Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Tranexamic acid for angiotensin converting enzyme inhibitor induced angioedema: A retrospective multicenter study.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-Is) prevent the breakdown of bradykinin and can lead to life threatening angioedema. Tranexamic acid is an antifibrinolytic that inhibits formation of precursors involved in bradykinin synthesis and, in case reports, has been described as a potential treatment for ACE-I angioedema. METHODS: This retrospective study included patients who presented to the emergency department (ED) from January 2018 to August 2021 with angioedema while taking an ACE-I. Patients who received tranexamic acid (treatment group) were compared with patients who did not receive tranexamic acid (control group). Primary outcome was length of stay (LOS). Secondary outcomes evaluated included ICU admissions, intubations, and safety events. RESULTS: A total of 262 patients were included in this study (73 treatment; 189 control). Overall, the median ED LOS was longer in the treatment group than controls (20.9 h vs 4.8 h, p < 0.001). ICU admission rates were higher in the treatment group (45% vs 16%, p < 0.001). More patients were intubated in the treatment group (12% vs 3%, p = 0.018). No difference was seen between the treatment group and the controls for return within 7 days, complications related to thrombosis, and death. In patients presenting with severe angioedema symptoms who were admitted to the hospital, median LOS was not different between the two groups (58.7 h vs 55.7 h, p = 0.61). CONCLUSIONS: Patients who received tranexamic acid had increased ED LOS, rates of ICU admission, and need for intubation. This finding may be related to the severity of presentation. Administration of tranexamic acid appears safe to use in ACE-I angioedema. Prospective randomized controlled studies should be considered to determine whether tranexamic acid is an effective treatment for ACE-I angioedema.

A Case of Trauma-Related Angioedema of the Airway in a Patient on an Angiotensin Receptor Blocker.

BACKGROUND Angioedema is non-pitting edema that occurs in the deep layers of the skin and subcutaneous tissue due to vascular leakage of plasma resulting from 1 of 2 major pathophysiological processes: mast cell-mediated angioedema and bradykinin-mediated angioedema. While it is a well-recognized adverse reaction of angiotensin-converting enzyme inhibitors, the association of angioedema with angiotensin receptor blockers is relatively less studied. Direct local trauma, although rarely, has been suggested to induce angioedema under certain conditions. We present a unique case of direct, local, trauma-related angioedema in a patient on an angiotensin receptor blocker. CASE REPORT The patient, an 83-year-old woman on telmisartan for hypertension, hit her neck against the edge of a chair during a fall. Shortly thereafter, she developed progressive airway compromise due to airway angioedema, as noted on direct laryngoscopy. A contrast CT scan of the neck also noted edema of the periglottic and supraglottic regions. She required intravenous corticosteroid administration and intubation in the emergency room and was successfully extubated 3 days after admission. She had no prior history of angioedema or allergy. We hypothesize that increased levels of circulatory bradykinin in the setting of telmisartan, combined with a local release of bradykinin from trauma, was the main pathophysiologic cause of the angioedema. CONCLUSIONS This case report highlights the rare and often forgotten adverse reaction of angioedema with use of angiotensin receptor blockers and confirms the finding of local trauma as a possible trigger.

Tenecteplase-associated orolingual angioedema: A case report and literature review.

PURPOSE: Orolingual angioedema (OA) secondary to administration of thrombolytic therapy is a rare, but serious, known adverse effect. Despite the lack of robust evidence for their use, C1 esterase inhibitors are recommended by guidelines for the treatment of refractory thrombolytic-associated OA. This report highlights the use of a C1 esterase inhibitor in a patient with tenecteplase-associated OA unresolved by antihistamine and corticosteroid therapy. SUMMARY: A 67-year-old white male with a history of hypertension managed with lisinopril presented to the emergency department with acute onset of slurred speech and left-sided hemiparesis. Following workup, an outside hospital's neurology stroke team suspected an acute infarct and determined the patient to be a candidate for tenecteplase. Approximately 1 hour after tenecteplase administration, the patient began complaining of dyspnea and mild oral angioedema. Immediate interventions for OA management included intravenous therapy with dexamethasone 10 mg, diphenhydramine 25 mg, and famotidine 20 mg. After an additional 30 minutes, the patient's OA symptoms continued to progress and a C1 esterase inhibitor (Berinert) was administered. Shortly after administration of the C1 esterase inhibitor, the patient's symptoms continued to worsen, ultimately leading to endotracheal intubation. Following intubation, symptom improvement was noted, and the patient was safely extubated after 30 hours. CONCLUSION: Although rare, OA is a potentially life-threatening complication of tenecteplase therapy and requires prompt pharmacological intervention to optimize patient outcomes. Currently, no single agent or treatment algorithm exists that has shown significant efficacy or safety in the setting of thrombolytic-associated OA. Until data are available for C1 esterase inhibitors in this application, these inhibitors should only be considered if there is continued symptom progression after intravenous administration of corticosteroids and antihistamines.

Ipsilateral orolingual angioedema following rhTNK-tPA administration for acute ischemic stroke.

Recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA), a genetically modified variant of conventional alteplase with longer half-life and higher fibrin specificity, has now emerged as a reasonable choice for thrombolytic treatment of acute ischemic stroke (AIS) in China. Orolingual angioedema is a rare but potentially life-threatening complication of intravenous thrombolysis. Currently, there is no documented evidence of orolingual angioedema occurring after thrombolysis with rhTNK-tPA. In this report, we present a unique case of a 75-year-old Chinese man who developed ipsilateral orolingual angioedema following the administration of rhTNK-tPA for AIS. Our case emphasizes the need for caution when using rhTNK-tPA due to its potential to induce ipsilateral orolingual angioedema.

Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

The real-world safety of sacubitril / valsartan among older adults (≥75): A pharmacovigilance study from the FDA data.

BACKGROUND: Heart failure is a major cause of morbidity and mortality among older adults. Sacubitril-Valsartan (Sac/Val) has been shown to improve patients' outcomes; however, its safety profile among older adults has not been adequately examined. We therefore aimed to examine its safety profile among this population. METHODS: We conducted a retrospective pharmacovigilance study utilizing the FDA's database of safety reports (FAERS). We employed disproportionality analysis comparing Sac/Val to angiotensin receptor blockers (ARBs). We aim to evaluate the reporting of pre-defined adverse events associated with Sac/Val (hypotension, acute kidney injury (AKI), hyperkalemia and angioedema) in two age groups: adults (< 75 years) and older adults (≥ 75). For each subgroup, we calculated reporting odds ratio (ROR) and compared them by calculating P for interaction. RESULTS: The FAERS database encompassed 18,432 unique reports of Sac/Val. Of them, 12,630 (68.5%) subjects were adults (< 75 years), and 5802 (31.5%) were older adults (≥ 75 years), with a median age (IQR) of 68 (59-77). When compared to ARBs, Sac/Val was associated with higher reporting of hypotension, lower reporting of acute kidney injury (AKI) and hyperkalemia, and similar reporting of angioedema. Notably, we did not observe a significant interaction between the age subgroups and the risk estimates (AKI: Pinteraction = 0.72, hyperkalemia: Pinteraction = 0.94, hypotension: Pinteraction = 0.31, and angioedema: Pinteraction = 0.61). CONCLUSIONS: In this postmarking study, none of the prespecified adverse events was reported more frequently in older adults. These findings provide reassurance for safety use of Sac/Val in older adults.

Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension.

BACKGROUND: Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study. OBJECTIVE: To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension. METHODS: The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing. RESULTS: An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed. CONCLUSION: The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Icatibant averting mechanical ventilation in acute ischemic stroke patient with alteplase-induced orolingual angioedema.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline. METHODS: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant. RESULTS: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration. CONCLUSIONS: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke.

Pharmacogenomic knowledge and awareness among diverse patients treated with angiotensin converting enzyme inhibitors.

We developed novel electronic phenotyping algorithms for the BioMe biobank data, which accurately identified angiotensin converting enzyme inhibitor (ACEi)-induced angioedema cases and controls. A survey was mailed to all 1075 patients and 91 were returned. Over a third reported that prescribing physicians had not discussed with them the concepts of interindividual drug response variability or adverse event risk, and 73% of patients were previously unaware of pharmacogenomics; however, most patients were interested in having pharmacogenomic testing. Moreover, 67% of patients indicated that pharmacogenomic testing would positively influence their medication compliance. In addition to identifying an innovative approach to define biobank cohorts for pharmacogenomic studies, these results indicate that patients are interested in pharmacogenomic testing, which could translate to improved adherence.

A Rare Case of Losartan-Induced Visceral Angioedema.

The following describes a case of isolated visceral angioedema related to an angiotensin II receptor blocker (ARB) medication. Additionally, we discuss the pathophysiology of drug-induced angioedema, various presentations that can be encountered, and the leading theorized mechanisms of how renin-angiotensin-aldosterone system (RAAS) blocking medications lead to angioedema. The goal of sharing this case is to help increase awareness of the possibility of ARB-induced angioedema and to recommend keeping visceral angioedema as part of the differential diagnosis when presented with a patient who is taking an angiotensin converting enzyme inhibitor (ACEI) or ARB medication that is experiencing gastrointestinal symptoms of unclear etiology.

Losartan-Induced Angioedema with Acute Hypoxemic Respiratory Failure (Anaphylaxis): A Case Report.

Angioedema is a condition characterized by swelling of the skin or mucosa resulting from loss of vascular integrity that leads to swelling of mucosal tissues and can lead to life-threatening respiratory compromise. Drug-induced angioedema is not a frequent side effect seen with angiotensin receptor blockers (ARBs), particularly when there are no other contributing risk factors like a prior episode. Few studies reported subsequent angioedema episodes after ARB use in patients who had a prior episode with angiotensin converting enzyme inhibitors; however, there are very few cases that documented non-fatal angioedema after ARB as the only therapy. We report a rare case of life-threatening anaphylaxis after losartan use. We hope that our case will bring awareness to this rare but fatal side effect in order to quickly recognize it and encourage further research.

Angioedema without urticaria after recent initiation of celecoxib.

Angioedema is potentially life-threating swelling of integument and mucosa that has multiple potential aetiologies with varying mechanisms. Drug-induced angioedema is often easily correlated with the offending agent and can be prevented with discontinuation of the medication. Many medications have now been implicated in drug-induced angioedema but the two most common are ACE inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). This case highlights severe angioedema secondary to celecoxib and reviews varying aetiologies of angioedema and NSAID hypersensitivity reactions.

Late-onset postoperative angioedema triggered by angiotensin-converting enzyme inhibitor: An emergent airway forethought.

Angioedema is a potentially life-threatening condition due to the risk of airway compromise leading to deterioration of respiratory function, hypoxia, and ultimately, cardiopulmonary arrest. It can be either unprovoked or triggered by pharmaceutical agents, emotional or physiologic factors, upper airway trauma, or surgical stress. A 46-year-old man previously prescribed perindopril developed angioedema of the tongue 4 h after being discharged from the Post Anesthesia Care Unit (PACU). A multidisciplinary team was called and they outlined an airway management strategy to use in the event of worsening. The strategy consisted of either fiberoptic intubation by an anesthesiologist or surgical tracheostomy performed by the surgical team, both performed with the patient awake and in spontaneous ventilation. The aim of this case report is to raise awareness that angioedema is a potentially life-threatening condition. For optimal management, it is important to prepare in advance a detailed airway management strategy to be implemented by a multidisciplinary team.

Concomitant medication in patients with bradykinin-mediated angioedema - there's more than ACE inhibitors.

Bradykinin-mediated angioedema is a rare, non-allergic, potentially life-threatening disease. ACE inhibitor-induced angioedema and hereditary angioedema (HAE) are the two most common presentations. Therapeutic options, pathophysiology and diagnosis continue to be investigated, with considerable progress in HAE over the last few decades. For all patients with bradykinin-mediated angioedema, there are several medications that should be avoided or administered with caution. Some of the triggering medications are well known, while others are suspected or of unknown significance. A common denominator is that there is no approved therapy for bradykinin-mediated angioedema as a drug side effect. Some medications, such as tissue plasminogen activator, have a higher incidence of angioedema with potential airway compromise than ACE inhibitors, although this fact is widely underappreciated. In this review, we aim to summarize what is currently known and recommended about concomitant medication in HAE patients and the interaction of other bradykinin-influencing drugs.

Bradykinin Metabolism and Drug-Induced Angioedema.

Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many cardiovascular and diabetic drugs may cause BK-mediated AE. Angiotensin-converting enzyme inhibitors (ACEIs) and neprilysin inhibitors impair BK catabolism. Dipeptidyl peptidase-IV (DPP-IV) inhibitors reduce the breakdown of BK and substance P (SP). Moreover, angiotensin receptor blockers, thrombolytic agents, and statins may also induce BK-mediated AE. Understanding pathophysiological mechanisms is crucial for preventing and treating drug-induced AE.