https://orcid.org/0009-0009-5717-4435
Abstract
Aspirin has been known for a long time and currently stays as a cornerstone of antithrombotic therapy in cardiovascular disease. In patients with either acute or chronic coronary syndromes undergoing percutaneous coronary intervention aspirin is mandatory in a dual antiplatelet therapy regimen for prevention of stent thrombosis and/or new ischaemic events. Aspirin is also currently a first-option antithrombotic therapy after an aortic prosthetic valve replacement and is occasionally required in addition to oral anticoagulants after implantation of a mechanical valve. Presumed or demonstrated aspirin hypersensitivity is a main clinical problem, limiting the use of a life-saving medication. In the general population, aspirin hypersensitivity has a prevalence of 0.6%–2.5% and has a plethora of clinical presentations, ranging from aspirin-exacerbated respiratory disease to anaphylaxis. Although infrequent, when encountered in clinical practice aspirin hypersensitivity poses for cardiologists a clinical dilemma, which should never be trivialized, avoiding—as much as possible—omission of the drug. We here review the epidemiology of aspirin hypersensitivity, provide an outline of pathophysiological mechanisms and clinical presentations, and review management options, starting from a characterization of true aspirin allergy—in contrast to intolerance—to suggestion of desensitization protocols.
Aspirin allergy: a practical guide for cardiologists. ACS, acute coronary syndrome; CAD, coronary artery disease; CCS, chronic coronary syndrome; GPI, glycoprotein IIb/IIIa inhibitor; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; TAVI, transcatheter aortic valve implantation.
Case vignette 1
A 53-year-old male patient is admitted to the emergency department because of an anterior ST-elevation myocardial infarction (STEMI). He refers having had an allergic reaction to aspirin a few years before, in the form of a cutaneous rash. Since then, he has abstained from the intake of aspirin-containing medications but often uses other non-steroidal anti-inflammatory drugs (NSAIDs) as pain killers, without ensuing problems. Emergency coronary angiography performed within 90 min of pain onset reveals a single-vessel coronary artery disease (CAD), with complete thrombotic occlusion of the mid-left anterior descending coronary artery. A percutaneous coronary intervention (PCI) with stent implantation [zotarolimus-eluting 18 × 4 mm (Resolute Onyx®)] is performed despite concerns related to aspirin hypersensitivity, judging the benefits of PCI here higher than risks. Immediately after coronary angiography and before primary PCI, the patient is first loaded with intra-muscular 6-methylprednisolone 80 mg and promethazine 25 mg, and then receives oral aspirin 325 mg and prasugrel 60 mg loading. The subsequent course of repeated aspirin intake upon gradual withdrawal of corticosteroids and antihistamines is uneventful.
Case vignette 2
A 60-year-old male patient candidate to aortic valve replacement with a bioprosthesis ‘refers’ of a non-better-specified allergic reaction to aspirin, which is reported in the medical charts. Because of this, in the immediate post-operative phase, he is started on a course of enoxaparin at anticoagulant doses (1 mg/kg twice daily, in the presence of normal creatinine clearance) as a bridge to warfarin, aiming at an international normalized ratio (INR) between 2 and 3. The patient shows a slow rise of INR values reaching an INR value of 1.9 on Day 10. On Day 11, he develops a severe pleuro-mediastinal bleeding requiring the suture of a small leak from the right internal mammary artery, possibly related to the recent surgery. Because of ‘aspirin allergy’ reported in his history, despite this severe bleeding complication, bridging therapy with enoxaparin and warfarin is resumed. After 10 days, with an INR value of 1.9 and while on enoxaparin and warfarin 5 mg/day, he experiences a severe, deadly, intracranial haemorrhage.
Introduction
The intake of aspirin [acetylsalicylic acid (ASA)], as well as of other non-steroidal anti-inflammatory agents, can lead to several hypersensitivity (allergic) and intolerance reactions, developing within minutes to hours since drug administration. Hypersensitivity reactions (HRs) are abnormal, immunologic or non-immunologic, reactions to the ingested drugs, while pharmacological, non-allergic ‘intolerance’ reactions are non-immunologic side effects believed to result from a higher-than-expected effect of the drug due to its expected mechanism of action.1,2
The most common symptoms of HRs to aspirin include rhino-conjunctivitis, bronchospasm, urticaria/angioedema, and anaphylaxis, but rarer and more dreadful reactions such as the Stevens–Johnson syndrome/toxic epidermal necrolysis or interstitial nephritis have been described as well3 (Table 1).
Classification of aspirin hypersensitivity reactions
| Cross-reactive (pharmacological) | Selective (immunological) | Intolerance (pseudo-allergy) | Rare reactions | |
|---|---|---|---|---|
| Subtypes | NERD, NECD, NIUA | SNIUAA, SNIDHR | None | None |
| Mechanism | COX-1 inhibition→LT hyperproduction | Type I HS/IgE mediated (SNIUAA) Type IV HS/T cell mediated (SNIDHR) | COX-1 inhibition→PG hypoproduction Psychosomatic | Variable, mostly idiopathic |
| Selectivity for specific NSAIDs | None | Yes | None | Yes |
| Clinical picture | Respiratory triad of rhino-conjunctivitis, nasal polyps, and asthma (NERD), urticaria (NECD), anaphylaxis | Asthma, urticaria/angioedema, anaphylaxis, maculo-papular exanthemas, delayed urticaria | Dyspepsia, GI bleeding | Aseptic meningitis, Stevens–Johnson syndrome, erythema multiforme |
| Desensitization possible | Yes for NERD, less effective in NECD; not in severe anaphylaxis | Yes for asthma and urticaria/angioedema; not in severe anaphylaxis and delayed reactions | Unnecessary, consider PPI use | Not advisable |
| Cross-reactive (pharmacological) | Selective (immunological) | Intolerance (pseudo-allergy) | Rare reactions | |
|---|---|---|---|---|
| Subtypes | NERD, NECD, NIUA | SNIUAA, SNIDHR | None | None |
| Mechanism | COX-1 inhibition→LT hyperproduction | Type I HS/IgE mediated (SNIUAA) Type IV HS/T cell mediated (SNIDHR) | COX-1 inhibition→PG hypoproduction Psychosomatic | Variable, mostly idiopathic |
| Selectivity for specific NSAIDs | None | Yes | None | Yes |
| Clinical picture | Respiratory triad of rhino-conjunctivitis, nasal polyps, and asthma (NERD), urticaria (NECD), anaphylaxis | Asthma, urticaria/angioedema, anaphylaxis, maculo-papular exanthemas, delayed urticaria | Dyspepsia, GI bleeding | Aseptic meningitis, Stevens–Johnson syndrome, erythema multiforme |
| Desensitization possible | Yes for NERD, less effective in NECD; not in severe anaphylaxis | Yes for asthma and urticaria/angioedema; not in severe anaphylaxis and delayed reactions | Unnecessary, consider PPI use | Not advisable |
COX, cyclooxygenase; GI, gastrointestinal; HS, hypersensitivity; LT, leukotriene; NECD, NSAID-exacerbated cutaneous disease; NERD, NSAID-exacerbated respiratory disease; NIUA, NSAID-induced urticaria/angioedema; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PPI, proton pump inhibitor; SNIDHR, single NSAID-induced delayed hypersensitivity reaction; SNIUAA, single NSAID-induced urticaria/angioedema and anaphylaxis.
Classification of aspirin hypersensitivity reactions
| Cross-reactive (pharmacological) | Selective (immunological) | Intolerance (pseudo-allergy) | Rare reactions | |
|---|---|---|---|---|
| Subtypes | NERD, NECD, NIUA | SNIUAA, SNIDHR | None | None |
| Mechanism | COX-1 inhibition→LT hyperproduction | Type I HS/IgE mediated (SNIUAA) Type IV HS/T cell mediated (SNIDHR) | COX-1 inhibition→PG hypoproduction Psychosomatic | Variable, mostly idiopathic |
| Selectivity for specific NSAIDs | None | Yes | None | Yes |
| Clinical picture | Respiratory triad of rhino-conjunctivitis, nasal polyps, and asthma (NERD), urticaria (NECD), anaphylaxis | Asthma, urticaria/angioedema, anaphylaxis, maculo-papular exanthemas, delayed urticaria | Dyspepsia, GI bleeding | Aseptic meningitis, Stevens–Johnson syndrome, erythema multiforme |
| Desensitization possible | Yes for NERD, less effective in NECD; not in severe anaphylaxis | Yes for asthma and urticaria/angioedema; not in severe anaphylaxis and delayed reactions | Unnecessary, consider PPI use | Not advisable |
| Cross-reactive (pharmacological) | Selective (immunological) | Intolerance (pseudo-allergy) | Rare reactions | |
|---|---|---|---|---|
| Subtypes | NERD, NECD, NIUA | SNIUAA, SNIDHR | None | None |
| Mechanism | COX-1 inhibition→LT hyperproduction | Type I HS/IgE mediated (SNIUAA) Type IV HS/T cell mediated (SNIDHR) | COX-1 inhibition→PG hypoproduction Psychosomatic | Variable, mostly idiopathic |
| Selectivity for specific NSAIDs | None | Yes | None | Yes |
| Clinical picture | Respiratory triad of rhino-conjunctivitis, nasal polyps, and asthma (NERD), urticaria (NECD), anaphylaxis | Asthma, urticaria/angioedema, anaphylaxis, maculo-papular exanthemas, delayed urticaria | Dyspepsia, GI bleeding | Aseptic meningitis, Stevens–Johnson syndrome, erythema multiforme |
| Desensitization possible | Yes for NERD, less effective in NECD; not in severe anaphylaxis | Yes for asthma and urticaria/angioedema; not in severe anaphylaxis and delayed reactions | Unnecessary, consider PPI use | Not advisable |
COX, cyclooxygenase; GI, gastrointestinal; HS, hypersensitivity; LT, leukotriene; NECD, NSAID-exacerbated cutaneous disease; NERD, NSAID-exacerbated respiratory disease; NIUA, NSAID-induced urticaria/angioedema; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PPI, proton pump inhibitor; SNIDHR, single NSAID-induced delayed hypersensitivity reaction; SNIUAA, single NSAID-induced urticaria/angioedema and anaphylaxis.
The cornerstone role of aspirin in secondary prevention of CAD, as well as in other pro-thrombotic conditions, may render the omission of aspirin extremely problematic, often posing a true therapeutic dilemma, as described in the two introductory case vignettes. We here review current knowledge on aspirin hypersensitivity, eventually focusing on practical approaches to circumvent the problem in cardiology clinical settings.
Definitions
Aspirin belongs to the class of NSAIDs, inhibiting inflammation mostly through inhibition of the cyclooxygenase (COX)-2 isozyme expressed in inflammatory cells. Aspirin has also, however, unique properties as an antithrombotic agent, exerted by irreversible covalent binding of platelet COX-1, in turn inhibiting the production of thromboxane (TX) A2 and, consequently, of TXA2-mediated platelet aggregation. The irreversible binding of the acetyl moiety to COX-1, prolonging its inactivation for the entire platelet life span, makes aspirin also unique among antiplatelet agents, with antithrombotic effects occurring, upon repeated administration, even at doses 10 times lower—in the order of 75–150 mg/day—than those necessary for an anti-inflammatory action.4
Notably, and similar to all drugs,5 aspirin can elicit HRs. Aspirin side effects can be classified based on pathophysiological mechanisms or on their clinical presentation (Table 1). Pathophysiological mechanisms of true aspirin hypersensitivity include immunologic [aspirin-specific immunoglobulin (Ig) E-mediated responses and T cell responses] and non-immunologic (also termed pharmacological) mechanisms.2 The latter are the result of direct COX-1 and COX-2 inhibition by aspirin, shifting arachidonic acid (AA) metabolism from COX metabolites towards unbalanced lipoxygenase metabolites, most notably towards an overproduction of leukotrienes (LTs), responsible for vasoconstriction, bronchoconstriction, and pro-inflammatory consequences. Clinically, three major scenarios are observed for HRs: respiratory manifestations, collectively defined as aspirin-exacerbated respiratory disease (AERD, epitomized by the triad of rhinitis, asthma, and nasal polyps); cutaneous manifestations (urticaria and/or angioedema); and systemic reactions, up to anaphylaxis. In addition to these manifestations, aspirin is also often considered responsible for intolerance (‘pseudo-allergy’) symptoms of various kinds, as well as of rare syndromes, such as aseptic meningitis, the Stevens–Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), and erythema multiforme, mostly thought to occur on an immunologic basis as well (Table 1).
Epidemiology and clinical presentations
The prevalence of aspirin hypersensitivity in the general population has been found to range from 0.6% to 2.5%.6 In a cohort of 9565 patients with CAD, 142 patients (1.5%) reported a history of some manifestations of aspirin hypersensitivity. Of these, a minority (30 patients) had a clinical history compatible with cutaneous and/or respiratory reactions. The other patients described a variety of disparate adverse effects, mostly consisting of gastrointestinal (GI) intolerance and bleeding, not truly classifiable as aspirin hypersensitivity.7 A recent study8 assessed the prevalence of aspirin hypersensitivity and classified the different types of reactions and their clinical implications in both an ambulatory cardiology setting and among patients admitted for a PCI. Through a review of medical records related to a total of 11 375 patients, reported prevalence was 1.88% (n = 214). Skin reactions were the most common presentation [40 (19%)], followed by angioedema [10 (4.6%)], respiratory reactions [9 (4.2%)], and anaphylaxis [6 (2.8%)]. Of the entire cohort, 69 patients (32.2%) were mistakenly labelled as ‘allergic’ for having GI symptoms instead.
These data reveal the difficulty in having correct estimates of the true prevalence of aspirin hypersensitivity due to frequent mislabelling of adverse effects.1 Discriminating between true aspirin hypersensitivity and other adverse effects to aspirin is essential, as misclassification may lead to unnecessary avoidance in patients who might otherwise benefit from aspirin use.
Mechanisms
The latest European Academy of Allergy and Clinical Immunology (EAACI) classification of HRs to NSAIDs,9 including aspirin, considers underlying mechanisms leading to different clinical manifestations. According to this classification, true HRs to NSAIDs are divided into cross-reactive HRs (CRHRs), characterized by frequent episodes also triggered by chemically unrelated NSAIDs, and selective HRs (SHRs) induced by one or more NSAIDs belonging to the same chemical group. While CRHRs recognize a pharmacological mechanism common to all NSAIDs linked to COX-1 and COX-2 inhibition, SHRs are mainly due to immune-mediated mechanisms (IgE or T cell mediated).9,10 Notably, not all phenotypes of HRs to NSAIDs fall into this classification, as in the case of mixed phenotypes, suggesting that other disease pathways may be involved.11
Cross-reactive hypersensitivity reactions
Cross-reactive hypersensitivity reactions to NSAIDs occur in susceptible individuals and include three main clinical phenotypes (Figure 1):
NSAID-exacerbated respiratory diseases (NERDs).
NSAID-exacerbated cutaneous diseases (NECDs).
NSAID-induced urticaria/angioedema (NIUA).
Mechanisms for cross-reactive hypersensitivity among non-steroidal anti-inflammatory drugs and mediators involved. Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase activity, shifting arachidonic acid metabolism towards production of leukotrienes. LTA4 produced by eosinophils and basophils is reduced in activated mast cells to LTB4, with relevant chemoattractive properties, and LTC4, which in turn is further metabolized to LTD4 and LTE4, all with relevant bronchoconstrictive activity. Enhanced production of other mediators such as IL-33 and tissue stromal lymphopoietin produced by the inflamed respiratory epithelium activates innate lymphoid cell 2, with further release of pro-inflammatory IL-5 and IL-13 and subsequent recruitment of eosinophils. Created with BioRender.com. 5-LO, 5 lipoxygenase; COX, cyclooxygenase; LT, leukotriene; NSAIDs, non-steroidal anti-inflammatory drugs; PG, prostaglandin
These side effects are the result of COX-1 and COX-2 inhibition by NSAIDs, with consequent reduction in prostaglandin (PG) synthesis, mainly PGE2, and a concurring deviation of AA metabolism towards the production of cysteinyl LTs (cysLTs), including LTC4, LTD4, and LTE4.12 These LTs, produced by mast cells, are responsible for the development of bronchial hyperreactivity and exacerbation of nasal symptoms. The involvement of the innate immune system in NERDs has also been proposed, through activation of innate lymphoid cell type 2, with the subsequent release of type 2 inflammatory mediators, including interleukin (IL)-5 and IL-13. Here IL-5, together with PGD2 produced by activated mast cells, actively contributes to the recruitment of eosinophils in the airways, leading to tissue eosinophilia and the amplification of airway inflammation.13 Initially identified and characterized in patients with NERDs, the pharmacological mechanisms of CRHRs linked to COX inhibition were then extended to other CRHR phenotypes, including NECDs and NIUA.
Selective hypersensitivity reactions
Besides CRHRs, all NSAIDs, including aspirin, can trigger SHRs characterized by immediate or non-immediate/delayed onset of symptoms, lack of cross-reactivity with other NSAIDs, and variable clinical presentations (Figure 2). Unlike CRHRs, SHRs recognize immune-mediated mechanisms, including type I (IgE-mediated), as in the case of single NIUA and anaphylaxis (SNIUAA), and type IV (cell-mediated) mechanisms, as in the case of single NSAID-induced delayed HRs (SNIDHRs).9,14 Single NSAID-induced urticaria/angioedema and anaphylaxis typically occurs within 1 h after NSAID administration and, according to the intensity of symptoms, can range from mild to severe. Due to their low molecular weight, NSAIDs or their metabolites need to conjugate with proteins to trigger a reaction, which requires a previous contact with the drug (sensitization). During the sensitization phase, dendritic cells can process and present drug–protein components, inducing antigen-specific B lymphocytes to trigger T-helper (Th) 2 lymphocytes to produce IgEs specific to NSAIDs. Following a subsequent drug exposure, the antigen crosslinks a membrane-bound IgE on the surface of mast cells and basophils, stimulating the release of pre-formed mediators (e.g. histamine and tryptase) and the production of newly generated mediators (e.g. cysLTs, PGD2, kinins, and cytokines). Histamine is the principal mediator of IgE-mediated reactions, determining—within few minutes—vasodilatation, bronchial and smooth muscle contraction, glandular secretion, and pruritus, all variably present in anaphylaxis.15,16 Unlike SNIUAA, SNIDHRs may occur several hours, but also many days after the initial drug administration, and are often associated with a delayed T cell-dependent mechanism. Maculo-papular exanthemas and delayed urticaria are the most common clinical presentations of this phenotype of SCRHRs induced by NSAIDs. The immunologic mechanisms underlying SNIDHR involve mainly different phenotypes of T lymphocytes, including both CD4+ and CD8+ T cells. Re-exposure to the culprit drug triggers the release of T cell-derived mediators, according to the cell phenotypes activated, including interferon (IFN)-γ, perforin, and granzyme B, with the consequent development of inflammation and/or cell lysis.14 In SNIDHR, other immune cells, such as macrophages, neutrophils, and mast cells, may be involved, contributing to the amplification of inflammatory processes.
Main immune mechanism occurring in single non-steroidal anti-inflammatory drug-induced urticarial and anaphylaxis. After protein conjugation, non-steroidal anti-inflammatory drugs are taken up by dendritic cells (sensitization) and presented to Th2 cells and B cells with subsequent production of specific IgE, which bind to the surface of basophils and mast cells. Upon re-exposure to the same antigen, IgE-mediated degranulation of mast cells occurs, with release of pre-formed mediators such as histamine. Histamine is the main agent responsible for the clinical manifestations of the allergic reaction, namely diffuse vasodilation, bronchial and smooth muscle contraction, mucus secretion, and pruritus. Newly formed mediators (cysteinyl leukotrienes, PGD2, and kinins) are responsible for delayed inflammation. Created with BioRender.com. CysLTs, cysteinyl leukotrienes; Ig, immunoglobulin; NSAIDs, non-steroidal anti-inflammatory drugs; PG, prostaglandin
The clinical challenge for cardiologists
Even just the suspicion of aspirin hypersensitivity represents quite a complex challenge for cardiologists, especially in the setting of CAD, where aspirin has historically played a pivotal role both in primary and secondary prevention of atherothrombotic events.
The 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndromes (CCSs) state that such patients with documented aspirin allergy may receive clopidogrel in primary prevention (class I recommendation, level of evidence B). Prasugrel or ticagrelor monotherapy may be considered after PCI if dual antiplatelet therapy (DAPT) is not a viable option due to aspirin intolerance (class IIb recommendation, level of evidence C), evidently with poor evidence and based on expert consensus opinion.17,18 Dual antiplatelet therapy consisting of aspirin combined with the thienopyridine clopidogrel or—in selected cases and with scanty evidence base—prasugrel or ticagrelor is the standard approach in patients undergoing PCI,19 but so far, the efficacy of single oral antiplatelet agents—without or with an anticoagulant—to prevent stent thrombosis in cases of exclusion of aspirin in the very acute phase after elective stenting has not been investigated in randomized controlled trials.
As much as European guidelines attempt to give alternative options for patients with CCS, albeit with a weak level of evidence, the situation is even more problematic for patients presenting with an acute coronary syndrome (ACS). The most recent 2023 ESC guidelines on ACS,20 as well as previous ones for STEMI21 or non-ST-elevation ACS (NSTE-ACS; unstable angina, non-STEMI),22 do not address the issue of how to deal with patients self-reporting or demonstrating the occurrence of HRs after aspirin intake. The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines, on the other hand, suggest that patients presenting with NSTE-ACS and who are treated conservatively without stent placement may receive clopidogrel monotherapy in case of aspirin hypersensitivity (class I recommendation, level of evidence B).23 Unfortunately, just like European guidelines, the American guidelines do not provide recommendations on how to proceed in the case of ACS patients undergoing PCI and requiring DAPT including aspirin, thus reflecting, once again, the paucity of safe and effective alternatives we have here after stent implantation.
What to do then?
A careful medical history: is it really aspirin hypersensitivity?
A useful, simple, yet extremely effective first step to undertake, especially possible when presented with patients affected by a CCS or generally undergoing elective procedures, is to take a detailed medical history. Just by carefully reviewing the nature of the adverse reactions referred by the patient and accurately noting symptoms experienced, it is often quite simple to discern true HRs from intolerance to aspirin. A history of dyspepsia, GI disturbances, or bleeding is consistent with aspirin intolerance. In this situation, the use of proton pomp inhibitors (PPIs) with or without a concurrent reduction in aspirin dosage (down to 75 mg daily) is sufficient to resolve symptoms in the vast majority of cases and allows patients to safely take their medication. The administration of aspirin twice daily (50 mg b.i.d.)24 can be reasonably extended also to such situations.
If the patient reports a history of respiratory symptoms (rhino-conjunctivitis, asthma or respiratory difficulties, or angioedema), skin manifestations (erythema or urticaria), or systemic manifestations (including anaphylaxis) after aspirin or other NSAID intake, these point to the past occurrence of true hypersensitivity to aspirin either due to pharmacological reactions caused by COX-1 inhibition (probable with AERDs/NERDs) or immunologic (IgE- or T cell-mediated) responses (more probable for NECDs or NIUA). This subset of patients, usually a minority, requires a different therapeutical approach, as none of the measures detailed above would be of any benefit.
Desensitization
Over the years, various desensitization protocols have been proposed that would make aspirin use possible in patients with less severe forms of true aspirin hypersensitivity. Aspirin desensitization protocols consist of administering increasing doses of the drug over fixed time periods, until the therapeutic dose is reached. If HRs occur during the procedure, symptomatic treatment is administered, and the patient is subsequently given the same dose of aspirin until he/she becomes tolerant.1,2,25
After 1980, in the General Clinical Research Center at the Scripps Clinic, a desensitization protocol has been consistently applied, consisting of a full day of placebos, followed by oral aspirin challenges with escalating doses every 3 h of 30, 60, and 100 mg on Day 2 and 150, 325, and 650 mg on Day 3. If a reaction occurred, doses were paused, antiallergic treatment provided, and then doses were repeated starting from the tolerated one, leading to effective desensitization.26 While effective, such a slow protocol consumed, in the best scenario, at least 3 days of hospital time and at one point appeared prohibitive for cost and time. In addition, it was shown that there is a poor correlation between history of severe asthmatic reactions to anti-inflammatory doses of aspirin and oral aspirin challenges, with mild and easily manageable asthmatic reactions occurring with as low as 60 mg.27 This led to the acknowledgement that aspirin desensitization can also be safely performed in outpatient clinics. Severe bronchospasm was always infrequent even in the absence of premedication. Subsequently, the introduction of montelukast, a cysLT receptor inhibitor, led to the practical disappearance of severe bronchospasm,28 so that such treatment is now widely adopted in cases of AERD, which can be suspected with high reliability in patients who have rhinosinusitis and asthma exacerbated by exposure to NSAIDs. It has been reported that if the patient gives a clear history of ingesting a NSAID followed by respiratory symptoms, he/she has a >80% chance of having AERD elicited by aspirin challenge.29
At the same time, shortened intervals between escalating doses (from 180 to 90 min) proposed by an international expert committee30 have been widely adopted without relevant safety concerns. A history of the evolution of desensitization protocols has been published,26 showing the relevant progress in this area, leading to faster and faster protocols,31–34 still requiring, in any case, a few hours to completion. A comparison of the details of the original Scripps (slow) protocol and the Wong (as an example of a widely tested rapid) protocol is provided in Table 2,26,31 and a shorter summary of five selected protocols proposed after 2003 in prospective studies is provided in Table 3.35–39 A meta-analysis of 15 reports consisting of 480 ACS patients with known previous hypersensitivity to aspirin reported a pooled desensitization success rate of 98.3%.40 There were no statistical differences in outcomes between protocols ≤2 h and >2 h in duration. Protocols including escalations with >6 doses were associated with success rates higher than those with ≤6 doses. At a follow-up between 1 and 46 months (mode at 12 months), no hypersensitivity adverse events were reported. The authors concluded that aspirin desensitization therapy is safe and effective in patients with ACS. Protocols with >6 dose escalations may be optimal for such patients,40 and those with a shorter duration appear more suitable in cases of ACS requiring prompt coronary stenting.
Desensitization protocols for aspirin allergy
| Scripps (slow)26 | Wong (fast)31 | |
|---|---|---|
| Protocol duration | 3 days | 85–135 min |
| Pre-treatment | Leukotriene antagonists optional | Antihistamine agents, prednisone |
| Steps of the protocol | Day 1: placebo administration at 0, 3, and 6 h Day 2: ASA 30 mg 0 h, ASA 60 mg 3 h, ASA 120 mg 6 h Day 3: ASA 150 mg 0 h, ASA 325 mg 3 h, ASA 650 mg 6 h | Time 0: ASA 0.1 mg 15 min: 0.3 mg 30 min: 10 mg 45 min: 30 mg 60 min: 40 mg 85 min: 81 mg 110 min: 162 mg 135 min: 325 mg |
| Response assessment | FEV1 (spirometry) Vital parameters | Symptoms (respiratory, cutaneous) Vital parameter assessment (BP, HR, RF, SatO2) |
| Mostly indicated in | NECD | NERD |
| Scripps (slow)26 | Wong (fast)31 | |
|---|---|---|
| Protocol duration | 3 days | 85–135 min |
| Pre-treatment | Leukotriene antagonists optional | Antihistamine agents, prednisone |
| Steps of the protocol | Day 1: placebo administration at 0, 3, and 6 h Day 2: ASA 30 mg 0 h, ASA 60 mg 3 h, ASA 120 mg 6 h Day 3: ASA 150 mg 0 h, ASA 325 mg 3 h, ASA 650 mg 6 h | Time 0: ASA 0.1 mg 15 min: 0.3 mg 30 min: 10 mg 45 min: 30 mg 60 min: 40 mg 85 min: 81 mg 110 min: 162 mg 135 min: 325 mg |
| Response assessment | FEV1 (spirometry) Vital parameters | Symptoms (respiratory, cutaneous) Vital parameter assessment (BP, HR, RF, SatO2) |
| Mostly indicated in | NECD | NERD |
ASA, acetylsalicylic acid; BP, blood pressure; FEV1, forced expiratory volume at 1 s; HR, heart rate; NECD, NSAID-exacerbated cutaneous disease; NERD, NSAID-exacerbated respiratory disease; RF, respiratory frequency; SatO2, oxygen saturation.
Desensitization protocols for aspirin allergy
| Scripps (slow)26 | Wong (fast)31 | |
|---|---|---|
| Protocol duration | 3 days | 85–135 min |
| Pre-treatment | Leukotriene antagonists optional | Antihistamine agents, prednisone |
| Steps of the protocol | Day 1: placebo administration at 0, 3, and 6 h Day 2: ASA 30 mg 0 h, ASA 60 mg 3 h, ASA 120 mg 6 h Day 3: ASA 150 mg 0 h, ASA 325 mg 3 h, ASA 650 mg 6 h | Time 0: ASA 0.1 mg 15 min: 0.3 mg 30 min: 10 mg 45 min: 30 mg 60 min: 40 mg 85 min: 81 mg 110 min: 162 mg 135 min: 325 mg |
| Response assessment | FEV1 (spirometry) Vital parameters | Symptoms (respiratory, cutaneous) Vital parameter assessment (BP, HR, RF, SatO2) |
| Mostly indicated in | NECD | NERD |
| Scripps (slow)26 | Wong (fast)31 | |
|---|---|---|
| Protocol duration | 3 days | 85–135 min |
| Pre-treatment | Leukotriene antagonists optional | Antihistamine agents, prednisone |
| Steps of the protocol | Day 1: placebo administration at 0, 3, and 6 h Day 2: ASA 30 mg 0 h, ASA 60 mg 3 h, ASA 120 mg 6 h Day 3: ASA 150 mg 0 h, ASA 325 mg 3 h, ASA 650 mg 6 h | Time 0: ASA 0.1 mg 15 min: 0.3 mg 30 min: 10 mg 45 min: 30 mg 60 min: 40 mg 85 min: 81 mg 110 min: 162 mg 135 min: 325 mg |
| Response assessment | FEV1 (spirometry) Vital parameters | Symptoms (respiratory, cutaneous) Vital parameter assessment (BP, HR, RF, SatO2) |
| Mostly indicated in | NECD | NERD |
ASA, acetylsalicylic acid; BP, blood pressure; FEV1, forced expiratory volume at 1 s; HR, heart rate; NECD, NSAID-exacerbated cutaneous disease; NERD, NSAID-exacerbated respiratory disease; RF, respiratory frequency; SatO2, oxygen saturation.
A selection of recent aspirin desensitization protocols proposed in patients with coronary artery disease
| Silberman et al.35 | De Luca et al.36 | Córdoba-Soriano et al.37 | Rossini et al.38 | Al-Ahmad et al.39 | |
|---|---|---|---|---|---|
| Type of study | Case series | Prospective | Prospective | Prospective multicentre | Prospective |
| Patient population | Total 16 patients 5 (31%) recent STEMI, 2 (12.5%) NSTEMI, 1 healed MI, 2 silent ischaemia, 6 (37.5%) stable CAD | Total 43 patients 5 patients (11%) STEMI, 18 (41%) patients NSTEMI, 20 (46.5%) stable CAD | Total 24 patients 8 patients (33%) STEMI, 16 patients (67%) NSTEMI/unstable angina | Total 330 patients 78 patients (23.6%) STEMI, 111 patients (33.6%) NSTEMI, 67 patients (20%) stable CAD | Total 23 patients 1 patient (4%) pericarditis, 8 patients (35%) NSTEMI, 11 patients (48%) ‘ACS/stable’, 3 patients (13%) ‘ACS/unstable’ |
| Protocol duration | Protocol A: 3.5 h Protocol B: 2.5 h | 4 h | 1.8 h | 5.5 h | Minimum 1 h (low-risk patients) Maximum 3 h (high-risk patients) |
| Aspirin administration route | Oral | Intravenous | Oral | Oral | Oral |
| Pre-treatment | None | None | Antihistamines, corticosteroids, antileukotrienes | None | Antihistamines, antileukotrienes |
| Aspirin dosages (mg) | Protocol A: 1, 2, 4, 8, 16, 32, 64, 100 Protocol B: 5, 10, 20, 40, 75 | 1, 2, 4, 8, 16, 32, 64, 125, 250 | 0.1, 0.3, 1, 3, 10, 25, 50, 100 | 1, 5, 10, 20, 40, 100 | 10, 21, 41, 81, 162 |
| Desensitization effectiveness | 14 patients (87.5%) successfully desensitized | 42 patients (97.6%) successfully desensitized | 24 patients (100%) successfully desensitized | 315 patients (95.4%) successfully desensitized | 23 patients (100%) successfully desensitized |
| Major adverse eventsa | None | None | None | None | None |
| Reference | 35 | 36 | 37 | 38 | 39 |
| Silberman et al.35 | De Luca et al.36 | Córdoba-Soriano et al.37 | Rossini et al.38 | Al-Ahmad et al.39 | |
|---|---|---|---|---|---|
| Type of study | Case series | Prospective | Prospective | Prospective multicentre | Prospective |
| Patient population | Total 16 patients 5 (31%) recent STEMI, 2 (12.5%) NSTEMI, 1 healed MI, 2 silent ischaemia, 6 (37.5%) stable CAD | Total 43 patients 5 patients (11%) STEMI, 18 (41%) patients NSTEMI, 20 (46.5%) stable CAD | Total 24 patients 8 patients (33%) STEMI, 16 patients (67%) NSTEMI/unstable angina | Total 330 patients 78 patients (23.6%) STEMI, 111 patients (33.6%) NSTEMI, 67 patients (20%) stable CAD | Total 23 patients 1 patient (4%) pericarditis, 8 patients (35%) NSTEMI, 11 patients (48%) ‘ACS/stable’, 3 patients (13%) ‘ACS/unstable’ |
| Protocol duration | Protocol A: 3.5 h Protocol B: 2.5 h | 4 h | 1.8 h | 5.5 h | Minimum 1 h (low-risk patients) Maximum 3 h (high-risk patients) |
| Aspirin administration route | Oral | Intravenous | Oral | Oral | Oral |
| Pre-treatment | None | None | Antihistamines, corticosteroids, antileukotrienes | None | Antihistamines, antileukotrienes |
| Aspirin dosages (mg) | Protocol A: 1, 2, 4, 8, 16, 32, 64, 100 Protocol B: 5, 10, 20, 40, 75 | 1, 2, 4, 8, 16, 32, 64, 125, 250 | 0.1, 0.3, 1, 3, 10, 25, 50, 100 | 1, 5, 10, 20, 40, 100 | 10, 21, 41, 81, 162 |
| Desensitization effectiveness | 14 patients (87.5%) successfully desensitized | 42 patients (97.6%) successfully desensitized | 24 patients (100%) successfully desensitized | 315 patients (95.4%) successfully desensitized | 23 patients (100%) successfully desensitized |
| Major adverse eventsa | None | None | None | None | None |
| Reference | 35 | 36 | 37 | 38 | 39 |
Studies included in the table were selected by publication year (range 2005–2023), language (English literature only), type of study (prospective), reported characteristics of study population (total number of patients and inclusion of ACS/STEMI patients), and diversification of steps of the protocol used. Notably, no study reported major adverse events following desensitization.
aIncluding anaphylaxis, severe asthma attack, and severe cutaneous reactions.
A selection of recent aspirin desensitization protocols proposed in patients with coronary artery disease
| Silberman et al.35 | De Luca et al.36 | Córdoba-Soriano et al.37 | Rossini et al.38 | Al-Ahmad et al.39 | |
|---|---|---|---|---|---|
| Type of study | Case series | Prospective | Prospective | Prospective multicentre | Prospective |
| Patient population | Total 16 patients 5 (31%) recent STEMI, 2 (12.5%) NSTEMI, 1 healed MI, 2 silent ischaemia, 6 (37.5%) stable CAD | Total 43 patients 5 patients (11%) STEMI, 18 (41%) patients NSTEMI, 20 (46.5%) stable CAD | Total 24 patients 8 patients (33%) STEMI, 16 patients (67%) NSTEMI/unstable angina | Total 330 patients 78 patients (23.6%) STEMI, 111 patients (33.6%) NSTEMI, 67 patients (20%) stable CAD | Total 23 patients 1 patient (4%) pericarditis, 8 patients (35%) NSTEMI, 11 patients (48%) ‘ACS/stable’, 3 patients (13%) ‘ACS/unstable’ |
| Protocol duration | Protocol A: 3.5 h Protocol B: 2.5 h | 4 h | 1.8 h | 5.5 h | Minimum 1 h (low-risk patients) Maximum 3 h (high-risk patients) |
| Aspirin administration route | Oral | Intravenous | Oral | Oral | Oral |
| Pre-treatment | None | None | Antihistamines, corticosteroids, antileukotrienes | None | Antihistamines, antileukotrienes |
| Aspirin dosages (mg) | Protocol A: 1, 2, 4, 8, 16, 32, 64, 100 Protocol B: 5, 10, 20, 40, 75 | 1, 2, 4, 8, 16, 32, 64, 125, 250 | 0.1, 0.3, 1, 3, 10, 25, 50, 100 | 1, 5, 10, 20, 40, 100 | 10, 21, 41, 81, 162 |
| Desensitization effectiveness | 14 patients (87.5%) successfully desensitized | 42 patients (97.6%) successfully desensitized | 24 patients (100%) successfully desensitized | 315 patients (95.4%) successfully desensitized | 23 patients (100%) successfully desensitized |
| Major adverse eventsa | None | None | None | None | None |
| Reference | 35 | 36 | 37 | 38 | 39 |
| Silberman et al.35 | De Luca et al.36 | Córdoba-Soriano et al.37 | Rossini et al.38 | Al-Ahmad et al.39 | |
|---|---|---|---|---|---|
| Type of study | Case series | Prospective | Prospective | Prospective multicentre | Prospective |
| Patient population | Total 16 patients 5 (31%) recent STEMI, 2 (12.5%) NSTEMI, 1 healed MI, 2 silent ischaemia, 6 (37.5%) stable CAD | Total 43 patients 5 patients (11%) STEMI, 18 (41%) patients NSTEMI, 20 (46.5%) stable CAD | Total 24 patients 8 patients (33%) STEMI, 16 patients (67%) NSTEMI/unstable angina | Total 330 patients 78 patients (23.6%) STEMI, 111 patients (33.6%) NSTEMI, 67 patients (20%) stable CAD | Total 23 patients 1 patient (4%) pericarditis, 8 patients (35%) NSTEMI, 11 patients (48%) ‘ACS/stable’, 3 patients (13%) ‘ACS/unstable’ |
| Protocol duration | Protocol A: 3.5 h Protocol B: 2.5 h | 4 h | 1.8 h | 5.5 h | Minimum 1 h (low-risk patients) Maximum 3 h (high-risk patients) |
| Aspirin administration route | Oral | Intravenous | Oral | Oral | Oral |
| Pre-treatment | None | None | Antihistamines, corticosteroids, antileukotrienes | None | Antihistamines, antileukotrienes |
| Aspirin dosages (mg) | Protocol A: 1, 2, 4, 8, 16, 32, 64, 100 Protocol B: 5, 10, 20, 40, 75 | 1, 2, 4, 8, 16, 32, 64, 125, 250 | 0.1, 0.3, 1, 3, 10, 25, 50, 100 | 1, 5, 10, 20, 40, 100 | 10, 21, 41, 81, 162 |
| Desensitization effectiveness | 14 patients (87.5%) successfully desensitized | 42 patients (97.6%) successfully desensitized | 24 patients (100%) successfully desensitized | 315 patients (95.4%) successfully desensitized | 23 patients (100%) successfully desensitized |
| Major adverse eventsa | None | None | None | None | None |
| Reference | 35 | 36 | 37 | 38 | 39 |
Studies included in the table were selected by publication year (range 2005–2023), language (English literature only), type of study (prospective), reported characteristics of study population (total number of patients and inclusion of ACS/STEMI patients), and diversification of steps of the protocol used. Notably, no study reported major adverse events following desensitization.
aIncluding anaphylaxis, severe asthma attack, and severe cutaneous reactions.
Notwithstanding, desensitization is still largely underutilized in overall clinical practice, especially in cardiology settings,41 and no explicit protocols are provided in current European or American guidelines on the management of ACS or CCS (see above). Physicians are generally cautious or afraid to use desensitization protocols, particularly in patients presenting with ACS, since manifestations of hypersensitivity such as asthma or histamine-mediated coronary spasm may rapidly precipitate the haemodynamic profile of critically ill patients.42 An important aspect to consider, particularly in patients presenting with STEMI, is the time delay that implementation of such protocols would imply. Indeed, even ‘rapid’ desensitization strategies, such as the Wong protocol,31 take too long (hours) to be set up and enacted and would interfere with the urge of revascularization. Cook and White43 suggested that alternative antiplatelet regimens (including a P2Y12 inhibitor alone or oral anticoagulants) according to the cardiologist's experience or preference could be used in unstable patients as a ‘bridge’ until aspirin challenge or desensitization is performed. The same authors, however, recognize that this is not an ideal solution, due to consolidated experience that anticoagulants do not suffice to prevent stent thrombosis.44 Some studies, though, have shown promising outcomes with the use of desensitization protocols not only in patients with NSTEMI, in most cases not ushered immediately to PCI, but also in STEMI patients—in such cases after primary PCI.42,43 One of our previous studies included 69 patients with a history of angioedema, 65 of asthma, and 19 of anaphylactic shock. This series also included 79 STEMI patients.38 Limitations of most, but not all, such studies included relatively small, heterogeneous populations reporting various types of adverse reactions to aspirin, from intolerance to true hypersensitivity, partially hindering their quality. Despite caution in giving general recommendations, and despite the difficulty in the general routine application of desensitization protocols, we emphasize that desensitization may also be attempted in patients who have suffered severe reactions, such as those with a history of anaphylactic reactions after aspirin intake (19 patients in our series).38 Desensitization protocols have, however, not included patients who had suffered from rarer though most severe reactions, including DRESS or the Stevens–Johnson syndrome. It also appears that desensitization is less effective for those forms of aspirin hypersensitivity presenting with cutaneous manifestations such as NECDs, when compared to respiratory forms.3,45
A not-always-possible interdisciplinary approach
As the management of patients with CAD and documented or referred aspirin hypersensitivity is so complex, the choice of the best therapeutic strategy for each patient should ideally be made by an interdisciplinary team that includes cardiologists and immunologists/allergologists. Early co-operation with immunologists and allergologists first allows to better educate cardiologists at identifying those patients who would benefit from aspirin desensitization and separate them from the minority of patients who are unsuitable to desensitization due to the severity of their reported symptoms. An interdisciplinary approach also allows to choose the specific (slow vs. fast) desensitization protocol that better suits individual patients’ needs. In cases of dubious symptoms or unclear history of allergy, aspirin challenge, consisting of a trial of aspirin exposure to test for adverse reactions in a safe, monitored setting with the help of immuno-allergologists, can help to better define the patient's condition and subsequently direct the correct management, progressing to desensitization.46 Last, but not least, interdisciplinary counselling and a follow-up of patients after successful aspirin desensitization ensure that they are correctly taking aspirin thereafter without interruption, as aspirin interruption would result not only in a rebound increase of the risk of thrombotic events47 but also in re-sensitization, at which point the desensitization protocol should be repeated in order to guarantee again the safety of aspirin intake. It should also be highlighted that, after successful desensitization, aspirin tolerance is provided only for the dosage reached during the procedure.
There are, however, frequent cases in cardiology practice where consultation with immuno-allergologists is precluded. This typically occurs in cases of STEMI, when there is a need for rapid myocardial reperfusion of a myocardial territory downstream an occluded coronary artery. Here, a desensitization protocol can be performed also after primary PCI,48 as previously documented by us.38 Our prospective, multicentre, observational study included 7 Italian centres enrolling 330 patients with a history of aspirin hypersensitivity undergoing coronary angiography with intent to undergo a PCI. Adverse effects qualifying the history of aspirin hypersensitivity included urticaria (53.6%), angioedema (20.9%), asthma (19.7%), and anaphylactic reactions (5.8%). Among patients with urticaria/angioedema, 13 patients (3.9%) had a history of idiopathic chronic urticaria. All patients underwent a rapid (5.5 h) aspirin desensitization procedure, performed after cardiac catheterization in 78 patients (23.6%) presenting with STEMI. The desensitization procedure was successful in 95.4% of patients and—notably—in all those with a history of anaphylactic reaction. Among the 15 patients (4.6%) who did not successfully respond to the desensitization protocol, adverse reactions were minor and responded to treatment with corticosteroids and antihistamines. Among patients with successful in-hospital aspirin desensitization, 80.3% continued aspirin for at least 12 months, while aspirin discontinuations (19.7%) occurred because of medical decisions unrelated to HRs.38 Similar findings have been reported in a series of 23 patients with a previous history of respiratory or cutaneous manifestations of aspirin hypersensitivity and presenting with an ACS, including five STEMI cases.36 Notably, unlike the Scripps Clinic protocol that used 400–650 mg of aspirin, in these studies, only up to 100 mg of aspirin was administered. In case of failure of a desensitization attempt, it may be reasonable to proceed with a second attempt, prolonging intervals between the administration of increasing aspirin doses.
A practical algorithm for managing suspected cases of aspirin hypersensitivity in a cardiology setting is depicted in Figure 3, emphasizing the practical aspects of proceeding without consultation with immuno-allergologists in selected cases, when such consultation turns out to be impractical, colliding with the urgency of the cardiological contingency (see also the Graphical Abstract).
A decisional algorithm for management of suspected cases of aspirin hypersensitivity in a cardiology setting. A first essential step in any situation, either acute or non-acute, is to inquire about the nature of the symptoms reported by patients referring aspirin ‘allergy’ to determine the likelihood of true aspirin hypersensitivity. After exclusion of aspirin intolerance, the approach to true aspirin hypersensitivity changes according to the occurrence of an acute (i.e. acute coronary syndrome) or a non-acute situation. In the former case, the need for emergent percutaneous coronary intervention will determine the timing of aspirin desensitization. In situations such as elective percutaneous coronary intervention or aortic valve replacement, choice of appropriate desensitization protocol can be made in most cases in concert with immuno-allergologists. Created with BioRender.com. ACS, acute coronary syndrome; CAD, coronary artery disease; CCS, chronic coronary syndrome; GPI, glycoprotein IIb/IIIa inhibitor; PCI, percutaneous coronary intervention: PPI, proton pump inhibitor
Case vignette discussion
Case 1
In this clinical scenario, the patient suffered from a STEMI. He referred a history of allergic reaction to aspirin (cutaneous rash), with subsequent uneventful use of other NSAIDs. This points to a likely SHR to aspirin, without cross-reactivity with other drugs belonging to the same class. In this case, clinicians weighed the benefits of immediate revascularization against the harm of postponing PCI and decided to proceed to primary PCI after pre-treating the patient with corticosteroids and promethazine. No adverse events subsequently occurred upon withdrawal of the antiallergic medications. This case highlights the challenge cardiologists face when dealing with urgent revascularization in patients felt to be truly allergic to aspirin. In the absence of guideline indications, the decision on how to proceed is left entirely to the clinicians’ judgement. Although effective in an acute setting, the use of corticosteroids and promethazine or similar antihistamines is not a viable option for long-term antiallergic treatment, and particular care should be used when using such drugs due to their potential to ‘mask’ adverse reactions after withdrawal, while on aspirin. A second possible alternative could have been the use of a combination of a P2Y12 inhibitor (possibly prasugrel or ticagrelor, occasionally cangrelor20) and an anticoagulant (unfractionated heparin or a low molecular weight heparin) as a temporary ‘bridge’ after stent deployment to aspirin desensitization with the help of immunologists/allergologists to safely introduce, later on, the lowest reasonable aspirin dose of 75 mg/day, under the (unproven) hypothesis that P2Y12 inhibitors are more effective, when given alone, than aspirin in preventing stent thrombosis. A third alternative—our preferred one and supported by data deriving from previous studies36,38,42—would have been to perform primary PCI on a P2Y12 inhibitor only (ticagrelor, prasugrel, or cangrelor—second choice: clopidogrel20) and proceed to a rapid desensitization protocol without the possible masking effect of corticosteroids and antihistamines. Such a strategy, with desensitization protocols performed safely soon before or soon after PCI, has been proven safe in our experience,38,42 avoiding delaying emergency PCI.
The latter two strategies are—in our opinion—the most viable, even in cases of STEMI, knowing that the occurrence of acute stent thrombosis (<24 h) is mostly related to procedural factors, while what is here most feared is the more insidious subacute stent thrombosis, usually occurring between 24 h and 1 month after the procedure,49 leaving therefore enough time, even after stent deployment, to effectively prevent this ominous complication.
Case 2
Here, the patient presented with an aortic stenosis requiring elective valve replacement with a bioprosthesis. His medical chart reported a history of a non-better-characterized adverse reaction to aspirin, which in this case led the clinicians to choose, after valve replacement, an anticoagulant regimen with enoxaparin bridging to warfarin (target INR 2–3) instead of aspirin. The patient then experienced two major bleeding events during treatment, ultimately passing away due to intracranial bleeding. This case highlights the importance of taking a careful medical history. With a better inquiry, it could have been possible to define the type of adverse reaction that the patient had experienced after aspirin intake, possibly ruling out true aspirin hypersensitivity and thus allowing the use of aspirin. This would have been associated with a much lower risk of intracranial or other major bleeding compared to receiving a vitamin K antagonist with low molecular weight heparin bridging. In case of persisting doubts after a careful history of the previous adverse event, since the patient was scheduled for an elective procedure, aspirin challenge and desensitization in case of confirmed aspirin hypersensitivity could have been enacted.
Conclusions
Aspirin allergy is a conundrum of situations possibly dreadful for cardiologists, especially in the setting of ACS requiring stenting and the subsequent DAPT. The first challenge for the cardiologist is to differentiate true aspirin hypersensitivity from ‘pseudo-allergy’, in the form of aspirin intolerance, as often the two conditions are not clearly referred by the patient unless specifically and meticulously inquired. Not taking a careful history may lead to an overdiagnosis of aspirin allergy and to the unnecessary withholding of an extremely useful drug. Identification of patients with true aspirin hypersensitivity allows the selection of those (few) patients who may benefit from aspirin desensitization strategies, which would re-enable the use of aspirin especially in the context of DAPT. Although promising and apparently effective, these protocols appear effective even in cases of ACS and can obviously be adopted also in cases of uncertain medical history of aspirin hypersensitivity. An interdisciplinary approach consisting of a joined effort of cardiologists and immuno-allergologists could help improve the selection of the right candidates to desensitization procedures and should be as much as possible enacted to train cardiologists to better diagnose such conditions. Occasionally, however, in urgent conditions, cardiologists are called to act independently and should therefore be prepared to take educated decisions.
Declarations
Disclosure of Interest
All authors declare no disclosure of interest for this contribution.
Data Availability
No data were generated or analysed for or in support of this paper.
Funding
All authors declare no funding for this contribution.
