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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension.Design: - Multicenter, randomized, double-blind, parallel-group clinical trial.Setting: - Four academic clinical research units in the United States.Participants: - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities.Interventions: - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity.Main Outcome Measures: - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years.Results: - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up.Conclusions: - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in the United States. Hypertension is the most common single reason for visits to primary care physicians accounting for more than 35 million visits annually. Pharmacotherapy can achieve adequate control of blood pressure. Multiple interventions compares to single therapies are more efficacious in treating hypertension, and this fact supports using the holistic approach to hypertension treatment. Implementing an optimal healing environment (OHE) in a hypertension treatment regimen has the potential to impact not only health care costs, but also to optimize blood pressure control, and thus decrease the total cardiovascular disease burden. The research questions for the study of OHE in hypertension may differ between the individual patient perspective and the public health perspective. The use of a 2 x 2 factorial design would allow analysis of both perspectives simultaneously. Using an OHE setting with multiple interventions in formulating an individualized approach to hypertension management merits further exploration and research. [ABSTRACT FROM AUTHOR]

Background: Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension.Methods: Participants with repeated measurements of systolic pressure of 130 to 139 mm Hg and diastolic pressure of 89 mm Hg or lower, or systolic pressure of 139 mm Hg or lower and diastolic pressure of 85 to 89 mm Hg, were randomly assigned to receive two years of candesartan (Atacand, AstraZeneca) or placebo, followed by two years of placebo for all. When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial.Results: A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group; mean age, 48.5 years; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent; P<0.001). After four years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent; P<0.007). Serious adverse events occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo.Conclusions: Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated prehypertension (the placebo group). Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of prehypertension appears to be feasible. (ClinicalTrials.gov number, NCT00227318.). [ABSTRACT FROM AUTHOR]

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., (© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: This study was supported by contracts NO1-HC-35130 and HHSN268201100036C with the National Heart, Lung, and Blood Institute. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial investigators acknowledge study medications contributed by Pfizer, Inc (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer, Inc. William Cushman has received honoraria from Takeda. Dr. Oparil has received honoraria from Daiichi Sankyo and Novartis., (Copyright © 2016 American Society of Hypertension. All rights reserved.)

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., (© 2014 by the American Diabetes Association.)

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., (©2013 Wiley Periodicals, Inc.)

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.

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., (© 2011 Wiley Periodicals, Inc.)

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.

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.).

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.

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., (Copyright 2010 Elsevier Ltd. All rights reserved.)

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.

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.), (2010 Massachusetts Medical Society)

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.), (2010 Massachusetts Medical Society)

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.

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.

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.

Background: Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors., Methods: In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up., Results: At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001)., Conclusions: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.), (2008 Massachusetts Medical Society)

Most patients with type 2 diabetes mellitus develop cardiovascular disease (CVD), with substantial loss of life expectancy. Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes. The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge. Despite the importance of this health problem, there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality. All participants are in the glycemia trial, which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin (HbA1c) level of <6.0% will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9%. The lipid trial includes 5,518 of the participants, who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether, in the context of good glycemic control, a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo. The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of <120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of <140 mm Hg. The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Upon the expected completion of participant follow-up in 2009, the ACCORD trial should document for the first time the benefits and risks of intensive glucose control, intensive blood pressure control, and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes.

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

The incidence of ESRD is increasing rapidly. Limited information exists regarding early markers for the development of ESRD. This study aimed to determine over 25 yr the risk for ESRD associated with proteinuria, estimated GFR (eGFR), and hematocrit in men who did not have identified kidney disease and were randomly assigned into the Multiple Risk Factor Intervention Study (MRFIT). A total of 12,866 men who were at high risk for heart disease were enrolled (1973 to 1975) and followed through 1999. Renal replacement therapy was ascertained by matching identifiers with the United States Renal Data System's data; vital status was from the National Death Index. Men who initiated renal replacement therapy or died as a result of kidney disease were deemed to have developed ESRD. Dipstick urine for proteinuria, eGFR, and hematocrit were related to development of ESRD. During 25 yr, 213 (1.7%) men developed ESRD. Predictors of ESRD were dipstick proteinuria of 1+ or > or =2+ (hazard ratio [HR] 3.1 [95% confidence interval (CI) 1.8 to 5.4] and 15.7 [95% CI 10.3 to 23.9] respectively) and an eGFR of <60 ml/min per 1.73 m(2) (HR 2.4; 95% CI 1.5 to 3.8). Correlation between eGFR and serum creatinine was 0.9; the risk for ESRD with a 1-SD difference of each was identical (HR 1.21). Bivariate analysis demonstrated a 41-fold increase in ESRD risk in those with an eGFR <60 ml/min per 1.73 m(2) and > or =2+ proteinuria (95% CI 15.2 to 71.1). There was no association between hematocrit and ESRD. Other baseline measures that independently predicted ESRD included age, cigarette smoking, BP, low HDL cholesterol, and fasting glucose. Among middle-aged men who were at high risk for cardiovascular disease but had no clinical evidence of cardiovascular disease or significant kidney disease, dipstick proteinuria and an eGFR value <60 ml/min per 1.73 m(2) were strong predictors of long-term development of ESRD. It remains unknown whether intervention for proteinuria or early identification of those with chronic kidney disease reduces the risk for ESRD.

Background: Blood pressure (BP) is controlled to recommended goal in less than one-third of people with hypertension. There has been little recent research on physician beliefs and practices with regard to the treatment of hypertension., Methods: In late 1999, we surveyed 104 primary care physicians in the 18 owned clinics of a large staff model, non-profit health maintenance organization. The survey included questions about demographics, BP treatment goals for patients with uncomplicated hypertension, and beliefs about hypertension., Results: The reported systolic BP treatment goal was < or =140 mm Hg for 97% and the diastolic BP goal was < or =90 mm Hg for 100%. The systolic BP goal for patients with isolated systolic hypertension was < or =140 mm Hg for 82%, but 34% stated that they would treat to a different goal depending on the diastolic BP. The proportions of physicians who would intensify treatment for BP of 140/90 mm Hg, 150/95 mm Hg, 165/75 mm Hg, and 165/65 mm Hg were 64%, 97%, 89% and 77%, respectively. Although 93% believed that medication was necessary to control BP in most cases, a majority (55%) agreed with the statement that BP could be controlled in most patients with only one drug. Although 42% reported that they often had to change drugs because of side effects, only 16% believed that it was time-consuming to find a well-tolerated drug regimen., Conclusions: In this setting, primary care physicians' self-reported practices were in good agreement with national guidelines put forth in the late 1990s, and their beliefs were favorable to therapy. Our data point to a need for interventions to emphasize that combination drug therapy is frequently required to achieve BP control, and that more aggressive intervention is often warranted for isolated systolic hypertension.

Context: Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial., Objective: To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease., Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results., Intervention: Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed., Main Outcome Measures: First occurrence of stroke, myocardial infarction, or cardiovascular disease-related death., Results: Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P =.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease-related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease-related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P =.003). More cardiovascular disease-related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53)., Conclusions: The CONVINCE trial did not demonstrate equivalence of a COER verapamil-based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or beta-blocker treatment.

The calcium channel blocker amlodipine and angiotensin II receptor blocker losartan, with or without hydrochlorothiazide (HCTZ), were compared for the treatment of mild to moderate hypertension in a multicenter, double-blind, parallel-group clinical trial. Following a 2-week placebo run-in, 440 adults (45-80 years old) were randomized to receive either amlodipine 5 mg once daily or losartan 50 mg once daily. Patients who failed to meet the sitting diastolic blood pressure (BP) reduction goal of

Design: We report the results of a 24-week, placebo-controlled, two-period, crossover trial of sodium supplementation in 112 normotensive African Americans, aged 25 to 64 years, with average blood pressure (BP) of 105/70 mm Hg. Estimated 24-hour urinary sodium excretion was 133.6 mmol; the average urinary sodium-to-creatinine ratio was 0.74., Methods: Variability-adjusted BP change was the difference in BP level after the respective treatment periods, divided by the intra-person standard deviation of the average BP obtained at 3 consecutive screening visits during a 4-week period., Results: The urinary sodium-to-creatinine ratio and the total urine sodium content were 37.8% and 26.5% higher, respectively, at the end of the sodium treatment period. Twenty-four hour ambulatory BP change (mm Hg) (95% CI) was systolic 1.2 (0, 2.4), and diastolic 0.7 (-0.3, 1.8); cuff BP change was systolic 0.9 (-1, 2.9), and diastolic 1.4 (0.1, 2.7). Variability-adjusted BP change was systolic 0.2 (-0.4, 0.8) and diastolic 0.4 (-0.1, 0.9). Though variability-adjusted and unadjusted SBP change correlated highly (r = 0.941, P<.001), only the former correlated with body mass index (r = 0.224, P<.05), a known correlate of salt sensitivity. While total urinary sodium content in timed urine collections and urinary sodium-to-creatinine ratio correlated (r = 0.727, P<.001), neither correlated with cuff BP changes. Change in urinary sodium-to-creatinine ratios of 3 consecutive pooled overnight 8-hour urine collections correlated with changes in 24-hour ambulatory SBP (r = 0.294, P<.001) and DBP (r = 0.193, P<.05); however, change in total urinary sodium content was uncorrelated. Total urinary sodium content of these pooled collections (P = .001), but not the urinary sodium-to-creatinine ratio, was positively related to urinary creatinine excretion per kilogram of body weight, the latter being an indicator of urine collection duration., Conclusions: The lack of effect of the duration of urine collection on the urinary sodium-to-creatinine ratio is advantageous in individuals who may report inaccurately the duration of their urine collection. Sequential regression analyses demonstrated that the urinary sodium-to-creatinine ratio conveyed all of the changes in urinary sodium excretion information contained in aggregate urinary sodium excretion-and more. Variability-adjusted BP change was the more sensitive metric of BP response to dietary sodium manipulations, than unadjusted BP change. Thus, variability-adjusted BP change and the urinary sodium-to-creatinine ratio appear to be incrementally better metrics of salt sensitivity than those traditionally used.

Context: Blood pressure control (<140/90 mm Hg) rates for hypertension fall far short of the US national goal of 50% or more. Achievable control rates in varied practice settings and geographic regions and factors that predict improved blood pressure control are not well identified., Objective: To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings., Design: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002., Setting: A total of 623 centers in the United States, Canada, and the Caribbean., Participants: A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor., Interventions: Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control (<140/90 mm Hg)., Main Outcome Measures: The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control (<140/90 mm Hg), and the number of drugs required to achieve control in all three groups combined., Results: Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was <140/90 mm Hg in only 27.4% of participants. After 5 years of follow-up, the percent controlled improved to 66%. Systolic blood pressure was <140 mm Hg in 67% of participants, diastolic blood pressure was <90 mm Hg in 92%, the mean number of drugs prescribed was 2.0+/-1.0, and the percent on > or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants., Conclusions: These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure <140/90 mm Hg with the antihypertensive medications available today., (Copyright 2002 Le Jacq Communications, Inc.)

Objectives: To assess attitudes of physicians, clinic administrators, and patients within a health maintenance organization (HMO) toward using financial incentives to improve the control of hypertension., Study Design: Descriptive study of attitudes toward use of financial incentives paid to physicians or to clinic systems., Methods: Data were collected through physician survey (n = 104), interviews with clinic administrators (n = 24), and patient focus groups (n = 3) during the winter of 1999 and the spring of 2000. Analyses included both qualitative and quantitative approaches., Results: Most physicians (80%) supported additional funding to clinics to create systems to improve hypertension care. However, less than half supported direct payment to either groups of physicians (38%) or individual physicians (24%). Sixty-four percent of clinic administrators supported incentive payments to clinics to improve quality of care, whereas only 42% favored incentives to physicians. Patients had a uniformly favorable view of incentives paid to clinics, but were strongly opposed to direct physician incentives. Written feedback was supported by both clinic administrators (54%) and physicians (74%)., Conclusions: In this nonprofit HMO, none of the stakeholder groups supported direct incentive payments to physicians to improve hypertension control. Trials of financial incentives within managed care organizations should include study arms with clinic-based incentives. Further study is needed to determine if incentives to clinics, which appear to be acceptable, can actually improve blood pressure control.

The study was to compare the effects of amlodipine (calcium channel antagonist), chlorthalidone (diuretic), and placebo in adults more than 50 years of age with stage 1 isolated systolic hypertension (ISH). After a 4-week placebo run-in phase, 150 patients were randomly assigned in a double-blind fashion to treatment with 5 mg of amlodipine (n = 48), 15 mg of chlorthalidone (n = 50), or placebo (n = 52). Patients who failed to meet the systolic blood pressure (BP) reduction goal by week 4 had their dose increased to 10 mg of amlodipine or 30 mg of chlorthalidone, and maintained at this increased dose for 12 weeks. Results showed a mean reduction (mean +/- SD) in sitting systolic BP from baseline to the last treatment visit of -14.6+/-12.2 mm Hg (95% confidence interval [CI] -18.2, -11.0), -14.0+/-13.46 mm Hg (95% CI -17.8, -10.2), and -3.4+/-11.83 mm Hg (95% CI -6.7, -0.1) for the amlodipine, chlorthalidone, and the placebo treatment groups, respectively. Both active treatments showed significantly greater reductions than the placebo group (P < or = .001), but were not significantly different from each other. Sixty-seven percent of the amlodipine, 69% of the chlorthalidone, and 25% of the placebo-treated patients reached the protocol defined systolic BP goal (P = .001). Both active treatment groups showed a trend of better systolic BP response in older patients (> or =65 years). Secondary efficacy measures including pulse pressure, standing systolic, diastolic, and the 24-h ambulatory BP were also statistically significantly improved for both active treatments at the end of treatment, except for chlorthalidone in standing diastolic BP. Adverse events that occurred during the study were as expected and were well tolerated. The results of this study support the efficacy and safety of amlodipine and chlorthalidone for the treatment of stage 1 ISH during 20 weeks of treatment.

Therapeutic treatment of hypertension has been achieved successfully with both pharmacologic and nonpharmacologic interventions. Clinical trials have shown that various approaches to treatment result in different levels of blood pressure reduction as well as varying effects on quality of life. Standardizing the approach to measuring quality of life would be beneficial to the assessment of treatment outcomes in hypertension trials. This article reviews some of the strengths and weaknesses of both pharmacologic and nonpharmacologic treatments of hypertension, with special emphasis placed on effects of quality of life.

The Treatment of Mild Hypertension Trial was a randomized, double-blind clinical trial conducted from 1986 to 1992 comparing the efficacy of six antihypertensive treatment regimens in 902 participants with stage I hypertension. To satisfy a secondary objective of the study, follow-up information on mortality and cardiovascular morbidity was collected. For this objective the aim was to ascertain the vital and cardiovascular event status as of the last day of the trial. This was accomplished by inviting each participant to attend a closeout visit shortly after the closeout date. In addition to serving as verification of vital status, this visit allowed data collection on nonfatal events that occurred between the last clinic visit and the closeout date. During this visit the patient was unblinded to study medication and given a medical summary of their participation during the trial, as well as a bottle of open-label medication. The advantages of a closeout visit are discussed along with a call for studies to provide clearer definitions of lost to follow-up and censoring times used in life-table analyses, especially when the primary event includes both fatal and nonfatal events. Control Clin Trials 2001;22:56-61