Angioedema Risk No Higher With ARNI Than With ACE Inhibitors, ARBs

Amid debate over HF drug initiation and titration: a new study supports starting with sacubitril/valsartan, not switching to it.

Angioedema Risk No Higher With ARNI Than With ACE Inhibitors, ARBs

Patients with heart failure who start taking sacubitril/valsartan (Entresto; Novartis) do not appear to have a greater risk of angioedema than do those who opt for an ACE inhibitor or ARB instead, an analysis of administrative claims data shows.

In fact, new users of the angiotensin receptor-neprilysin inhibitor (ARNI), as well as those who switched from an ACE inhibitor to sacubitril/valsartan, had lower risks of the adverse event compared with new ACE inhibitor users, Efe Eworuke, PhD (IQVIA Real World Solutions, Falls Church, VA), and colleagues report. This result is contrary to what was suggested by randomized data.

Risk of angioedema was higher, however, when patients switched from an ACE inhibitor or an ARB to sacubitril/valsartan when compared with initial treatment with the ARNI, particularly when the change in treatment occurred recently.

Those findings came from an analysis of the US Food and Drug Administration’s Sentinel system published online ahead of the January 31, 2023, issue of the Journal of the American College of Cardiology.

At the time the study was conducted, Eworuke worked for the FDA’s Center for Drug Evaluation and Research. She said her comments to TCTMD reflect her personal opinions and not the positions of the FDA or the US Department of Health & Human Services.

Clinically, what the findings suggest, according to Eworuke, is that there should be “more focus on continuous surveillance” for potential adverse events when patients are substituting sacubitril/valsartan for an ACE inhibitor or ARB, and on “reiterating to patients to wait 36 hours before switching” consistent with practice guidelines.

“For future studies,” she added, “it would be nice to do something more prospective and actually think of a time frame that would be safer for patients to initiate the [ARNI].”

Concerns About Angioedema

Sacubitril/valsartan was first approved by the FDA in July 2015 for use in patients with chronic heart failure with reduced ejection fraction (HFrEF), gaining a broader indication that includes at least some patients with preserved ejection fraction (HFpEF) in February 2021. Those approvals were based on findings from the PARADIGM-HF and PARAGON-HF trials, respectively.

Eworuke et al note that the potential risk of angioedema is of interest because of what happened with omapatrilat, a combination of an ACE inhibitor and ARNI whose development was sunk due to a higher rate of the complication versus an ACE inhibitor in patients with hypertension.

Angioedema occurred more frequently with sacubitril/valsartan than with the comparator agent in both PARADIGM-HF and PARAGON-HF, particularly in Black patients, although the difference reached significance only in the latter trial. “In both trials, the angioedema events appeared mild, not requiring treatment or the use of antihistamines as rescue therapy,” Eworuke et al point out.

Still, a history of angioedema related to previous ACE inhibitor/ARB therapy is listed as a contraindication on the label of sacubitril/valsartan, and a 36-hour washout period is advised when switching to or from an ACE inhibitor.

To explore the issue outside of the trial setting as part of the FDA’s surveillance activities, the investigators turned to claims data within the agency’s Sentinel system. They compared angioedema risks in several groups of patients: new users of sacubitril/valsartan, news users of ACE inhibitors or ARBs, and patients who switched from an ACE inhibitor or ARB to the ARNI. After propensity-score matching, the comparisons encompassed patient numbers ranging from 35,702 to 69,639.

The primary analysis focused on new users of the agents and showed that those who were initially treated with sacubitril/valsartan had a significantly lower risk of angioedema compared with those on an ACE inhibitor (HR 0.18; 95% CI 0.11-0.29). There was a similar trend when the comparator was new users of ARBs, but the difference didn’t reach statistical significance (HR 0.59; 95% CI 0.35-1.01).

These findings contrast with those from the clinical trials, in which angioedema was at least numerically higher with sacubitril/valsartan. As a potential explanation for the discrepancy, Eworuke et al point to differences in the designs of the studies: the trials included run-in periods on ACE inhibitor/ARB treatment to weed out patients with an increased risk for angioedema; most of the angioedema in the trials was mild, and these types of events might not be captured in claims data; and the observational data set includes all ACE inhibitors and ARBs, not just enalapril and valsartan, which were the comparators in the trials.

The researchers also looked at risks among patients who started on an ACE inhibitor or ARB and then switched to the ARNI. Those who switched to sacubitril/valsartan from an ACE inhibitor had a lower risk of angioedema compared with new users of ACE inhibitors (HR 0.31; 95% CI 0.23-0.43), but there was no difference in risk between those who switched from an ARB to the ARNI versus new ARB users.

Compared with the group initially treated with sacubitril/valsartan, it appeared that switching to the ARNI from an ARB was associated with a greater risk of angioedema than switching from an ACE inhibitor, particularly if the change was recent (within the last 14 days).

“Although our data are unable to delineate the exact timing of the switch in relation to angioedema diagnosis, this finding suggests that continued surveillance of new initiators of sacubitril/valsartan who recently switch from an ACE inhibitor to an ARB may be needed to monitor for angioedema,” the investigators write. “Additional studies will be needed to characterize the risk of angioedema in relation to the timing of the switch.”

As for why the risk of angioedema might be higher when switching from an ARB versus an ACE inhibitor, they say, “it is possible that prescribers and patients may not be as vigilant when switching from an ARB because an ACE inhibitor is a well-known risk factor for angioedema.”

Support for First-line ARNI?

Commenting for TCTMD, Robert Page II, PharmD (University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora), who wrote an accompanying editorial, said the real-world study “has a significant impact on practice actually, and shows where pharmacovigilance crosses into implementation into clinical practice.”

What all of the different comparisons suggest is that “perhaps instead of trialing an ACE and an ARB before an ARNI . . . just go directly to de novo ARNI. And that is a strategy that’s now recommended within the 2022 heart failure guideline,” he said, adding the caveat that these observational data cannot be used to prove causation.

Page acknowledged that an obstacle to going with the ARNI over an ACE inhibitor or an ARB is the high cost of the newer drug, but he pointed out that many third-party plans, Medicaid, and the Veterans Health Administration have started to cover it.

Eworuke, too, pointed to cost as one consideration—along with safety and efficacy—when choosing between the agents, noting that sacubitril/valsartan has been shown to improve clinical outcomes in the trials. “That would be a clinical decision based on the desired effectiveness and also the history of safety in making a treatment selection,” she said.

Page said the study raises some interesting questions, pointing to uncertainty about why patients who switch from an ACE inhibitor or ARB to sacubitril/valsartan have a higher risk of angioedema compared with new ARNI users; why switching to sacubitril/valsartan from an ARB would be riskier than switching from an ACE inhibitor; and whether the washout period after ACE inhibitor/ARB treatment should be longer before starting the ARNI.

But the main take-home point right now, he said, is: “Start with your ARNI first. It not only gives you the bigger bang for your buck in terms of mortality, but it looks like it may actually be safer from the standpoint of angioedema.”

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Eworuke E, Welch EC, Haug N, et al. Comparative risk of angioedema with sacubitril-valsartan vs renin-angiotensin-aldosterone inhibitors. J Am Coll Cardiol. 2023;81(4):321-331.

  • This project was supported by Task Order 75F40119F19002 under Master Agreement 75F40119D10037 from the FDA.
  • Eworuke and Page report no relevant conflicts of interest.