The research team
analyzed electronic health records of almost 5 million patients who were on
. The analysis revealed that
patients who received thiazide diuretics as the first-line therapy had 15 percent fewer cardiovascular events,
such as stroke,
. Importantly, patients receiving
also experienced fewer side effects.
The research team
calculated that approximately 3,100 major cardiovascular events could have been
averted if the patients who received ACE inhibitors as the first-line therapy
were prescribed thiazide diuretics instead. The study has been published in the
prestigious medical journal The Lancet
Mechanism of Blood Pressure Control by ACE
Inhibitors and Thiazide Diuretics
enzyme (ACE) is a molecule responsible for the conversion of Angiotensin I to
Angiotensin II, which causes constriction of the blood vessels. ACE inhibitors
are drugs that block this conversion so that Angiotensin II is not produced,
which results in relaxation of the blood vessel walls, thereby decreasing BP.
are drugs that promote diuresis (increased urine flow)
by blocking the reabsorption of sodium (Na+
) and chloride (Cl-
) ions from the
distal convoluted tubules of the nephrons in the kidneys. This increases urine
flow, resulting in the lowering of BP.
The study was jointly led by Dr.
George Hripcsak, MD, MS, and Dr. Patrick Ryan, PhD. Dr. Hripcsak is the Vivian Beaumont Allen Professor of
Biomedical Informatics and Chair of the Department of Biomedical Informatics at
Columbia University, New York. He is also the Director of Medical Informatics
Services at New York-Presbyterian Hospital, New York, USA.
Dr. Ryan is an Adjunct Assistant
Professor of Biomedical Informatics at Columbia
University Vagelos College of Physicians and Surgeons, New York. He is also
Vice President, Observational Health Data Analytics at Janssen Research &
Development, LLC, a subsidiary of Johnson & Johnson, based in Raritan, New
What are the Drawbacks of Current Guidelines
on Antihypertensive Drugs?
for the use of antihypertensive
are available from the American College of Cardiology and the American
Heart Association. These guidelines recommend that treatment of hypertension
could be started with any of the following 5
classes of antihypertensive drugs:
- Thiazide diuretics
- ACE inhibitors
- Angiotensin II receptor blockers (ARBs)
- Dihydropyridine calcium channel blockers
- Non-dihydropyridine calcium channel blockers
However, there is
no clear consensus among physicians on which drug to choose from the above 5
classes for initiating treatment for hypertension
on randomized, controlled clinical trials that are available in the medical
literature only include 31,000 patients worldwide, which make it extremely
difficult to extrapolate and apply the results to the whole global population.
Importantly, these trials did not include any patients who were just initiating
antihypertensive therapy. Due to this drawback, most clinical guidelines are
formulated on the basis of expert opinion rather than hard evidence.
trials demonstrate a drug's effectiveness and safety in a highly defined
says Hripcsak. "But
they're not good at making comparisons among multiple drug classes in a diverse
group of patients that you would encounter in the real world."
Observational studies are sometimes useful for detecting
effects that may be missed in randomized clinical trials. However, these are
usually small-scale studies, which make it difficult to draw meaningful
conclusions due to the scanty data generated.
not, journals and authors tend to publish studies that have exciting results,
and researchers may even select analytical methods that are best suited to
getting the results that fit their hypotheses,"
says Hripcsak. "It comes down to a cherry-picking exercise,
which makes the results less reliable."
How Did the New Study Overcome the Drawbacks?
In order to
overcome the drawbacks, a team of researchers analyzed electronic health
records of millions of patients, which took into account tens of thousands of
variables that are crucial for the exclusion of any confounding factors. The
analytical technique used is termed Large-Scale
Evidence Generation and Evaluation across a Network of Databases (LEGEND)
. This technique
was developed by a consortium of scientists who were part of the Observational Health Data Science Initiative (OHDSI)
. The LEGEND
technique enabled the scientists to share their methodology and refine the
data, thereby significantly reducing bias.
"LEGEND provides a
systematic framework that can reproducibly generate evidence by applying
advanced analytics across a network of disparate databases for a wide array of
exposures and outcomes,"
says Ryan. "Not
only does LEGEND offer a path to scale to the real needs of the healthcare community,
it also provides the complementary diagnostics to help us understand how much
we can trust the evidence we've produced."
- 4.9 million electronic health records and insurance
claims of patients from 4 countries were analyzed
- The analyzed data accounted for 10 percent of
- The patients were starting antihypertensive therapy
with a single drug
- The algorithm used identified the following
- Several techniques were used to minimize bias for
approximately 60,000 variables
- ACE inhibitors were the most
popular first-line antihypertensive drugs, prescribed to 48 percent of
- Thiazides were prescribed as
first-line antihypertensive therapy to only 17 percent of patients
- Patients who received thiazides
had 15 percent fewer cardiovascular events than those who received other
- Patients who first received ACE
inhibitors had higher rates of 19 side effects compared to those who
received thiazides first
- Non-dihydropyridine calcium
channel blockers were the least effective among all first-line
- 3,100 major cardiovascular events
could have been averted if thiazides were prescribed as a first-line drug
instead of ACE inhibitors
"With LEGEND, we have found a way to fill in the gaps
left by randomized, controlled trials and help guide physicians in their
clinical decision making,"
The study was
funded by the US National Science Foundation, the National Institutes of
Health, the Australian National Health and Medical Research Council, Janssen
Research & Development, and IQVIA, a Consultancy Company headquartered in
Durham, North Carolina, USA.
- Comprehensive Comparative Effectiveness and Safety of First-line Antihypertensive Drug Classes: A Systematic, Multinational, Large-scale Analysis - (https://doi.org/10.1016/S0140-6736(19)32317-7)