Showing papers by "Bruce Neal published in 2008"

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

Abstract: BACKGROUND: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials.

Abstract: Objective To quantify the relative risk reductions achieved with different regimens to lower blood pressure in younger and older adults. Design Meta-analyses and meta-regression analyses used to compare the effects on the primary outcome between two age groups ( or =65 years). Evidence for an interaction between age and the effects of treatment sought by fitting age as a continuous variable and estimating overall effects across trials. Primary outcome total major cardiovascular events. Results 31 trials, with 190 606 participants, were included. The meta-analyses showed no clear difference between age groups in the effects of lowering blood pressure or any difference between the effects of the drug classes on major cardiovascular events (all P> or =0.24). Neither was there any significant interaction between age and treatment when age was fitted as a continuous variable (all P>0.09). The meta-regressions also showed no difference in effects between the two age groups for the outcome of major cardiovascular events ( or =65; P=0.38). Conclusions Reduction of blood pressure produces benefits in younger ( or =65 years) adults, with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial.

Abstract: Summary Background There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. Methods Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150–220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. Findings Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12·7 mL, SD 11·6) than in the intensive group (14·2 mL, SD 14·5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13·3 mm Hg, 95% CI 8·9–17·6 mm Hg; p Interpretation Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. Funding National Health and Medical Research Council of Australia.

Intensive blood pressure reduction in acute cerebralhaemorrhage trial (INTERACT): a randomised pilot trial

Abstract: BACKGROUND There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. METHODS Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. FINDINGS Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. INTERPRETATION Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. FUNDING National Health and Medical Research Council of Australia.

Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials.

Abstract: Aims Large-scale observational studies show that lower blood pressure is associated with lower cardiovascular risk in both men and women although some studies have suggested that different outcomes between the sexes may reflect different responses to blood pressure-lowering treatment. The aims of these overview analyses were to quantify the effects of blood pressure-lowering treatment in each sex and to determine if there are important differences in the proportional benefits of treatment between men and women. Methods and results Thirty-one randomized trials that included 103 268 men and 87 349 women contributed to these analyses. For each outcome and each comparison summary estimates of effect and 95% confidence intervals were calculated for men and women using a random-effects model. The consistency of the effects of each treatment regimen across the sexes was examined using χ2 tests of homogeneity. Achieved blood pressure reductions were comparable for men and women in every comparison made. For the primary outcome of total major cardiovascular events there was no evidence that men and women obtained different levels of protection from blood pressure lowering or that regimens based on angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, or diuretics/beta-blockers were more effective in one sex than the other (all P -homogeneity > 0.08). Conclusion All of the blood pressure-lowering regimens studied here provided broadly similar protection against major cardiovascular events in men and women. Differences in cardiovascular risks between sexes are unlikely to reflect differences in response to blood pressure-lowering treatments.

Associations of Proinflammatory Cytokines With the Risk of Recurrent Stroke

Abstract: Background and Purpose— There are few reports on proinflammatory cytokines and risk of primary or recurrent stroke. We studied the association of interleukin (IL)-6, IL-18, and tumor necrosis factor-α (TNF-α) with recurrent stroke in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). Methods— We performed a nested case-control study of 591 strokes (472 ischemic, 83 hemorrhagic, 36 unknown subtype) occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial. Results— IL-6 and TNF-α, but not IL-18, were associated with risk of recurrent ischemic stroke independently of conventional risk markers. Adjusted odds ratios comparing the highest to lowest third of their distributions were 1.33 (95% CI, 1.00 to 1.78) for IL-6 and...

Do we need to adjudicate major clinical events

Abstract: Purpose The use of centralized systems to adjudicate clinical events is common in large clinical trials, in spite of relatively little published literature concerning the rationale and justification. The purpose of this manuscript is to review the reasons for central adjudication and to discuss whether trials could be simplified by limiting or streamlining the adjudication process.Methods We reviewed the literature concerning central adjudication and documented the experience of adjudication in several clinical trials. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification. Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is perfor...

APOE genotype, ethnicity, and the risk of cerebral hemorrhage

Abstract: Objective: The apolipoprotein E ( APOE ) polymorphism is an established risk factor for intracerebral hemorrhage (ICH) that is related to cerebral amyloid angiopathy in the white population. Among Asian populations, although ICH represents up to one third of all strokes and has high rates of mortality and morbidity, the role of the APOE polymorphism has not been well studied. Methods: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind, placebo-controlled trial of a blood pressure lowering regimen in subjects with prior cerebrovascular disease. APOE status was determined for 5,671 patients, including 2,148 Asians (38%). Results: During the 3.9 years of follow-up, ICH occurred in 99 patients. Overall, carrying an e2 or e4 allele of the APOE polymorphism was associated with an adjusted hazard ratio (HR a ) of 1.85 (95% CI = 1.24 to 2.76). In Asian patients the risk of ICH for e2 or e4 carriers was 2.11 (95% CI = 1.28 to 3.47) and 1.48 (95% CI = 0.76 to 2.87) in Europeans. Carriers of the e2 or e4 allele had an increased risk of both incident and recurrent ICH, and both cortical and deep ICH, and most risk estimates were higher in Asians than in Europeans. For both ethnic groups and for subtypes of ICH active treatment more than halved the risk of ICH and the treatment effects were not different in carriers of the e2 or e4 allele and in those with the e3e3 genotype. Conclusions: There is a strong association between APOE genotype and the risk of intracerebral hemorrhage (ICH). In Asian patients the role of APOE polymorphisms in ICH is much broader than was previously supposed.

The effects of a reduced-sodium, high-potassium salt substitute on food taste and acceptability in rural northern China.

Abstract: A potassium chloride-containing salt substitute lowers blood pressure levels, but its overall acceptability has been of concern due to its potential adverse effects on food taste. In a large-scale, blinded randomised trial evaluating the comparative effects of a salt substitute (65 % sodium chloride, 25 % potassium chloride and 10 % magnesium sulphate) and a normal salt (100 % sodium chloride) on blood pressure, we collected data on the saltiness, flavour and overall acceptability of food. We performed this at baseline, 1, 6 and 12 months post-randomisation using 100 mm visual analogue scales for assessments of both home-cooked foods and a standard salty soup. The mean age of the 608 participants from rural northern China was 60 years and 56 % of them were females. In the primary analyses, the changes in the saltiness, flavour and overall acceptability of both home-cooked foods and a standard salty soup were not different between the randomised groups (all P>0.08). In the secondary analyses, weighting each of the data points according to the lengths of the respective follow-up intervals, the flavour of both home-cooked foods (mean difference = - 1.8 mm, P = 0.045) and a standard salty soup (mean difference = - 1.9 mm, P = 0.03) was slightly weaker in the salt substitute group. We conclude that salt substitution is both an effective and an acceptable means of blood pressure control. Possible small differences in flavour did not importantly deter the use of the salt substitute in this study group, although the acceptability of the salt substitute by a more general population group would need to be confirmed.

The burden of fatal and non-fatal injury in rural India

Abstract: Background: Little is known about the burden or causes of injury in rural villages in India. Objective: To examine injury-related mortality and morbidity in villages in the state of Andhra Pradesh, India. Methods: A verbal-autopsy-based mortality surveillance study was used to collect mortality data on all ages from residents in 45 villages in 2003–2004. In early 2005, a morbidity survey in adults was carried out using stratified random sampling in 20 villages. Participants were asked about injuries sustained in the preceding 12 months. Both fatal and non-fatal injuries were coded using classification methods derived from ICD-10. Results: Response rates for the mortality surveillance and morbidity survey were 98% and 81%, respectively. Injury was the second leading cause of death for all ages, responsible for 13% (95% CI 11% to 15%) of all deaths. The leading causes of fatal injury were self-harm (36%), falls (20%), and road traffic crashes (13%). Non-fatal injury was reported by 6.7% of survey participants, with the leading causes of injury being falls (38%), road traffic crashes (25%), and mechanical forces (16.1%). Falls were more common in women, with most (72.3%) attributable to slipping and tripping. Road traffic injuries were sustained mainly by men and were primarily the result of motorcycle crashes (48.8%). Discussion: Injury is an important contributor to disease burden in rural India. The leading causes of injury—falls, road traffic crashes, and suicides—are all preventable. It is important that effective interventions are developed and implemented to minimize the impact of injury in this region.

Quantifying the importance of interleukin-6 for coronary heart disease.

Abstract: For many years it was widely believed that known vascular risk factors could explain only about half of all cardiovascular disease [1], leaving much to be discovered about other causes of stroke and heart attack. There has been considerable interest in the possible aetiological role of inflammation in vascular disease. Interleukin-6 (IL-6) is one of a number of inflammatory markers that have been studied [2]. There are, however, substantial and often unrecognised challenges to quantifying the full effects of risk factors such as IL-6. A particular problem in establishing the true nature of the association between exposures and outcomes arises from the difficulty of achieving a good estimate of the true level of the risk factor of interest. It is very difficult to establish an individual's usual level of exposure to an inflammatory marker such as IL-6, because it has a short half life and is complex to assay. The same challenge also applies to well-established, and apparently easier to measure, determinants of risk such as blood pressure and cholesterol because they also fluctuate substantially over relatively short time periods [3]. Therefore a key strength of a new study by John Danesh and colleagues, reported in this issue of PLoS Medicine [4], is the substantial effort undertaken to overcome this problem and obtain reliable estimates of the association between IL-6 and coronary heart disease [5]. Whether the findings for IL-6 provide substantial new insight into the causation of cardiovascular disease is, however, rather less clear.

High prevalence of chronic kidney disease in

Abstract: We describe the prevalence of stage III and IV chronic kidney disease in Thailand from a representative sample of individuals aged 35 years and above using a stratified, multistage, cluster-sampling method. Population estimates were calculated by applying sampling weights from the 2000 Thai census. Glomerular filtration rates were estimated from serum creatinine using the Cockroft–Gault and the simplified Modification of Diet in Renal Disease (MDRD) formulae. The prevalence of stage III disease among individuals aged 35 years and above was estimated to be about 20% using the Cockroft–Gault formula and about 13% from the MDRD formula. Stage IV disease was present in about 0.9 and 0.6% of this population using the respective formulae. The highest prevalence rates were observed in less well-developed rural areas and the lowest in developed urban areas. The prevalence of chronic kidney disease was significantly higher than that reported in individuals over 40 years old from the United States for both stage III and IV disease and higher than the reported incidence in Taiwan and Australia. This high prevalence of chronic kidney disease in Thailand has obvious implications for the health of its citizens and for the allocation of health-care resources.