Antihypertensive And Lipid-Lowering Treatment To Prevent Heart Attack Trial Study Research Articles

Chlortalidone

Chlortalidone

Contributions of Systolic and Diastolic Blood Pressures to Cardiovascular Outcomes in the ALLHAT Study

BackgroundSBP and DBP have important associations with cardiovascular events, but are seldom considered simultaneously. ObjectivesThis study sought to simultaneously analyze systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements on the associated risk of a primary composite outcome of all-cause mortality, myocardial infarction (MI), congestive heart failure (CHF), or stroke. MethodsThis study analyzed ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data, which randomized adults to chlorthalidone, amlodipine, or lisinopril. The authors evaluated the simultaneous association of repeated SBP and DBP measurements on the primary composite outcome, and each outcome using proportional hazards regression. The authors report hazard ratios using a “heat map” to represent high and low risk according to SBP and DBP combinations. ResultsDuring a median follow-up of 4.4 years (interquartile range: 3.6-5.4 years), 33,357 participants experienced 2,636 MIs, 866 CHF events, 936 strokes, and 3,700 deaths; 8,138 patients (24.4%) had at least 1 event. For the composite outcome, all-cause mortality, MI, and CHF, a U-shaped association was observed with SBP and DBP, but the SBP and DBP associated with the lowest hazards differed for each outcome. For example, SBP/DBP of 140-155/70-80 mm Hg was associated with the lowest HR for all-cause mortality, compared with 110-120/85-90 mm Hg for MI and 125-135/70-75 mm Hg for CHF. In contrast, the association of SBP and stroke was linear. ConclusionsThe risk pattern of SBP and DBP differs by clinical outcomes, and the SBP and DBP associated with the lowest risk. Our results suggest individualization of blood pressure targets may depend in part on the cardiovascular event for which the patient is most at risk.

Prevention of Heart Failure in Hypertension-Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering: The ALLHAT Study.

BackgroundHypertension is a known risk factor for heart failure (HF), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy (LVH). We studied the extent to which blood pressure (BP) change and evolving LVH contribute to the effect that lisinopril, doxazosin, and amlodipine have on HF compared with chlorthalidone.Methods and ResultsWe conducted causal mediation analysis of ALLHAT (Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial) data (1994‐2002; in‐trial follow‐up). ALLHAT participants with available serial ECGs and BP measurements were included (n=29 892; mean age 67±4 years; 32% black; 56% men): 11 008 were randomized to chlorthalidone, 5967 to doxazosin, 6593 to amlodipine, and 6324 to lisinopril. Evolving ECG LVH and BP lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator‐outcome confounders (demographic and clinical characteristics known to be associated both with both LVH/hypertension and HF). A large majority of participants (96%) had ECG LVH status unchanged, but 4% developed evolving ECG LVH. On average, BP decreased by 11/7 mm Hg. In adjusted Cox regression analyses, progressing ECG LVH (hazard ratio [HR] 1.78 [95% CI 1.43‐2.22]), resolving ECG LVH (HR 1.33 [95% CI 1.03‐1.70]), and baseline ECG LVH (1.17 [95% CI 1.04‐1.31]) carried risk of incident HF. After full adjustment, evolving ECG LVH mediated 4% of the effect of doxazosin on HF. Systolic BP lowering mediated 12% of the effect of doxazosin, and diastolic BP lowering mediated 10% of the effect of doxazosin, 7% of the effect of amlodipine, and borderline 9% of the effect of lisinopril on HF.ConclusionsEvolving ECG LVH and BP change account for 4% to 13% of the mechanism by which antihypertensive medications prevent HF.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Visit-to-Visit Glycemic Variability and Risks of Cardiovascular Events and All-Cause Mortality: The ALLHAT Study.

The prognostic value of long-term glycemic variability is incompletely understood. We evaluated the influence of visit-to-visit variability (VVV) of fasting blood glucose (FBG) on incident cardiovascular disease (CVD) and mortality. We conducted a prospective cohort analysis including 4,982 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) who attended the baseline, 24-month, and 48-month visits. VVV of FBG was defined as the SD or variability independent of the mean (VIM) across FBG measurements obtained at the three visits. Participants free of CVD during the first 48 months of the study were followed for incident CVD (coronary heart disease [CHD], stroke, and heart failure [HF]) and all-cause mortality. Over a median follow-up of 5 years, there were 305 CVD events (189 CHD, 45 stroke, and 81 HF) and 154 deaths. The adjusted hazard ratio (HR) comparing participants in the highest versus lowest quartile of SD of FBG (≥26.4 vs. <5.5 mg/dL) was 1.43 (95% CI 0.93-2.19) for CVD and 2.22 (95% CI 1.22-4.04) for all-cause mortality. HR for VIM was 1.17 (95% CI 0.84-1.62) for CVD and 1.89 (95% CI 1.21-2.93) for all-cause mortality. Among individuals without diabetes, the highest quartile of SD of FBG (HR 2.67 [95% CI 0.14-6.25]) or VIM (HR 2.50 [95% CI 1.40-4.46]) conferred a higher risk of death. Greater VVV of FBG is associated with increased mortality risk. Our data highlight the importance of achieving normal and consistent glycemic levels for improving clinical outcomes.

Resistant Hypertension: An Update of Experimental and Clinical Findings.

An estimated 10% to 30% of hypertensive patients can be considered to be resistant to treatment defined as controlled or uncontrolled blood pressure (BP) with use of ≥4 medications, including a diuretic.1–4 A large number of cross-sectional and longitudinal studies have demonstrated that patients with treatment-resistant hypertension compared with patients with more easily controlled hypertension have increased cardiovascular risk, including coronary artery disease, congestive heart failure, stroke, and chronic kidney disease (CKD). Since publication of the first Scientific Statement on the Diagnosis, Evaluation, and Treatment of Resistant Hypertension by the American Heart Association in 2008, which coincided with development of device-based strategies for treating resistant hypertension, resistant hypertension has become a major focus of intensive experimental and clinical investigation.1 In that context, this review highlights scientific advances specific for resistant hypertension that have occurred in the last 2 years, including important findings related to prognosis, medication adherence, clinical use of aldosterone antagonists, and application of device-based therapies. Multiple cross-sectional studies have related resistant hypertension to prevalent cardiovascular and renal diseases.2–8 Recent analyses have strengthened those associations with use of longitudinal or prospective assessments. From a secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) results, which included 1870 participants with resistant hypertension, Muntner et al9 reported that compared with study participants without resistant hypertension, participants with resistant hypertension had a 44%, 57%, 23%, 88%, 95%, and 30% higher risk of incident coronary heart disease, stroke, peripheral artery disease, heart failure, end-stage renal disease, and all-cause mortality, respectively, during the almost 5-year duration of the study after adjustment for multiple traditional risk factors, such as age, smoking, diabetes mellitus, and low-density lipoprotein cholesterol. Because of the ALLHAT study design, diuretic use in this analysis was not required to …

Abstract 100: Hip and Pelvic Fracture Risk in Adults Treated with Three Different Classes of Antihypertensive Medications: The ALLHAT Study

Observational studies suggest that thiazide-type diuretics reduce fracture risk compared to other antihypertensive medications. The effects of calcium channel blockers (CCB) and angiotensin converting-enzyme inhibitors (ACEi) on fracture risk have not been well studied. We examined the relationship of antihypertensive drug therapy and hip and pelvic fracture hospitalizations in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ). It included &gt;33,000 participants randomized to the thiazide-type diuretic chlorthalidone (C), ACEi lisinopril (L), or CCB amlodipine (A) as first line hypertension (HTN) therapy. Mean follow up was 4.9 years during the randomized phase (in-trial), and 5 additional years after the conclusion of the trial (post-trial) using linkage to national data bases. Risks of hip and pelvic fractures for L and A relative to C were derived from Cox models. There were 341 hip and pelvic fractures in-trial. Participants assigned C had the lowest risk and those assigned L the highest ( Figure 1a). The adjusted risk for L compared to C was 1.33 (95% CI 1.02-1.73; p=.04). Participants assigned A had intermediate risk compared to C (HR 1.22, 95% CI 0.93-1.59). During the combined in-trial and post-trial periods ( Figure 1b ), there were 646 fractures; the results were similar to the in-trial results, although differences were not statistically significant. Participants randomized to C continued to have the lowest risk of fractures after in-trial period, suggesting a legacy effect from prior C use. These findings have public health importance given the high prevalence of HTN in older adults and the widespread use of A and L in older adults.

Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

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.

Treatment resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

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.

Time trends in the use of anti‐hypertensive medications: results from the Multi‐Ethnic Study of Atherosclerosis

Previous reports have suggested that new evidence of the comparative effectiveness of different medication classes from randomized controlled trials (RCTs) does not always alter treatment decisions for first-line anti-hypertensive therapy. To evaluate the association of RCT evidence in December 2002 from the Anti-hypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications in a multi-ethnic cohort. The Multi-Ethnic Study of Atherosclerosis (MESA) study, a prospective cohort study of 6814 adults from four ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of anti-hypertensive medications. After the exclusion of anti-hypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHAT was associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (relative risk (RR): 1.31; 95% confidence interval (CI): 1.09-1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR: 1.28; 95%CI: 1.04-1.57). The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use.

Impact of ALLHAT publication on antihypertensive prescribing patterns in Regione Emilia-Romagna, Italy

Studies from the US and Canada observed changes in antihypertensive prescribing patterns in accordance with Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study findings immediately after the study's publication, but little is known about the impact of ALLHAT in Italy. The objective of this study was to examine antihypertensive prescribing patterns in Regione Emilia-Romagna (RER), Italy, following the publication of the ALLHAT main results. We conducted a time series analysis using automated pharmacy data of approximately 4 million RER residents between 1 January 2000 and 31 December 2003. We computed monthly relative percentages of prescriptions for all antihypertensive medications and separately for all new antihypertensives defined as no recorded antihypertensive use in the previous year. A stepwise auto-regressive forecasting model based on data prior to the ALLHAT publication was used to estimate predicted relative percentages for the 12 months following the ALLHAT publication. Observed and predicted values were compared. Use of thiazide-type diuretics showed a general increasing trend over the study period, but the difference between the observed and predicted values reached statistical significance only for new prescriptions in October 2003 (3.71% vs. 2.32%; P = 0.0170). The relative percentage of new angiotensin-converting enzyme inhibitor and angiotensin receptor blocker (ACE/ARB) prescriptions was higher than predicted for the months May to August 2003 (P < 0.05), but no significant differences were observed for total ACE/ARB prescriptions. Modest changes in patterns of prescribing of calcium channel blockers and alpha-blockers were observed. We found little evidence that the ALLHAT study had an impact on antihypertensive prescribing patterns in RER in the year following their publication.

The ALLHAT Study Revisited: Do Newer Data From This Trial and Others Indicate Changes in Treatment Guidelines?

Following a hypertension symposium in Washington, DC, in November 2006, a panel was convened to discuss new data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and to revisit the significance of this trial in the management of hypertension. Based on these data and information from other trials, the expert panel also addressed the questions, "Is it time for a new Joint National Committee report?" and "Should the 2003 hypertension treatment recommendations be updated or are they still valid?" The panel was moderated by Marvin Moser, MD, Clinical Professor of Medicine, Yale University School of Medicine, New Haven, CT. On the panel were Suzanne Oparil, MD, Professor of Medicine at the University of Alabama in Birmingham, and President of the American Society of Hypertension (ASH); William Cushman, MD, Professor of Preventive Medicine and Medicine at the University of Tennessee in Memphis and attending physician at the Washington, DC, VA Medical Center; and Vasilios Papademetriou, MD, Professor of Medicine at Georgetown University in Washington, DC, and attending physician at the Washington, DC, VA Medical Center. This expert panel discussion was supported by Pfizer Inc and each author received an honorarium from Pfizer Inc for time and effort spent participating in the discussion and reviewing the transcript for important intellectual content prior to publication. The authors maintained full control of the discussion and the resulting content of this article; Pfizer had no input in the choice of topic, speakers, or content.

The ASCOT Trial

Hypertension remains one of the primary causes of preventable death in developed countries. Universally accepted clinical practice guidelines based on well designed trials are needed to ensure standardized treatment for these patients. It has been hypothesized that agents such as calcium channel antagonists and ACE inhibitors may be more effective than beta-adrenoceptor antagonist (beta-blocker)- or diuretic-based regimens. However, until recently, there have been limited data on the efficacy of 'newer' antihypertensive regimens, particularly combination therapy, relative to standard therapeutic options. The ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm), a prospective, randomized, controlled trial in >19 250 patients with hypertension, highlights the benefit of a combined amlodipine plus perindopril regimen over an atenolol plus diuretic-based combination in terms of significant reductions (p < 0.05) in all-cause mortality, total cardiovascular events and procedures, and fatal and nonfatal stroke. The ASCOT-BPLA trial underlines the cardiovascular benefit of ACE inhibitors, specifically perindopril, beyond that provided by BP reduction, and potentially reflects a mechanistic feature of the ACE inhibitors. It also suggests that the combination of amlodipine plus perindopril may provide broad-spectrum cardiovascular protection, as well as reduce the incidence of new-onset diabetes mellitus and renal impairment, in addition to its efficacy in lowering BP. The ASCOT-BPLA trial provides evidence of the need to reconsider traditional prescribing recommendations in patients with hypertension, particularly conclusions reached in the US after the publication of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study. The recently published National Institute for Health and Clinical Excellence (NICE) guidelines in the UK emphasize the efficacy of ACE inhibitors as first-line agents for hypertensive patients <55 years of age and recommend ACE inhibitor therapy at any stage of hypertension management.

Relationship between blood glucose control, pathogenesis and progression of diabetic nephropathy.

The present review briefly discusses evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is >200 mg/dl. The capacity to accomplish and to maintain steadily tightly controlled blood glucose levels is scanty using the currently implemented hypoglycemic drugs. Moreover, it must be highlighted that most patients with type 2 diabetes, particularly when renal damage does occur, have arterial hypertension. Several studies suggested that the development of ESRD is prevented significantly better by drugs that modulate the renin angiotensin system than by other compounds in patients with type 1 and 2 diabetes with overt diabetic nephropathy. However, a recent trial, the study Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared lisinopril, chlorthalidone, and amlodipine in a large population of patients with arterial hypertension, either associated or not with diabetes, demonstrated that the development of both coronary heart diseases and renal complications was equally prevented by the three drugs. One word of caveat, however, needs to be raised concerning one of the results of the ALLHAT study: the higher risk of developing new-onset diabetes among hypertensive patients who are not treated with lisinopril. Even if it is true that this latter side effect was not accompanied by a worse outcome of macrovascular and renal complications during the 5-yr follow-up period, one cannot rule out the possibility that this might be the case during more prolonged periods of follow-up in the future. Thus, the advantage of a lower cost in the treatment of hypertension with diuretics as compared with other drugs, with similar degree of success in the prevention of vascular complications, should be weighed also taking into consideration the burden of a higher rate of occurrence of new-onset diabetes.

Comments on ALLHAT and Other Papers in This Issue of the JCH

Comments on ALLHAT and Other Papers in This Issue of the <i>JCH</i>

National Heart, Lung, and Blood Institute Halts Part of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

The National Heart, Lung, and Blood Institute (NHLBI) halted one part of the large ALLHAT high blood pressure study because one of the drugs, an α-adrenergic blocker, was found to be less effective than the traditional diuretic in reducing some forms of heart disease (http://www.nhlbi.nih.gov/new/press/mar08-00.htm). The ALLHAT study was designed to have 2 parts. One compared newer drug treatments for high blood pressure with more conventional and less costly treatment. The other compared treatments for …