SynopsisRevised.pdf

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

REVISED Synopsis:

The Coordinating Center will optimize scientific advancement from the ALLHAT study by using

1) the administrative, data, and analytical resources to support continued manuscript preparation and development of ancillary studies and 2) the ALLHAT governance structure to provide overall scientific leadership. The Coordinating Center will foster scientific contributions based on extensive ALLHAT resources and will expand collaborations with relevant clinical and scientific communities outside of ALLHAT, including development of and collaboration with investigators from academic institutions not recently involved in ALLHAT manuscripts or ancillary studies. Collaborations might include scientists with interest in clinical trials, pharmacogenetics, biomarkers, epidemiology, and clinical practice as these interests relate to hypertension and lipid-lowering treatments. This contract provides funds to preserve key study resources, continue the passive follow-up of the ALLHAT cohort, expand access to the ALLHAT datasets, and assure open, efficient, and active use of the ALLHAT data by the entire scientific community.

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

(CHD). 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 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 the participants have 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 that understands the intricacies of the study and the 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. 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 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 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.