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Recurrent events can occur more than once in the same individual; such events may be of different types, known as multitype recurrent events. They are very common in longitudinal studies. Often there is a terminating event, after which no further events can occur. The risk of any event, including terminating events such as death or cure, is typically affected by prior events. We propose a flexible joint multitype recurrent-events model that explicitly provides estimates of the change in risk for each event due to subject characteristics, including number and type of prior events and the absolute risk for every event type (terminating and nonterminating), and predicts event-free survival probability over a desired time period. The model is fully parametric, and therefore a standard likelihood function and robust standard errors can be constructed. We illustrate the model with applications to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (1994-2002) and provide discussion of the results and model features., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Sustaining SBP control reduces the risk for cardiovascular events that impair function but its association with nursing home admission has not been well studied., Methods: We conducted an analysis of sustained SBP control and long-term nursing home admissions using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) linked to Medicare claims restricted to participants with fee-for-service coverage, at least eight study visits with SBP measurements, who were not living in a nursing home during a 48-month baseline BP assessment period (n = 6557). Sustained SBP control was defined as less than 140 mmHg at less than 50%, 50% to less than 75%, 75% to less than 100%, and 100% of visits. Nursing home admissions were identified using the Medicare Long Term Care Minimum Data Set., Results: The mean age of participants was 73.8 years and 44.3% were men. Over a median follow-up of 9.2 years, 844 participants (12.8%) had a nursing home admission. Rates of nursing home admission per 100 person-years were 16.3 for participants with SBP control at less than 50%, 14.1 at 50% to less than 75%, 7.8 at 75% to less than 100%, and 5.3 at 100% of visits. Compared with those with sustained SBP control at less than 50% of visits, hazard ratios (95% confidence intervals) for nursing home admission were 0.79 (0.66-0.93), 0.70 (0.58-0.84), and 0.57 (0.44-0.74) among participants with SBP control at 50% to less than 75%, 75% to less than 100%, and 100% of visits, respectively., Conclusion: Among Medicare beneficiaries in ALLHAT, sustained SBP control was associated with a lower risk of long-term nursing home admission., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them., Methods: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test., Results: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes., Conclusions: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials., (© 2021. The Author(s).)

Objectives: The authors aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function., Background: The authors hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) participants randomized to lisinopril and chlorthalidone, in comparison with those randomized to amlodipine and doxazosin., Methods: Causal mediation analysis of ALLHAT data (1994 to 2002) included participants with available baseline and 24- to 48-month estimated glomerular filtration rate (eGFR) (N = 27,918; mean age 66 ± 7.4 years; 32.4% Black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors., Results: There were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF. In participants with diabetes, the relative change in eGFR mediated nearly 50% of the effect of lisinopril on incident symptomatic HF, whereas in diabetes-free participants, only 17%., Conclusions: On the risk difference scale, change in eGFR accounts for up to 50% of the mechanism by which antihypertensive medications affect HF. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542)., Competing Interests: Funding Support and Author Disclosures Dr. Tereshchenko was partially supported by HL118277 from the National Heart, Lung, and Blood Institute. The ALLHAT study was supported by the National Heart, Lung, and Blood Institute grant NO1-HC-35130. The ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol Myers Squibb (pravastatin); and financial support provided by Pfizer. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Gout is a common complication of blood pressure management and a frequently cited cause of medication nonadherence. Little trial evidence exists to inform antihypertensive selection with regard to gout risk., Methods: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized clinical trial on the effects of first-step hypertension therapy with amlodipine, chlorthalidone, or lisinopril on fatal coronary heart disease or nonfatal myocardial infarction (1994-2002). Trial participants were linked to CMS and VA gout claims (ICD9 274.XX). We determined the effect of drug assignment on gout with Cox regression models. We also determined the adjusted association of self-reported atenolol use (ascertained at the 1-month visit for indications other than hypertension) with gout., Results: Claims were linked to 23 964 participants (mean age 69.8 ± 6.8 years, 45% women, 31% black). Atenolol use was reported by 928 participants at the 1-month visit. Over a mean follow-up of 4.9 years, we documented 597 gout claims. Amlodipine reduced the risk of gout by 37% (hazard ratio 0.63; 95% CI 0.51--0.78) compared with chlorthalidone and by 26% (hazard ratio 0.74; 95% CI 0.58--0.94) compared with lisinopril. Lisinopril nonsignificantly lowered gout risk compared with chlorthalidone (hazard ratio 0.85; 95% CI 0.70--1.03). Atenolol use was not associated with gout risk (adjusted hazard ratio 1.18; 95% CI 0.78--1.80). Gout risk reduction was primarily observed after 1 year of follow-up., Conclusion: Amlodipine lowered long-term gout risk compared with lisinopril or chlorthalidone. This finding may be useful in cases where gout risk is a principal concern among patients being treated for hypertension.This trial is registered at clinicaltrials.gov, number: NCT00000542.

Objectives: To investigate legacy effects at 14-year follow-up of all-cause and cardiovascular disease (CVD) mortality in 'treatment-naive' or 'previous treatment' groups based on blood pressure (BP)-lowering treatment status at baseline., Methods: A post-hoc observational study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. We excluded participants with a previous history of CVD events. Cox proportional hazard model and 95% confidence interval were used to estimate the effects of treatment naive on mortality outcomes. Moreover, a subgroup analysis by estimated 10-year Framingham risk score was performed., Results: In multivariable models adjusting for baseline and in-trial characteristics (BP values and number of BP medications as time-dependent variables), there was no statistically significant difference in 5 and 14-year all-cause mortality with a hazard ratio of 0.93 (95% confidence interval 0.80-1.09) and hazard ratio 0.95 (0.88-1.03) and in 5 and 14-year CVD mortality hazard ratio 0.94 (0.72-1.23) and hazard ratio 0.93 (0.80-1.08). In subgroup by absolute CVD risk, no heterogeneity of the association between treatment naive and short-term or long-term all-cause or CVD mortality were found. All comparisons are between the treatment-naive and previous treatment groups., Conclusion: Physicians are concerned about 'legacy effects' of not treating individuals with a BP of 140 mmHg or over and low absolute risk. When treatment intensification was taken into consideration in the primary prevention population in this study, no adverse legacy effect as a result of baseline BP 'treatment naivety' was evident in 14 years of follow-up. The nonsignificant associations were consistent across the CVD risk subgroups. However, the results may be biased due to unobserved residual confounding and therefore should be interpreted with caution.

Achieving blood pressure (BP) control is associated with lower cardiovascular disease (CVD) risk, but less is known about CVD risk associated with sustained BP control over time. This observational analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was restricted to participants with four to seven visits with systolic BP (SBP) measurements during a 22-month period (n = 24 309). The authors categorized participants as having sustained BP control (SBP < 140 mm Hg) at 100%, 75% to <100%, 50% to <75%, and <50% of visits during this period. Outcomes included fatal coronary heart disease (CHD)/nonfatal myocardial infarction (MI), stroke, heart failure (HF), a composite CVD outcome (fatal CHD/nonfatal MI, stroke, or HF), and mortality. Hazard ratios (HRs) for the association of category of sustained BP control for each outcome were obtained using proportional hazards models. SBP control was present among 20.0% of participants at 100%, 16.4% at 75% to less than 100%, 27.0% at 50% to less than 75%, and 36.6% at less than 50% of visits. Compared to those with SBP control at 100% visits, adjusted HR (95% CI) among those with SBP control at <50% of visits was 1.16 (0.93-1.44) for fatal CHD/nonfatal MI, 1.71 (1.26-2.32) for stroke, 1.63 (1.30-2.06) for HF, 1.39 (1.20-1.62) for the composite CVD outcome, and 1.14 (0.99-1.30) for mortality. Sustained SBP control may be beneficial for preventing stroke, HF, and CVD outcomes in adults taking antihypertensive medication., (©2019 Wiley Periodicals, Inc.)

Background: Although atrial fibrillation (AF) guidelines indicate that pharmacological blockade of the renin-angiotensin system may be considered for primary AF prevention in hypertensive patients, previous studies have yielded conflicting results. We sought to determine whether randomization to lisinopril reduces incident AF or atrial flutter (AFL) compared with chlorthalidone in a large clinical trial cohort with extended post-trial surveillance., Methods and Results: We performed a secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), a randomized, double-blind, active-controlled clinical trial that enrolled hypertensive individuals ≥55 years of age with at least one other cardiovascular risk factor. Participants were randomly assigned to receive amlodipine, lisinopril, or chlorthalidone. Individuals with elevated fasting low-density lipoprotein cholesterol levels were also randomized to pravastatin versus usual care. The primary outcome was the development of either AF or AFL as diagnosed by serial study ECGs or by Medicare claims data. Among 14 837 participants without prevalent AF or AFL, 2514 developed AF/AFL during a mean 7.5±3.2 years of follow-up. Compared with chlorthalidone, randomization to either lisinopril (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15; P =0.46) or amlodipine (hazard ratio, 0.93; 95% confidence interval, 0.84-1.03; P =0.16) was not associated with a significant reduction in incident AF/AFL., Conclusions: Compared with chlorthalidone, treatment with lisinopril is not associated with a meaningful reduction in incident AF or AFL among older adults with a history of hypertension., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542., (© 2017 American Heart Association, Inc.)

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.)

Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability (VVV) of blood pressure (BP). We assessed the association between antihypertensive medication adherence and VVV of BP in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of BP was calculated using SD independent of mean, SD, and average real variability across study visits conducted 6 to 28 months after randomization. Participants who reported taking <80% of their antihypertensive medication at ≥1 study visits were categorized as nonadherent. Participants were followed up for cardiovascular events and mortality after the assessment of adherence and VVV of BP. SD independent of mean of BP was higher for nonadherent (n=2912) versus adherent (n=16 878) participants; 11.4±4.9 versus 10.5±4.5 for systolic BP; 6.8±2.8 versus 6.2±2.6 for diastolic BP (each P<0.001). SD independent of mean of BP remained higher among nonadherent than among adherent participants after multivariable adjustment (0.8 [95% confidence interval, 0.7-1.0] higher for systolic BP and 0.4 [95% confidence interval, 0.3-0.5] higher for diastolic BP]. SD and average real variability of systolic BP and diastolic BP were also higher among nonadherent than among adherent participants. Adjustment for nonadherence did not explain the association of VVV of BP with higher fatal coronary heart disease or nonfatal myocardial infarction, stroke, heart failure, or mortality risk. In conclusion, improving medication adherence may lower VVV of BP. However, VVV of BP is associated with cardiovascular outcomes independent of medication adherence., (© 2016 American Heart Association, Inc.)

Background: In this study, we aimed to translate the average relative effect of statin therapy from trial data to the individual patient with type 2 diabetes mellitus by developing and validating a model to predict individualized absolute risk reductions (ARR) of cardiovascular events., Methods and Results: Data of 2725 patients with type 2 diabetes mellitus from the Lipid Lowering Arm of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) study (atorvastatin 10 mg versus placebo) were used for model derivation. The model was based on 8 clinical predictors including treatment allocation (statin/placebo). Ten-year individualized ARR on major cardiovascular events by statin therapy were calculated for each patient by subtracting the estimated on-treatment risk from the estimated off-treatment risk. Predicted 10-year ARR by statin therapy was <2% for 13% of the patients. About 30% had an ARR of >4% (median ARR, 3.2%; interquartile range, 2.5%-4.3%; 95% confidence interval for 3.2% ARR, -1.4% to 6.8%). Addition of treatment interactions did not improve model performance. Therefore, the wide distribution in ARR was a consequence of the underlying distribution in cardiovascular risk enrolled in these trials. External validation of the model was performed in data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT; pravastatin 40 mg versus usual care) and Collaborative Atorvastatin Diabetes Study (CARDS; atorvastatin 10 mg versus placebo) of 3878 and 2838 patients with type 2 diabetes mellitus, respectively. Model calibration was adequate in both external data sets, discrimination was moderate (ALLHAT-LLT: c-statistics, 0.64 [95% confidence interval, 0.61-0.67] and CARDS: 0.68 [95% confidence interval, 0.64-0.72])., Conclusions: ARRs of major cardiovascular events by statin therapy can be accurately estimated for individual patients with type 2 diabetes mellitus using a model based on routinely available patient characteristics. There is a wide distribution in ARR that may complement informed decision making., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00327418 (CARDS) and NCT00000542 (ALLHAT)., (© 2016 American Heart Association, Inc.)

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of ≥3 antihypertensive medication classes or controlled hypertension while treated with ≥4 antihypertensive medication classes. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14 684 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants to determine the association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined aTRH as blood pressure not at goal (systolic/diastolic blood pressure ≥140/90 mm Hg) while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996-2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002. The multivariable adjusted hazard ratios (95% confidence intervals) comparing participants with versus without aTRH were as follows: coronary heart disease (1.44 [1.18-1.76]), stroke (1.57 [1.18-2.08]), all-cause mortality (1.30 [1.11-1.52]), heart failure (1.88 [1.52-2.34]), peripheral artery disease (1.23 [0.85-1.79]), and end-stage renal disease (1.95 [1.11-3.41]). aTRH was also associated with the pooled outcomes of combined coronary heart disease (hazard ratio, 1.47; 95% confidence interval, 1.26-1.71) and combined cardiovascular disease (hazard ratio, 1.46; 95% confidence interval, 1.29-1.64). These results demonstrate that aTRH increases the risk for cardiovascular disease and end-stage renal disease. Studies are needed to identify approaches to prevent aTRH and reduce risk for adverse outcomes among individuals with aTRH., (© 2014 American Heart Association, Inc.)

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.)

To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration- clinicaltrials.gov; Identifier: NCT00000542.

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.

Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a large practice-based clinical trial, made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone (C) versus amlodipine or lisinopril as a first-step drug were stratified by year-1 potassium. Postyear-1 outcomes among hypokalemics (potassium, <3.5 mmol/L) and hyperkalemics (potassium, >5.4 mmol/L) were compared with normokalemics (potassium, 3.5-5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in C (12.9%) differed from amlodipine (2.1%; P<0.001) and lisinopril (1.0%; P<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than in C (1.2%; P<0.01) or amlodipine (1.9%; P<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than in normokalemics (Cox hazard ratio, 1.21 [95% CI, 1.02-1.44]) with statistically significant (interaction, P<0.01) disparity in hazard ratios for the 3 treatment arms (hazard ratios, C=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio, 1.58 [95% CI, 1.15-2.18]) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of C. Thus, for most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5-25.0 mg of C).

Purpose of Review: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is re-evaluated considering information from recent subgroup and exploratory analyses, other new clinical trials, and meta-analyses. The ALLHAT analyses specifically emphasize heart failure findings, results in Black participants and those with chronic kidney disease, selection and doses of thiazide and similar diuretics, and the association of antihypertensive drug use with new-onset diabetes and its cardiovascular consequences., Recent Findings: The initial ALLHAT conclusion, that thiazide diuretics are superior to angiotensin-converting enzyme inhibitors (ACEIs), calcium antagonists (CCBs) and alpha-blockers in preventing one or more major clinical outcomes, including heart failure and stroke, and unsurpassed in significantly preventing any cardiovascular or renal outcome, has been further validated for patients with diabetes, renal disease, and/or metabolic syndrome. The evidence is even more compelling for Black patients. New-onset diabetes associated with thiazides did not increase cardiovascular outcomes. The diuretic was superior to all in preventing heart failure with preserved left-ventricular ejection fraction (LVEF) and similar to the ACEI in preventing heart failure with impaired LVEF. It was also unsurpassed in preventing atrial fibrillation., Summary: The totality of evidence re-affirms the initial ALLHAT conclusion that thiazide and similar diuretics (at evidence-based doses) are the preferred first-step therapy in most patients with hypertension.

Objectives: The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) determined that treatment with amlodipine, lisinopril, or doxazosin was not superior to thiazide-like diuretic (chlorthalidone) in preventing coronary heart disease (CHD) or other cardiovascular events. This subanalysis examines baseline prevalence and in-trial incidence of new-onset atrial fibrillation (AF) or atrial flutter (AFL) and their influence on clinical outcomes., Background: Limited information is available on whether atrial fibrillation incidence is affected differentially by different classes of antihypertensive medications or treatment with statins., Methods: AF/AFL was identified from baseline and follow-up electrocardiograms performed biannually. Analyses were performed to identify characteristics associated with baseline AF/AFL and its subsequent incidence., Results: AF/AFL was present at baseline in 423 participants (1.1%), more frequent in men (odds ratio: 1.72; 95% confidence interval [CI]: 1.37 to 2.17) and nonblacks (odds ratio: 2.09; 95% CI: 1.58 to 2.75). Its prevalence increased with age (p < 0.001) and was associated with CHD, cardiovascular disease, obesity, and high-density lipoprotein cholesterol <35 mg/dl. New-onset AF/AFL was associated with the same baseline risk factors plus electrocardiogram left ventricular hypertrophy. It occurred in 641 participants (2.0%) and, excluding doxazosin, did not differ by antihypertensive treatment group or, in a subset of participants, by pravastatin versus usual care. Baseline AF/AFL was associated with increased mortality (hazard ratio [HR]: 2.82; 95% CI: 2.36 to 3.37; p < 0.001), stroke (HR: 3.63; 95% CI: 2.72 to 4.86; p < 0.001), heart failure (HR: 3.17; 95% CI: 2.38 to 4.25; p < 0.001), and fatal CHD or nonfatal myocardial infarction (HR: 1.64; 95% CI: 1.22 to 2.21; p < 0.01). There was a nearly 2.5-fold increase in mortality risk when AF/AFL was present at baseline or developed during the trial (HR: 2.42; 95% CI: 2.11 to 2.77; p < 0.001)., Conclusions: In this high-risk hypertensive population, pre-existing and new-onset AF/AFL were associated with increased mortality. Excluding doxazosin, treatment assignment to either antihypertensive drugs or pravastatin versus usual care did not affect AF/AFL incidence. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is reevaluated considering information from new clinical trials, meta-analyses, and recent subgroup and explanatory analyses from ALLHAT, especially those regarding heart failure (HF) and the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences. Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13-1.27), especially HF (RR, 1.80; 95% CI, 1.40-2.22) and stroke (RR, 1.26; 95% CI, 1.10-1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05-1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09-1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88-2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.

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.

Background: Hypertension is a well-established risk factor for myocardial infarction (MI), but its prognostic importance in survivors of an acute MI is less clear., Methods: We used Cox proportional hazards models to examine the risk of any major cardiovascular event (cardiovascular death, heart failure, recurrent MI, or stroke)-combined or individual components-and all-cause death and evaluate the efficacy of captopril in 906 patients with hypertension and 1325 patients without hypertension in the Survival and Ventricular Enlargement (SAVE) clinical trial. All patients had survived an acute MI with resultant left ventricular (LV) systolic dysfunction, but without overt heart failure, and were randomized within 3 to 16 days after the index MI to receive either captopril or placebo. The mean (+/- SD) follow-up period was 42 +/- 10 months., Results: After adjustment for known risk factors, medication use at enrollment, and baseline systolic blood pressure, patients with hypertension had a significant increase in the risk of experiencing a combined cardiovascular event (47.7% vs 31.3%; hazard ratio [HR], 1.49; 95% CI, 1.28-1.74), cardiovascular death (23.4% vs 15.9%; HR, 1.40; 95% CI, 1.12-1.74), heart failure (27.7% vs 15.5%; HR, 1.64; 95% CI, 1.34-2.02), and all-cause death (27.4 vs 19.3%; HR, 1.25; 95% CI, 1.02-1.53), and a similar but statistically non-significant increase in the risk of non-fatal or fatal recurrent MI (17.4% vs 10.9%; HR, 1.27; 95% CI, 0.98-1.65), and non-fatal or fatal stroke (5.0% vs 3.6%; HR, 1.31; 95% CI, 0.81-2.09). Captopril resulted in similar benefits for both patients with and patients without hypertension. The number of combined cardiovascular events prevented for every 100 patients treated with captopril was 7.0 (95% CI, 0.5-13.5) in patients with hypertension and 7.5 (95% CI, 2.6-12.5) in patients without hypertension., Conclusions: In survivors of an acute MI with LV systolic dysfunction, antecedent hypertension was associated with a greater risk of subsequent adverse cardiovascular events, not directly explained by elevated blood pressure levels. Captopril use was beneficial in both patients with and patients without hypertension.

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.)

AimsThe effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events.Methods and resultsWe searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring

Diabetic patients undergoing coronary interventions have worse clinical and angiographic outcomes than do patients without diabetes. Metformin, an insulin sensitizer, may decrease the occurrence of these outcomes. Diabetic patients in the Prevention of Restenosis with Tranilast and its Outcomes Trial were identified through their medical records (n = 2,772). In this trial, 1,110 diabetic patients received nonsensitizer therapy (insulin and/or sulfonylureas) and 887 received sensitizer therapy (metformin with or without additional therapy). Logistic regression was used to obtain odds ratios (ORs) (sensitizer vs nonsensitizer therapy) of any clinical event (death, myocardial infarction, or ischemia-driven target vessel revascularization) and adjusted for multiple risk factors. Multivariate analysis showed no effect of lesion characteristics on clinical outcomes. Compared with patients on nonsensitizer therapy, those on sensitizer therapy showed an adjusted OR of 0.72 (95% confidence interval [CI] 0.57 to 0.91, p = 0.005) for any clinical event. The differences between the nonsensitizer therapy group and the sensitizer group were attributable mainly to decreased rates of death (OR 0.39, 95% CI 0.19 to 0.77, p = 0.007) and myocardial infarction (OR 0.31, 95% CI 0.15 to 0.66, p = 0.002). In our retrospective analysis, use of metformin in diabetics undergoing coronary interventions appeared to decrease adverse clinical events, especially death and myocardial infarction, compared with diabetic patients treated with nonsensitizer therapy.

Objectives: This post-trial data linkage analysis was to utilize the data of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants linked with their Medicare data to examine the risk of hospitalized and non-hospitalized gastrointestinal (GI) bleeding associated with antihypertensives. Settings: ALLHAT was a multicenter, randomized, double-blind, active-controlled trial conducted in a total of 42,418 participants aged ≥55 years with hypertension in 623 North American centers. Data for ALLHAT participants who were aged at ≥65 have been linked with their Medicare claims data. Participants: A total of 16,676 patients (4,480 for lisinopril, 4,537 for amlodipine, and 7,659 for chlorthalidone) with complete Medicare claims data were available for the final analysis. Results: The cumulative incidences through March 31, 2002 of hospitalized GI bleeding were 5.4%, 5.8% and 5.4% for amlodipine, lisinopril, and chlorthalidone arms, respectively, but were not statistically significant among the 3 arms after adjusting for confounders in Cox regression models. The cumulative incidences of non-hospitalized GI bleeding were also similar across the 3 arms (12.0%, 12.2% and 12.0% for amlodipine, lisinopril, and chlorthalidone, respectively). The increased risk of GI bleeding by age was statistically significant after adjusting for confounders (HR = 1.04 per year, 95% CI: 1.03–1.05). Smokers also had a significantly higher risk of having hospitalized GI bleeding (1.45, 1.19–1.76). Hispanics, those who used aspirin or atenolol in-trial, had diabetes, more education, and a history of stroke had a significantly lower risk of having GI bleeding than their counterparts. Other factors such as gender, history of CHD, prior antihypertensive use, use of estrogen in women, and obesity did not have significant effects on the risk of GI bleeding. Conclusion: There were no statistically significant differences on the risk of hospitalized or non-hospitalized GI bleeding among the 3 ALLHAT trial arms (amlodipine, lisinopril, and chlorthalidone) during the entire in-trial follow-up. [ABSTRACT FROM AUTHOR]

Multi-type recurrent event data occur frequently in longitudinal studies. Dependent termination may occur when the terminal time is correlated to recurrent event times. In this article, we simultaneously model the multi-type recurrent events and a dependent terminal event, both with nonparametric covariate functions modeled by B-splines. We develop a Bayesian multivariate frailty model to account for the correlation among the dependent termination and various types of recurrent events. Extensive simulation results suggest that misspecifying nonparametric covariate functions may introduce bias in parameter estimation. This method development has been motivated by and applied to the lipid-lowering trial component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. [ABSTRACT FROM AUTHOR]

Background: Bayesian and adaptive clinical trial designs offer the potential for more efficient processes that result in lower sample sizes and shorter trial durations than traditional designs.Objective: To explore the use and potential benefits of Bayesian adaptive clinical trial designs in comparative effectiveness research.Design: Virtual execution of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) as if it had been done according to a Bayesian adaptive trial design.Setting: Comparative effectiveness trial of antihypertensive medications.Patients: Patient data sampled from the more than 42 000 patients enrolled in ALLHAT with publicly available data.Measurements: Number of patients randomly assigned between groups, trial duration, observed numbers of events, and overall trial results and conclusions.Results: The Bayesian adaptive approach and original design yielded similar overall trial conclusions. The Bayesian adaptive trial randomly assigned more patients to the better-performing group and would probably have ended slightly earlier.Limitations: This virtual trial execution required limited resampling of ALLHAT patients for inclusion in RE-ADAPT (REsearch in ADAptive methods for Pragmatic Trials). Involvement of a data monitoring committee and other trial logistics were not considered.Conclusion: In a comparative effectiveness research trial, Bayesian adaptive trial designs are a feasible approach and potentially generate earlier results and allocate more patients to better-performing groups.Primary Funding Source: National Heart, Lung, and Blood Institute. [ABSTRACT FROM AUTHOR]

Background: Patient characteristics are associated with adherence, which has implications for planning clinical research or designing payment systems that reward superior outcomes. It is unclear to what extent clinician efforts to improve adherence can attenuate these associations.Methods: To identify factors predicting visit and medication adherence in settings designed to optimize adherence, we did a retrospective analysis of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants at 632 sites in North America, Puerto Rico, and the U.S. Virgin Islands for random assignment to antihypertensive treatment with amlodipine, chlorthalidone, or lisinopril. Site investigators reported clinic characteristics at the time they applied to participate in the study and research coordinators used standardized methods to measure patient characteristics. We defined adequate visit adherence as attending at least 80 % of scheduled visits; adequate medication adherence was defined as taking 80 % or more of the randomly assigned medication at all study visits.Results: The 31,250 ALLHAT participants eligible for the visit adherence analysis attended 78.5 % of scheduled study visits; 68.9 % attended more than 80 % of scheduled visits. Clinic setting was predictive of both forms of adherence; adherence was worst at private clinics; clinics that enrolled more study participants had superior adherence. Adjusting for clinic characteristics and clinical factors, women, younger participants, Blacks and smokers were less likely to have adequate visit adherence. Among the 28,967 participants eligible for the medication adherence analysis, 21,261 (73.4 %) reported adequate medication adherence. In adjusted analyses, younger and less educated participants, Blacks, and smokers were less likely to report adequate adherence.Conclusions: Participant demographics were associated with adherence despite strenuous efforts to optimize adherence. Our results could inform decisions by researchers planning trials and policymakers designing payment systems.Trial Registration: NCT00000542 . Registered 27 October 1999. [ABSTRACT FROM AUTHOR]

Background: Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes.Methods and Findings: Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints.Conclusions: In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment.Review Registration: PROSPERO CRD42014014404. [ABSTRACT FROM AUTHOR]

Background: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD. [ABSTRACT FROM AUTHOR]

The article presents a research study that compares the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. The methods employed are explained involving the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with mortality and secondary end points. Results are discussed with appropriate analysis.

The article presents a study on the impact of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial/Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (ALLHAT/JNC7) Dissemination Project on thiazide-type diuretic use. The study used IMS Health databases to compare prescribing practices of physicians before the project started in 2004 and after its completion in 2007. The study found that the project was associated with a small effect on the use of thiazide-type diuretic.

Objective: To evaluate the cost-effectiveness of first-line treatments for hypertension.Background: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint, so differences in costs may be critical for optimizing decision-making.Methods: Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty.Results: Over a patient's lifetime, chlorthalidone was always least expensive (mean $4,802 less than amlodipine, $3,700 less than lisinopril). Amlodipine provided more life-years (LYs) than chlorthalidone in 84% of bootstrap samples (mean 37 days) at an incremental cost-effectiveness ratio of $48,400 per LY gained. Lisinopril provided fewer LYs than chlorthalidone in 55% of bootstrap samples (mean 7-day loss) despite a higher cost. At a threshold of $50,000 per LY gained, amlodipine was preferred in 50%, chlorthalidone in 40%, and lisinopril in 10% of bootstrap samples, but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen. Incorporating quality of life did not appreciably alter the results. Overall, no reasonable combination of assumptions led to 1 treatment being preferred in over 90% of bootstrap samples.Conclusions: Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine, but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative. A randomized trial with power to exclude "clinically important" differences in survival will often have inadequate power to determine the most cost-effective treatment. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion-deletion (ID) polymorphism interacts with pravastatin to modify the risk of coronary heart disease (CHD) and other cardiovascular end points in a large clinical trial.Methods: GenHAT is an ancillary study of the ALLHAT. The ACE ID genotyped population in the lipid-lowering arm of ALLHAT included 9467 participants randomly assigned to pravastatin (n = 4741) or to usual care (n = 4726). The efficacy of pravastatin in reducing the risk of primary outcome (all-cause mortality) and secondary outcomes (fatal CHD and nonfatal myocardial infarction, cardiovascular disease [CVD] mortality, CHD, stroke, other CVD, non-CVD mortality, stroke, and heart failure) was compared between the genotype strata (dominant model ID + II vs DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional hazards model.Results: The relative risk of fatal CHD and nonfatal myocardial infarction among subjects randomized to pravastatin compared with subjects randomized to usual care was similar in subjects with the II genotype (hazard ratio [HR] 0.84, 95% CI 0.59-1.18), the ID genotype (HR 0.84, 95% CI 0.68-1.03), and the DD genotype (HR 0.99, 95% CI 0.77-1.27).Conclusions: We found no evidence that the ACE ID genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Background: ALLHAT, a randomized, double-blind, active-controlled hypertension treatment trial in 42418 patients, reported that a thiazide-type diuretic (chlorthalidone) was superior to a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an α1-blocker (doxazosin) in preventing the new onset of heart failure (HF). However, questions have been raised regarding the validity of the HF diagnosis. Methods: The ALLHAT HF Validation Study was designed to validate and elucidate the significance of HF events in ALLHAT. Records for 2778 HF hospitalizations in 1935 patients were centrally reviewed using several prespecified algorithms (based on ALLHAT and Framingham criteria) and reviewers'' global clinical judgment. Percent agreement with diagnoses assigned by ALLHAT site physicians, relative risks across randomized comparisons, incidence rates, and mortality after HF hospitalization were evaluated for first events validated by each of the criteria sets. Results: Percent agreements with site physician diagnoses were 71%, 80%, and 84% for ALLHAT, Framingham, and reviewers'' judgment, respectively. Using these 3 criteria, relative risks (95% CI) for new-onset HF compared with chlorthalidone were, respectively, 1.46 (1.27-1.68), 1.42 (1.25-1.62), and 1.45 (1.28-1.64) for amlodipine; 1.18 (1.02-1.28), 1.13 (0.99-1.30), and 1.15 (1.01-1.32) for lisinopril; and 1.79 (1.51-2.11), 1.71 (1.46-2.00), and 1.80 (1.55-2.10) for doxazosin. Conclusions: An independent review of source documentation showed a high degree of agreement with the HF diagnoses assigned by site physicians and confirmed the higher risk of HF associated with first-step therapy using amlodipine, lisinopril, or doxazosin compared with chlorthalidone. Thiazide-type diuretics should be the preferred first-step therapy for prevention of HF in high-risk patients with hypertension. [Copyright &y& Elsevier]

The findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have generated worldwide reaction from clinicians and researchers, including a recent commentary in this journal. Such response was expected for a trial of ALLHAT's size and scope, especially since its results challenged some widely held beliefs. This paper reviews key aspects of the ALLHAT design, analyses, findings, and conclusions to provide a perspective on the commentary about the trial's results and implications for clinical practice. Several of the most frequent comments regarding the study's results are addressed, particularly with respect to heart failure and diabetes outcomes. Responses to these comments reinforce the investigators' original conclusion that thiazide-type diuretics should remain the preferred first-step drug class for treating hypertension and should generally be a part of any multidrug regimen. [ABSTRACT FROM AUTHOR]

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance. The authors studied the effects of these two classes of hypertension medications (doxazosin, an a blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in adults aged > 55 years with hypertension and glucose disorders who were participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly diagnosed glucose disorder [fasting glucose =110 mg/dL ]). There was no difference in either group between the chlorthalidone-and doxazosin-based treatments with regard to fatal or non-fatal myocardial infarction or all-cause mortality. There was, however, a difference for combined cardiovascular disease (myocardial infarction, revascularization procedures, angina, stroke, heart failure, and peripheral arterial disease) in favor of the diuretic. This difference was due primarily to an increased heart failure risk in those treated with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56-2.19)in the known diabetes mellitus group and a relative risk of 1.63 (95% confidence interval, 1.05-2.55) in those with a newly diagnosed glucose disorder despite lower glucose levels on follow-up in those treated with a blockers. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders incurs the same risk of coronary heart disease as treatment with chlorthalidone; however, treatment with doxazosin increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels. [ABSTRACT FROM AUTHOR]

Purpose: To determine the prevalence and correlates of symptomatic peripheral atherosclerosis in individuals with a history of myocardial infarction (MI) and cholesterol levels lower than 240 mg/dL. Materials and Methods: A cross-sectional analysis was conducted at baseline of 4159 participants in the Cholesterol and Recurrent Events (CARE) Study. Symptomatic diffuse atherosclerosis was defined as a history of MI plus lower extremity or cerebrovascular atherosclerosis or claudication by Rose questionnaire. Results: The prevalence of symptomatic diffuse atherosclerosis was 12.9%; 353 participants (8.5%) had lower extremity disease and 219 (5.3%) had cerebrovascular disease. After controlling for other variables, diffuse atherosclerosis was associated with age (Odds Ratio [OR] = 1.44 per ten-year increase), systolic blood pressure (OR= 1.13 per 10 mm Hg increase), a history of multiple myocardial infarctions (OR= 1.76), diabetes (OR= 1.76), hypertension (OR= 1.38), reduced exercise performance (OR= 1.55), current smoking status (OR= 2.87), and lower alcohol intake (OR= 0.97 per drink per week). There was no association with race, gender, or lipid levels. Conclusions: The presence of clinically evident diffuse atherosclerosis is common and is associated with several modifiable risk factors. Early identification of these individuals could affect treatment and clinical outcomes. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) findings revisited in the context of subsequent analysis, other trials and meta-analyses," by J. T. Wright Jr. and colleagues that was published in the 2009 issue is presented.

A response by Mahboob Rahman to a letter to the editor about his article "Renal Outcomes in High-Risk Hypertensive Patients Treated with an Angiotensin-Converting Enzyme Inhibitor or a Calcium Channel Blocker vs. a Diuretic: A Report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" in the 2005 issue is presented.

Presents the reply to those who submitted letters to the editor concerning the study conducted on antihypertensive and lipid-lowering treatment to prevent heart attacks.

The goal of this study was to determine if restenosis is increased in mild and moderate chronic kidney disease (CKD) patients after percutaneous coronary intervention (PCI).Mortality is increased in CKD after PCI. Restenosis may contribute to increased late mortality.We analyzed 11,187 patients with a creatinine <1.8 mg/dl from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial, grouped by estimated creatinine clearance (CrCl) (<60, 60 to 89, >89 ml/min). The Cox proportional hazards models investigated the association between CrCl group and death, myocardial infarction, and target vessel revascularization (TVR). Generalized estimating equation regression models determined the association between CrCl group and lesion-specific restenosis.At 30 days, there was no difference in myocardial infarction, death, or TVR between the CrCl groups. At nine months, mortality was higher in the lowest CrCl group (2.2%, 1.2%, 0.8%; p < 0.001), which was no longer significant after adjusting for confounding variables. Myocardial infarction and TVR were not different between the groups. In patients undergoing protocol follow-up angiography, restenosis (≥50%) was not increased with CKD (32%, 32%, 37%; p = 0.02).Mortality nine months after PCI is mildly increased in mild or moderate CKD patients. However, restenosis is not and does not account for the increased mortality. [Copyright &y& Elsevier]

Background: In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. Methods: In a double-blind trial lasting five years, we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. Results: The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P = 0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P = 0.01). The frequency of stroke was reduced by 31 percent (P = 0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. Conclusions: These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels. (N Engl J Med 1996;335:1001-9.) [ABSTRACT FROM AUTHOR]