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.

Electrocardiographic measures of left ventricular hypertrophy in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

Left ventricular hypertrophy (LVH) predicts cardiovascular risk in hypertensive patients. We analyzed baseline/follow-up electrocardiographies in 26,376 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to amlodipine (A), lisinopril (L), or chlorthalidone (C). Prevalent/incident LVH was examined using continuous and categorical classifications of Cornell voltage. At 2 and 4 years, prevalence of LVH in the C group (5.57%; 6.14%) was not statistically different from A group (2 years: 5.47%; P = .806, 4 years: 6.54%; P = .857) or L group (2 years: 5.64%; P = .857, 4 years: 6.50%; P = .430). Incident LVH followed similarly, with no difference at 2 years for C (2.99%) compared to A (2.57%; P = .173) or L (3.16%; P = .605) and at 4 years (C = 3.52%, A = 3.29%, L = 3.71%; P = .521 C vs. A, P = .618 C vs. L). Mean Cornell voltage decreased comparably across treatment groups (Δ baseline, 2 years = +3 to -27 µV, analysis of variance P = .8612; 4 years = +10 to -17 µV, analysis of variance P = .9692). We conclude that risk reductions associated with C treatment in secondary end points of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial cannot be attributed to differential improvements in electrocardiography LVH.

Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial.

OBJECTIVE: To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS: ACCORD enrolled 10,251 type 2 diabetes patients aged 40-79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0-7.9% (53-63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction [MI], and nonfatal stroke) and secondary outcomes. RESULTS: In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio [HR] 0.67; 95% CI 0.50-0.91), BP (HR 0.74; 95% CI 0.55-1.00), or both (HR 0.71; 95% CI 0.52-0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02-1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group. CONCLUSIONS: In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.

Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE-inhibitor, or calcium-channel blocker in ALLHAT.

Calcium channel blockers (CCBs) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal (GI) hemorrhage. Using administrative databases, the authors re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the CCB amlodipine had a greater risk of hospitalized GI bleeding (a prespecified outcome) compared with those randomized to the diuretic chlorthalidone or the angiotensin-converting enzyme inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for GI bleeding hospitalizations compared with participants randomized to amlodipine (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.92-1.28). Those randomized to lisinopril were at increased risk of GI bleeding compared with those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned to lisinopril therapy had a higher risk of hospitalized GI hemorrhage (HR, 1.27; 95% CI, 1.06-1.51) vs those assigned to amlodipine. In-study use of atenolol prior to first GI hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). Hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared with those taking either chlorthalidone or lisinopril.

Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR.

BACKGROUND AND OBJECTIVES: CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged ≥55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4-8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m(2)) as follows: normal/increased (≥90; n=8027), mild reduction (60-89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD. RESULTS: After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD. CONCLUSIONS: CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD.

Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.

Spinal manipulation, medication, or home exercise with advice for acute and subacute neck pain: a randomized trial.

BACKGROUND: Mechanical neck pain is a common condition that affects an estimated 70% of persons at some point in their lives. Little research exists to guide the choice of therapy for acute and subacute neck pain. OBJECTIVE: To determine the relative efficacy of spinal manipulation therapy (SMT), medication, and home exercise with advice (HEA) for acute and subacute neck pain in both the short and long term. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00029770) SETTING: 1 university research center and 1 pain management clinic in Minnesota. PARTICIPANTS: 272 persons aged 18 to 65 years who had nonspecific neck pain for 2 to 12 weeks. INTERVENTION: 12 weeks of SMT, medication, or HEA. MEASUREMENTS: The primary outcome was participant-rated pain, measured at 2, 4, 8, 12, 26, and 52 weeks after randomization. Secondary measures were self-reported disability, global improvement, medication use, satisfaction, general health status (Short Form-36 Health Survey physical and mental health scales), and adverse events. Blinded evaluation of neck motion was performed at 4 and 12 weeks. RESULTS: For pain, SMT had a statistically significant advantage over medication after 8, 12, 26, and 52 weeks (P ≤ 0.010), and HEA was superior to medication at 26 weeks (P = 0.02). No important differences in pain were found between SMT and HEA at any time point. Results for most of the secondary outcomes were similar to those of the primary outcome. LIMITATIONS: Participants and providers could not be blinded. No specific criteria for defining clinically important group differences were prespecified or available from the literature. CONCLUSION: For participants with acute and subacute neck pain, SMT was more effective than medication in both the short and long term. However, a few instructional sessions of HEA resulted in similar outcomes at most time points. PRIMARY FUNDING SOURCE: National Center for Complementary and Alternative Medicine, National Institutes of Health.

Long-term effects of chlorthalidone versus hydrochlorothiazide on electrocardiographic left ventricular hypertrophy in the multiple risk factor intervention trial.

Chlorthalidone (CTD) reduces 24-hour blood pressure more effectively than hydrochlorothiazide (HCTZ), but whether this influences electrocardiographic left ventricular hypertrophy is uncertain. One source of comparative data is the Multiple Risk Factor Intervention Trial, which randomly assigned 8012 hypertensive men to special intervention (SI) or usual care. SI participants could use CTD or HCTZ initially; previous analyses have grouped clinics by their main diuretic used (C-clinics: CTD; H-clinics: HCTZ). After 48 months, SI participants receiving HCTZ were recommended to switch to CTD, in part because higher mortality was observed for SI compared with usual care participants in H-clinics, whereas the opposite was found in C-clinics. In this analysis, we examined change in continuous measures of electrocardiographic left ventricular hypertrophy using both an ecological analysis by previously reported C- or H-clinic groupings and an individual participant analysis where use of CTD or HCTZ by SI participants was considered and updated annually. Through 48 months, differences between SI and usual care in left ventricular hypertrophy were larger for C-clinics compared with H-clinics (Sokolow-Lyon: -93.9 versus -54.9 µV, P=0.049; Cornell voltage: -68.1 versus -35.9 µV, P=0.019; Cornell voltage product: -4.6 versus -2.2 µV/ms, P=0.071; left ventricular mass: -4.4 versus -2.8 g, P=0.002). At the individual participant level, Sokolow-Lyon and left ventricular mass were significantly lower for SI men receiving CTD compared with HCTZ through 48 months and 84 months of follow-up. Our findings on left ventricular hypertrophy support the idea that greater blood pressure reduction with CTD than HCTZ may have led to differences in mortality observed in the Multiple Risk Factor Intervention Trial.

Alpha 1 adrenoreceptor antagonists.

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • α Antagonists lower blood pressure by selectively blocking post-synaptic α(1) -adrenoreceptors, which antagonizes catecholamine-induced constriction of the arterial and venous vascular beds. • α(1) -Adrenoreceptor antagonists are not indicated for initial, first-line antihypertensive therapy; however, they can be added to most other antihypertensive drug classes in--preferably diuretic-containing--drug regimens. • When used over time, these agents cause expansion of the extracellular fluid and plasma volumes that typically manifests as weight gain and an attenuation of the blood pressure-lowering efficacy in persons who are consuming usual amounts of dietary sodium. • Utilization of α(1) -adrenoreceptor antagonists with diuretics such as chlorthalidone or hydrochlorothiazide is beneficial because these agents minimize the α antagonist-induced expansion of the extracellular and plasma volumes while providing significant incremental reductions in blood pressure. • α(1) -Adrenoreceptor antagonists are especially useful in men with benign prostatic hypertrophy because they increase mean and peak urinary flow rates as well as reduce lower urinary tract symptoms. • α(1) -Adrenoreceptor antagonists are contraindicated in persons with heart failure because of their aforementioned ability to expand extracellular and plasma volumes.

Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial.

BACKGROUND CONTEXT: Several conservative therapies have been shown to be beneficial in the treatment of chronic low back pain (CLBP), including different forms of exercise and spinal manipulative therapy (SMT). The efficacy of less time-consuming and less costly self-care interventions, for example, home exercise, remains inconclusive in CLBP populations. PURPOSE: The purpose of this study was to assess the relative efficacy of supervised exercise, spinal manipulation, and home exercise for the treatment of CLBP. STUDY DESIGN/SETTING: An observer-blinded and mixed-method randomized clinical trial conducted in a university research clinic in Bloomington, MN, USA. PATIENT SAMPLE: Individuals, 18 to 65 years of age, who had a primary complaint of mechanical LBP of at least 6-week duration with or without radiating pain to the lower extremity were included in this trial. OUTCOME MEASURES: Patient-rated outcomes were pain, disability, general health status, medication use, global improvement, and satisfaction. Trunk muscle endurance and strength were assessed by blinded examiners, and qualitative interviews were performed at the end of the 12-week treatment phase. METHODS: This prospective randomized clinical trial examined the short- (12 weeks) and long-term (52 weeks) relative efficacy of high-dose, supervised low-tech trunk exercise, chiropractic SMT, and a short course of home exercise and self-care advice for the treatment of LBP of at least 6-week duration. The study was approved by local institutional review boards. RESULTS: A total of 301 individuals were included in this trial. For all three treatment groups, outcomes improved during the 12 weeks of treatment. Those who received supervised trunk exercise were most satisfied with care and experienced the greatest gains in trunk muscle endurance and strength, but they did not significantly differ from those receiving chiropractic spinal manipulation or home exercise in terms of pain and other patient-rated individual outcomes, in both the short- and long-term. CONCLUSIONS: For CLBP, supervised exercise was significantly better than chiropractic spinal manipulation and home exercise in terms of satisfaction with treatment and trunk muscle endurance and strength. Although the short- and long-term differences between groups in patient-rated pain, disability, improvement, general health status, and medication use consistently favored the supervised exercise group, the differences were relatively small and not statistically significant for these individual outcomes.

Long-term effects of intensive glucose lowering on cardiovascular outcomes.

BACKGROUND: Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. METHODS: We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. RESULTS: Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. CONCLUSIONS: As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).

Management of high blood pressure in Blacks: an update of the International Society on Hypertension in Blacks consensus statement.

Since the first International Society on Hypertension in Blacks consensus statement on the "Management of High Blood Pressure in African American" in 2003, data from additional clinical trials have become available. We reviewed hypertension and cardiovascular disease prevention and treatment guidelines, pharmacological hypertension clinical end point trials, and blood pressure-lowering trials in blacks. Selected trials without significant black representation were considered. In this update, blacks with hypertension are divided into 2 risk strata, primary prevention, where elevated blood pressure without target organ damage, preclinical cardiovascular disease, or overt cardiovascular disease for whom blood pressure consistently <135/85 mm Hg is recommended, and secondary prevention, where elevated blood pressure with target organ damage, preclinical cardiovascular disease, and/or a history of cardiovascular disease, for whom blood pressure consistently <130/80 mm Hg is recommended. If blood pressure is ≤10 mm Hg above target levels, monotherapy with a diuretic or calcium channel blocker is preferred. When blood pressure is >15/10 mm Hg above target, 2-drug therapy is recommended, with either a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous and/or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker. Effective multidrug therapeutic combinations through 4 drugs are described. Comprehensive lifestyle modifications should be initiated in blacks when blood pressure is ≥115/75 mm Hg. The updated International Society on Hypertension in Blacks consensus statement on hypertension management in blacks lowers the minimum target blood pressure level for the lowest-risk blacks, emphasizes effective multidrug regimens, and de-emphasizes monotherapy.

Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.

BACKGROUND: Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. METHODS: ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS: 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05). INTERPRETATION: Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. FUNDING: US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.

Effects of combination lipid therapy in type 2 diabetes mellitus.

BACKGROUND: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS: We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). CONCLUSIONS: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

BACKGROUND: There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS: A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS: After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

OBJECTIVE: Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS: CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS: During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55-2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (P(interaction) > 0.7). CONCLUSIONS: Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium.

BACKGROUND: Evidence supporting the benefit of low-dose thiazide-based regimens to reduce cardiovascular events is primarily derived from studies using chlorthalidone, yet low-dose hydrochlorothiazide (HCTZ) (12.5-25 mg) remains more widely prescribed. We sought to describe their comparative dose-response relationships for changes in systolic blood pressure (SBP) and potassium. METHODS: PubMed from 1948 to July 2008 was systematically searched to identify clinical trials using either HCTZ or chlorthalidone monotherapies. A total of 108 clinical trials with HCTZ and 29 with chlorthalidone were analyzed. Data were pooled to evaluate the effects on SBP and potassium of both drugs throughout their respective dose-response curves. Equivalence analysis was performed for the clinically recommended low-dose range of 12.5-25 mg, grouped by study duration, using the two one-sided tests procedure described by Schuirmann. RESULTS: When evaluated on a milligram-per-milligram basis using pooled data, chlorthalidone generally produces slightly greater reductions in SBP and potassium than HCTZ. In the low-dose range of 12.5-25 mg, equivalence analysis reveals that the reductions in SBP are not equivalent between the two drugs, using upper and lower equivalence bounds of 4 mm Hg. Within the same dosing range, the mean changes in potassium were determined to be equivalent when upper and lower equivalence bounds of 0.29 mEq/l are used. CONCLUSIONS: Equivalence analysis using data from several studies suggests that the SBP reductions achieved with HCTZ and chlorthalidone cannot be considered equivalent within the low-dose range currently recommended. However, within this dosing range, reductions in potassium can be considered equivalent.

Heart failure in ALLHAT: did blood pressure medication at study entry influence outcome?

J Clin Hypertens (Greenwich). 2009;11:466-474. (c)2009 Wiley Periodicals, Inc.Lower heart failure (HF) rates in individuals taking chlorthalidone vs amlodipine, lisinopril, or doxazosin were unanticipated in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). HF differences appeared early, leading to questions about the possible influence of pre-enrollment antihypertensive drugs. A post hoc study evaluated hospitalized HF events. During year 1479 individuals had HF, with pre-entry antihypertensive medication data obtained on 301 patients (63%). Case-only analysis examined interactive effects (interaction odds ratio [OR, ratio of ORs]) of previous medication and ALLHAT treatment on HF outcomes, eg, did treatment effect differ by pre-entry antihypertensive class? Among cases, 39%, 37%, 17%, and 47% were taking pre-entry diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers, respectively. Interaction OR for year 1 HF for amlodipine vs chlorthalidone for patients taking vs not taking diuretics pre-entry was 1.08 (95% confidence interval [CI], 0.53-2.21; P=.83); for lisinopril vs chlorthalidone, 1.33 (95% CI, 0.65-2.74; P=.44); and for doxazosin vs chlorthalidone, 1.13 (95% CI, 0.57-2.25; P=.73). Controlling for other pre-entry antihypertensives yielded similar results. There was no significant evidence that pre-entry drug type explained observed hospitalized HF differences by ALLHAT treatment.

Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial.

Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI: -0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI: -0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI: 0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.