Real-world study shows better safety profile although antihypertensives were equally effective

Angiotensin receptor blockers (ARBs) are a better bet than angiotensin-converting enzyme (ACE) inhibitors for first-line hypertension therapy, according to results of a real-world study.

The study, done with data from eight databases in four countries from 1996 to 2018, found no statistically significant difference in the primary outcome of acute myocardial infarction (MI) for ACE versus ARBs (hazard ratio 1.11, 95% CI 0.95 to 1.32), reported George Hripcsak, MD, MS, of Columbia University Irving Medical Center in New York City, and co-authors.

Additionally, there was no statistically significant difference for heart failure (HF), stroke, or composite cardiovascular (CV) events, they noted in Hypertension.

However, patients on ARBs had significantly lower risk of angioedema, pancreatitis, cough, and gastrointestinal (GI) bleeding, leading the authors to conclude that ARBs offered “a better safety profile. These findings support preferentially prescribing ARBs over ACE inhibitors when initiating treatment for hypertension.”

The study was part of the large-scale LEGEND-HTN project and included data from 2.3 million patients starting treatment with ACE and about 674,000 starting on ARBs. Patients came from databases in the U.S., Germany, and South Korea. The LEGEND project “applies high-level analytics to perform observational research on hundreds of millions of patient records within OHDSI’s [Observational Health Data Sciences and Informatics] international database network,” according to a 2019 press release from Columbia University.

“LEGEND was developed by the OHDSI collaborative to do clinical research that fills in evidence gaps left by randomized controlled trials and gives doctors and patients the information they need to support the best care,” explained Hripcsak in the release. “Patients may not realize that we don’t know all the side effects and comparative efficiency of most drugs.” A 2020 analysis of national data showed that the U.S. public’s awareness and control of hypertension declined in 2017-2018.

In previous findings from the LEGEND network, thiazide diuretics turned in better effectiveness, with fewer side effects, than ACE inhibitors as first-line antihypertensive drugs. In 2019 American College of Cardiology perspective on those results, Melvyn Rubenfire, MD, of University of Michigan Health in Ann Arbor, noted that “[t]rialists and hypertension specialists might consider this ’fake news,’ but the list of authors is very impressive. The [LEGEND] method equates to 22,000 traditional observational studies, which could have had the bias of investigators for both results and publication (p-hacking).”

In 2020, a LEGEND-driven study revealed that chlorthalidone, which is the guideline-recommended diuretic for lowering blood pressure (BP), causes more serious side effects than hydrochlorothiazide. “Every day, doctors and patients face a decision about which thiazide diuretic to use—and are waiting for evidence—so this high-quality study provides the best evidence so far and suggests that the one we have been using most often, hydrochlorothiazide, is better,” commented co-author Harlan Krumholz, MD, SM, of Yale University in New Haven, Conn., in an OHDSI statement. “Unless shown otherwise, that is the choice I am recommending. Until now I had been leaning toward chlorthalidone as many have thought that it was better, having been tested versus placebo in some of the classic studies. I didn’t expect that we would see hydrochlorothiazide to be superior in real-world practice.”

More recently, LEGEND researchers assessed the effectiveness and safety of third-generation β-blockers as first-line treatment for hypertension, and found that they were associated with significantly higher risk of stroke than ACE inhibitors and thiazide. In a supporting study, the authors showed “high internal validity” of the LEGEND results, and that “evidence generated by LEGEND is of high quality and can inform medical decision-making where evidence is currently lacking.”

For the current study, they used a “retrospective new-user comparative cohort design and included all patients initiating antihypertensive treatment with a single agent, either an ACE inhibitor or an ARB.” The primary outcome was acute MI, HF, stroke, and composite CV events of the three previous outcomes plus sudden cardiac death.

“We chose these outcomes due to their clinical importance to patients and providers, which also reflects the design of previous blood pressure trials such as SPRINT,” Hripcsak and co-authors explained.

The largest database included in the study, the IMB MarketScan Commercial Claims and Encounters had >779,000 patients on ACE inhibitors and >230,000 on ARBs, for <785,000 total years of follow-up, they added. About 39% of these patients were female, while 27% had dyslipidemia, 17% had diabetes, and 9% had pre-existing heart disease.

The majority of new users on ACE inhibitors took lisinopril (80%) followed by ramipril and enalapril. The most common ARB was losartan (45%) followed by valsartan and olmesartan.

The authors reported the following for the primary outcomes:

  • HF: HR 1.03 (95% CI 0.87-1.24).
  • Stroke: HR 1.07 (95% CI 0.91-1.27).
  • Composite CV events: HR 1.06 (95% CI 0.90-1.25).

For secondary and safety outcome, ACE inhibitors showed an increased risk for the following versus ARBs:

  • Acute pancreatitis: HR 1.32 (95% CI 1.04-1.70, P=0.02).
  • Angioedema: HR 3.31 (95% CI 2.55-4.51, P<0.01).
  • Cough: HR 1.32 (95% CI 1.11-1.59, P<0.01).
  • GI bleed: HR 1.18 (95% CI 1.01-1.41, P=0.04).
  • Abnormal weight loss: HR 1.1 (95% CI 1.01-1.41, P=0.04) with a decreased risk for abnormal weight gain (HR 0.84, 95% CI 0.74-0.98, P=0.04).

Hripcsak’s group pointed out that previous studies has offered similar results for ACE inhibitors and ARBs for a variety of outcomes, including mortality, stroke, and HF. “However, these studies also note the numerous limitations of existing literature,” such as “the scarcity of head-to-head studies, particularly [randomized clinical trials, RCT],” they wrote, while the current study offers a head-to-head comparison of first-line therapy in treatment-naive patients with high BP.

And in professional guidelines, “several classes of medications are equally recommended as first-line therapies. With so many medicines to choose from, we felt we could help provide some clarity and guidance to patients and health care professionals,” wrote co-author RuiJun Chen, MD, MA, of the Geisinger Medical Center in Danville, Penn., in an American Heart Association statement.

Study limitations included its observational nature; the fact that the results only apply to first-line antihypertensives, and may not be relevant to patients who are switching medications; and the dominance of lisinopril, which “may have a disproportionately large effect on the drug class comparison as compared with other ACE inhibitors,” the authors wrote.

They acknowledged that some experts have argued that ACE inhibitors have a longer history and have been studies in placebo-controlled RCTs, but “given the length of time both drug classes have been on the market, wide availability of inexpensive generic forms, proven efficacy in hypertension, and widespread use, it is unlikely that future large RCTs will be conducted to directly compare ACE inhibitors for ARBs for the treatment of hypertension… real-world evidence… maybe both the most appropriate and only context in which to compare the effects of these 2 commonly used medications.”

  1. In a real-world study, there was no statistically significant difference in the primary outcome of acute myocardial infarction, heart failure, stroke, or composite cardiovascular events, for angiotensin-converting enzyme (ACE) inhibitors versus angiotensin receptor blockers (ARBs).

  2. Patients on ARBs had significantly lower risk of angioedema, pancreatitis, cough, and gastrointestinal bleeding versus those on ACE inhibitors.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was supported by the NIH, the National Science Foundation, the Bio Industrial Strategic Technology Development Program/Ministry of Trade, Industry & Energy (MOTIE, Korea), and the Korea Health Technology R&D Project/Korean Health Industry Development Institute/Ministry of Health and Welfare, Republic of Korea.

Hripcsak reported support from the National Library of Medicine (NLM) and Janssen Research & Development. Krumholz reported relationships with, and/or support from, UnitedHealth, IBM Watson Health, Element Science, Aetna, Facebook, the National Center for Cardiovascular Diseases (Beijing), Hugo Health, Refractor Health, Centers for Medicare & Medicaid Services, Medtronic/FDA, Medtronic/Johnson & Johnson, and the Shenzen Center for Health Information, as well as the law firms Siegfried & Jensen, Arnold & Porter, and Ben C. Martin. Chen reported being an NLM post-doctoral fellow at Columbia University during the study.

Co-authors reported support from, and/or relationships with, the NIH, the National Science Foundation, Janssen Research & Development, Johnson & Johnson, the National Heart, Lung, and Blood Institute, the Health Services and Resources Administration, Shire, Bayer, and the Australian National Research and Medical Council, as well as the law firms Simon Greenstone Panatier, Williams Hart, Lanier, and Kazan Mcclain Satterley & Greenwood. Two co-authors are employees of Janssen Research & Development.

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Topic ID: 74,6,730,6,192,916,925