Drug-induced AED due to bradykinin excess may be overdiagnosed

Researchers in France cite use of blood pressure meds ACEIs and ARBs

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
An illustration of a woman making an announcement using a megaphone.

A significant proportion of people diagnosed with drug-induced angioedema due to using certain blood pressure medications — namely angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin 2 receptor blockers (ARBs) — were misdiagnosed, according to a recent report from France.

These patients, who continued to experience recurrent angioedema attacks more than six months after stopping the medications, were largely considered to have a different type of angioedema driven by immune mast cells, rather than the bradykinin-signaling molecule normally implicated in the medication-induced form of the condition.

Researchers believe that this overdiagnosis of ACEI/ARB-induced angioedema could lead not only to improper use of certain bradykinin-targeted medications, but also to unneeded discontinuations of ACEI/ARB treatment that will “deteriorate the management of severe cardiovascular conditions.”

The study, “Over diagnosis of bradykinin angioedema in patients treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers,” was published in the World Allergy Organization Journal.

Recommended Reading
This illustration shows an intravenous or into-the-vein infusion being administered via a patient's right arm.

Possible treatment of ACE inhibitor-induced angioedema symptoms ID’d

ACEIs and ARBs are classes of medications commonly used to treat and manage high blood pressure and to prevent cardiovascular disease. Both ultimately lead to increases in a blood pressure-regulating molecule called bradykinin.

However, bradykinin is a known mediator of the under-the-skin swelling attacks that characterize angioedema. As such, bradykinin-mediated angioedema may be a rare, but serious side effect of using these medications, particularly in the case of ACEIs.

Of note, this type of drug-induced angioedema is not an allergic reaction to the medication, but rather a consequence of its mechanism. As such, this type of angioedema is typically unresponsive to treatment with allergy medications like antihistamines and is not accompanied by hives, or welts.

Drug-induced angioedema diagnosis often difficult

Diagnosing drug-induced angioedema can be difficult because attacks may not be immediate. Indeed, they can appear days to months after treatment begins.

According to international recommendations, a diagnosis of drug-induced angioedema means swelling attacks may occur up to six months after stopping treatment. If they occur outside of that window, patients may be re-categorized as having a different type of angioedema.

Targeting prevalence of recurrence

In this study, scientists in France aimed to determine the prevalence of recurrent angioedema in patients who had stopped using ACEIs or ARBs more than six months ago.

The study included a total of 121 people who were referred to the clinic between 2007 and 2018 for suspected angioedema while being treated with ACEIs and ARBs. All patients were unresponsive to antihistamines and none had welts.

All participants were prompted to stop using the medications once angioedema occurred.

A total of 93 patients with a mean age of 66.7 years, who were compliant with this recommendation and were not lost to follow-up, were included in the analysis. Overall, the mean time using ACEI/ARB treatment before angioedema first occurred was 55 months, or about 4.5 years.

Ultimately, 27 patients (29%) experienced angioedema recurrence more than six months after they stopped using ACEI/ARBs. The mean time to recurrence outside of that six-month window was 10.5 weeks.

Moreover, 11 patients developed hives, which was linked to recurrent angioedema in nine of them.

Per current guidelines, patients who did not have recurrent angioedema or hives more than six months after stopping treatment were still considered to have a final, accurate diagnosis of ACEI/ARB-induced, bradykinin-mediated angioedema (59%).

The remaining 41% of patients who had recurrent attacks and/or hives were instead diagnosed with chronic spontaneous urticaria — hives with no known cause — or idiopathic non-histaminergic angioedema, also known as mast cell-driven angioedema (cases without hives).

While drug-induced angioedema normally is driven by bradykinin excess, mast cell-driven angioedema is instead thought to arise from chronic dysregulation of immune mast cells, which can be a long-term consequence of medications or other exposures.

Good responses to Firazyr (icatibant) — an on-demand angioedema treatment that counteracts the effects of bradykinin — were predictive of ultimately being diagnosed with ACEI/ARB-induced angioedema, whereas facial (but not oral) localization of swelling attacks was more frequent in the mast-cell angioedema group.

Bradykinin-targeted therapies overused?

According to scientists, the results generally indicate that ACEI/ARB-induced angioedema might be overdiagnosed at the time angioedema first emerges. This also might mean that bradykinin-targeted therapies like Firazyr are overused.

“Overdiagnosis of ACEI/ARB-induced bradykinin angioedema could lead to overuse of [Firazyr] and consequently high medico-economic costs,” the researchers wrote.

Moreover, the misdiagnosis could mean that patients are kept off of ACEI or ARB medications when they may not need to be.

Future studies are needed to “establish the long-term safety of continuing ACEI/ARB in case of mast-cell driven angioedema,” the researchers wrote.

The scientists believe that future studies also should investigate potential biomarkers that can distinguish bradykinin from mast cell-driven angioedema. According to the team, such markers would “facilitate the management of these patients.”