The Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT)

A single contract awarded as a result of this acquisition will provide support to a coordinating center for the ALLHAT trial to enable and foster scientific contribution based on extensive ALLHAT data and other resources and to expand collaborations with relevant clinical and scientific communities outside of ALLHAT. Hypertension affects one third of the U.S. adult population and is associated with substantially increased risks of heart failure, stroke, atrial fibrillation, renal failure and coronary heart disease. Because of high prevalence and associated morbidity and disability, it contributes significantly to health care costs. ALLHAT was funded in 1993. It was a randomized, double-blinded, practice-based trial designed to determine whether the incidence of major coronary heart disease (CHD) events (primary endpoint) is reduced in high-risk patients with hypertension treated with a calcium channel blocker (CCB; amlodipine), an angiotensin converting enzyme (ACE) inhibitor (lisinopril), or an alpha-blocker (doxazosin), each compared with a diuretic (chlorthalidone) as first-step therapy. The Lipid-Lowering Trial, conducted in a subgroup of the ALLHAT participants (N=10,355), was designed to compare open-label pravastatin with usual care for prevention of total mortality (primary endpoint). Between 1994 and 1998, 42,418 participants were recruited from 623 clinics, mostly primary care, across the United States, Canada, Puerto Rico and the U.S. Virgin Islands. After an average of 4.9 years of follow-up (3.2 for the doxazosin arm, which was terminated early), the investigators reported that the primary endpoint, a composite of fatal CHD and non-fatal myocardial infarction, did not differ across the randomized treatment comparisons - despite better metabolic profiles in the participants randomized to receive the newer antihypertensive agents. In addition, the diuretic-based therapy was superior to the alpha-blocker, ACE inhibitor and CCB-based therapies in preventing one or more major forms of cardiovascular disease (CVD), including stroke and heart failure. The ALLHAT participants have been followed since the end of the trial in 2002 through national administrative data bases, including the National Death Index (NDI), Centers for Medicare and Medicaid Services (CMS), United States Renal Data System (USRDS), and Social Security Administration (SSA). Outcomes data through 2006 are currently being analyzed. During the combined active and passive average follow-up of nearly 9 years, about a third of participants died. The purpose of this renewal is to optimize scientific advancement from the study by leveraging NHLBI's investment in the existing resources. The renewal will complement the ALLHAT public access data base. While it is important to have databases publicly available, and many research objectives (including training of early stage investigators) can be met this way, complex concepts and analyses (especially those involving merging data sources) will be best achieved (or in some cases may only be accomplished) through collaboration with an experienced investigative team who understands the intricacies of the study and nuances of the original data set. Given the modest amount of funding, the extension is envisioned as complementary to the existing and future investigator-initiated sources of funding. Potential research areas that can be engaged during the proposed extension under the leadership of the ALLHAT Steering Committee and, where appropriate, in collaboration with the GenHAT Steering Committee are described below. Funding for some of the components, primarily to obtain pilot data or synthesize available information to stimulate and enable investigator-initiated grant writing, would be provided by the contract funds while major research questions would be addressed through other funding mechanisms. Selected Research Examples In this next phase, ALLHAT investigators in collaboration with outside researchers and practitioners will further evaluate predictors of long-term clinical outcomes, overall and by randomized treatment assignment, in complex demographic and clinical phenotypes represented in the ALLHAT study population. These analyses could include multimorbid conditions in 2,772 participants with new-onset heart failure during the main trial; 22,551 with mild chronic kidney disease (CKD; eGFR 60-89 mL/min per 1.73 m2) at baseline; 15,740 with Type II diabetes at baseline and 1,458 with incident diabetes during 4-8 years of active follow-up. Additional hospitalized and fatal events have been collected from the administrative databases. The extension is also expected to take to a new level ALLHAT's contribution to pharmacogenetics of hypertension as data emerging from the genetic ancillary study (GenHAT) show potential for contribution to genetically-guided personalized medicine. Recently completed pilot analysis of a limited frozen sera resource offers a possibility of assessing relevant biomarkers such as NTproBNP and adiponectin in a context of randomized treatment assignments. The following examples of research areas that may be engaged under this extension illustrate the rich potential of continued support for the ALLHAT infrastructure. Long-term follow-up and hypertension decision/economic model ALLHAT's large and diverse population with long-term follow-up offers a unique opportunity to inform development of a decision model for patients with hypertension. There is an established model for CHD but not for hypertension. Extension of the passive follow-up, which by the end of 2011 will result in an average overall follow-up of about 14 years, is a cost-effective way to learn about long-term outcomes in high CVD risk elderly patients with hypertension. The resulting database will also provide opportunities for health services research. Evaluation of atrial fibrillation (AF) at baseline and during follow-up ALLHAT baseline and follow-up (bi-annual) ECGs have been centrally coded (University of Minnesota) for AF. In addition, the ALLHAT Heart Failure Validation Study collected information on AF occurring in the context of nearly 3,000 hospitalizations with heart failure. To date, only one manuscript on this topic has been written, which describes factors associated with prevalent AF at baseline (N=423) and baseline characteristics associated with development of new-onset AF (N=641) during the randomized phase of the trial. The incidence of AF was analyzed by randomized treatment assignment, and in-trial clinical outcomes in those with prevalent and new-onset AF were reported for the entire cohort. Future research may focus on genetic and other markers of racial and gender differences in AF prevalence, incidence and response to antihypertensive treatment. In addition, because ALLHAT excluded individuals with symptomatic heart failure or known LVEF<35% at baseline, an opportunity exists to evaluate the occurrence and prognosis of AF in a context of randomized antihypertensive and lipid-lowering treatment in participants without heart failure and in ~2,000 participants who developed new-onset heart failure during the active follow-up phase of the trial. Additional information on hospitalized and outpatient AF diagnoses may be obtained from administrative databases. Contribution to personalized medicine The ALLHAT/GenHAT collaboration has the potential for bringing closer to reality a promise of personalized medicine with respect to pharmacotherapy of hypertension through 1) the richness of phenotypes, 2) genetic information obtainable on almost all ALLHAT participants, which can be analyzed in a randomized setting to evaluate how genotype modifies treatment effects on major clinical outcomes, and 3) assessment of predictive role of baseline levels of several important biomarkers on long-term clinical outcomes, overall and by randomized treatment assignment.