Angioedema is a life-threatening adverse drug reaction associated with renin-angiotensin-aldosterone system (RAAS) inhibitors, characterized by localized swelling in the deep layers of the skin. Well-established evidence indicates an up to fivefold higher incidence of RAAS inhibitor-induced angioedema in self-identified Black patients compared to White patients. The mechanisms underlying this health disparity remain poorly understood and are often attributed to race, a poor proxy for interindividual genetic similarity and social stressors. Here, we investigate the genetic and social determinants of RAAS inhibitor-induced angioedema as well as the etiology of this racial difference. In particular, we (1) discovered OTULINL and CRABP1 as novel loci for RAAS inhibitor-induced angioedema, (2) confirmed the importance of bradykinin for this adverse drug reaction, (3) reported the first significant genome-wide association in self-identified Black participants, (4) identified alcohol use as an important social determinant, (5) demonstrated the strong role of variants enriched in 1000 Genomes African superpopulation-like genomes as the driver of racially differential angioedema risk, and (6) demonstrated the combined role of polygenic effect size and allele frequency differences in explaining these racial differences. Our results suggest that a clinical precision medicine tool may more precisely predict for whom RAAS inhibitors should be avoided (to prevent angioedema) compared to using race. These findings ultimately underscore the value of an evidence-based approach to removing race from treatment guidelines, which carries less potential harm than other removal strategies.

To summarize the efficacy and safety of angiotensin II receptor blockers (ARBs) compared to angiotensin-converting enzyme inhibitors (ACEIs) in primary hypertension and other compelling indications, focusing on cardiovascular and renal outcomes. Relevant randomized controlled trials and systematic reviews were identified through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases. Additional clinical evidence was manually retrieved from the PubMed database. Inhibitors of the renin-angiotensin-aldosterone system are cornerstone therapies in the management of primary hypertension with or without comorbidities. ACEIs have traditionally been preferred by many clinicians due to their long-standing use, robust efficacy, and low cost. However, current evidence supports comparable efficacy between ARBs and ACEIs in managing primary hypertension, cardiovascular disease, heart failure, chronic kidney disease, and diabetes. Importantly, ARBs consistently demonstrate a more favourable safety profile in head-to-head trials, particularly in reducing cough and angioedema. With most agents now available as generics, ARBs are also cost comparable. That said, in patients with stage 3 to 5 chronic kidney disease, limited evidence suggests that ACEIs may confer superior renoprotective benefits. In 2022, approximately 11.3% of Canadians were prescribed an ACEI, compared with only 7.7% prescribed an ARB. These findings suggest a disconnect between current prescribing patterns and current evidence, warranting reconsideration of ARBs as a preferred first-line option in many patients. While ARBs and ACEIs demonstrate comparable cardiovascular and renal efficacy across hypertension and other compelling indications, ARBs show a substantially better safety profile in head-to-head comparisons, supporting their broader use in clinical practice. Résumer l’efficacité et l’innocuité des antagonistes des récepteurs de l’angiotensine II (ARA) par rapport à celles des inhibiteurs de l’enzyme de conversion de l’angiotensine (IECA) dans les cas d’hypertension primaire et d’autres indications importantes, en insistant sur les issues cardiovasculaires et rénales. Des revues systématiques et des essais contrôlés randomisés pertinents ont été recensés dans les bases de données MEDLINE, Embase et du Cochrane Central Register of Controlled Trials. D’autres données cliniques probantes ont été extraites manuellement de la base de données PubMed. Les inhibiteurs du système rénine-angiotensine-aldostérone constituent des thérapies fondamentales dans la prise en charge de l’hypertension primaire avec ou sans comorbidités. Les IECA ont traditionnellement été privilégiés par de nombreux cliniciens en raison de leur utilisation de longue date, de leur efficacité robuste et de leur coût peu élevé. Par ailleurs, des données probantes actuelles étayent une efficacité comparable entre les ARA et les IECA dans la prise en charge de l’hypertension primaire, de la maladie cardiovasculaire, de l’insuffiwsance cardiaque, de la néphropathie chronique et du diabète. Avant tout, les ARA démontrent uniformément un profil de sécurité plus favorable dans des essais de comparaison directe, en particulier pour réduire la toux et l’angioœdème. Étant donné que la plupart des agents sont maintenant disponibles sous formes génériques, les ARA sont aussi comparables sur le plan des coûts. Cela étant, chez les patients atteints d’une néphropathie chronique de stade 3 à 5, des données probantes limitées portent à croire que les IECA procureraient des bienfaits supérieurs sur le plan de la protection rénale. En 2022, environ 11,3 % des Canadiens ont reçu une prescription d’IECA par rapport à seulement 7,7 % à qui on a prescrit un ARA. Ces constatations mettent l’accent sur une déconnexion entre les habitudes actuelles de pratique et les données probantes récentes, ce qui mériterait de reconsidérer les ARA comme une option de première intention à privilégier chez de nombreux patients. Si les ARA et les IECA démontrent une efficacité cardiovasculaire et rénale comparable pour l’hypertension et d’autres indications impérieuses, les ARA ont un profil de sécurité considérablement meilleur dans des comparaisons directes, ce qui étaye une utilisation plus généralisée dans la pratique clinique.

Identifying risk factors for hospital admission, intensive care unit (ICU) admission, and intubation in patients presenting to the emergency department (ED) with renin-angiotensin-aldosterone system inhibitor (RAASi) induced angioedema. This single hospital-based retrospective cohort study examined ED visits of adult RAASi angioedema patients between January 1, 2006, and August 31, 2016. Clinical events were recorded over the ED visit and the next 2 months. Data extracted included demographics (age, sex, race), symptoms, exam findings, comorbidities, and medication history, intubation details (including difficulty, methods used), and adverse events (hypoxia, cardiac arrest, death). Patient courses, ICU care need, clinical deterioration, therapies, and length of stay were also documented. Of the 755 patients meeting inclusion criteria from our cohort of 1299 patients, 16.2% required intubation during their admission, with 33% admitted to the ICU and 57% to regular hospital floors. Laryngeal swelling was the strongest predictor of adverse outcomes (OR 133.79, p < 0.001), followed by anterior tongue swelling (OR 4.15, p < 0.001), supporting fiberoptic exam as a valuable step in evaluating RAASi angioedema patients. Lip swelling was associated with a decreased likelihood of adverse outcomes such as intubation (OR 0.55, p = 0.049). Shortness of breath did not reliably predict advanced airway outcomes (p = 0.278). Efficiency models incorporating laryngeal swelling, anterior tongue swelling, and body mass index (BMI) achieved excellent predictive performance (AIC 364.43). In the largest study of single-site RAASi angioedema patients who underwent fiberoptic laryngoscopy at admission, we identified key clinical factors for more effectively triaging patients at risk for significant angioedema complications.

Thrombolytic therapy is linked to angioedema, a serious adverse event, with higher risk when co-administered with renin-angiotensin-aldosterone system inhibitors (RAAS-i), particularly ACE inhibitors. However, this interaction remains incompletely characterized. A multi-modal analysis: (1) USFDA Adverse Event Reporting System (AERS) disproportionality analysis including reporting odds ratio (ROR); (2) case report review; and (3) meta-analysis and trial sequential analysis of observational studies was performed. Drug interactions were evaluated using multiplicative models. Primary outcomes were mortality and life-threatening events. Among 521 USFDA AERS reports, disproportionality signals were noted for alteplase (ROR: 3.1) and tenecteplase (ROR 2.85); and signal strength increased with RAAS-i co-administration. Mortality rates were comparable between thrombolytic monotherapy and thrombolytic - RAAS-i combination. Meta-analysis (24 studies; n = 3,007) confirmed increased risk with RAAS-i (OR: 3.12; 95% CI: 2.01-4.85). Case review (n = 60) showed mainly orofacial presentation (n = 59) within 3 hours, with 42 receiving RAAS-i and 16 requiring advanced airway management. This analysis suggests a consistent association increased angioedema risk with thrombolytic-RAAS-i combination therapy. Findings underscore the importance of careful risk assessment and monitoring in patients receiving RAAS-i therapy, especially those on ACEIs.

Background: Amlodipine has recently been incidentally reported with angioedema and is frequently prescribed with renin-angiotensin-aldosterone system inhibitors (RAAS-i) for hypertension management. While RAAS-i drugs are known to cause angioedema, the risk associated with amlodipine alone or in combination with RAAS-i drugs remains unclear. This study aimed to evaluate the association between amlodipine use and angioedema using pharmacovigilance data. Methods: We analyzed adverse event reports from the US FDA Adverse Event Reporting System using both frequentist and Bayesian approaches. Drug-drug interactions were assessed using multiplicative models. Additionally, we conducted a systematic review of published case reports of amlodipine-associated angioedema. Results: Among 29,661,136 reports, 2076 cases of angioedema were identified (1067 with amlodipine alone, 1009 with amlodipine-RAAS-i combinations). Significant safety signals were detected for amlodipine alone and in combination with aliskiren, specific ACE inhibitors (quinapril, benazepril, trandolapril, fosinopril, perindopril), and certain ARBs (candesartan, losartan). No significant interactions were observed between amlodipine and RAAS-i drugs except for the amlodipine-trandolapril combination. A review of published cases demonstrated definite causality in two cases and possible association in others, with most patients presenting with oropharyngeal/facial edema and achieving complete recovery following drug discontinuation and standard therapy. Conclusions: Our findings suggest a potentially increased risk of angioedema with amlodipine, both as monotherapy and in specific RAAS-i combinations. While these results should not discourage appropriate clinical use, they emphasize the importance of monitoring for angioedema, particularly during therapy initiation. The findings from this study need to be validated in prospective studies for further elucidation of the underlying mechanisms.