Angioedemas associated with renin-angiotensin system blocking drugs: Comparative analysis of spontaneous adverse drug reaction reports

Abstract

Introduction Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes. Methods All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162). Results More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6-2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5-57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0-17.9]) and fibrinolytics (OR 7.8 [1.1-57.2]) was reported more often in ACEi versus ARBs angioedema reports.

Descriptive analysis of adverse drug reaction reports in children and adolescents from Germany: frequently reported reactions and suspected drugs

“…Additionally, due to the large number of ADR reports, an individual case assessment of all ADR reports with regard to the causal association and the quality of the ADR report was not performed. However, all submitted ADR reports are suspected cases of ADRs and 77.0% of our random sample had an at least possible causal relationship which is in line with observations of other previous analyses [21,22,61]. Although, the completeness score of our random sample was 0.6 [0.6-0.7] and thus below the 0.8 expected for a well-documented report [30], it should be noted, that certain minimal criteria have to be present to allow the submission to EudraVigilance [20].…”

“…A more detailed description about reporting obligations and reporting channels can be found elsewhere [1,21,22].…”

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019

“…The BfArM is responsible for chemically defined drugs, the PEI is responsible for monoclonal antibodies, vaccines etc. [ 14 – 16 ]. The competent authorities forward these ADR reports to EudraVigilance, the ADR database of the European Medicines Agency (EMA).…”

内服中止後も発作が続いたアンギオテンシンII受容体拮抗薬とDPP4阻害薬による血管性浮腫の1例(Case of recurrent angioedema after discontinuation of angiotensin II receptor antagonists and DPP4 inhibitor)

“…海外の大規模比較臨床試験では，ARBを投与された2,954例の0.07%に血管性浮腫が出現したと報告された 9)。本邦においてもARBによる血管性浮腫の報告は散見される。長嶋らは，1983年から2010年までの報告例をまとめ 10)，その後，2019年12月までに医学中央雑誌で検索しえたARBによる血管性浮腫の本邦報告症例は6例 11), 12), 13), 14), 15), 16)であった。以上をまとめると，ARBによる血管性浮腫は1983年から2019年までに10例報告があり，内訳は男性6例，女性4例，年齢は62歳から77歳（平均69.0歳）であった。全例が顔面に浮腫を来し，そのうち舌の浮腫も伴った例が7例であった。経口気管挿管を要した例が3例，輪状甲状靭帯切開を要した例が1例であった。ARBによる血管性浮腫の特徴として，ACE阻害薬に比較して基礎にアレルギー素因を持つことが多いと報告されている 9)。また同文献において，ARB阻害薬内服中に血管性浮腫を発症した群は非発症群と比較して有意にDPP4阻害薬を併用していた 9)と報告された。本症例も同様にARBを内服中DPP4阻害薬を開始後に症状の増悪を認めた。…”

“…ARB内服中の血管性浮腫の再発に関しての文献は非常に少ないが，薬剤中止後10日以上経過して再発した症例も散見される 19), 23)。血管性浮腫14例を報告したTakiらは，ACE阻害薬による血管性浮腫6例は全例で無再発であったが，ARBによる血管性浮腫3例は2例で再発し，うち1例は1か月以上経過して初回再発を認めたとし，ARBではより再発を認めやすく，かつ遅発性となる可能性について言及した 19)。近年の報告においてもARBはACE阻害薬に比較して初発後1か月以上経過しての再発が多いとされ 9)，本症例のように薬剤中止後も遅発性に再発を認めうる点には注意が必要である。また，本症例からはARBによる薬剤性浮腫においてもACE阻害薬による血管性浮腫と同様に，薬剤中止後3か月程度までは再発を認めうると示唆された。…”