Aspirin hypersensitivity and intolerance

Thanks to its broad availability, low-cost, and solid evidence supporting its safety and efficacy in patients with atherosclerotic cardiovascular disease, aspirin represents the backbone of antiplatelet therapy worldwide for over 40 years.1 Although low-dose aspirin is usually well tolerated, it is relatively common in clinical practice to deal with patients in which its use is contraindicated because of a history of hypersensitivity or intolerance. The issue arising from the inability to use aspirin as antiplatelet treatment is particularly relevant in the acute setting of the management of patients with acute coronary syndrome (ACS), given that aspirin is a life-saving therapy in these patients.2 Moreover, it represents a relevant issue also in patients with an indication to dual antiplatelet therapy (DAPT), such as chronic coronary syndrome (CCS) patients undergoing percutaneous coronary interventions.3 Surprisingly, the management of these patients remains uncertain, with clinical algorithms mostly limited to local internal protocols, and international guidelines often lacking specific recommendations on how to deal with patients with aspirin hypersensitivity or intolerance.4,5 Specifically, there is no mention on how to manage patients with aspirin hypersensitivity or intolerance in the latest 2023 European Society of Cardiology (ESC) guidelines on ACS.4 With regards to patients with CCS, 2019 ESC guidelines only provide specific recommendations for patients with aspirin intolerance, suggesting the use of clopidogrel in patients requiring single antiplatelet therapy [Class I, level of evidence (LoE), B] and the use of prasugrel or ticagrelor in patients requiring DAPT (Class IIb, LoE C).5 Collectively, ESC guidelines do not provide any advice for ACS patients with a history of aspirin hypersensitivity or intolerance, and only provide recommendations for CCS patients with a history of aspirin intolerance, with no mention to patients with aspirin hypersensitivity.4,5 Notably, the use of prasugrel or ticagrelor monotherapy in lieu of DAPT is only based on expert consensus, lacking supporting evidence (LoE C).3 For cardiologists to deal with these patients, it is key to acknowledge that aspirin hypersensitivity and aspirin intolerance represent two different conditions, with underlying different pathophysiological mechanisms requiring different clinical approaches. There are two different types of adverse drug reactions: type A (‘augmented’), which are often dose-dependent and predictable on the basis of the pharmacology of the drug, and type B (‘bizarre’), which are idiosyncratic and not predictable on the basis of the pharmacology.6 Aspirin intolerance represents a type A reaction, mostly characterized by gastro-intestinal symptoms (i.e. dyspepsia) or bleeding related to its use. Conversely, aspirin hypersensitivity represents a type B reaction, which, as in the case of hypersensitivity to aspirin and/or other non-steroideal anti-inflammatory drugs, is rare and unpredictable, occurring in a limited subset of patients. A detailed description of the classification of aspirin hypersensitivity goes beyond the aim of this article.7 In general, aspirin hypersensitivity is mainly characterized by respiratory or cutaneous manifestations resulting from non-allergic hypersensitivity reactions (i.e. pseudoallergic reactions), but, more rarely, allergic hypersensitivity reactions (i.e. allergic reactions) have also been reported.7 The distinction of these two entities as separate is key for the implementation of clinical strategies. For patients with suspected aspirin intolerance, the use of alternative antithrombotic regimens such as P2Y12 inhibitors, indobufen, or rivaroxaban 2.5 mg twice daily represents the strategy of choice.8–10 On the other, for patients with suspected aspirin hypersensitivity, aspirin desensitization or low-dose aspirin challenge protocols have shown to be safe and effective in both ACS and CCS settings, allowing for the long term use of low-dose of aspirin for the vast majority of patients.11–13 Recommendations within practice guidelines on implementation of strategies to be used in patients with aspirin hypersensitivity or intolerance is warranted to enhance the ability of treating patients with standardized and effective protocols. Conflict of interest: M.G. declares that he has received honoraria from Terumo, outside the present work. G.O. has no disclosures to declare. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol–Myers Squibb, Chiesi, CSL-Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, outside the present work; D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and Scott R. MacKenzie Foundation. No new data were generated or analysed in support of this research.