1, 1996. DATA EXTRACTION: Two reviewers independently selected trials for inclusion and individual patient data were sought. DATA SYNTHESIS: Data were analyzed from 12 trials that included 1984 patients with Alzheimer disease. At 12 weeks, cognitive performance, as measured by the Mini-Mental State Examination (score range, 0-30), was better in patients receiving tacrine than in patients receiving placebo by 0.62 points (95% confidence interval [CI], 0.23-1.00; P=.002). Compared with similar untreated patients who would be expected to deteriorate by 0.50 to 1.00 points on the Mini-Mental State Examination during 12 weeks, the progress of patients receiving tacrine would be expected to range between an improvement of 0.12 and a deterioration of 0.38 points. The odds ratio for improvement on the Clinical Global Impression of Change scale (range, 1-7) for patients receiving tacrine compared with those receiving placebo was 1.58 (95% CI, 1.18-2.11; P=.002). The behavioral noncognitive subscale of the Alzheimer's Disease Assessment Scale (range, 0-50) showed a difference in favor of tacrine of 0.58 points (95% CI, 0.17-1.00; P= .006). Improvement on the Progressive Deterioration Scale, largely an index of functional activities, was not significant (0.75; 95% CI, -0.43 to 1.93; P=.21). Age, severity of dementia, and exposure to tacrine prior to randomization had no clear influence on the treatment effect. There was a nonsignificant trend toward increasing effect with increasing dose for cognitive function and the Clinical Global Impression of Change. For patients without prior exposure to tacrine, the odds of patients' withdrawing during the study while they were receiving tacrine compared with placebo was 3.63 (95% CI, 2.80- 4.71; P<.001). Eleven (95% CI, 7-31) patients would need to be treated to achieve any improvement on the Clinical Global Impression scale, and 42 (95% CI, 23-125) to achieve a moderate or marked improvement. One patient would be expected to withdraw for every 4 (95% CI, 3-5) patients treated. CONCLUSIONS: Cholinesterase inhibition with tacrine appears to reduce deterioration in cognitive performance during the first 3 months and increase the odds of global clinical improvement. Effects observed on measures of behavioral disturbance were of questionable clinical significance, and functional autonomy was not significantly affected. The clinical relevance of the benefits of cholinesterase inhibition remains controversial, and long-term trials with clinically relevant end points are required.

Are risk factors for stroke and coronary disease the same?

Many risk factors operate in both coronary heart disease and stroke, especially ischaemic stroke--age, sex, social class, blood pressure, pre-existing vascular disease (angina, myocardial infarction, cardiac failure, diabetes and peripheral vascular disease, transient ischaemic attack and stroke), atrial fibrillation and fibrinogen, smoking, alcohol and height. Total cholesterol has also recently been recruited to this list. The various mechanisms involved in stroke and its subtypes and the epidemiological problems in evaluating aetiological factors in stroke make the comparison with coronary heart disease more difficult. The recent discrepancy between much of the epidemiology and the clinical trials evaluating the role of lipids in stroke has spurred the systematic review (meta-analysis) of major prospective observational studies. These will provide a clearer assessment about the quantitative comparison of some of the more important risk factors for stroke and coronary heart disease in the near future.

Von Willebrand factor and risk of ischemic stroke.

We carried out a case-control study to determine whether von Willebrand factor (vWF) antigen (and factor VII and tissue plasminogen activator [tPA] antigens) are associated with ischemic stroke. Ninety-five patients with transient ischemic attack or minor ischemic stroke recruited from the Oxfordshire Community Stroke Project and one neurology clinic were compared with 236 controls, group-matched for age and sex, from the same general practitioners as the incident cases. In crude analyses, concentrations of vWF antigen were significantly higher in cases than in controls (p = 0.004). The age- and sex-adjusted odds ratios from lowest (referent) to highest quartile of vWF antigen were 1.00, 1.15, 2.34, and 2.36 (trend test, p = 0.006). Factor VII antigen and tPA antigen were not significantly different between cases and controls. Although adjustment for other potential risk factors abolished the statistical significance of the association between vWF and disease, this was largely due to the influence of history of ischemic heart disease. We conclude that vWF is a potent and independent risk factor for transient ischemic attack, minor ischemic stroke, and, by extrapolation, ischemic stroke in general. The data also suggest that vWF may be a risk factor for both ischemic stroke and ischemic heart disease. We found no evidence to implicate factor VII and tPA as risk factors for ischemic stroke.

Repeat measurement of case-control data: corrections for measurement error in a study of ischaemic stroke and haemostatic factors.

BACKGROUND: Haemostatic factors are suspected to be involved in the aetiology of cerebrovascular events. METHODS: In a case-control study of 105 cases of transient ischaemic attack and minor ischaemic stroke, and 241 controls, data were available on levels of the haemostatic factors-von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI), tissue plasminogen activator (TPA) and factor VII (FVII). These are subject to measurement error and within-person fluctuation of true levels, which may bias relative risk estimates. For all subjects, two determinations were performed on the same blood sample, which allowed estimation of pure measurement error. For estimation of within-person fluctuation, levels were measured from a repeat blood sample on 81 of the controls one year later. RESULTS: The pure measurement error accounted for a very small proportion of the total variation in all cases. Uncorrected for within-person fluctuation, the odds ratio estimates associated with exceeding the median of vWF, PAI, TPA and FVII respectively were 1.88, 0.87, 1.30 and 0.93. After correction for within-person fluctuation odds ratios were 3.56, 0.80, 1.41 and 0.91. Because the PAI determination was not robust to storage conditions, it was estimated that 75% of the variation in this factor was within-person rather than between-persons. Thus, estimates of relative risk relation to PAI cannot be regarded as reliable in this study. CONCLUSIONS: It is likely that elevated levels of vWF are associated with increased risk of ischaemic stroke, but interpretation must be tentative, due to relatively large within-person fluctuation of vWF levels.

Fibrinogen and cerebrovascular disease.

The importance of fibrinogen has been identified in two prospective observational studies. Reactive elevations in fibrinogen levels that occur within hours of a major stroke invalidate most cross-sectional case-control studies evaluating fibrinogen as a risk factor. However, as no elevation is seen following fresh episodes of transient ischaemic attacks, reliable conclusions drawn from a case-control study using such patients support the findings of the prospective studies. The association is related to occlusive stroke, but the relationship with intracerebral haemorrhage is unclear. The relationship has been found to be independent of other haemostatic and haemorheological factors (e.g. von Willebrand factor, tissue plasminogen activator and packed cell volume). Adjustment for regression dilution bias would further strengthen the observed relationship. Therefore, after blood pressure, fibrinogen is the most important potentially treatable risk factor for ischaemic stroke. There are several mechanisms whereby fibrinogen could promote athero-thromboembolism: thrombosis through a hypercoagulable state; the acceleration of atherosclerosis; or the reduction of blood flow due to high blood or plasma viscosity. The mechanism, however, is unlikely to be mediated through high blood viscosity per se as secondary erythrocytosis (another major determinant of blood viscosity) has not consistently been found to be a risk factor for stroke. Studies relating fibrinogen levels to the degree of carotid artery stenosis support the accelerating influence of fibrinogen on atherosclerosis. Fibrinogen should be considered a risk factor for ischaemic stroke and included in the assessment of individual risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)