Gail T. Louis

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

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.

Progression of Kidney Disease in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin Versus Usual Care: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

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.

Association of 3 different antihypertensive medications with hip and pelvic fracture risk in older adults secondary analysis of a randomized clinical trial

Importance On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. Objective To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Design, Setting, and Participants Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. Main Outcomes and Measures Hip and pelvic fracture hospitalizations. Results A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. Conclusions and Relevance These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications. Trial Registration clinicaltrials.gov Identifier: NCT00000542

EXPERIMENTAL APPROACHES TO DETERMINING THE CHOICE OF FIRST-STEP THERAPY FOR PATIENTS WITH HYPERTENSION

Detection, treatment and control of hypertension is one of the best proven approaches to prevention of cardiovascular disease. Antihypertensive treatment trials have convincingly demonstrated that diuretics and beta-blockers reduce the risk of stroke and coronary heart disease. Corresponding information is not yet available for newer classes of antihypertensive drug therapy such as calcium channel blockers, angiotensin converting enzyme inhibitors and alpha 1 receptor blockers. Several experimental studies are now addressing this question. The largest such trial (n = 40,000) is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This manuscript describes two studies (TOMHS and the VA study on antihypertensive agents) that compared several classes of antihypertensive drugs with regard to blood pressure outcomes and ALLHAT, which is comparing the effect of four first-step approaches to antihypertensive therapy on combined incidence of fatal coronary heart disease and non-fatal myocardial infarction.

Pravastatin and cardiovascular outcomes stratified by baseline eGFR in the lipid-lowering component of ALLHAT

Background/Aims: The role of statins in preventing cardiovascular outcomes in patients with chronic kidney disease (CKD) is unclear. This paper compares cardiovascular outcomes with pravastatin vs. usual care, stratified by baseline estimated glomerular filtration rate (eGFR). Methods: Post-hoc analyses of a prospective randomized open-label clinical trial; 10,151 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (lipid-lowering component) were randomized to pravastatin 40 mg/day or usual care. Mean follow-up was 4.8 years. Results: Through Year 6, total cholesterol declined in pravastatin (–20.7%) and usual-care groups (–11.2%). Use of statin therapy in the pravastatin group was 89.8% (Year 2) and 87.0% (Year 6). Usual-care group statin use increased from 8.2% (Year 2) to 23.5% (Year 6). By primary intention-to-treat analyses, no significant differences were seen between groups for coronary heart disease (CHD), total mortality or combined cardiovascular disease; findings were consistent across eGFR strata. In exploratory “as-treated” analyses (patients actually using pravastatin vs. not using), pravastatin therapy was associated with lower mortality (HR = 0.76 (0.68 – 0.85), p < 0.001) and lower CHD (HR = 0.84 (0.73 – 0.97), p = 0.01), but not combined cardiovascular disease (HR = 0.95 (0.88 – 1.04), p = 0.30). Total cholesterol reduction of 10 mg/dl from baseline to Year 2 was associated with 5% lower CHD risk. Conclusions: In hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing total mortality or CHD independent of baseline eGFR level. However, exploratory “as-treated” analyses suggest improved mortality and CHD risk in participants using pravastatin, and decreased CHD events associated with achieved reduction in total cholesterol. Potential benefit from statin therapy may depend on degree of reduction achieved in total and LDL-cholesterol and adherence to therapy.