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LEGEND-HTN: Thiazide, thiazide-like diuretics superior to ACE inhibitors
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Drug classes used as monotherapy for hypertension were shown to be comparable, although thiazide or thiazide-like diuretics were superior to ACE inhibitors, according to results from the LEGEND-HTN study published in The Lancet.
The study also found that nondihydropyridine calcium channel blockers were inferior to the other four drug classes.
“It for the most part confirms the current U.S. guideline about first-line drugs to treat hypertension, that most of them are roughly equivalent,” George Hripcsak, MD, MS, Vivian Beaumont Allen Professor of Biomedical Informatics and chair of the department of biomedical informatics at Columbia University and director of medical informatics services at NewYork-Presbyterian Hospital/Columbia, told Cardiology Today. “The finding of greater effectiveness and overall safety for thiazide and thiazide-like diuretics over ACE inhibitors is a new result and an important one given the number of people who take ACE inhibitors. The finding that nondihydropyridine calcium channel blockers are not as effective or as safe as the others is not surprising.”
Real-world evidence
Marc A. Suchard, MD, PhD, professor in the departments of biomathematics and of human genetics at the David Geffen School of Medicine at the University of California, Los Angeles, and colleagues analyzed data from 4,893,591 patients from six administrative claims and three electronic health record databases. The data were used to generate 22,000 effect estimates to assess 55 outcomes in nine databases.
Patients were considered new users of these drug classes if their first hypertension treatment was monotherapy with an ingredient in one of the five drug classes in the 2017 American Heart Association/American College of Cardiology guideline, which included thiazide or thiazide-like diuretics (17%), angiotensin receptor blockers (15%), ACE inhibitors (48%), dihydropyridine calcium channel blockers (16%) and nondihydropyridine calcium channel blockers (3%).
The three primary endpoints were HF hospitalization, acute MI and stroke. There were also six secondary effectiveness outcomes and 46 safety outcomes.
There were no significant differences between classes in more than half of the comparisons in the study. Despite this, patients taking thiazide or thiazide-like diuretics had a significantly lower risk for HF hospitalization (HR = 0.83; 95% CI, 0.74-0.95), acute MI (HR = 0.84; 95% CI, 0.75-0.95) and stroke (HR = 0.83; 95% CI, 0.74-0.95) compared with those taking ACE inhibitors. Thiazide or thiazide-like diuretics had a more favorable safety profile compared with ACE inhibitors.
Compared with other drug classes, nondihydropyridine calcium channel blockers were found to be significantly inferior.
“The finding about diuretics and ACE inhibitors needs to be taken seriously,” Hripcsak told Cardiology Today. “There could be an actual difference in the efficacy of the two drugs or there could be a difference when they are both put into practice. For example, if ACE inhibitors have more side effects and patients stop taking the drug because of them, that could lead to an overall difference in effectiveness.”
Unique study method
Christopher W. Ives, MD, resident at the University of Alabama at Birmingham, and Suzanne Oparil, MD, director of the vascular biology and hypertension program at the University of Alabama at Birmingham, wrote a related editorial, in which they wrote: “The study describes a unique method for future analysis of large quantities of observational data gathered from real-world health care settings. Going forward, use of this analytical technique in this scenario might allow new insights and clarify otherwise unanswerable questions to empower clinicians to practice evidence-based medicine.” – by Darlene Dobkowski
For more information:
George Hripcsak, MD, MS, can be reached at 622 W. 168th St., PH20, New York, NY 10032; email: hripcsak@columbia.edu.
Disclosure s : This study was funded by Australian National Health and Medical Research Council, IQVIA, Janssen Research and Development, NIH, U.S. National Science Foundation and South Korean Ministry of Health and Welfare. Suchard and Hripcsak report they received grant funding from Janssen. Ives and Oparil report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Franz H. Messerli, MD, HonD, FACC, FESC
The most provocative findings of this gargantuan study is that patients initiating treatment with a thiazide or thiazide-like diuretic had a significantly lower risk of seven effectiveness outcomes, including acute MI, hospitalization for HF and stroke, than those initiating treatment with ACE inhibitors. Even the safety profile was markedly better with thiazides than with ACE inhibitors.
This is puzzling, given that the most commonly used thiazide was hydrochlorothiazide, which has been documented to be a weak antihypertensive and the most commonly used ACE inhibitor was lisinopril, which is considered to be a useful drug as attested in ALLHAT. That patients who initiated treatment with a nondihydropyridine calcium channel blockers had a significantly higher risk of poor effectiveness outcomes is not unexpected since no solid outcome study with these agents against placebo has been put forward.
In a nutshell, this study, until further notice, demotes lisinopril and other short-acting ACE inhibitors as well as nondihydropyridine calcium channel blockers to second-class antihypertensive agents. To my way of thinking, there is, at this day and age, little if any reason to start a hypertensive patient on either ACE inhibitor or on a nondihydropyridine calcium channel blocker.
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