Search

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts., Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes., Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P  < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers., Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial., Methods: ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7-16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death., Findings: Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81-1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53-0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67-0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72-0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo., Interpretation: Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes., Funding: Pfizer., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials., Methods: In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum., Results: The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users., Interpretation: These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects., Funding: Pfizer, Servier Research Group, and Leo Laboratories., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Essentials Dimeric high-affinity collagen receptor glycoprotein VI (GPVI) is present on resting platelets. Spatio-temporal organization of platelet GPVI-dimers was evaluated using advanced microscopy. Upon platelet adhesion to collagenous substrates, GPVI-dimers coalesce to form clusters. Clustering of GPVI-dimers may increase avidity and facilitate platelet activation SUMMARY: Background Platelet glycoprotein VI (GPVI) binding to subendothelial collagen exposed upon blood vessel injury initiates thrombus formation. Dimeric GPVI has high affinity for collagen, and occurs constitutively on resting platelets. Objective To identify higher-order oligomerization (clustering) of pre-existing GPVI dimers upon interaction with collagen as a mechanism to initiate GPVI-mediated signaling. Methods GPVI was located by use of fluorophore-conjugated GPVI dimer-specific Fab (antigen-binding fragment). The tested substrates include Horm collagen I fibers, soluble collagen III, GPVI-specific collagen peptides, and fibrinogen. GPVI dimer clusters on the platelet surface interacting with these substrates were visualized with complementary imaging techniques: total internal reflection fluorescence microscopy to monitor real-time interactions, and direct stochastic optical reconstruction microscopy (dSTORM), providing relative quantification of GPVI cluster size and density. Confocal microscopy was used to locate GPVI dimer clusters, glycoprotein Ib, integrin α 2 β 1 , and phosphotyrosine. Results Upon platelet adhesion to all collagenous substrates, GPVI dimers coalesced to form clusters; notably clusters formed along the fibers of Horm collagen. dSTORM revealed that GPVI density within clusters depended on the substrate, collagen III being the most effective. Clusters on fibrinogen-adhered platelets were much smaller and more numerous; whether these are pre-existing oligomers of GPVI dimers or fibrinogen-induced is not clear. Some GPVI dimer clusters colocalized with areas of phosphotyrosine, indicative of signaling activity. Integrin α 2 β 1 was localized to collagen fibers close to GPVI dimer clusters. GPVI clustering depends on a dynamic actin cytoskeleton. Conclusions Platelet adhesion to collagen induces GPVI dimer clustering. GPVI clustering increases both avidity for collagen and the proximity of GPVI-associated signaling molecules, which may be crucial for the initiation and persistence of signaling., (© 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: To conduct a prospective, individual participant data (IPD) meta-analysis of randomised controlled trials comparing a polypill-based approach with usual care in high risk individuals., Methods and Results: Three trials comparing polypill-based care with usual care in individuals with CVD or high calculated cardiovascular risk contributed IPD. Primary outcomes were self-reported adherence to combination therapy (anti-platelet, statin and ≥ two blood pressure (BP) lowering agents), and difference in mean systolic BP (SBP) and LDL-cholesterol at 12 months. Analyses used random effects models. Among 3140 patients from Australia, England, India, Ireland, New Zealand and The Netherlands (75% male, mean age 62 years), median follow-up was 15 months. At baseline, 84%, 87% and 61% respectively were taking a statin, anti-platelet agent and at least two BP lowering agents. At 12 months, compared to usual care, participants in the polypill arm had higher adherence to combination therapy (80% vs. 50%, RR 1.58; 95% CI, 1.32 to 1.90; p < 0.001), lower SBP (-2.5 mmHg; 95% CI, -4.5 to -0.4; p = 0.02) and lower LDL-cholesterol (-0.1 mmol/L; 95% CI, -0.2 to 0.0; p = 0.04). Baseline treatment levels were a major effect modifier for adherence and SBP (p-homog < 0.0001 and 0.02 respectively) with greatest improvements seen among those under-treated at baseline., Conclusions: Polypill therapy significantly improved adherence, SBP and LDL-cholesterol in high risk patients compared with usual care, especially among those who were under-treated at baseline., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To measure the impact of complications on summary measures of health-related quality of life among people with type 2 diabetes., Methods: Patients participating in the Action in Diabetes and Vascular Disease:Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial were administered a health-related quality-of-life questionnaire, the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L), on four occasions over a 5-year period. We used two-way fixed-effects longitudinal regression models to investigate the impact of incident diabetes complications (stroke, heart failure, myocardial infarction, ischemic heart disease, renal failure, blindness, and amputation) on EQ-5D-3L utility score (where 1 = perfect health), while controlling for characteristics of individuals that do not vary over time., Results: The effect of having any one of the seven complications was to reduce the EQ-5D-3L utility score by 0.054 (95% confidence interval 0.044-0.064), and this was not significantly affected by baseline age, sex, economic region, or the value set used to derive utilities. The complication with the largest disutility was amputation (0.122), followed by stroke (0.099), blindness (0.083), renal failure (0.049), heart failure (0.045), and myocardial infarction (0.026). Ischemic heart disease did not significantly reduce the utility score. Quality of life also declined with elapsed time-by an average of 0.006 per year, in addition to the effect of complications., Conclusions: Common complications significantly reduce health-related quality of life. Utility scores derived from the EQ-5D-3L provide a potential measure that can be used to summarize patient-reported outcomes and inform health economic models. Prevention of complications is critical to reduce the progressive burden of declining quality of life for people with diabetes., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy., Methods: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis., Findings: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT., Interpretation: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy., Funding: National Institutes of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Hypertension is the leading risk factor contributing to the global burden of disease. We aimed to assess the change in blood pressure management between 1994 and 2011 in England with a series of annual surveys., Methods: We did a serial cross-sectional study of five Health Survey for England surveys based on nationally representative samples of non-institutionalised adults (aged ≥16 years). Mean blood pressure levels and rates of awareness, treatment, and control of hypertension were assessed. Hypertension was defined as systolic blood pressure 140 mm Hg or higher, diastolic blood pressure 90 mm Hg or higher, or receiving treatment for high blood pressure., Findings: The mean blood pressure levels of men and women in the general population and among patients with treated hypertension progressively improved between 1994 and 2011. In patients with treated hypertension, blood pressure improved from 150·0 (SE 0·59)/80·2 (0·27) mm Hg to 135·4 (0·58)/73·5 (0·41) mm Hg. Awareness, treatment, and control rates among men and women combined also improved significantly across each stage of this 17-year period, with the prevalence of control among treated patients almost doubling from 33% (SE 1·4) in 1994 to 63% (1·7) in 2011. Nevertheless, of all adults with survey-defined hypertension in 2011, hypertension was controlled in only 37%., Interpretation: If the same systematic improvement in all aspects of hypertension management continues until 2022, 80% of patients with treated hypertension will have controlled blood pressure levels with a potential annual saving of about 50,000 major cardiovascular events., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: An international collaboration of investigators will assess the benefits and risks of fixed dose combination (FDC) based care compared with usual care in populations at high risk of cardiovascular disease (CVD). Several trials are being conducted, as the effectiveness and economic impact of a FDC-based strategy may vary substantially between countries, given the varying influence of the health-care system within which the intervention is delivered., Methods: Individual patient data (IPD) will be provided by participating trials for combined IPD meta-analysis., Results: Primary outcomes will include self-reported current use of antiplatelet, statin, and combination (≥ 2) blood pressure lowering therapies at 12 months, and change in systolic blood pressure (SBP) and LDL cholesterol from baseline to 12 months. Non-inferiority margins of 3 mm Hg for SBP and 0.3 mmol/L for LDL cholesterol have been pre-specified. Secondary outcomes will include change in cholesterol fractions, diastolic blood pressure and creatinine from baseline to 12 months, quality of life, new onset diabetes mellitus, mortality (cardiovascular, non-cardiovascular and all cause) and a composite outcome of cardiovascular events (including all coronary heart disease events, heart failure events leading to death or requiring hospital admission, cerebrovascular events and peripheral arterial events)., Conclusion: The SPACE group of trials will assess, in a variety of healthcare settings, whether a FDC strategy for delivery of preventive medication has the potential to significantly improve prevention of cardiovascular disease in patients at high risk., (© 2013.)

The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

Albuminuria and a reduced glomerular filtration rate are conventional predictors of a future decline in kidney function in patients with type 2 diabetes mellitus. Using a nested case-control study we assessed whether circulating transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7) levels more accurately predict renal end points than the conventional markers. Cases were defined as those who developed a renal end point (doubling of serum creatinine to at least 200 μmol/l, the need for renal replacement therapy, or death due to renal disease) during the study. Using propensity scoring, two controls were selected for each of 281 cases. Participants who developed renal end points had significantly higher total TGF-β1, lower BMP-7 levels, and a higher total TGF-β1 to BMP-7 ratio at baseline. A graded increase in risk was found in individuals with lower BMP-7 levels (odds ratio 24.07, for the lowest to the highest tertile), or significantly higher TGF-β1 levels (odds ratio for the highest to the lowest tertile, 8.43). The area under the receiver operating characteristic curve (c-statistic) for the conventional predictors was 0.73. Using BMP-7 and total and active TGF-β1, the c-statistic was 0.94 (significantly higher to conventional predictors). Thus, our results suggest these novel kidney markers are better predictors of renal progression than the conventional predictors in patients with type 2 diabetes mellitus.

Background: Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs., Methods: The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925., Findings: After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline., Interpretation: Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

Objective: Results of investigations into the impact of seasonal variation on the incidence of cardiovascular diseases (CVD) have been inconsistent. Using the WHO Collaborative Study of CVD and Steroid Hormone Contraception database, we attempted to examine the relationship between variation in three climatic variables and risk of hospitalization for venous thromboembolism (VTE), arterial stroke, and acute myocardial infarction (AMI)., Study Design and Setting: We compared the monthly mean temperature, rainfall, and humidity with rates of hospitalized VTE, stroke, and AMI among young women aged 15-49 from 17 different countries in Africa, Asia, Europe, Latin America, and the Caribbean by using a negative binomial regression model., Results: The study included 1146, 2,269, and 369 cases of VTE, stroke, and AMI, respectively. Significant associations between temperature and hospital admission rates of stroke and AMI, but not VTE, were apparent. Lagging the effects of temperature suggested that these effects were relatively acute, within a period of a month., Conclusion: These data may help in understanding the mechanisms whereby stroke and AMI events are triggered.

Antiretrovirals are standard treatment for HIV-1-positive women during pregnancy in the UK, but little is known about maternal or fetal safety. In our cohort study of 214 pregnant women with HIV-1 infection, those who received no antiretroviral therapy had a rate of pre-eclampsia significantly lower (none of 61) than those on triple antiretroviral therapy (8 of 76; odds ratio 15.3, 95% CI 0.9-270, p=0.0087). However, the rate of pre-eclampsia in HIV-1-positive women on treatment did not differ from that in uninfected controls (12 of 214; p=0.2). The association of HIV-1-related immune deficiency with a low rate of pre-eclampsia, and the restoration of this rate in women treated with triple antiretroviral therapy to the expected rate indicates a pivotal role of the immune system in the pathogenesis of pre-eclampsia. The clinical presentation of pre-eclampsia and toxic effects of antiretroviral therapy could overlap and complicate diagnosis and management in these patients.

There is unequivocal evidence that reduction of modifiable risk factors for coronary heart disease (CHD), such as elevated serum cholesterol, high blood pressure and smoking, decreases cardiovascular mortality. However, levels of intervention appear to be poor and there is often little evidence of a combined multiple risk factor approach to intervention, which is likely to be the optimal way to lower a patients overall risk of developing CHD. Attention has recently focused on bridging the gap between knowledge in the field of preventive cardiology and its application in everyday clinical practice. This can only be accomplished by the development of uncomplicated, practical guidelines that are evidenced-based and that provide specific targets for risk factors and indications for drug therapy.

Purpose and Method: A hospital based case-control study was designed to investigate what aspects of smoking and what co-factors of smoking are associated with the development of peripheral arterial disease (PAD). Cases were 291 smokers, newly referred with PAD, and controls were 828 age and sex matched smokers without PAD., Results: Reported recent tobacco usage was similar in cases and controls but total tobacco exposure was associated with the risk of PAD-adjusted odds ratios (ORs) increasing with tertile of pack-years smoked to reach 1.63 (95% CI, 1.11-2.39; P = 0.011), for the highest tertile ( > 48 pack-years) compared with smokers in the lowest tertile (< 31 pack-years). Cases reported smoking significantly lower tar and nicotine yield cigarettes than controls, but tended to inhale more deeply, and had significantly higher plasma concentrations of cotinine. ORs for PAD were significantly and independently increased by systolic blood pressure > 160 mmHg (8.1 (5.2 13.0); P < 0.0001), history of hypertension (2.4 (1.5-3.2); P = 0.0003) and apolipoprotein B > 0.9 g/l(3.8 (2.3-7.6); P = 0.008)., Conclusions: Increased total exposure to tobacco and the ability to smoke tobacco in a way which maximises nicotine yield are associated with increased risk of smokers developing PAD. There is no evidence that smoking low tar cigarettes reduces this risk, whereas both hypertension (particularly systolic) and high levels of apolipoprotein B, increase this risk.

Objective: To investigate whether smoking and other cardiovascular risk factors were associated with deterioration of ankle/brachial pressure index or onset of critical ischaemia in patients with mild to moderate intermittent claudication., Design and Setting: Longitudinal study in a London teaching hospital., Subjects: 415 consecutive smokers, with symptoms of intermittent claudication and an ankle/brachial pressure index of <0.9, referred for a surgical opinion between April 1985 and December 1990, who were not considered for an immediate surgical procedure., Main Outcome Results: Reduction in ankle/brachial pressure index of >0.14, onset of critical limb ischaemia., Results: After one year of follow up 183 patients (44%) had stopped smoking (as evaluated by biochemical markers). With longer follow up only 110 patients (27%) had maintained smoking cessation. There were no differences in age, sex, and previous tobacco exposure between stoppers and smokers, but the proportion of diabetics among stoppers (20%) was greater than among those who continued smoking (10%) [p=0.01]. The annual rate of deterioration of ABPI was 21, 16 and 17% respectively in the first, second and third year of follow-up and the onset of critical ischaemia was observed in 52 patients (12.5%) during the period of follow-up. In univariate analyses, continued smoking, diabetes and presence of ischaemic heart disease were not associated with an increased risk of deterioration of ABPI, but hypertriglyceridaemia (> or = 2.2 mmol/l) was, [relative risk 1.7(95% CI 1.21-2.37), p=0.003], and patients having systolic blood pressure in the middle tertile (153-170 mmHg had a reduced risk of deterioration of ABPI, p=0.026. Hypertriglyceridaemia (> or = 2.2mmol/l) was the only independent factor associated with deterioration of ABPI in multivariate analysis [relative risk 1.8(95% CI:1.23-2.59), p=0.003] and also was associated with a relative risk of onset of critical ischaemia of 1.9 [(95% CI: 1.08-2.87), p=0.035], compared with triglyceride levels of <2.2mmol/l., Conclusion: For those with mild to moderate claudication, the lack of immediate benefit from cessation of smoking appears to be associated with a gradual return to smoking. Hypertriglyceridaemia was identified as the most important independent factor associated with the progression of peripheral arterial disease and onset of critical ischaemia.

In order to assess the long term effects of antihypertensive treatment on left ventricular diastolic function, 26 hypertensive patients were followed up for a mean of 4.25 years with two-dimensional and Doppler echocardiography. A significant reduction in left ventricular mass index was first apparent after 9 months of therapy (mean (S.D.) 124 (22) vs. 114 (18) g/m2, P < 0.01), and this was maintained over the 4.25 year period (124 (22) vs. 117 (17) g/m2, p < 0.05). At 9 months there was no change in either isovolumic relaxation time (108 (26) vs. 108 (17) ms, P = N.S.) or left ventricular filling as assessed by peak flow velocity E/A ratio (0.94 (0.22) vs. 0.95 (0.27), P = N.S.). However, after 4.25 years there was a significant improvement in IVRT (108 (26) vs. 83 (11) ms, P < 0.01) with a trend towards an improved peak flow velocity E/A ratio, although this did not reach statistical significance (0.95 (0.27) vs. 1.02 (0.26), P = N.S.). Of the 14 patients who had an abnormal isovolumic relaxation time at baseline, 12 normalised and 2 improved. These findings suggest that left ventricular diastolic dysfunction in hypertension may be reversed by prolonged antihypertensive treatment.

Water-soluble fiber has been reported to reduce serum cholesterol and consequently, oat bran, which has a high soluble-fiber content, has been recommended as part of a lipid-lowering diet. However, a recent small study of 20 volunteers with low mean serum cholesterol concentrations (4.8 mmol/L) demonstrated no lipid-lowering effect of oat bran. The present study investigated 64 volunteers with cholesterol concentrations much more typical of the UK population (6 mmol/L). Subjects were randomly allocated to receive either a normal-sized helping of an oat-based cereal or a cereal containing no oats for 4 wk and then crossed over to the alternative regimen for a further 4 wk. Small (2.23% and 4.55%) but significant (P < 0.04 and P < 0.05) reductions in total and low-density-lipoprotein cholesterol, respectively, were observed in association with the consumption of oat-based cereal. These data support the view that consumption of oat-based cereals may well contribute usefully to a lipid-lowering diet.

Konzo is a distinct form of tropical myelopathy characterised by abrupt onset of spastic paraparesis. Epidemics in East Africa have been attributed to dietary cyanide exposure from insufficiently processed cassava but a study done in Zaire disputed such an aetiology. We investigated a konzo-affected population in rural Zaire and measured the cyanogen content of cassava flour, determined urinary thiocyanate as an indicator of cyanide intake, and compared blood cyanide concentrations in cases and controls. The affected population consumed flour made from short-soaked (one day) cassava roots and thus had high dietary cyanide exposure (urinary thiocyanate in 31 children = 757 mumol/l) compared with the unaffected population (urinary thiocyanate in 46 children = 50 mumol/l) that ate cassava that had been soaked for three days before consumption. 3 konzo patients, but only 2 of 23 controls, had blood cyanide concentrations above 4 mumol/l (p less than 0.01), although serum thiocyanate concentrations were similar. Our findings indicate a causal role in konzo of sustained high blood cyanide concentrations maintained by a deficient sulphur intake impairing cyanide to thiocyanate conversion. The underlying causes of konzo are poverty and food shortage, but a minor improvement of food processing may, as in beri-beri, be preventive.

The effect of antihypertensive therapy on regression of left ventricular hypertrophy and left ventricular diastolic function was investigated in 25 hypertensive patients for up to 18 months after initiation of treatment. Left ventricular mass index was calculated by two-dimensional echocardiography and left ventricular diastolic function assessed by transmitral pulsed doppler ultrasound. Significant reduction in left ventricular mass index was observed after 9 months of treatment. Only 13 patients had a reduction in mass greater than the intraobserver variability of the technique. There was no change in doppler indices of left ventricular diastolic function. In 7 patients who were studied for a further 9 months after regression had occurred there was still no appreciable difference in left ventricular diastolic function. These findings indicate that there is no direct relation between left ventricular mass and abnormal left ventricular diastolic function.

The protein-bound 3-methylhistidine content of meat species has been shown to be of value in predicting the meat content of food products. The present paper deals with the development of a rapid method for the detection and estimation of the dinitrophenyl (DNP) derivatives of the methylamino acids and dipeptides, and in particular 3-methylhistidine. The DNP derivatives of methylated and non-methylated basic amino acids and dipeptides were shown to have differing solubilities in diethyl ether and aqueous solution. These differences allowed preliminary purification of hydrolysed meat extracts, thereby allowing rapid determination of 3-methylhistidine using a short ion-exchange resin column., (Copyright © 1980. Published by Elsevier Ltd.)

Protein-bound 3-methylhistidine, which is present at similar concentrations in various meat species but absent from non-meat proteins, was used to estimate the lean meat content of a range of retailed meat products. The results of the application of this novel method were compared and contrasted with those using standard methods of product analysis. The presence of textured soya protein in products was determined using polyacrylamide gel electrophoresis. Formulae for the calculation of the fat-free lean meat content on the bases of (i) the 3-methylhistidine index for muscle protein and (ii) the connective tissue content, are given. The lean meat contents of products calculated on these bases were found to be of the same order as, but generally lower than, those obtained using standard methods. This was considered to be due to the presence of non-meat proteins, of added connective tissue and/or certain types of offal. These would not be included in the lean meat content, as calculated by the 3-methylhistidine index, but could be legitimately included in the meat content calculated using standard methods according to current practice. A new interpretation of 'meat' in terms of 3-methylhistidine content is given., (Copyright © 1980. Published by Elsevier Ltd.)