Factors Associated With Treatment and Control of Hypertension in a Healthy Elderly Population Free of Cardiovascular Disease: A Cross-sectional Study.

BACKGROUND: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP. METHODS: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control. RESULTS: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US). CONCLUSIONS: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population. CLINICAL TRIALS REGISTRATION: NCT01038583.

Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly.

BACKGROUND: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly.

BACKGROUND: In the primary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, now published in the Journal, we report that the daily use of aspirin did not provide a benefit with regard to the primary end point of disability-free survival among older adults. A numerically higher rate of the secondary end point of death from any cause was observed with aspirin than with placebo. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. Deaths were classified according to the underlying cause by adjudicators who were unaware of trial-group assignments. Hazard ratios were calculated to compare mortality between the aspirin group and the placebo group, and post hoc exploratory analyses of specific causes of death were performed. RESULTS: Of the 19,114 persons who were enrolled, 9525 were assigned to receive aspirin and 9589 to receive placebo. A total of 1052 deaths occurred during a median of 4.7 years of follow-up. The risk of death from any cause was 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio, 1.14; 95% confidence interval [CI], 1.01 to 1.29). Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years. Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56). CONCLUSIONS: Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death. In the context of previous studies, this result was unexpected and should be interpreted with caution. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Effect of Aspirin on Disability-free Survival in the Healthy Elderly.

BACKGROUND: Information on the use of aspirin to increase healthy independent life span in older persons is limited. Whether 5 years of daily low-dose aspirin therapy would extend disability-free life in healthy seniors is unclear. METHODS: From 2010 through 2014, we enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or physical disability. Participants were randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally. The primary end point was a composite of death, dementia, or persistent physical disability. Secondary end points reported in this article included the individual components of the primary end point and major hemorrhage. RESULTS: A total of 19,114 persons with a median age of 74 years were enrolled, of whom 9525 were randomly assigned to receive aspirin and 9589 to receive placebo. A total of 56.4% of the participants were women, 8.7% were nonwhite, and 11.0% reported previous regular aspirin use. The trial was terminated at a median of 4.7 years of follow-up after a determination was made that there would be no benefit with continued aspirin use with regard to the primary end point. The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person-years in the aspirin group and 21.2 per 1000 person-years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). The rate of adherence to the assigned intervention was 62.1% in the aspirin group and 64.1% in the placebo group in the final year of trial participation. Differences between the aspirin group and the placebo group were not substantial with regard to the secondary individual end points of death from any cause (12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group), dementia, or persistent physical disability. The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). CONCLUSIONS: Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Baseline Characteristics of Participants in the ASPREE (ASPirin in Reducing Events in the Elderly) Study.

BACKGROUND: There are no primary prevention trials of aspirin with relevant geriatric outcomes in elderly people. ASPirin in Reducing Events in the Elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin that will determine whether 5 years of daily 100-mg enteric-coated aspirin extends disability-free and dementia-free life in a healthy elderly population and whether these benefits outweigh the risks. METHODS: Set in primary care, this randomized double-blind placebo-controlled trial has a composite primary endpoint of death, incident dementia or persistent physical disability. Participants aged 70+ years (non-minorities) or 65+ years (U.S. minorities) were free of cardiovascular disease, dementia, or physical disability and without a contraindication to, or indication for, aspirin. Baseline data include physical and lifestyle, personal and family medical history, hemoglobin, fasting glucose, creatinine, lipid panel, urinary albumin:creatinine ratio, cognition (3MS, HVLT-R, COWAT, SDMT), mood (CES-D-10), physical function (gait speed, grip strength), Katz activities of daily living and quality of life (SF-12). RESULTS: Recruitment ended in December 2014 with 16,703 Australian and 2,411 U.S. participants, a median age of 74 (range 65-98) years and 56% women. Approximately 55% of the U.S. cohort were from minority groups; 9% of the total cohort. Proportions with hypertension, overweight, and chronic kidney disease were similar to age-matched populations from both countries although lower percentages had diabetes, dyslipidemia, and osteoarthritis. DISCUSSION: Findings from ASPREE will be generalizable to a healthier older population in both countries and will assess whether the broad benefits of daily low-dose aspirin in prolonging independent life outweigh the risks.

Short- and long-term survival in treated elderly hypertensive patients with or without diabetes: findings from the Second Australian National Blood Pressure study.

BACKGROUND: We sought to determine the incidence of newly diagnosed diabetes in treated elderly hypertensive patients and the prognostic impact of diabetes on long-term survival. METHODS: The Second Australian National Blood Pressure (ANBP2) study randomized 6,083 hypertensive patients aged 65-84 years to angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic-based therapy and followed them for a median of 4.1 years. Long-term survival was determined in 5,678 patients over an additional median of 6.9 years after ANBP2 (post-trial). RESULTS: After ANBP2, the cohort was classified into preexisting (7.2%), newly diagnosed (5.6%), and no diabetes (87.2%) groups. A 44% higher incidence of newly diagnosed diabetes was observed in patients randomized to thiazide diuretic compared with ACEI-based treatment. The other predictors of newly diagnosed diabetes were having a higher body mass index, having a higher random blood glucose, and living in a regional location compared to major cities (a geographical classification based on accessibility) at study entry. After completion of ANBP2, compared with those with no diabetes, the preexisting diabetes group experienced higher cardiovascular (hazards ratio (HR) = 1.65; 95% confidence interval (CI) = 1.03-2.65) and all-cause mortality (HR = 1.40; 95% CI = 1.02-1.92) when adjusted for age, sex, and treatment. A similar pattern was observed after including the post-trial period for cardiovascular (HR = 1.52; 95% CI = 1.20-1.93) and all-cause mortality (HR = 1.50; 95% CI = 1.29-1.73). However, when the newly diagnosed group was compared with the no diabetes group, no significant difference was observed in cardiovascular (HR = 0.33; 95% CI = 0.11-1.05) or all-cause mortality (HR = 0.76; 95% CI = 0.47-1.23) either during the ANBP2 trial or including post-trial follow-up (cardiovascular: HR = 0.82; 95% CI = 0.58-1.17; all-cause mortality: HR = 1.04; 95% CI = 0.85-1.27). CONCLUSIONS: Long-term presence of diabetes reduces survival. Compared with thiazide diuretics, ACEI-based antihypertensives may delay the development of diabetes in those at risk and thus potentially improve cardiovascular outcome in the elderly.

Age-dependent regulation of renal vasopressin V(1A) and V2 receptors in rats with genetic hypertension: implications for the treatment of hypertension.

The role of arginine vasopressin (AVP) as a hypertensive hormone remains controversial. We have previously reported that intervention with a V(1A) receptor antagonist in 6-week-old prehypertensive spontaneously hypertensive rats (SHR) for 4 weeks attenuated the subsequent development of hypertension in adult SHR. This study assessed the age-dependent regulation of plasma AVP levels and kidney V(1A) and V2 receptor expression during the development of hypertension in SHR and in normotensive Sprague Dawley rats. Systolic blood pressure (SBP), plasma AVP, and plasma renin activity (PRA) and kidney V(1A) and V2 receptor expression were assessed. SHR were studied at three ages: prehypertensive (6 weeks), developed hypertension (10 weeks), and established hypertension (16 weeks). SBP increased with age in SHR (P < .01) and both plasma AVP (P < .01) and PRA (P < .05) were increased in 10-week-old SHR. Renal medulla V(1A) receptor gene expression decreased in 10-week and 16-week-old SHR (P < .01), with a reduction in V(1A) receptor protein in the inner medulla of 16-week-old SHR (P < .05) compared with young SHR. There was no change in V2 receptor expression during the development of hypertension. In normotensive rats, plasma AVP, PRA, and kidney V(1A) and V2 receptor expression were unchanged over time. These data suggest that in SHR, activation of plasma AVP and the renal V(1A) receptor occurs during developing hypertension, with downregulation when hypertension is established. The use of V(1A) receptor antagonists in prehypertension may provide a unique opportunity for the prevention of hypertension in high-risk individuals.

High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage.

BACKGROUND: Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). METHODS: Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. RESULTS: A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. CONCLUSION: One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII.

Cholesterol complacency in Australia: time to revisit the basics of cardiovascular disease prevention.

AIMS AND OBJECTIVES: Community awareness of the importance of hypercholesterolemia and the need for appropriate therapy is an important part of global efforts to reduce the population burden of cardiovascular disease. The aim of this study was to assess the knowledge and attitudes about cholesterol and to determine adherence to taking cholesterol-lowering medication among patients at high risk for cardiovascular events. BACKGROUND: In spite of the availability of lifestyle and medical treatments for lipid management, an estimated 50% of adult Australians (6.4 million) remain at risk for a cardiovascular-related event because they have total blood cholesterol levels which exceed recommended limits. It is within this context that a significant gap remains in meeting cholesterol goals, despite easy to meet targets with readily available therapeutic options. DESIGN: A two-page national self-report postal survey was conducted from August-October 2006. METHODS: A total of 508 Australian adults previously treated for hypercholesterolemia were surveyed to determine their understanding about cholesterol and their adherence to treatment. The mean age of participants was 67 (SD 10) years (72% male). Many participants (72%) were at risk of a cardiovascular event based on a prior history and 18% had type II diabetes. RESULTS: Participants had been prescribed lipid-lowering therapy (94% statin therapy) for an average of 10 years and visited their general practitioner on average three times per year. For those who knew their most recent cholesterol reading (67%), the total cholesterol was on average 4.5 (SD 1.1) mmol/l. This level was above the recommended limits for 40% of participants. Overall, 85% of participants reported knowing that there was high- and low-density lipoprotein forms of cholesterol, but only 56% and 38%, respectively, said that they understood or showed signs of clearly understanding the different types of cholesterol when their knowledge was assessed further. On the whole, therefore, participants had a limited understanding about cholesterol and its potential impact on cardiovascular events. Moreover, 25% of participants admitted to being non-compliant in taking their medication and only 51% correctly identified modifiable risk factors as most important for heart disease. Encouragingly, despite 85% of participants finding lifestyle changes challenging, most still identified their potential benefits. CONCLUSIONS: This study highlights that there are many unresolved issues in relation to educating high-risk patients who regularly visit their general practitioner to learn about and optimise their cholesterol levels via appropriate treatment and monitoring. RELEVANCE TO CLINICAL PRACTICE: There is a need for urgent public education and management by individuals and the health community. Strategies to address 'cholesterol complacency', in the sense of a willingness to accept sub-optimal standards of cholesterol control at both the patient and healthcare system levels (general practitioners in particular), are urgently needed to truncate an anticipated rising tide of cardiovascular disease in Australia.

Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study.

AIM: To determine the feasibility of performing a large clinical trial of the use of aspirin for the primary prevention of cardiovascular disease in older participants--the ASPirin in Reducing Events in the Elderly (ASPREE) trial. DESIGN AND PARTICIPANTS: A randomised double-blind placebo-controlled pilot trial of 100 mg of enteric-coated aspirin tablets daily, in men and women aged 70 years and over who did not have overt cardiovascular disease, and who were followed for 12 months. Participants were identified from the computer databases of general practitioners who were co-investigators in a previous trial. SETTING: The Melbourne metropolitan area between March 2003 and June 2005. MAIN OUTCOME MEASURES: The level of response to participation by GPs; the level of response from potential trial participants; the screening-to-randomisation rate to ensure the recruitment target could be achieved; and the retention of participants in the trial after 12 months. RESULTS: Forty-two GPs (23% of 180 mailed) expressed interest in participating in the pilot trial. Nineteen became co-investigators, of whom six were not required to meet recruitment targets. Letters were sent to 2614 patients, of whom 243 were screened and 209 (86%) were randomly allocated to receive aspirin or placebo. At 12 months,192 (92%) returned for follow-up, and 153 of these (80%) were still taking trial medication. There was a significant reduction in mean haemoglobin level in those taking aspirin. CONCLUSIONS: The recruitment strategy for ASPREE, based on methods developed for the conduct of a previous large-scale trial conducted in general practice, was successfully redeployed in this pilot study, with improved efficiency resulting from computerised database searching, telephone pre-screening, a simpler run-in phase and participant familiarity with the trial drug. We conclude that conducting ASPREE in Australian general practice with 18 000 participants is feasible. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register ISRCTN83772183.

Smaller aortic dimensions do not fully account for the greater pulse pressure in elderly female hypertensives.

This study examined the importance of aortic dimensions in determining pulse pressure in elderly hypertensives participating in the 2nd Australian National Blood Pressure Study, including a substantial number not previously receiving blood pressure lowering medication. Aortic dimensions were determined by ultrasound at the transverse arch and at the insertion of the aortic valve. Unadjusted data showed negative (P<0.001) correlations between central (carotid) and (brachial) peripheral pulse pressure and both arch (-0.200, -0.181) and outflow tract (-0.238, -0.238) diameters. Correlations were similar in those previously treated with blood pressure lowering medication and in the treatment naïve. Central pulse pressure (84+/-26 versus 75+/-28 mm Hg, P<0.001) was higher and aortic dimensions (transverse arch 2.56+/-0.31 versus 2.88+/-0.35 mm, P<0.001) smaller in women than men. Women had greater aortic stiffness (beta index 29.4+/-36.1 versus 22.1+/-21.3, P<0.03). Other bivariate correlates of central pulse pressure were age, mean arterial pressure, height, heart rate, augmentation index, aortic stiffness (all P<0.001), and weight (P=0.027). In multivariate analyses gender remained a predictor of central pulse pressure (P<0.001) even with inclusion of aortic dimensions (P=0.013) height and weight. Other significant terms were age, heart rate, mean blood pressure, and aortic stiffness (all P<0.001). These findings demonstrate an independent inverse relation between aortic size and pulse pressure in older hypertensive subjects. Differences in aortic dimensions and stiffness between genders do not fully account for the observed blood pressure differences, suggesting that a contributory factor to gender differences in pulse pressure is an increased age-related mismatch in ventricular function and aortic stiffness in women compared with men.

Similar effects of treatment on central and brachial blood pressures in older hypertensive subjects in the Second Australian National Blood Pressure Trial.

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6+/-4.7 years (mean+/-SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145+/-1 (mean+/-SEM), 143+/-1, 72+/-1, and 70+/-1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were -17+/-2, -16+/-2, -9+/-1, and -7+/-1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144+/-2, 144+/-2, 71+/-2, and 72+/-2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were -15+/-2, -17+/-2, -6+/-2, and -8+/-2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.

Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives.

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88+/-12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure > or =81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice.

OBJECTIVE: To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury. DESIGN: The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury. METHODS: Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls. RESULTS: Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response. CONCLUSIONS: These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.

Who's really hypertensive?--Quality control issues in the assessment of blood pressure for randomized trials.

The characterization of blood pressure in treatment trials assessing the benefits of blood pressure lowering regimens is a critical factor for the appropriate interpretation of study results. With numerous operators involved in the measurement of blood pressure in many thousands of patients being screened for entry into clinical trials, it is essential that operators follow pre-defined measurement protocols involving multiple measurements and standardized techniques. Blood pressure measurement protocols have been developed by international societies and emphasize the importance of appropriate choice of cuff size, identification of Korotkoff sounds, and digit preference. Training of operators and auditing of blood pressure measurement may assist in reducing the operator-related errors in measurement. This paper describes the quality control activities adopted for the screening stage of the 2nd Australian National Blood Pressure Study (ANBP2). ANBP2 is cardiovascular outcome trial of the treatment of hypertension in the elderly that was conducted entirely in general practices in Australia. A total of 54 288 subjects were screened; 3688 previously untreated subjects were identified as having blood pressure >140/90 mmHg at the initial screening visit, 898 (24%) were not eligible for study entry after two further visits due to the elevated reading not being sustained. For both systolic and diastolic blood pressure recording, observed digit preference fell within 7 percentage points of the expected frequency. Protocol adherence, in terms of the required minimum blood pressure difference between the last two successive recordings, was 99.8%. These data suggest that adherence to blood pressure recording protocols and elimination of digit preferences can be achieved through appropriate training programs and quality control activities in large multi-centre community-based trials in general practice. Repeated blood pressure measurement prior to initial diagnosis and study entry is essential to appropriately characterize hypertension in these elderly patients.

Predictors of failure to initiate randomized treatment in a large trial of antihypertensive drug therapy in the aged.

BACKGROUND: The identification of factors that contribute to noncompliance with trial drug initiation where virtually complete compliance might be expected, may help identify patients whose management is least likely to comply with clinical guidelines and study protocols. METHODS: Examination of cross-sectional and longitudinal data arising from the Second Australian National Blood Pressure Study. Prevalence rate ratios (RR) and 95% confidence intervals (CI) estimated from log-binomial models were used to assess associations between subject characteristics and whether the randomized drug was prescribed at trial randomization. The study population consisted of 6083 hypertensive Australians aged 65 to 84 years. RESULTS: After adjusting for each variable in a multivariate model the following were significant predictors of failure to prescribe RR (95% CI): not previously prescribed antihypertensive drugs 2.89 (2.52-3.32); lower systolic blood pressure (BP) 1.51 (1.59-1.43) or diastolic BP 1.18 (1.22-1.13); younger age 80 to 84 v 65 to 79 years 0.75 (0.59-0.95); total cholesterol >or=6.6 v

Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes.

Recent trials have suggested that inhibitors of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may reduce the incidence of new-onset diabetes in patients with or without hypertension and at high risk of developing diabetes. In this review, we critically evaluate the evidence from recent clinical trials for such a potential preventive effect of ACE inhibitors and ARBs, including a meta-analysis of these recent trials. The reduced incidence of diabetes in patients at high risk of developing diabetes by ACE inhibitors or ARBs has been explained by haemodynamic effects, such as improved delivery of insulin and glucose to the peripheral skeletal muscle, and non-haemodynamic effects, including direct effects on glucose transport and insulin signalling pathways, all of which decrease insulin resistance. There is now evidence that the pancreas may contain an in situ active RAS, which appears to be upregulated in an animal model of type 2 diabetes. Thus, ACE inhibitors and ARBs may act by attenuating the deleterious effect of angiotensin II on vasoconstriction, fibrosis, inflammation, apoptosis and beta-cell death in the pancreas, thereby protecting a critical beta-cell mass essential for insulin production. New evidence is presented that ACE inhibitors and ARBs may delay or prevent the development of insulin resistance and diabetes, for which novel mechanisms are suggested. The actions of agents that interrupt the RAS on insulin resistance, obesity and diabetes warrant further investigation in other animal models. Prospective clinical studies with the primary endpoint of the prevention of diabetes are now indicated to (i) further explore whether the inhibitors of the RAS are superior compared to other antihypertensive agents such as calcium channel blockers (CCBs) and (ii) to evaluate the potential beneficial effects of combination antihypertensive regimens on the development of diabetes.

Myocardial infarction increases ACE2 expression in rat and humans.

AIMS: Angiotensin converting enzyme (ACE) 2 catalyses the cleavage of angiotensin (Ang) I to Ang 1-9 and of Ang II to Ang 1-7. ACE2 deficiency impairs cardiac contractility and upregulates hypoxia-induced genes, suggesting a link with myocardial ischaemia. We studied the expression of ACE2 after myocardial infarction (MI) in the rat as well as in human failing hearts. METHODS AND RESULTS: Rats were killed at days 1, 3, and 28 after MI, or treated for 4 weeks with the ACE inhibitor ramipril (1 mg/kg). Cardiac gene and protein expression of ACE and ACE2 were assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry/activity assays/in vitro autoradiography, respectively. Both ACE (P = 0.022) and ACE2 (P = 0.015) mRNA increased in the border/infarct area compared with the viable area at day 3 after MI. By day 28, increases in ACE (P = 0.005) and ACE2 (P = 0.006) mRNA were also seen in the viable myocardium of MI rats compared with myocardium of control rats. ACE2 protein localized to macrophages, vascular endothelium, smooth muscle, and myocytes. Ramipril attenuated cardiac hypertrophy and inhibited cardiac ACE. In contrast, ramipril had no effect on cardiac ACE2 mRNA, which remained elevated in all areas of the MI rat heart. Immunoreactivity of both ACE and ACE2 increased in failing human hearts. CONCLUSION: The increase in ACE2 after MI suggests that it plays an important role in the negative modulation of the renin angiotensin system in the generation and degradation of angiotensin peptides after cardiac injury.