Homocysteine, B vitamins, and cardiovascular disease.
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Biomedical subjects
Publications and source records attributed to David J Stott.
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OBJECTIVE: To determine whether a co-ordinated programme of geriatric assessment and multidisciplinary home-based rehabilitation reduces disability and prevents non-elective hospital readmission in high-risk elderly patients. DESIGN: Nested case-control study comparing usual post-discharge care versus usual care plus a comprehensive geriatric assessment and home-based rehabilitation service, comprising nursing, occupational therapy and physiotherapy with geriatric medical review. Patients were >or=65 years with >or=2 non-elective hospital admissions within the previous 12 months. Disability was assessed using the 100-point Barthel index and Nottingham extended activities of daily living (EADL) score. Non-elective hospital admissions were recorded over 1-year follow-up. RESULTS: We studied 84 patients; 56 receiving the new service were matched to 28 controls. Intervention subjects received a median of 19 h [interquartile range (IQR) (7,35)] rehabilitation over 19 [IQR (6,42)] domiciliary visits. At 3 months, there was improvement in median Barthel and Nottingham EADL scores in the intervention group of 3 and 2 points, respectively, compared with reductions in controls of 3 and 6 points (both P<0.001, changes in intervention group versus controls); similar differences persisted in survivors at 12 months. There was a non-significant trend for reduction in the proportion of patients with further non-elective hospital admission in the intervention group (36/56, 64%) compared with controls (21/28, 75%; OR 0.70, 95% CI 0.34, 1.46). CONCLUSIONS: A co-ordinated programme of geriatric assessment and multidisciplinary home-based rehabilitation reduced disability in elderly patients at high risk for non-elective hospital admission. Further research is required to determine whether this approach can reduce the need for hospital admission.
BACKGROUND AND PURPOSE: Plasma d-dimer levels, measured using a research laboratory assay, independently predict progressing ischemic stroke. We wished to confirm these findings using commercially available assays and to provide data to allow the design of intervention studies. METHODS: We studied 219 consecutive acute ischemic stroke admissions of whom 54 (25%) met criteria for progressing stroke. RESULTS: There were strong correlations between d-dimer results as measured by the Biopool AB, MDA and VIDAS assays; correlation coefficients r=0.91 to 0.94; all P<0.001. In binary logistic regression analyses, d-dimer, as measured by the 3 different assays, was an independent predictor of progressing stroke (odds ratios, 1.87 to 2.45; all P<0.001). This confirms the results of our original analysis (Biopool AB) using 2 commercial d-dimer assays, demonstrating the potential usefulness of d-dimer in providing early prognostic information after ischemic stroke in different clinical settings. We also provide information on the performance of the 3 assays in predicting progressing stroke at a variety of cutoff values. CONCLUSIONS: Ischemic stroke patients at high risk of early progression can be identified using commercial d-dimer measurements. This could allow selection of high-risk patients for inclusion in randomized trials of early antithrombotic treatments.
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BACKGROUND: Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). METHOD AND RESULTS: The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group (P=0.27), nor did on-treatment LDLc in the pravastatin group (P=0.12). HDLc was inversely associated with risk in subjects on placebo (P=0.0019) but not in those on pravastatin (P=0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc (P=0.38) but exhibited a significant interaction with HDLc (P=0.012). Subjects in the lowest 2 quintiles of HDLc (<1.15 mmol/L) had a risk reduction of 33% (hazard ratio, 0.67; 95% confidence limits, 0.55, 0.81; P<0.0001), whereas those with higher HDLc showed no benefit (RR, 1.06; 95% confidence limits, 0.88, 1.27; P=0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. CONCLUSIONS: In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc <1.15 mmol/L or an LDLc/HDLc ratio >3.3.
OBJECTIVE: to determine contributors to decline in functional capacity in elderly patients with known vascular risk factors or disease. DESIGN: secondary analysis of longitudinal data gathered over an average 3.2 years of follow-up. PARTICIPANTS: 5,804 community-dwelling subjects aged 70-82 years with a history of, or risk factors for, ischaemic vascular disease. MEASUREMENTS: basic activities of daily living were measured serially through the study using the 20-point Barthel index and extended activities using a 14-point Instrumental Activities of Daily Living (IADL). RESULTS: over the period of study 896/5,661 (16%) subjects had deterioration in Barthel (mean reduction 0.35, SD 1.76) and 1,270/5,662 (22%) had a reduction in IADL score (mean 0.63, SD 2.15). Independent risk factors at baseline for a reduction in Barthel and IADL were age, female gender and diabetes mellitus. A history of vascular disease and smoking were also significant predictors of reduction in IADL. The development of a new cerebrovascular event was associated with a greatly increased risk of reduction in the Barthel and IADL score (multivariate OR 3.71 (95% CI 2.94, 4.69) and 3.71 (95% CI 2.96, 4.66), respectively). A similar pattern was seen for non-fatal myocardial infarction. Incident cerebrovascular events and non-fatal myocardial infarction accounted for 31 and 11%, respectively, of the population decline in Barthel, and 24 and 10% of the decline in IADL. CONCLUSION: incident vascular events were important contributors to functional decline in this population, accounting for almost half of the observed deterioration in basic activities of daily living and approximately one-third of the reduction in IADL. Prevention of ischaemic vascular events over the short to medium term should reduce the burden of disability in high-risk older subjects.
BACKGROUND: High concentrations of homocysteine and low concentrations of vitamin B-12 and folic acid are frequently observed in subjects with dementia. OBJECTIVE: We assessed whether serum concentrations of homocysteine, vitamin B-12, or folic acid predict cognitive decline in old age. DESIGN: This was a prospective, population-based, longitudinal study of 599 subjects (Leiden 85-Plus Study, Netherlands). The subjects were administered a battery of cognitive tests (including the Mini Mental State Examination, the Stroop test, a letter digit coding test, and a word recall test) at 85 y of age and yearly thereafter until 89 y of age. Serum concentrations of homocysteine, vitamin B-12, and folic acid were measured at 85 and 89 y of age. Cross-sectional associations between serum concentrations and cognition were assessed at 85 and 89 y of age. The association between baseline serum concentrations and subsequent longitudinal cognitive decline was assessed with the use of mixed linear models. RESULTS: In the cross-sectional analyses, serum concentrations of homocysteine and folic acid were significantly associated with cognitive performance, but serum concentrations of vitamin B-12 were not. In the longitudinal analyses, there were no significant associations of serum concentrations of homocysteine, vitamin B-12, or folic acid with rate of cognitive decline. CONCLUSIONS: Elevated serum concentrations of homocysteine and reduced folic acid are associated with cognitive impairment in elderly persons but do not predict an increased rate of cognitive decline. The association of high serum concentrations of homocysteine and low folic acid with cognitive impairment in old age is likely to be a consequence of disease and not a contributory cause.
BACKGROUND: Homocysteine is an independent risk factor for vascular disease and is associated with dementia in older people. Potential mechanisms include altered endothelial and hemostatic function. OBJECTIVE: We aimed to determine the effects of folic acid plus vitamin B-12, riboflavin, and vitamin B-6 on homocysteine and cognitive function. DESIGN: This was a factorial 2 x 2 x 2, randomized, placebo-controlled, double-blind study with 3 active treatments: folic acid (2.5 mg) plus vitamin B-12 (500 microg), vitamin B-6 (25 mg), and riboflavin (25 mg). We studied 185 patients aged >or=65 y with ischemic vascular disease. Outcome measures included plasma homocysteine, fibrinogen, and von Willebrand factor at 3 mo and cognitive change (determined with the use of the Letter Digit Coding Test and on the basis of the Telephone Interview of Cognitive Status) after 1 y. RESULTS: The mean (+/-SD) baseline plasma homocysteine concentration was 16.5 +/- 6.4 micromol/L. This value was 5.0 (95% CI: 3.8, 6.2) micromol/L lower in patients given folic acid plus vitamin B-12 than in patients not given folic acid plus vitamin B-12 but did not change significantly with vitamin B-6 or riboflavin treatment. Homocysteine lowering with folic acid plus vitamin B-12 had no significant effect, relative to the 2 other treatments, on fibrinogen, von Willebrand factor, or cognitive performance as measured by the Letter Digit Coding Test (mean change: -1; 95% CI: -2.3, 1.4) and the Telephone Interview of Cognitive Status (-0.7; 95% CI: -1.7, 0.4). CONCLUSION: Oral folic acid plus vitamin B-12 decreased homocysteine concentrations in elderly patients with vascular disease but was not associated with statistically significant beneficial effects on cognitive function over the short or medium term.
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BACKGROUND AND PURPOSE: Early clinical progression of ischemic stroke is common and is associated with increased risk of death and dependency. We hypothesized that activation of the coagulation system is an important contributor in some cases of deterioration. We aimed to characterize alterations in circulating hemostatic markers in patients with progressing stroke. METHODS: Consecutive acute ischemic stroke admissions were recruited. Progressing stroke was defined by deterioration in components of the Scandinavian Stroke Scale. Hemostatic markers (coagulation factors VIIc, VIIIc, and IXc, prothrombin fragments 1+2 [F1+2], thrombin-antithrombin complexes [TAT], D-dimer, fibrinogen, von Willebrand factor [vWF] and tissue plasminogen activator) were measured within 24 hours of symptom recognition. RESULTS: Fifty-four (25%) of the 219 patients met criteria for progressing stroke. F1+2 (median 1.28 versus 1.06 nmol/L, P=0.01), TAT (5.28 versus 4.07 microg/L, P<0.01), D-dimer (443 versus 194 ng/mL, P<0.001) and vWF (216 versus 198 IU/dL, P<0.05) levels were higher in these patients than in stable/improving patients. In logistic regression analysis, with all important clinical and laboratory variables included, only natural log D-dimer (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.38 to 2.54; P=0.0001) and mean arterial blood pressure (OR: 1.26 per 10 mm Hg change; 95% CI: 1.05 to 1.51; P=0.01) remained independent predictors of progressing stroke. CONCLUSIONS: There is evidence of excess thrombin generation and fibrin turnover in patients with progressing ischemic stroke. Measurement of D-dimer levels can identify patients at high risk for stroke progression. Further research is required to determine whether such patients benefit from acute interventions aimed at modifying hemostatic function.
BACKGROUND: Cognitive impairment and dementia are very common after stroke. Telephone screening has potential advantages for clinical follow-up and population-based research in this group. We wished to test the validity of the Telephone Interview for Cognitive Status (TICS) for cognitive testing in post-stroke subjects. METHODS: Cognitive function in stroke outpatients was assessed using the R-CAMCOG (a modification of the cognitive part of the Cambridge Examination for Mental Disorders of the Elderly, for use in stroke subjects) along with the TICS and a modified version, the TICSm. The tests were administered in random order. A cut-off point of 33 on the R-CAMCOG was used to define post-stroke dementia. RESULTS: Sixty-four patients with a median age of 72 years were assessed. The Pearson correlation coefficients between the R-CAMCOG and the TICS and TICSm were 0.833 and 0.855 (both p <0.001) respectively. Twenty-four (38%) patients met R-CAMCOG criteria for post-stroke dementia. The area under the ROC curve for both the TICS and TICSm was 0.94. Using a cut-off of 28 or less on the TICS produced a sensitivity of 88% and a specificity of 85% for the diagnosis of post-stroke dementia. For the TICSm a cut-off of 20 or lower produced a sensitivity of 92% and a specificity of 80%. CONCLUSIONS: The TICS and TICSm telephone questionnaires are practicable and valid methods of assessing cognitive function in community outpatients following stroke. Scores of < or =28 and < or =20 respectively carry good sensitivity and specificity for the diagnosis of post-stroke dementia.
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BACKGROUND: Reliable estimation of severity of neurological impairments early after stroke is essential for research and audit of acute stroke care. Obtaining this information prospectively requires significant resources. We wished to assess the reliability of estimating the Scandinavian Stroke Scale (SSS) score retrospectively from routine hospital admission records. METHODS: Acute stroke admissions to a large urban hospital were examined and had their SSS scored by an experienced physician within 4 h of the examination performed by the medical admissions team. Two examiners (a trained research nurse and a second physician), blinded to the patients' clinical condition, later independently estimated retrospective SSS scores using information documented in the medical admission notes. RESULTS: Fifty patients were recruited [median age 73 years (interquartile range 61, 79)]. Weighted kappa statistics for agreement between domains of the face-to-face and retrospective SSS were as follows: consciousness 0.73, eye movements 0.60, arm motor power 0.83, hand motor power 0.71, leg motor power 0.81, orientation 0.81, speech 0.80, and facial palsy 0.53. The intraclass correlation coefficient for face-to-face and retrospective SSS composite scores was 0.97 (95% CI 0.96-0.98), p < 0.0001. Interobserver reliability for the different components of the retrospective SSS was excellent (kappa values greater than 0.75) apart from consciousness (0.71) and eye movements (0.58). CONCLUSIONS: The composite SSS score and most of its individual components can be reliably estimated retrospectively from routine hospital admission records. This method is potentially useful both in observational studies and in case-mix adjustment for audit purposes.
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BACKGROUND: Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS: We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS: Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.
BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.
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BACKGROUND: Early neurological deterioration after ischaemic stroke (stroke in progression) is reported to be common and associated with poor outcome or death. The causes of progressing stroke are, however, uncertain. OBJECTIVE: To determine whether prior drug treatment (with anticoagulant or antiplatelet agents) or early adverse physiological features (pyrexia, hypoxia, dehydration or hyperglycaemia) are associated with progressing ischaemic stroke. METHODS: The study used a case-control design. From a database of 873 consecutive acute stroke admissions, 196 cases of progressing ischaemic stroke (defined by point deterioration in components of the Scandinavian Stroke Scale or death over the first 72 h after hospital admission) were matched to 196 controls on the basis of age and stroke type. Univariate and conditional logistic regression techniques were used to explore predictors of progressing stroke. RESULTS: Cases and controls were well matched for baseline stroke severity. Warfarin use prior to admission was associated with a reduced risk of progressing stroke [odds ratio (OR) 0.10, p = 0.005]. Prior antiplatelet use was not related. A previous history of diabetes (OR 2.11, p = 0.039) and elevated systolic blood pressure on admission (OR 1.01 for each 1 mm Hg rise, p = 0.017) predicted progressing stroke. Although there were no differences in time to presentation or to brain imaging, a visible causative lesion on CT scanning was more common in the progressing stroke group (OR 2.30, p = 0.022). We found no evidence that adverse physiological features were associated with progressing stroke. Outcomes were worse in the progressing stroke group with 70% being dead or dependent by 30 days compared to 55% in the control group (p = 0.002). CONCLUSION: Prior warfarin use may be protective against progressing ischaemic stroke. A previous history of diabetes along with elevated admission systolic blood pressure predict deterioration. We found no evidence for an association between adverse physiological features and progressing stroke.