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.     

Association Between Antihypertensive Medication Adherence and Visit‐to‐Visit Variability of Blood Pressure

It has been hypothesized that high visit‐to‐visit variability (VVV) of systolic blood pressure (SBP) may be the result of poor antihypertensive medication adherence. The authors studied this association using data from 1391 individuals taking antihypertensive medication selected from a large managed care organization. The 8‐item Morisky Medication Adherence Scale, administered during 3 annual surveys, captured self‐report adherence, with scores <6, 6 to <8, and 8 representing low, medium. and high adherence, respectively. The mean (standard deviation [SD]) for SD of SBP across study visits was 12.9 (4.4), 13.5 (4.8), and 14.1 (4.5) mm Hg in participants with high, medium, and low self‐reported adherence, respectively. After multivariable adjustment and compared with those with high self‐report adherence, SD of SBP was 0.60 (95% confidence interval, 0.13–1.07) and 1.08 (95% confidence interval, 0.29–1.87) mm Hg higher among participants with medium and low self‐report adherence, respectively. Results were consistent when pharmacy fill was used to define adherence. These data suggest that low antihypertensive medication adherence explains only a small proportion of VVV of SBP. J Clin Hypertens (Greenwich). 2012; 00:00–00. ©2012 Wiley Periodicals, Inc.     

Cost-effectiveness of Chlorthalidone,Amlodipine, and Lisinopril as First-step Treatment for Patients with Hypertension: An Analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

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. American Society of Health-System Pharmacists (December 2003), American College of Cardiology (March 2006), Society for Clinical Trials (May 2007). ClinicalTrials.gov Identifier: NCT00000542 ()     

Blood Pressure Measurement Device,Number and Timing of Visits,and Intra‐Individual Visit‐to‐Visit Variability of Blood Pressure

J Clin Hypertens (Greenwich). 2012;14:744–750. ©2012 Wiley Periodicals, Inc. Visit‐to‐visit variability (VVV) of blood pressure is associated with cardiovascular disease. The authors examined the effects of visit number and timing and automated or manual measurement device on VVV in the placebo arm of the Trial of Preventing Hypertension (TROPHY) (N=225) and simulations. VVV was assessed using intra‐individual standard deviation (SD), range, maximum, coefficient of variation, successive variation, and average real variability of systolic blood pressure. VVV increased with number of visits used to calculate it in the TROPHY population (P for trend <.05 for all metrics) and simulations. Using consecutive visits in TROPHY, average SD was 5.6 mm Hg from 3 visits, 6.8 mm Hg from 7 visits, and 7.7 mm Hg from 18 visits. When 7 visits were spread out across 4 years, the average SD was higher (7.5 mm Hg) than when visits were consecutive over 18 months (P<.001). SD was higher using a single blood pressure measurement per visit (compared with the mean of 3 measurements per visit P<.001) and with automated vs manual devices (P<.001). In summary, number and timing of visits and device used to measure blood pressure influence VVV and need to be considered when designing, interpreting, and comparing studies.     

Visit‐to‐Visit Blood Pressure Variability and Cardiovascular Death in the Systolic Hypertension in the Elderly Program

Most studies of an association of visit‐to‐visit variability of blood pressure with increased risk of future adverse cardiovascular events are of short duration and rarely include a placebo group. Using data from the double‐blind, placebo‐controlled Systolic Hypertension in the Elderly Program, the authors examined mortality from cardiovascular causes up to 17 years of follow‐up using the National Death Index. Visit‐to‐visit blood pressure variability was associated with cardiovascular death after adjustment for sex, age, serum creatinine, diabetes, body mass index, smoking status, left ventricular failure, and high‐density lipoprotein cholesterol. The relationship was significantly stronger in the active treatment group compared with the placebo group. Although this could be the result of an effect of the medications used unrelated to visit‐to‐visit variability, the data are compatible with the hypothesis that inconsistent adherence leading to missing active medication doses may be an additional explanation for the relationship of visit‐to‐visit variability with cardiovascular death.     

Visit‐to‐Visit Variability of Blood Pressure and Renal Function Decline in Patients With Diabetic Chronic Kidney Disease

The authors previously reported that the visit‐to‐visit variability of blood pressure is correlated with renal function decline in nondiabetic chronic kidney disease. Little is known about the association between visit‐to‐visit variability and renal function decline in patients with diabetic chronic kidney disease. The authors retrospectively studied 69 patients with diabetic chronic kidney disease stage 3a, 3b, or 4. The standard deviation and coefficient of variation of blood pressure in 12 consecutive visits were defined as visit‐to‐visit variability of blood pressure. The median observation period was 32 months. In univariate correlation, the standard deviation and coefficient of variation of blood pressure were not significantly associated with the slope of estimated glomerular filtration rate. There was no significant association between the visit‐to‐visit variability of blood pressure and renal function decline in patients with diabetic chronic kidney disease, in contrast with our previous study of nondiabetic patients with chronic kidney disease.     

Prognostic Significance of Visit‐to‐Visit Systolic Blood Pressure Variability: A Meta‐Analysis of 77,299 Patients

In recent clinical investigations, visit‐to‐visit systolic blood pressure (SBP) variability was proven as a predictor of cardiovascular events and all‐cause mortality. However, inconsistent results exist in this association. A meta‐analysis of 13 prospective studies was conducted to evaluate the prognostic value of visit‐to‐visit SBP variability by different parameters in 77,299 patients with a mean follow‐up of 6.3 years. The pooled age‐ and mean SBP‐adjusted hazard ratios (HRs) for all‐cause mortality were 1.03 (95% confidence interval [CI], 1.02–1.04; P<.001) per 1‐mm Hg increase in SBP standard deviation (SD) and 1.04 (1.02–1.06, P<.001) per 1% in SBP coefficient of variation, and the corresponding values of cardiovascular mortality were 1.10 (1.02–1.17, P<.001) and 1.01 (0.99–1.03, P=.32), respectively. Moreover, a 1‐mm Hg increase in SD was significantly associated with stroke, with an HR of 1.02 (1.01–1.03, P<.001). Visit‐to‐visit SBP variability, independent of age and mean SBP, is a predictor of cardiovascular and all‐cause mortality and stroke.     

Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

-Diuretics and ss-blockers have been shown to reduce the risk of cardiovascular morbidity and mortality in people with hypertension in long-term clinical trials. No study has compared newer more costly antihypertensive agents (calcium antagonists, ACE inhibitors, and alpha-adrenergic blockers) with diuretics for reducing the incidence of cardiovascular disease in an ethnically diverse group of middle-aged and elderly hypertensive patients. The study is a randomized, double-blind, active-controlled clinical trial designed to determine whether the incidence of the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, differs between treatment initiation with a diuretic versus each of 3 other antihypertensive drugs. Men and women aged >/=55 years with at least 1 other cardiovascular disease risk factor were randomly assigned to chlorthalidone (12.5 to 25 mg/d), amlodipine (2.5 to 10 mg/d), lisinopril (10 to 40 mg/d), or doxazosin (2 to 8 mg/d) for planned follow-up of 4 to 8 years. This report describes the baseline characteristics of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants. A total of 42 448 participants were randomized from 625 sites in the United States, Canada, Puerto Rico, and the US Virgin Islands. The mean age was 67 years, with 35% aged >/=70 years. Among those randomized, 36% were black, 19% were Hispanic, and 47% were women. The sample includes a high proportion of people with diabetes (36%), patients with existing cardiovascular disease (47%), and smokers (22%). There were no important differences between the randomized treatment groups at baseline. ALLHAT will add greatly to our understanding of the management of hypertension by providing an answer to the following question: are newer antihypertensive agents similar, superior, or inferior to traditional treatment with diuretics?     

Long‐Term Follow‐Up of Moderately Hypercholesterolemic Hypertensive Patients Following Randomization to Pravastatin vs Usual Care: The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT‐LLT)

The authors conducted a randomized, controlled, multicenter trial, in which they assigned well‐controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4 to 8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for a total follow‐up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post‐trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. The primary outcome was all‐cause mortality and the secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end‐stage renal disease. No significant differences appeared in mortality for pravastatin vs usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89–1.03) or other secondary outcomes. Similar to the previously reported in‐trial result, there was a significant treatment effect for CHD in black patients (HR, 0.79; 95% CI, 0.64–0.98). However, the in‐trial result showing a significant treatment by race effect did not remain significant during the entire follow‐up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients.     

Ambulatory Blood Pressure,Blood Pressure Variability and Antihypertensive Treatment

Ambulatory blood pressure monitoring is frequently employed in the clinical practice to improve the diagnosis of hypertension and the appropriateness of the decision regarding initiation of antihypertensive treatment. It is also frequently employed to check the efficacy of this treatment in conditions resembling daily life. This paper will describe the effect of a number of antihypertensive drugs on ambulatory blood pressure, based on data collected by our group in the past 10 years. It will then discuss the advantages of ambulatory blood pressure in studies on efficacy of antihypertensive drugs and the importance of this approach for definition of the trough-to-peak ratio of the antihypertensive effect. Some technical and clinical problems inherent to the ambulatory blood pressure monitoring approach will also be discussed.     

Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.