Diuretic Better Bet Than ACE Inhibitor for New Hypertension?

Megan Brooks

October 31, 2019

An angiotensin-converting-enzyme (ACE) inhibitor, the most common first-line approach for newly diagnosed hypertension, is not as effective and causes more adverse effects than a thiazide diuretic, a large analysis of real-world data suggests.

"The finding of greater effectiveness and overall safety for thiazide and thiazide-like diuretics over ACE inhibitors is a new result and needs to be taken seriously," George Hripcsak, MD, chair of biomedical informatics at Columbia University in New York City, told theheart.org | Medscape Cardiology.

"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," Hripcsak added. "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."

Results of the LEGEND-HTN study were published online October 24 in the Lancet.

ACE Inhibitor Better First Choice?

Current American guidelines recommend multiple first-line drug classes for hypertension, including thiazide or thiazide-like diuretics (THZs), ACE inhibitors, angiotensin-receptor blockers (ARBs), calcium-channel blockers (CCBs), and, in some cases, beta blockers. The best one to start with in patients with newly diagnosed hypertension remains unclear.

Using six administrative claims and three electronic health record databases, the researchers analyzed data on nearly 4.9 million patients who initiated antihypertensive monotherapy from July 1996 to March 2018 and were followed for a median of 2 years; 25% of patients were followed for more than 5 years.

The researchers examined 55 health outcomes: three primary end points (acute myocardial infarction [AMI], heart failure [HF] hospitalization, and stroke); six secondary cardiovascular disease (CVD) outcomes: (CV) event, ischemic stroke, hemorrhagic stroke, HF, sudden cardiac death, and unstable angina); and 46 safety outcomes. They generated 22,000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all drug classes and outcomes across databases.

The most commonly initiated drug class was ACE inhibitor (48%), followed by THZ (17%), dihydropyridine CCB (dCCB; 16%), ARB (15%), and non-dihydropyridine CCB (ndCCB; 3%).

The most commonly prescribed agents within each class were lisinopril (80%), hydrochlorothiazide (94%), amlodipine (85%), losartan (45%), and diltiazem (62%).

Overall, the results showed generally comparable effectiveness between drug classes, "which confirms the current US guidelines about first-line drugs to treat hypertension, that most of them are roughly equivalent," Hripcsak said.

However, THZs showed better primary effectiveness than ACE inhibitors for all three primary end points, with event rates on initial treatment roughly 15% lower overall.

For AMI, the adjusted HR was 0.84 (95% CI, 0.75 - 0.95). For HF hospitalization, the aHR was 0.83 (95% CI, 0.74 - 0.95). For stroke, the aHR was 0.83 (95% CI, 0.74 - 0.95).

The safety profiles also favored THZs over ACE inhibitors. ACE inhibitors had a higher risk for all-cause mortality, CV mortality, angioedema, transient ischemic attack, dementia, renal disorders, thrombocytopenia, gastrointestinal side effects, and cough than THZs.

THZs had higher risk for hypokalemia and hyponatremia than other drug classes.

Cornerstone of Initial Therapy

Based on their results, the authors say initiating antihypertensive therapy with a thiazide instead of an ACE inhibitor "carries potential to avoid many major cardiovascular events and warrants further study."

They calculate that about 3100 major CV events among the patients who initiated an ACE inhibitor could have been avoided had they first started on a thiazide diuretic.

"Diuretics really should be the cornerstone of initial treatment unless the patient is intolerant of them," Suzanne Oparil, MD, coauthor of a Lancet Comment, told theheart.org | Medscape Cardiology.

"The importance of diuretics is under-rated by many clinicians," said Oparil, who is with the Division of Cardiology, University of Alabama at Birmingham.

"In this study, diuretics were only used for initial treatment of hypertension in 17% of the cases. I think people don't like diuretics because patients don't like having to urinate more frequently, but you can get around that by timing of the dosing," she added.

Oparil and coauthor Christopher Ives, MD, also from University of Alabama at Birmingham, say the lack of blood pressure measurements at baseline and after treatment and data on assessment of adherence to prescribed medication are limitations of the study.

The fact that it was limited to newly diagnosed hypertensive patients starting monotherapy is another limitation.

"Current hypertension guidelines recommend, on the basis of expert opinion, that combination therapy might be considered if initial blood pressure exceeds a specific threshold. Future analyses should compare initial combination therapies," Ives and Oparil suggest.

Funding for the study was provided by the US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council. Hripcsak has received grant funding from Janssen for research not directly related to this study. A complete list of author disclosures is available with the original article. Ives and Oparil have declared no competing interests.

Lancet. Published online October 24, 2019. Abstract, Comment

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