News Release

Research brief: New “burden-free” study method finds two blood pressure drugs equally effective

Peer-Reviewed Publication

University of Minnesota Medical School

MINNEAPOLIS/ST. PAUL (01/11/2023) — Published in the New England Journal Of Medicine, University of Minnesota Medical School researchers, in partnership with Veteran Affairs, conducted a large clinical trial and found that the blood pressure drug chlorthalidone (CTD) was not better than hydrochlorothiazide (HCTZ) for the prevention of cardiovascular disease or non-cancer death.

Current clinical guidelines say that CTD may be more effective than HCTZ in lowering blood pressure, but this recommendation is unsupported by direct evidence. Both medications have been used for over 50 years, and each is considered a first-line treatment for hypertension and are in a class of medications called thiazide diuretics — commonly known as water pills. They are used to help the body rid itself of excess fluid, which can lower blood pressure. 

"We were able to compare two commonly prescribed generic drugs using a low-cost methodology," said principal investigator Dr. Areef Ishani, MD, MS, a vice chair and professor at the U of M Medical School and director of the Minneapolis Veteran Affairs Health Care System's Primary Care and Specialty Care Integrated Care Community.  "This trial has shown that large, embedded trials are operationally feasible. They can be incorporated into the clinical workflow of providers by leveraging the electronic health record and other existing infrastructure."

The Diuretic Comparison Project (CSP 597) is a large pragmatic clinical trial that was conducted at 537 Veteran Affairs (VA) medical centers and community clinics in the U.S. The trial enrolled more than 4,000 providers and 13,500 veterans with high blood pressure who were taking HCTZ at baseline. 

Study participants were randomized to: 

  • Stay on their current dose of HCTZ
  • Or take an equivalent dose of CTD

95% of study participants took a lower dose of HCTZ, so the main study comparison was 12.5 mg CTD to 25 mg HCTZ.

The team found for the prevention of cardiovascular disease or non-cancer death, which included heart attack, stroke, heart failure or lack of blood flow requiring medical intervention:

  • no difference between the two drugs at these lower doses
  • a slight increase in the risk for low potassium in the CTD group, which quickly resolved with potassium supplements.

"In 2020, Medicare reported that approximately 1.5 million people were prescribed CTD compared to 11.5 million prescribed HCTZ, despite guideline recommendations. This discrepancy between clinical guidelines and real-world usage is possibly related to the belief that CTD has a greater risk of adverse effects without clear evidence for differences in cardiovascular outcomes," said Dr. Ishani.

The study was funded by the VA Cooperative Studies Program.


About the University of Minnesota Medical School
The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School, both the Twin Cities campus and Duluth campus, is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. For more information about the U of M Medical School, please visit

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