Paula T. Einhorn

Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [≥50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF. Methods and Results— HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthalidone reduced the risk of HFPEF compared with amlodipine, lisinopril, or doxazosin; the hazard ratios were 0.69 (95% confidence interval [CI], 0.53 to 0.91; P=0.009), 0.74 (95% CI, 0.56 to 0.97; P=0.032), and 0.53 (95% CI, 0.38 to 0.73; P<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; the hazard ratios were 0.74 (95% CI, 0.59 to 0.94; P=0.013) and 0.61 (95% CI, 0.47 to 0.79; P<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF (hazard ratio, 1.07; 95% CI, 0.82 to 1.40; P=0.596). After HF onset, death occurred in 29.2% of participants (chlorthalidone/amlodipine/lisinopril) with new-onset HFPEF versus 41.9% in those with HFREF (P<0.001; median follow-up, 1.74 years); and in the chlorthalidone/doxazosin comparison that was terminated early, 20.0% of HFPEF and 26.0% of HFREF patients died (P=0.185; median follow-up, 1.55 years). Conclusions— In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.

Atrial Fibrillation at Baseline and During Follow-Up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial)

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).

ALLHAT Findings Revisited in the Context of Subsequent Analyses, Other Trials, and Meta-analyses

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.

Clinical Outcomes by Race in Hypertensive Patients With and Without the Metabolic Syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

BACKGROUND Antihypertensive drugs with favorable metabolic effects are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an alpha-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril). METHODS A subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind hypertension treatment trial of 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women. RESULTS Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval, 1.18-1.90), 1.49 (1.17-1.90), and 1.88 (1.42-2.47) in black participants and 1.25 (1.06-1.47), 1.20 (1.01-1.41), and 1.82 (1.51-2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RRs, 1.24 [1.09-1.40] and 1.10 [1.02-1.19], respectively) and doxazosin-chlorthalidone comparisons (RRs, 1.37 [1.19-1.58] and 1.18 [1.08-1.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07-1.76] for the lisinopril-chlorthalidone comparison, and RR, 1.49 [1.09-2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13-2.55]) with lisinopril compared with chlorthalidone. CONCLUSIONS The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.

Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study

Context It is not clear whether variability in a patients outpatient blood pressure (BP) measurements has prognostic importance. Contribution Patients with greater visit-to-visit variability in BP readings had an increased risk for cardiovascular events and mortality, which was independent of their overall degree of BP control. Implication Further studies are warranted to assess whether reducing visit-to-visit BP variations will alter the risk for adverse cardiovascular outcomes. The prognostic value of blood pressure (BP) is mainly based on measurements obtained in a clinical setting, typically from a few visits (1). Until recently, variability of BP across outpatient visits was dismissed as random fluctuation around a patients true underlying BP (2, 3). Although some studies have reported associations between higher visit-to-visit variability (VVV) of systolic BP (SBP) and an increased risk for stroke and coronary heart disease (CHD), other analyses have failed to show such associations (410). The method applied in estimating VVV of BP varied widely across previous studies. In addition, studies have used as few as 3 visits and as many as 56 visits to estimate the VVV of BP, and the time between visits has ranged from 2 days to as long as 4 years (5, 11, 12). These factors not only influence VVV of BP but could also affect the strength of its association with cardiovascular disease (CVD) outcomes (4, 13). To address the inconsistent findings from previous studies, we did a secondary data analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to examine whether VVV of BP is associated with CVD and mortality events. ALLHAT provides the opportunity to evaluate the association between VVV of BP and major clinical outcomes in a large and diverse population with hypertension in which visits were conducted at set time intervals, BP was measured by following a standardized protocol, and outcomes were evaluated over several years of follow-up. Methods Study Design We did a cohort study as a secondary analysis using data from ALLHAT. Figure 1 shows the timeline for assessment of VVV of BP and outcome events within ALLHAT. The primary exposure of interest, VVV of SBP, was ascertained at the 7 study visits conducted between 6 and 28 months after randomization. We studied 4 outcomes: fatal CHD or nonfatal myocardial infarction (MI), all-cause mortality, stroke, and heart failure. Participants were followed from their 28-month visit until the occurrence of an outcome event or the end of active ALLHAT follow-up (October 2001 to March 2002). Participants who had an event before their 28-month visit were excluded from all analyses. Figure 1. Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT. ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; VVV = visit-to-visit variability. * Participants were followed for a mean of 2.7 to 2.9 y (maximum, 5.7 y) depending on the outcome after assessment of VVV of BP. ALLHAT was a multicenter, double-blind, randomized clinical trial sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. A complete description of the rationale and design of ALLHAT has been previously published (14). In brief, ALLHAT was designed to determine whether treatment initiated with a calcium-channel blocker (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or -blocker (doxazosin)each compared with treatment initiated with a diuretic (chlorthalidone)would lower major cardiovascular outcomes. The primary end point was incidence of fatal CHD or nonfatal MI. A total of 42418 hypertensive adults aged 55 years or older with 1 or more additional risk factor for CVD were enrolled at 623 clinical sites across the United States, Canada, Puerto Rico, and the U.S. Virgin Islands between February 1994 and January 1998. The doxazosin treatment group was discontinued in 2000 because of the small chance of finding a benefit on CHD outcomes and an increased risk for CVD than in the chlorthalidone group (15). The main results comparing participants randomly assigned to chlorthalidone, amlodipine, or lisinopril were published in December 2002 (16). The trial was approved by local institutional review boards, and all participants provided written informed consent. Our current analysis was approved by the Institutional Review Board at the University of Alabama at Birmingham. Study Visits, BP Measurements, and Calculation of VVV of BP To calculate intraindividual VVV of SBP and diastolic BP (DBP), we used data from 7 follow-up visits that occurred 6, 9, 12, 16, 20, 24, and 28 months after randomization. We chose to begin the assessment period at the 6-month follow-up visit to avoid confounding by the initial reduction in BP that occurred between randomization and this visit (SBP, 6 to 10 mm Hg; DBP, approximately 5 mm Hg) due to early medication titration. To increase the precision of estimates, we calculated VVV of BP for participants with BP measurements at 5, 6, or 7 visits conducted between month 6 and 28 after randomization. The VVV of BP was imputed for participants who attended fewer than 5 visits between months 6 and 28. To maximize follow-up time, we did not extend the assessment past the 28-month follow-up visit. At each follow-up visit, BP was measured twice by a trained observer by means of a standardized technique (17). Using the average BP at each visit, we defined VVV of BP by the intraindividual SD across visits. Average real variability (ARV) and SD independent of the mean (SDIM) were calculated as alternative metrics for VVV of BP (Appendix Figure) (18). The VVV of DBP was also calculated in secondary analyses. Appendix Figure. Formulas used to calculate VVV of BP metrics. ARV = average real variability; BP = blood pressure; SDIM = SD independent of the mean; VVV = visit-to-visit variability. Outcome Ascertainment We studied 4 outcomes, including fatal CHD or nonfatal MI, all-cause mortality, stroke, and heart failure. The event ascertainment process is detailed elsewhere (14, 16). Participants were followed from the end of the assessment period to the date of each outcome, their date of death, or the end of active ALLHAT follow-up (1 October 2001 through 31 March 2002). Covariate Information Covariates used for adjustment were selected a priori on the basis of their potential role as confounders. Baseline (before randomization) variables included age, sex, race/ethnicity, education, current cigarette smoking status, body mass index, use of aspirin, high-density lipoprotein cholesterol level less than 0.91 mmol/L (<35 mg/dL) (at 2 occasions in the 5 years before ALLHAT enrollment), total cholesterol level, estimated glomerular filtration rate (eGFR), diabetes, history of MI or stroke, documentation of other atherosclerotic CVD, history of revascularization, atrial fibrillation by electrocardiography, left ventricular hypertrophy (LVH), the presence of ST depression and T-wave inversion, and use of antihypertensive medication before ALLHAT randomization. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (19). Data collected at visits conducted 6 to 28 months after randomization were used to calculate mean SBP and DBP; pulse pressure; the use of antihypertensive medications beyond the randomization drug; changes in antihypertensive medication regimen (adding, stopping, or changing antihypertensive medications); use of statins; and low adherence, which is defined as a report of a participant receiving less than 80% of the randomization drug at any visit between months 6 and 28. Participants who reported taking 80% or more of their randomization drug at every visit between months 6 and 28 were considered to have high adherence. Statistical Analysis Because of limited follow-up available after the assessment period for participants randomly assigned to receive doxazosin, we restricted our analyses to the 33357 ALLHAT participants randomly assigned to receive chlorthalidone, amlodipine, or lisinopril. We excluded 7543 participants who had CVD events or died before the 28-month visit. We imputed VVV of BP for participants with fewer than 5 visits and BP measurements between months 6 and 28 of follow-up. In addition, missing data for covariates were imputed (Appendix Table 1). Imputation was performed with 10 data sets using chained equations. Appendix Table 1. Percentage of Missing Data for Participants Included in the Current Analyses Characteristics of participants included in the current analyses were calculated after participants were stratified into a quintile of SD of SBP. The KaplanMeier method was used to calculate the cumulative incidence of each outcome by quintile of SD of SBP. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HRs) for each outcome associated with a quintile of SD of SBP, with the lowest quintile serving as the reference. Four nested models were constructed. Model 1 included adjustment for age, race/ethnicity, sex, region of residence, and antihypertensive randomization assignment. Model 2 includes the variables in model 1 and additional adjustment for education, smoking status, body mass index, use of aspirin, low high-density lipoprotein cholesterol level, total cholesterol level, eGFR, diabetes, history of MI or stroke, history of other atherosclerotic CVD, history of coronary revascularization, atrial fibrillation by electrocardiography, major ST depression or T-wave inversion, LVH, use of antihypertensive medications before ALLHAT randomization, and statin use during the assessment period (months 6 through 28 of follow-up). Model 3 includes the variables in model 2 and additional adjustment for mean pulse pressure, medic

Thiazide-Induced Dysglycemia: Call for Research From a Working Group From the National Heart, Lung, and Blood Institute

There are >70-million hypertensive individuals in the United States, and >45-million persons take antihypertensive medications.1,2 Despite the results of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), other trials, and the recommendations in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, well under 50% of these regimens include a thiazide-type diuretic.2,3 In the Department of Veterans’ Affairs, which participated in several of the studies supporting the use of thiazide diuretics, ≈35% of hypertensive patients on pharmacotherapy had a thiazide diuretic included in their hypertension treatment regimens in 2003.4 In private patient encounters, thiazide diuretic use rose from 19% of all of the antihypertensive patient visits in 2002 to 26% in 2004.5 The recommendations for preferred use of thiazide-type diuretics are based on >4 decades of clinical trials, including active-controlled trials, where diuretics were tested against other drugs for their efficacy in preventing hard clinical outcomes, such as myocardial infarction, death, stroke, heart failure, and renal failure. ALLHAT, a randomized, double-blind, active-controlled antihypertensive treatment trial in 42 418 patients assigned to a thiazide-type diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel-blocker, (average follow-up: 4.9 years), or the doxazosin/chlorthalidone comparison (terminated early, average follow-up: 3.2 years) showed that the diuretic was at least as beneficial as the comparator drugs in lowering blood pressure (BP) and preventing cardiovascular (CV) and renal outcomes and was superior for preventing heart failure (versus each comparator arm), combined CV events (versus α-blocker and ACE-inhibitor arms), and stroke (versus ACE inhibitor [black subjects only] and α-blocker).6 The ongoing success of thiazide-type diuretics in large, adequately powered hypertension outcome trials and new guidelines have created the basis for increased diuretic use.2,6 However, clinical trials have also frequently shown potentially …

Blood Pressure Control by Drug Group in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow‐up, 4.9 years) by randomized groups: 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) in a randomized double‐blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group—a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Validation of heart failure events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants assigned to doxazosin and chlorthalidone

BackgroundThe Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17–1.33; P < .001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79–2.32; P < .001). Questions about heart failure diagnostic criteria led to steps to validate these events further.Methods and ResultsBaseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P < .05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67–1.38; P = 0.83).ConclusionResults of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.

Long-Term Effects of Incident Diabetes Mellitus on Cardiovascular Outcomes in People Treated for Hypertension: The ALLHAT Diabetes Extension Study

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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Clinical Significance of Incident Hypokalemia and Hyperkalemia in Treated Hypertensive Patients in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

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 clinicians decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5–25.0 mg of C).