–For decades physicians may have been prescribing the wrong diuretic. Now an innovative new trial will settle the question.
A radically innovative large new VA trial will finally shed light on a decades-old unresolved question that could have important public health implications.
According to guidelines thiazide diuretics are the first-line treatment for hypertension. Hydrochlorothiazide accounts for 95% or more of thiazide prescriptions, making it by far the most popular drug in its class. However, nearly all the evidence in support of thiazide diuretics has relied on different drugs, chlorthalidone and indapamide, and questions have been repeatedly raised— though ignored by the market— that the reduction in cardiovascular events seen with these drugs in clinical trials may not be matched by hydrochlorothiazide.
“Fifty million prescriptions for hydrochlorothiazide are dispensed each year in the United States, so if cardiovascular events were reduced by even a small amount with chlorthalidone, the public health effect could be considerable,” say the leaders of a new trial. Now, finally, the differences between hydrochlorothiazide and chlorthalidone will be studied in a large randomized VA Cooperative study, called the Diuretic Comparison Project.
The trial investigators discuss the trial design and rationale in a paper published in Annals of Internal Medicine. The trial will randomize 13,500 veterans over the age of 65 who currently receive hydrochlorothiazide monotherapy to either continued hydrochlorothiazide or open-label chlorthalidone. Patients in the trial will be followed for 3 years.
The trial is the first to emerge from the VA Point-of-Care Clinical Trial Initiative, which is seeking to perform “efficient, less expensive, clinically integrated trials by embedding processes within the VA electronic medical record (EMR).” Potential subjects will be identified through the VA EMR. The primary care physicians will then receive an order to approve or disapprove contact with eligible patients, followed by a “centralized recruitment and enrollment involving an ‘opt-out’ patient information letter, informed consent obtained by phone call from a central bank, an order to the primary care clinician to approve or disapprove each consenting patient’s enrollment, open-label randomization by the coordinating center, and remote placement of orders resulting from randomization to be signed by the primary care clinician.” Trial participants will then be managed as usual by their primary care physician. Trial data will automatically be collected through the VA EMR and other data bases.
The investigators point out that “several of these processes are, to our knowledge, unique to our study and may be useful in designing future pragmatic comparative effectiveness trials.”
“The principal purpose of our design innovations was to reduce the infrastructure and cost of a large randomized trial,” they write. The cost of the trial— about $10 million dollars, or $700 per patient enrolled, is “less than one twentieth of the $15 000 per-patient cost in SPRINT.”
Trial Long Overdue
Hypertension researchers Franz Messerli (Mt. Sinai) and Sripal Bangalore (NYU) have called attention to the hydrochlorothiazide issue in the past. They support the new VA trial and say that it is long overdue:
“For many decades JNC guidelines with the full blessing of the National Heart Lung and Blood Institute (NHLBI) have deceitfully promoted an inefficacious BP drug. Millions of patients have been and still are exposed to adverse effects, inconvenience and cost of hydrochlorothiazide (HCTZ), a drug that in its commonly used dose neither lowers BP over 24 hours nor reduces the risk of heart attack, stroke or death. In fact in the wake of ALLHAT, the NHLBI took it upon itself to uncritically promote ‘thiazides’.”
“For 99.9% of practicing physicians the term thiazide does not mean chlorthalidone or indapamide for which we have outcome data, but simply HCTZ in the dose of 12.5 to 25 mg/day. So can we agree that it is about time to do a trial (however simple) comparing outcomes between chlorthalidone and HCTZ serving hopefully to get rid of some preconceived notions? The design that is being proposed to make it cost efficient is greatly appreciated.”
Hydrochlorothiazide Versus Chlorthalidone
The overwhelming dominance of hydrochlorothiazide is due to “the legacy effect of marketing,” Messerli explained. Brand name versions of hydrochlorothiazide (such as Dyazide and Maxzide) were marketed by some of the biggest drug companies at the time, such as Ciba, Merck, SKF and Lederle. Chlorthalidone, by contrast, was never marketed by a major pharmaceutical company.
The trial investigators speculated about possible mechanisms for differences between the two drugs. These include a longer duration of action, leading to better nighttime blood pressure control, and “pleiotropic effects of chlorthalidone” (by which the authors mean it does something else but no one knows what that might be).