Search

BACKGROUND: Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment. [ABSTRACT FROM AUTHOR]

Hypertension treatment has been implicated in falls, syncope, and orthostatic hypotension (OH), common events among older adults. Whether the choice of antihypertensive agent influences the risk of falls, syncope, and OH in older adults is unknown. ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) was a randomized clinical trial that compared the effects of hypertension first-step therapy on fatal coronary heart disease or nonfatal myocardial infarction (1994-2002). In a subpopulation of ALLHAT participants, age 65 years and older, we determined the relative risk of falls, syncope, OH, or a composite based on Centers for Medicare and Medicaid Services and Veterans Affairs claims, using Cox regression. We also determined the adjusted association of self-reported atenolol use (ascertained at the 1-month visit for indications other than hypertension) on outcomes in Cox models adjusted for age, sex, and race. Among 23 964 participants (mean age 69.8±6.8 years, 45% women, 31% non-Hispanic black) followed for a mean of 4.9 years, we identified 267 falls, 755 syncopes, 249 OH, and 1157 composite claims. There were no significant differences in the cumulative incidences of events across randomized drug assignments. However, amlodipine increased risk of falls during the first year of follow-up compared with chlorthalidone (hazard ratio [95% CI]: 2.24 [1.06-4.74]; P=0.03) or lisinopril (hazard ratio [95% CI]: 2.61 [1.03-6.72]; P=0.04). Atenolol use (N=928) was not associated with any of the 3 individual or composite claims. In older adults, the choice of antihypertensive agent had no effect on risk of fall, syncope, or OH long-term. However, amlodipine increased risk of falls within 1 year of initiation. These short-term findings require confirmation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In the United States, up to 450,000 people per year die suddenly; an average of 1 sudden death every 70s. Strategies for preventing sudden cardiac death are urgently needed. Systemic arterial hypertension is a major risk factor for sudden cardiac death and the increasing burden of hypertension is a worldwide problem. The lifetime risk of sudden cardiac death at 30years of age is higher by 30% in individuals with hypertension. Each 20/10mmHg increase in systolic/diastolic blood pressure, is associated with a 20% additional increase in sudden cardiac death risk. Theoretically, antihypertensive treatment should be an effective strategy for sudden cardiac death prevention. However, a recent meta-analysis of 15 randomized controlled trials showed that antihypertensive treatment does not reduce the incidence of sudden cardiac death. This manuscript reviews ECG predictors of sudden cardiac death and the importance of risk stratification for appropriate management of hypertension. [ABSTRACT FROM AUTHOR]

Randomized trials of hypertension have seldom examined heterogeneity in response to treatments over time and the implications for cardiovascular outcomes. Understanding this heterogeneity, however, is a necessary step toward personalizing antihypertensive therapy. We applied trajectory-based modeling to data on 39 763 study participants of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to identify distinct patterns of systolic blood pressure (SBP) response to randomized medications during the first 6 months of the trial. Two trajectory patterns were identified: immediate responders (85.5%), on average, had a decreasing SBP, whereas nonimmediate responders (14.5%), on average, had an initially increasing SBP followed by a decrease. Compared with those randomized to chlorthalidone, participants randomized to amlodipine (odds ratio, 1.20; 95% confidence interval [CI], 1.10-1.31), lisinopril (odds ratio, 1.88; 95% CI, 1.73-2.03), and doxazosin (odds ratio, 1.65; 95% CI, 1.52-1.78) had higher adjusted odds ratios associated with being a nonimmediate responder (versus immediate responder). After multivariable adjustment, nonimmediate responders had a higher hazard ratio of stroke (hazard ratio, 1.49; 95% CI, 1.21-1.84), combined cardiovascular disease (hazard ratio, 1.21; 95% CI, 1.11-1.31), and heart failure (hazard ratio, 1.48; 95% CI, 1.24-1.78) during follow-up between 6 months and 2 years. The SBP response trajectories provided superior discrimination for predicting downstream adverse cardiovascular events than classification based on difference in SBP between the first 2 measurements, SBP at 6 months, and average SBP during the first 6 months. Our findings demonstrate heterogeneity in response to antihypertensive therapies and show that chlorthalidone is associated with more favorable initial response than the other medications. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including obesity, hypertension treatment and surveillance and measurement of blood pressure.

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double–blind, practice–based, active–control, comparative effectiveness trial in 33,357 high–risk hypertensive participants. ALLHAT compared cardiovascular disease outcomes in participants initially treated with an angiotensin–converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), or a thiazide–type diuretic (chlorthalidone). We report stroke outcomes in 1517 participants in–trial and 1596 additional participants during post–trial passive surveillance, for a total follow–up of 8–13 years. Stroke rates were higher with lisinopril (6-year rate/100 = 6.4) than with chlorthalidone (5.8) or amlodipine (5.5) in–trial but not including post–trial (10-year rates/100 = 13.2 [chlorthalidone], 13.1[amlodipine], and 13.7 [lisinopril]). In–trial differences were driven by race (race-by-lisinopril/chlorthalidone interaction P = .005, race-by-amlodipine/lisinopril interaction P = .012) and gender (gender-by-lisinopril/amlodipine interaction P = .041), separately. No treatment differences overall, or by race or gender, were detected over the 10-year period. No differences appeared among treatment groups in adjusted risk of all–cause mortality including post–trial for participants with nonfatal in-trial strokes. Among Blacks and women, lisinopril was less effective in preventing stroke in–trial than either chlorthalidone or amlodipine, even after adjusting for differences in systolic blood pressure. These differences abated by the end of the post–trial period. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 mmHg) 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. [ABSTRACT FROM AUTHOR]

The article focuses on study on association of rapid decreases in blood pressure from antihypertensive treatment ((HTDT), with increased cancer mortality in the Systolic Hypertension in the Elderly Program (SHEP). It mentions that angiogenesis may be a factor in the relationship between cancer and HTDT. It adds that the study was approved by the Robert Wood Johnson Medical School and the University of Texas Health Science Center Institutional Review Boards.

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. [ABSTRACT FROM AUTHOR]

The article examines whether lisinopril, an angiotensin-converting enzyme inhibitor, or amlodipine,a calcium channel blocker, is superior to a chlorthalidone, a diuretic, in reducing cardiovascular disease incidence in sex subgroups. In-trial rates of heart failure (HF), stroke, and combined cardiovascular disease were significantly greater for lisinopril compared with chlorthalidone, and rates of HF were substantially higher for amlodipine compared with chlorthalidone in both men and women.

The article examines clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in antihypertensive and lipid-lowering treatment to prevent heart attack trial. It is indicated that diuretics, an antihypertensive mainstay produces hypokalemia more frequently than other antihypertensive agents. Study showed that concerns about potassium levels for most patients should not influence clinician's decision of initiating low-moderate doses of thiazide diuretics.

Background: Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use.Methods and Results: A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction).Conclusions: The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. [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.

Background: Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy in the progression of kidney disease is unclear.Study Design: Prospective randomized clinical trial, post hoc analyses.Setting& Participants: 10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) stratified by baseline estimated glomerular filtration rate (eGFR): less than 60, 60 to 89, and 90 or greater mL/min/1.73 m(2). Mean follow-up was 4.8 years.Intervention: Randomized; pravastatin, 40 mg/d, or usual care.Outcomes& Measurements: Total, high-density lipoprotein, and low-density lipoprotein cholesterol; end-stage renal disease (ESRD), eGFR.Results: Through year 6, total cholesterol levels decreased in the pravastatin (-20.7%) and usual-care groups (-11.2%). No significant differences were seen between groups for rates of ESRD (1.36 v 1.45/100 patient-years; P = 0.9), composite end points of ESRD and 50% or 25% decrease in eGFR, or rate of change in eGFR. Findings were consistent across eGFR strata. In patients with eGFR of 90 mL/min/1.73 m(2) or greater, the pravastatin arm tended to have a higher eGFR.Limitations: Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual-care group with small cholesterol differential between groups.Conclusions: In hypertensive patients with moderate dyslipidemia and decreased eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on the degree of the cholesterol level decrease achieved. [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]