Showing papers by "Bruce Neal published in 2009"

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Abstract: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84–0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76–0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90–1.20) and 1.10 for cardiovascular death (95% CI 0.84–1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91–3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89–1.13, vs HR 0.84, 95% CI 0.74–0.94, respectively; interaction p = 0.04). Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

Abstract: There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes New results from the ADVANCE trial

Abstract: OBJECTIVE To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes. RESEARCH DESIGN AND METHODS This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR–based regimen (target A1C ≤6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models. RESULTS There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12–50%, P = 0.005), new onset of macroalbuminuria by 54% (35–68%, P < 0.0001), and new onset of microalbuminuria by 26% (17–34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1–32%, P = 0.04). CONCLUSIONS The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.

Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes

Abstract: BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.

Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

Abstract: Aims/hypothesis The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial.

Blood Pressure Variables and Cardiovascular Risk: New Findings From ADVANCE

Abstract: The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP; 1.20 (1.13 to 1.28) for PP; 1.12 (1.05 to 1.19) for mean arterial pressure; and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.

Fatal and Nonfatal Cardiovascular Disease and the Use of Therapies for Secondary Prevention in a Rural Region of India

Abstract: Background— The rate of cardiovascular disease is widely considered to be increasing throughout India. Precise and reliable data on fatal and nonfatal cardiovascular disease, however, are few, and ...

Long term monitoring in patients receiving treatment to lower blood pressure: analysis of data from placebo controlled randomised controlled trial

Abstract: Objective To determine the value of monitoring blood pressure by quantifying the probability that observed changes in blood pressure reflect true changes. Design Analysis of blood pressure measurements of patients in the perindopril protection against recurrent stroke study (PROGRESS). Setting Randomised placebo controlled trial carried out in 172 centres in Asia, Australasia, and Europe. Participants 1709 patients with history of stroke or transient ischaemic attack randomised to fixed doses of perindopril and indapamide. Measurements Mean of two blood pressure measurements in patients receiving treatment recorded to the nearest 2 mm Hg with a standard mercury sphygmomanometer at baseline and then at three months, six months, nine months, and 15 months and then every six months to 33 months. Results There was no change in the mean blood pressure of the cohort during the 33 month follow-up. Six months after blood pressure was stabilised on treatment, if systolic blood pressure was measured as having increased by >10 mm Hg, six of those measurements would be false positives for every true increase of ≥10 mm Hg. The corresponding value for an increase of 20 mm Hg was over 200. Values for 5 mm Hg and 10 mm Hg increases in diastolic blood pressure were 3.5 and 39, respectively. The likelihood that observed increases in blood pressure reflected true increases rose with the time between measurements such that the ratio of true positives to false positives reached parity at 21 months. Conclusions Usual clinical approaches to the monitoring of patients taking drugs to lower blood pressure have a low probability of yielding reliable information about true changes in blood pressure. Evidence based guidelines for monitoring treatment response are urgently required to guide clinical practice. Trial registration Australia and New Zealand Clinical Trial Registry.

The development of a national salt reduction strategy for Australia.

Abstract: Excess dietary salt is a well established cause of high blood pressure and vascular disease. National and international bodies recommend a significant reduction in population salt intakes on the basis of strong evidence for health gains that population salt reduction strategies could achieve. The Australian Division of World Action on Salt and Health (AWASH) coordinates the Drop the Salt! campaign in Australia. This aims to reduce the average amount of salt consumed by Australians to six grams per day over five years through three main implementation strategies targeting the food industry, the media and government. This strategy has the potential to achieve a rapid and significant reduction in dietary salt consumption in Australia. With industry and government engagement, this promises to be a highly effective, low cost option for preventing chronic disease.

Methodological trends in studies based on verbal autopsies before and after published guidelines.

Abstract: OBJECTIVE: To report on the uptake of guidelines published in the early 1990s with specific recommendations about the design of future studies based on verbal autopsy conducted for mortality surveillance. METHODS: We conducted a systematic literature search of all verbal autopsy studies published before January 2006 and extracted from the studies a standard set of data. We then compared studies designed before and after the recommendations were issued in terms of seven key methodological indicators. FINDINGS: We found 102 studies conducted in 39 countries; 60 were designed before and 42 after the guidelines were issued. The methods used in these 102 studies varied considerably. While some encouraging trends were noted, there is no evidence that the design recommendations have been systematically implemented. Specifically, there was no clear increase in the proportion of studies with a combined questionnaire (63% before recommendations versus 74% after; P = 0.3), a trained interviewer (70% versus 70%; P = 1.0), a suitable respondent (98% versus 100%; P = 1.0), an optimal recall period (84% versus 97%; P = 0.2), predefined algorithms (28% versus 38%; P = 0.4), an option for assigning multiple causes of death (30% versus 38%; P = 0.3), or a follow-up validation study (83% versus 72%; P = 0.7). CONCLUSION: Expert recommendations for optimal design of verbal autopsy studies have been incompletely implemented to date. Better uptake of design recommendations through enhanced collaboration between research teams is likely to produce better mortality statistics from an increasing number of verbal autopsy studies.

Recalibration of a Framingham risk equation for a rural population in India

Abstract: Background: Coronary heart disease (CHD) risk estimation tools are a simple means of identifying those at high risk in a community and hence a potentially cost-effective strategy for CHD prevention in resource-poor countries. Since India has few local data upon which to develop such a tool de novo, in this study a Framingham risk equation has been recalibrated to estimate CHD risks in a population from rural India and the sensitivity of the method to information resources examined. Recent surveys of this population have found high levels of cardiovascular risk factors, particularly metabolic risk factors and a high proportion of mortality due to cardiovascular diseases. Methods: The proportion of a rural Indian population at high risk of CHD using three risk estimation equations was estimated. The first a published version of the Framingham risk equation, the second a recalibrated equation using local mortality surveillance data and local risk factor data, and the third a recalibrated equation using national mortality data and local risk factor data. Results: The mean 10-year probability of CHD for adults >30 years was 10.4% (9.6% to 11.1%) for men and 5.3% (4.9% to 5.7%) for women using the Framingham equation; 10.7% (9.9% to 11.5%) for men and 4.2% (3.9% to 4.5%) for women using the local recalibration; and 18.9% (17.7% to 20.1%) for men and 8.2% (7.6% to 8.8%) for women using the national recalibration. Conclusion: These findings indicate that in India, equations recalibrated to summary national data are unlikely to be relevant to all regions of India and demonstrate the importance of local data collection to enable development of relevant CHD risk tools.

Effects of salt substitute on pulse wave analysis among individuals at high cardiovascular risk in rural China: a randomized controlled trial

Abstract: Reduced-sodium, increased-potassium salt substitutes lower blood pressure but may also have direct effects on vascular structure and arterial function. This study aimed to test the effects of long-term salt substitution on indices of these outcomes. The China Salt Substitute Study was a randomized, controlled trial designed to establish the effects of salt substitute (65% sodium chloride, 25% potassium chloride, 10% magnesium sulfate) compared with regular salt (100% sodium chloride) on blood pressure among 600 high-risk individuals living in six rural areas in northern China over a 12-month intervention period. Data on central aortic blood pressure, aortic pressure augmentation (AUG), augmentation index (AIx), the differences of the peak of first and baseline waves (P(1)-P(0)) and pulse wave reflection time (RT) were collected at randomization and at the completion of follow-up in 187 participants using the Sphygmocor pulse wave analysis system. Mean baseline blood pressure was 150.1/91.4 mm Hg, mean age was 58.4 years, 41% were male and three quarters had a history of vascular disease. After 12 months of intervention, there were significant net reductions in peripheral (7.4 mm Hg, P=0.009) and central (6.9 mm Hg, P=0.011) systolic blood pressure levels and central pulse pressure (4.5 mm Hg, P=0.012) and correspondingly there was a significant net reduction in P(1)-P(0) (3.0 mm Hg, P=0.007), borderline significant net reduction in AUG (1.5 mm Hg, P=0.074) and significant net increase in RT (2.59 ms, P=0.001). There were no detectable reductions in peripheral (2.8 mm Hg, P=0.14) or central (2.4 mm Hg, P=0.13) diastolic blood pressure levels or AIx (0.06%, P=0.96). In conclusion, over the 12-month study period the salt substitute significantly reduced not only peripheral and central systolic blood pressure but also reduced arterial stiffness.

Verbal autopsy coding: are multiple coders better than one?

Abstract: OBJECTIVE: To assess the impact on the reported cause-of-death patterns of a verbal autopsy coding strategy based on a review of every death by multiple coders versus a single coder. METHODS: Deaths in 45 villages (total population 180 162) in southern India were documented during 12 months in 2003-2004, and a standard verbal autopsy questionnaire was completed for each death. Two physician coders, each unaware of the other's decisions, assigned an underlying cause of death in accordance with the causes listed in the chapter headings of the International classification of diseases and related health problems, 10th revision (ICD-10). For the three chapter headings that applied to more than 100 of the deaths, agreement for subsets of causes of death within the chapter was also analysed. In the event of discrepancies, a third coder was used to finalize a cause of death. Cohen's kappa statistic (K) was used to measure levels of agreement between the two physician coders. FINDINGS: In total, 1354 deaths were documented, and a verbal autopsy was completed for 1329 (98%) of them. At the chapter heading level of the ICD-10, physician coders assigned the same cause to 1255 deaths (94%) (K = 0.93; 95% confidence interval: 0.92-0.94). The patterns of death derived from the causes assigned by each physician were all very similar to the patterns obtained through the consensus process, with the rank order of the 10 leading causes of death being the same for all three coding methods. CONCLUSION: Duplicate coding of verbal autopsy results has little advantage over a single-coder system for mortality surveillance or for identifying population patterns of death. Resources could be better diverted to other parts of the mortality surveillance process, such as validation.

Effects of the End Point Adjudication Process on the Results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)

Abstract: Background and Purpose— End point adjudication committees (EPAC) are widely used in large-scale clinical trials to ensure the robustness of diagnosis for end points. Methods— The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a double-blind randomized trial of blood pressure lowering in 6105 participants with pre-existing cerebrovascular disease. Separate estimates of the effects of randomized treatment were determined using Cox regression models that were based on the unadjudicated events initially reported by the investigator and on the final events assigned by the EPAC. Results— There were 992 strokes initially reported by the investigators and 894 (90%) retained these diagnoses after adjudication by the EPAC. The hazard ratios (95% CIs) for the effect of randomized treatment on stroke were 0.74 (0.64 to 0.85) based on the investigator diagnoses and 0.72 (0.62 to 0.83) based on the EPAC diagnoses (P homogeneity=0.7). For each stroke subtype reported, the corresponding numbers of d...

Determinants of heterotopic ossification after total hip replacement surgery

Abstract: The ability of various pre- or peri-operative variables to determine the risk of developing moderate to severe heterotopic ossification (HO) six to twelve months after surgery was investigated among 407 patients undergoing elective total hip replacement (THR) surgery and allocated to placebo in a randomised controlled trial evaluating NSA IDs-based prophylaxis for HO. Overall, 11 (30%) of the 37 patients undergoing revision surgery developed moderate to severe HO compared with 58 (16%) of the 370 patients undergoing primary THR; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1 to 4.9. Among patients undergoing primary THR , mutually adjusted analysis of collected independent risk factors demonstrated that receiving a transfusion of red cells or having general as well as epidural or spinal anaesthesia present as indicators of increased risk for developing moderate to severe HO. Patients who have undergone revision surgery have a significantly increased risk of clinically relevant ectopic bone, while among patients who have undergone primary THR surgery, those with indicators of excessive surgical bleeding are also at increased risk of clinically relevant HO.

Determinants of heterotopic ossification after total hip replacement surgery

Abstract: The ability of various pre- or peri-operative variables to determine the risk of developing moderate to severe heterotopic ossification (HO) six to twelve months after surgery was investigated among 407 patients undergoing elective total hip replacement (THR) surgery and allocated to placebo in a randomised controlled trial evaluating NSA IDs-based prophylaxis for HO. Overall, 11 (30%) of the 37 patients undergoing revision surgery developed moderate to severe HO compared with 58 (16%) of the 370 patients undergoing primary THR; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.1 to 4.9. Among patients undergoing primary THR , mutually adjusted analysis of collected independent risk factors demonstrated that receiving a transfusion of red cells or having general as well as epidural or spinal anaesthesia present as indicators of increased risk for developing moderate to severe HO. Patients who have undergone revision surgery have a significantly increased risk of clinically relevant ectopic bone, while among patients who have undergone primary THR surgery, those with indicators of excessive surgical bleeding are also at increased risk of clinically relevant HO.

Methodological Trends in Studies Based on Verbal Autopsies before and after Published guidelines/Tendances Methodologiques Des Etudes Reposant Sur Des Autopsies Verbales Avant et Apres la Publication De directives/Tendencias Metodologicas De Los Estudios Basados En Autopsias Verbales Antes Y Despues De la Publicacion De Directrices Al Respecto

Abstract: Introduction Information about the causes of death in a population is essential for monitoring health and planning appropriate health services. (1) While most higher-income countries have in place robust processes for documenting deaths and their causes, many developing countries lack such systems due to organizational and economic constraints and other factors. (2) Verbal autopsy-based cause of death recording systems are widely used in countries where vital registration and death certification systems are weak and most people die at home without medical certification of the cause of death. (3) A verbal autopsy is a method used to determine the cause of death from data collected about the symptoms and signs of illness and the events preceding death. (4,5) This method is based on the hypothesis that the symptoms and signs surrounding most causes of death can be recognized, recollected and reported by a person present during the period prior to death. (6,7) For the information provided by verbal autopsies to be maximally reliable, certain design characteristics need to be incorporated into studies based on verbal autopsy methods. To ensure that the data collected is of high quality, the data collection tool should have structured and unstructured questions, interviewers should be specially trained, interviewees should have remained close to the deceased during illness, and between death and data collection only a short time interval should have elapsed. Similarly, for cause of death to be accurately assigned, algorithms for translating the data into causes of death must be clearly defined and the possibility of assigning multiple causes of death (i.e. immediate, underlying and contributory) must be present. Finally, subsequent validation studies should be carried out. To optimize the use of these methods, in the early 1990s WHO convened a series of expert meetings that led to the publication of several reports (4,5,7,8) in which key design features for studies based on verbal autopsy methods were recommended. Three of the four reports--one of them the outcome of a workshop sponsored jointly by WHO and the United Nations Children's Fund--were published in international journals, and the fourth was published by WHO. However, the extent to which the guidelines were systematically disseminated to relevant parties and their effect on study design are unclear. Thus, the objective of this study was to determine whether the expert recommendations published from 1992 to 1994 influenced the way researchers conduct verbal autopsy studies. Methods Search strategy From June 2005 to May 2006, we conducted computerized searches of PubMed and WHO (9) databases using as key phrases "verbal autopsy", "mortality surveillance", "mortality statistics", "post mortem interview" and "cause of death". References quoted in original publications and in the websites of the International Network of Field Sites with Continuous Demographic Evaluation of Populations and their Health (INDEPTH Network) (10) and the Adult Morbidity and Mortality Project (11) were manually searched for additional information. Study inclusion and exclusion criteria To be included in this review, studies had to fulfil certain criteria. They had to: (i) have been published before 2006 in a peer reviewed journal or as a report accessible through a web search; (ii) describe the verbal autopsy method used, and (iii) be written in English or French. A study reporting data in more than one paper was included only once, and data from the paper which described the methods in the greatest detail were used. Data extraction Standard information was extracted from all eligible studies by one reviewer for English-language studies (RJ) and another for French-language studies (A-PK). The information included the following: country in which the data were collected; age group studied; number of deaths observed; approach used to classify deaths; questionnaire format; interviewers' education and gender; type of respondent from whom information was obtained; recall period; granting of consent; type and nature of adjudication process; number of causes of death assignable per case; and presence or absence of a validation study. …

How many Australian deaths from heart disease and stroke could be avoided by a small reduction in population cholesterol levels

Abstract: Aim: To quantify the number of premature deaths from coronary heart disease and ischaemic stroke that potentially could be avoided annually among the Australian population if a sustained 10% reduction in the mean population level of low-density lipoprotein cholesterol were to be achieved. Methods: Data were obtained on the number of deaths from coronary heart disease and stroke in the Australian population, subdivided into age and sex strata, and on the mean population level of low-density lipoprotein cholesterol. Published relative risks (95% CI) from a meta-analysis of lipid-lowering therapy were used to calculate the reduction in the relative risk for coronary heart disease and stroke associated with a 5%, 10% and 15% reduction in low-density lipoprotein cholesterol. The expected number of deaths from coronary heart disease and ischaemic stroke avoidable with a 10% reduction in low-density lipoprotein cholesterol was modelled. Secondary analyses were performed assuming reductions in low-density lipoprotein cholesterol of 5% and 15%. Results: A 10% reduction in low-density lipoprotein cholesterol would prevent 2279 deaths from coronary heart disease (95% CI: 2025-2531 deaths) and 641 deaths from ischaemic stroke (95% CI: 440-881 deaths). The projected benefits are greatest among the elderly, although some benefit would be expected in all age and sex groups and among individuals with a broad range of baseline levels of low-density lipoprotein cholesterol. Conclusions: A small leftward shift in the low-density lipoprotein cholesterol distribution of the adult Australian population has the potential to save about 3000 lives from coronary heart disease and stroke annually. Achieving this goal will require the active participation of key public health, food industry and government stakeholders.

Response to Letter by Kerr and Nasco

Abstract: Response: Kerr and Nasco advocate the use of an End Point Adjudication Committee in every large-scale trial and propose a number of plausible hypotheses for taking this position. Although their arguments are at face value appealing, a sounder basis for the use of an End Point Adjudication Committee would be clear evidence of added scientific value. Just as we seek to base our clinical practice in evidence, so too should our research endeavors be done on this basis. In undertaking our investigation of the impact of end point adjudication in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial,1 we …

ADVANCE: Blood Pressure Lowering in Diabetes

Abstract: To the Editor: We were surprised at a notable omission in the recently published ‘‘ASH Position Paper: Treatment of Hypertension in Patients With Diabetes—An Update,’’ by Bakris and Sowers for the American Society of Hypertension Writing Group. This update purports to focus on ‘‘clinical outcomes literature published within the last 3 years,’’ yet it fails to mention the largest-ever trial conducted on blood pressure lowering in patients with type 2 diabetes, the results of which were published in The Lancet in September 2007. The Action in Diabetes and Vascular Disease (ADVANCE) trial, which involved 11,140 patients from 20 countries, evaluated the effects on vascular events of, first, routine blood pressure lowering using a fixed-dose combination of an angiotensinconverting enzyme (ACE) inhibitor and a diuretic and, second, intensive blood glucose control. While the results of the glucose-lowering intervention were referenced in the update by Bakris and Sowers, there was no mention of the more relevant findings from the blood pressure intervention. In this part of the study, patients were randomized in a double-blind fashion to a fixed-dose combination of perindopril and indapamide or placebo. Participants were included regardless of initial blood pressure level, and randomized therapy was provided in addition to other blood pressure lowering and cardiovascular preventative treatments that patients were typically receiving, including ACE inhibitors. The mean blood pressure of participants at baseline was 145 ⁄81 mm Hg, and the ACE inhibitor ⁄diuretic combination reduced blood pressure by an average of 5.6 ⁄2.2 mm Hg compared with placebo. At the end of an average follow-up period of 4.3 years, active treatment reduced combined macrovascular and microvascular complications by 9% and also resulted in significant reductions in allcause mortality (14%), cardiovascular death (18%), total coronary events (14%), and total renal events (21%). The relative effects of treatment did not appear to vary according to initial blood pressure value or the use of concomitant therapies, including ACE inhibitors or angiotensin receptor blockers. Overall, adherence to randomized treatment was high, and there were no significant differences in glycemic status or the use of glucoselowering therapies between the randomized groups at the end of follow-up. We believe that the results of the ADVANCE trial have important and direct implications for the management of blood pressure in patients with diabetes. The findings point to a particular strategy and therapeutic regimen that improved blood pressure levels, produced reductions in important clinical outcomes, and was well tolerated with few adverse effects. Given the persistent difficulties in achieving blood pressure targets in patients with diabetes, alluded to by Bakris and Sowers, it might have been useful to refer to these findings and to this strategy for reducing cardiovascular mortality and morbidity in patients with type 2 diabetes.—Anushka Patel, MD, PhD; John Chalmers, MD, PhD; Stephen MacMahon, DSc, PhD; Bruce Neal, MD, PhD, The George Institute for International Health, University of Sydney, PO Box M201, Missenden Road, NSW 2050, Australia E-mail: apatel@george.org.au