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Massive VA Point-of-Care Trial Begins to Compare Two Diuretics

by U.S. Medicine

April 7, 2016

Study Using Primary Care Providers Touted As Much More Cost-Effective

By Annette M. Boyle

MINNEAPOLIS — Pioneering use of “point of care” research in a new study at the VA might finally answer the question of whether hydrochlorothiazide (HCTZ) or chlorthalidone more-effectively lowers blood pressure in patients with hypertension.  

The two thiazide diuretics have been mainstays of hypertension management for almost a half-century, but no large-scale, randomized trials have compared them directly. While long considered interchangeable antihypertensives, multiple studies in the past decade have indicated that chlorthalidone may reduce cardiovascular morbidity and be more effective.1

Chlorthalidone has a significantly longer duration of action, with a half-life of 24 to 55 hours, compared with hydrochlorothiazide’s 2.5 hours, and is about twice as potent. The two drugs also differ in their blood-pressure efficacy, effects on lipid profile and on serum potassium levels, uric acid and glucose levels. While chlorthalidone dominated through the 1970s, HCTZ is far more widely prescribed now.

More than one million veterans receive a thiazide-type diuretic every year as a first-line treatment for hypertension, and 95% of them are prescribed hydrochlorothiazide. Less than 2.5% receive chlorthalidone, according to the VA. Similar difference in prescription rates are also seen in hypertensive patients treated in other U.S. medical practices.2

The numbers involved and current prescribing practices give the study added significance. “If chlorthalidone reduces the risk of cardiovascular events by 15% to 20%, it could have a huge impact on whether the management of hypertension should be changed in a very large number of patients, inside and outside of the VA,” said Frank Lederle, MD, study chair, director of the Minneapolis VA Center for Epidemiological and Clinical Research, and core investigator at the VA’s Center for Chronic Disease Outcomes Research.

“Researchers have been trying to compare the two for many years, but it didn’t rise to the level of becoming a major trial of the decade for the National Institutes of Health to fund. Our methodology will allow us to do the study much more inexpensively,” Lederle told U.S. Medicine.

The study will enroll 13,500 veterans aged 65 years and older and follow them for an average of three years. Patients currently receiving HCTZ will be randomized to continue taking it or switching to an equivalent dose of chlorthalidone. The primary endpoint is defined as an event composite of stroke, myocardial infarction, noncancer death, urgent revascularization and hospitalization for acute congestive heart failure.

The VA study will embed as many research operations as possible into regular VA checkups, including screening, randomizing and follow-up. “The point-of-care research design removes the need for most trial infrastructure and personnel and also mimics clinical practice,” explained Katherine Armstrong, MPH, project manager, Massachusetts Veterans Epidemiology Research and Information Center in Boston. Patients will be identified, enrolled and followed up through the VA’s electronic medical record (CPRS).

As an additional benefit, the study format will allow researchers to look at effective practice and see the differences in the drugs’ outcomes in the real clinical setting. Primary care providers will also be participants in the study to allow researchers to analyze the implementation of the point-of-care protocol design, as well as the performance of the two diuretics.

Lederle_re“All patient care, including the study drug, will be managed by the veteran’s regular primary care provider. It’s a clinically-integrated design,” Lederle said. That will keep the cost of the study down and, if all goes as planned, increase the commitment to the study and its results.

The novel structure also will allow the study to be completed for far less than other studies its size. Lederle anticipates a cost of $750 per patient, or less than $10 million for the total number of participants. By comparison, “the SPRINT hypertension study cost more than 20 times that, enrolling 9,000 patients at a cost of $150 million,” he noted.

The researchers plan to use a multipronged approach to contact primary care providers, according to Armstrong. Techniques will include establishing a local liaison at each site, speaking at staff meetings and other forums, sending letters and emails with more detailed information and using test-station orders through CPRS to ask providers to accept or decline receiving more information about the study.

The study started in Boston in March and will roll out to Minneapolis, Memphis, Houston, Cleveland and the community of West Los Angeles next. Ultimately, Armstrong and Lederle said they expect 30 to 50 sites to participate.

“Because of the unique features of the study design, once we bring on one center and have it going full speed, it can proceed as quickly, as if we had all the sites on together,” Armstrong explained. “One could be nearly finished before some of the later sites come online.”

The trial will answer two research questions, according to Lederle, who pointed out, “We’ll find out, is chlorthalidone better? Second, we’ll learn is it feasible to do a trial this way? If so, others could use this methodology to conduct large trials much more cost-effectively.”

1 Tziomalos K, Athyros VG, Mikhailidis DP, Karagiannis A. Hydrochlorothiazide vs. chlorthalidone as the optimal diuretic for the management of hypertension. Curr Pharm Des. 2013;19(21):3766-72. Review.

2 Kaplan N. Chlorthalidone Versus Hydrochlorothiazide. Editorial Comment. Hypertension. 2011;58:994-995.


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