Prominent Research Team Finds in Blood Pressure Study that the Less Effective Medications Prescribed More than More Effective Ones

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It turns out that the most common first-line treatment for hypertension may not be as effective, and pose more risk for side effects, than an alternative that is not prescribed as often, according to a new multinational study. How could this be? Columbia University researchers study results reveal why.

Published in The Lancet, researchers George Hripcsak, MD and Patrick Ryan, PhD, reviewed and analyzed electronic health records and claims data form nearly 5 million patients who were undergoing hypertension treatment. Their findings were surprising:  that patients who were first prescribed thiazide diuretics experienced 15% less heart attacks, strokes and hospitalizations for heart failure as compared to patients who were prescribed ACE inhibitors. Moreover, those in the former group had fewer side effects than those in the latter group.

With an estimated 3,100 major cardiovascular events under study, it is speculated that they could have been avoided had they first been treated with thiazide diuretic.

What is Thiazide Diuretic

Thiazide diuretics are a type of diuretic (a drug that increases urine flow). They act directly on the kidneys and promote diuresis (urine flow) by inhibiting the sodium/chloride cotransporter located in the distal convoluted  tubule of a nephron—a functional unit of a kidney. Thiazides moreover lowers sodium reabsorption purportedly gaining from loss in urine, which thereafter lowers extracellular fluid and plasma volume reports the Scienceblog.  Apparently, this can lead to a reduction of cardiac output (how much work the heart must do to pump blood through the body)—and lowers the blood pressure. It also helps lower blood pressure as well as potassium loss.         

Current Guidelines Not Clear

There is little evidence to aid physicians on the challenging decision of what drug class to start treatment with for hypertension. This is made more challenging by the fact that there are five classes of therapy to choose from including: thiazide diuretics, ACE inhibitors, angiotensin  II receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers. The Scienceblog and research report that most clinical guidelines are based on expert opinion and not data.

The Dilemma

Researcher Dr. George Hripcsak noted, “Randomized clinical trials demonstrate a drug’s effectiveness and safety in a highly defined population.” Dr. Hripcsak continued, “But they are not good at making comparisons among multiple drug classes in a diverse group of patients that you would encounter in the real world.” And real-world observational studies are tools to detect effects that may not be apparent in clinical trials. However as noted by the Scienceblog, they may be too small to form meaningful conclusions. They can also suffer from other types of bias.

Large-Scale Evidence Generation and Evaluation across a Network of Database (LEGEND)

Enter LEGEND for addressing these limitations. The research team analyzed millions of patient health records while accounting for tens of thousands of multiple variables in an attempt to eliminate confounding factors. This method was originated by a consortium of scientists who participated in the Observational Health Data Science Initiative (OHDSI) network. This methodology was set up to minimize bias. By applying advanced analytics across a network of disparate databases the researchers have found a method to secure a wider array of “exposures and outcomes” reported Patrick Ryan, PhD.

The team analyzed data from insurance claims and electronic health records from 4.9 million patients in four countries initiating antihypertensive therapy with one drug. They developed sophisticated approaches to minimize bias.

Study Findings

The Columbia University-based team found that ACE inhibitors were the first antihypertensive drug prescribed to 48% of the patients. However, they found that those patients that were prescribed thiazide diuretics experienced 15% fewer heart attacks, hospitalizations for heart failure, and strokes when compared with those treated with other first-line therapies.  Additionally, those patients treated with ACE inhibitors experienced higher rates of 19 side effects as compared to thiazide patients.

Lead Research/Investigator

Dr. George Hripcsak, MD, Professor of Bioinformatics, Columbia University Vagelos College of Physicians and Surgeons

Patrick Ryan, PhD, adjunct assistant professor of biomedical informatics, Columbia University Vagelos College of Physicians and Surgeons and vice president, Observational Health Data Analytics, Janssen Research and Development.


  • U.S. National Science Foundation
  • National Institutes of Health
  • Australian National Health and Medical Research Council
  • Janssen Research and Development