Introduction of aspirin to patients with aspirin hypersensitivity requiring cardiovascular interventions

INTRODUCTION — Daily therapy with aspirin (acetylsalicylic acid) can lower the likelihood of adverse cardiovascular events in patients at risk for or with established cardiovascular disease. Aspirin in the former group is termed "primary prevention" and in the latter, "secondary prevention." (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Aspirin is often withheld in patients who report having an allergy or sensitivity to it or to other nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin sensitivity is particularly problematic for patients who need an urgent or emergency cardiac or neurologic procedure, such as stenting of an artery (coronary, carotid, or other) or following the diagnosis of an ischemic neurologic event. This topic will discuss an approach for safely introducing low-dose aspirin (75 to 100 mg daily) to patients reporting past reactions to aspirin or other NSAIDs.

INDICATIONS FOR URGENT ASPIRIN THERAPY — The following patients may need to have aspirin started on an urgent basis:

●Those suspected of acute coronary syndrome (ACS) or an ischemic neurologic event with revascularization not planned

●Those suspected of ACS or an acute ischemic neurologic event with revascularization planned or already executed with stent placement, in whom aspirin was not started due to concerns about hypersensitivity

●Those presenting for nonurgent coronary artery revascularization, who have not been taking aspirin

OVERVIEW OF ASPIRIN HYPERSENSITIVITY

Types — Hypersensitivity to aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) is a relatively complicated area of drug allergy, with six distinct types of hypersensitivity reactions (table 1). They are divided into two general categories: reactions that occur with multiple NSAIDs (types 1 to 4) and those that occur with just one NSAID (types 5 and 6), although types 5 and 6 have not been reported with aspirin specifically. Various forms of NSAID hypersensitivity are discussed in detail separately. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Aspirin-exacerbated respiratory disease".)

However, for the purpose of introducing low-dose aspirin urgently to patients with a cardiovascular or neurologic indication, in-depth knowledge of NSAID hypersensitivity reactions is not necessary. Rather, it is primarily important to identify patients whose reactions to NSAIDs involved respiratory symptoms (types 1 and 4) (table 1) because, if-low dose aspirin is to be initiated, these patients require premedication to minimize the asthmatic component of a possible reaction. Without premedication, these reactions can involve potentially severe bronchospasm. (See 'Premedication agents and doses' below.)

Respiratory reactions — Patients who report past reactions to NSAIDs that involved the respiratory tract (ie, wheezing, cough, chest tightness) should be assumed to have a disorder called aspirin-exacerbated respiratory disease (AERD) for the purpose of introducing aspirin. AERD (also called NSAID-exacerbated respiratory disease [NERD]) is a disorder that presents as the combination of three conditions:

●Asthma

●Adverse reactions to aspirin or other NSAIDs that involve upper and/or lower respiratory symptoms

●Chronic rhinosinusitis with nasal polyposis

AERD affects approximately 5 to 7 percent of all patients with asthma and typically develops during adulthood over a period of years [1]. For example, the patient may initially have sinus problems, followed after several years by the development of asthma, and then some years after that by adverse reactions to NSAIDs. Many have significant sinus disease that results in reduced or absent sense of smell, and some have had sinus surgery to remove nasal polyps. Patients with AERD may also report severe nasal congestion after drinking alcoholic beverages, which can be another clue to the presence of the disorder. AERD is reviewed in greater detail separately. (See "Aspirin-exacerbated respiratory disease".)

Respiratory reactions to NSAIDs in patients with AERD typically begin 30 minutes to three hours after ingestion of an NSAID and present as a dramatic worsening of asthma and nasal congestion with conjunctival injection and facial flushing. A minority of patients also have gastrointestinal symptoms, urticaria/angioedema, or macular rashes. Severe reactions can resemble anaphylaxis, although the mechanism is not immunoglobulin E (IgE) mediated, but rather related to dose-dependent inhibition of the cyclooxygenase 1 (COX-1) enzyme. Some patients with AERD can react to doses of aspirin as low as 60 mg, and nearly all will react to 325 mg.

In the absence of premedication, the asthmatic component of these reactions can be severe, with reductions in forced expiratory volume in one second (FEV₁) of 50 percent or more. Thus, it is important to premedicate patients with AERD, as described below, prior to the introduction of low-dose aspirin. (See 'Premedication agents and doses' below.)

Cutaneous reactions — Cutaneous reactions to NSAIDs are common and usually involve urticaria and/or angioedema. These are classified as types 2, 3, and 5 (table 1). Patients with type 2 hypersensitivity have underlying chronic spontaneous urticaria (CSU), which is defined as unexplained urticaria most days of the week for a period of six weeks or more, even in the absence of aspirin or other triggers. CSU affects approximately 1 percent of the general population. Angioedema (usually of the lip or face) accompanies some urticarial outbreaks in up to 50 percent of affected patients. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

Patients with type 3 hypersensitivity have no underlying skin disorder and only get urticaria after ingesting NSAIDs, although they may tolerate NSAIDs on some occasions and not others. Patients with type 5 hypersensitivity develop urticaria or angioedema to just one NSAID, although this has not been reported with aspirin specifically.

Other reactions (including anaphylaxis) — IgE-mediated anaphylaxis to NSAIDs, which is type 6 hypersensitivity, occurs most commonly to ibuprofen (table 1). It has never been conclusively documented with aspirin specifically, and low-dose aspirin can be given to patients reporting possible anaphylaxis to a different NSAID, although consultation with an allergist is prudent. Patients reporting reactions that resemble anaphylaxis to aspirin specifically should be assumed to have AERD because this is the most likely explanation for severe aspirin reactions.

Slow introduction versus desensitization — The term desensitization is used in the field of drug allergy to describe methods of slowly introducing medications to patients with documented hypersensitivity. The introduction of low-dose aspirin to patients with an unconfirmed allergy would not technically be a desensitization in most patients, because the patient may not actually be allergic. In addition, for most forms of NSAID hypersensitivity, reactions are variable, and it is quite possible that the patient will not react at all to any dose of aspirin at the time or only react to relatively high doses but tolerate low doses. The important exceptions are types 1 and 4 (involving respiratory reactions), which do reliably occur with most or all exposures to NSAIDs.

DETERMINING THE TYPE OF REACTION

Important questions to ask — To obtain an accurate history of past nonsteroidal antiinflammatory drug (NSAID) reactions, the clinician should ask the following:

●Did you have an unwanted reaction to aspirin in the past? What exactly happened? What dose was taken?

•Some patients will report symptoms that are not allergic in nature, but rather are known adverse effects of aspirin, such as gastrointestinal pain, tinnitus, or bleeding. Many of these patients can tolerate low-dose aspirin without recurrence of these adverse effects.

•The majority of patients with true aspirin hypersensitivity will either describe cutaneous symptoms (ie, hives, angioedema) or reactions that involve respiratory symptoms (wheezing, cough, chest tightness, severe nasal congestion, flushing) (table 1). Respiratory reactions may be accompanied by throat tightness (caused by laryngospasm) or gastrointestinal symptoms.

●Have you reacted to other NSAIDs (eg, ibuprofen, naproxen) (table 2) in the past? Are there NSAIDs that you can take without problems?

•Reactions to multiple NSAIDs narrows the diagnosis to hypersensitivity types 1, 2, 3, or 4 (table 1). These forms of hypersensitivity are not immunologic reactions, but rather are biochemical reactions due to an abnormal response to inhibition of the cyclooxygenase 1 (COX-1) enzyme.

•Patients who reacted to one NSAID but are known to tolerate others likely have types 5 or 6 hypersensitivity to a single agent. This single NSAID is usually one which had been taken repeatedly over long periods of time.

●How was the reaction treated?

The answer to this question helps the clinician estimate the severity of the past reaction. Severe reactions may have required emergency care or hospitalization.

●Since the initial reaction, have you taken the culprit drug or any other NSAID again? What do you take for pain or fever?

The answer to these questions may provide further information about the patient's ability to tolerate different NSAIDs. Patients who were told to avoid all NSAIDs sometimes unknowingly take some other medication in the NSAID group, thus providing information about whether they are reactive to just one NSAID or multiple agents. Acetaminophen has extremely weak NSAID properties and is tolerated at usual doses by most patients with NSAID hypersensitivity.

●Do you have asthma and/or a history of sinus problems?

This question should help identify patients with aspirin-exacerbated respiratory disease (AERD), which is the combination of asthma, chronic sinusitis (with nasal polyps), and NSAID hypersensitivity. These patients have types 1 or 4 reactions (table 1). Patients with AERD most commonly have respiratory reactions to NSAIDs but occasionally have a mixture of respiratory and cutaneous reactions. These individuals should be premedicated prior to aspirin desensitization because they may react during it. (See 'Premedication agents and doses' below.)

●Have you had hives (urticaria)? If the patient reports hives, how frequently? Does the patient think there are clear triggers?

Patients with urticaria +/– angioedema in response to aspirin typically have types 2 or 3 hypersensitivity (table 1), but many will tolerate low-dose aspirin (75 to 100 mg) without developing symptoms.

Contraindications to aspirin — NSAIDs should not be given to patients reporting past reactions involving either desquamation of the skin or mucous membranes (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), organ involvement (eg, drug-induced hepatitis or vasculitis), or drug-induced cytopenias, unless supervised by a drug allergy expert. These severe forms of hypersensitivity are rare in response to aspirin but do occur with other NSAIDs. The recommendation to avoid all NSAIDs in this setting is conservative since there is no evidence that these severe immunologic drug reactions to NSAIDs are related to the underlying action of NSAIDs (ie, inhibition of the COX-1 enzyme), and thus a structurally dissimilar compound like aspirin might well be tolerated.

Severe reactions in this category include:

●Toxic epidermal necrolysis (TEN) (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis")

●Stevens-Johnson syndrome (SJS)

●Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS) (see "Drug reaction with eosinophilia and systemic symptoms (DRESS)")

●Other exfoliating dermatoses/erythroderma (see "Erythroderma in adults")

●Serum sickness-like reactions (see "Serum sickness and serum sickness-like reactions")

●Drug-induced cytopenias (see "Drug-induced immune thrombocytopenia" and "Drug-induced hemolytic anemia" and "Drug-induced neutropenia and agranulocytosis")

●Drug-induced hepatic or other specific organ damage (see "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Drug-induced liver injury")

Referral — The approach described here is usually carried out by allergists, although it can be administered by clinicians who are not allergy specialists [2]. Consultation with an allergist is strongly advised if the patient's past reaction to NSAIDs was a severe respiratory reaction or the clinician is not sure how to categorize the past reaction.

OUR APPROACH — Low-dose (75 to 100 mg daily) aspirin can be introduced safely to patients with any type of nonsteroidal antiinflammatory drug (NSAID) hypersensitivity using the standardized protocol described below (see 'Protocol for aspirin introduction' below). Patients with past respiratory reactions to NSAIDs should be premedicated, while those with cutaneous reactions do not require premedication. The protocol takes three to five hours to perform and can be carried out as an outpatient, prior to an elective stenting procedure, or as an inpatient, either before or after the procedure, based on the patient's stability and the urgency with which the procedure is required.

Timing of aspirin introduction — The patient's clinical status determines when the procedure can be performed. We defer the introduction of aspirin in patients who are both medically unstable and have aspirin-exacerbated respiratory disease (AERD) and a history of respiratory reactions because, although respiratory symptoms are usually blunted by premedication prior to the protocol, some bronchospasm can still occur, and both the symptoms and the inhaled beta-agonists used as treatment can further stress a fragile patient. When the cardiologist feels the patient can be given beta-agonists safely, we prefer to use levalbuterol rather than albuterol.

Patients generally fall into one of the following categories:

●For aspirin-sensitive patients in whom the interventional procedure can be postponed for several hours, low-dose aspirin can be introduced before the interventional procedure.

●For aspirin-sensitive patients who need to undergo percutaneous coronary intervention (PCI) prior to the introduction of aspirin, the optimal antithrombotic approach is not known. Our experts use one of the following two approaches, which have not been formally evaluated:

•Administer a P2Y₁₂ receptor blocker alone. With this approach, most experts prefer one of the more potent agents, prasugrel or ticagrelor, to clopidogrel.

•Administer an intravenous glycoprotein (GP) IIb/IIIa antagonist during the procedure. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'GP IIb/IIIa inhibitors'.)

Dosing of antiplatelet agents (other than aspirin) is discussed separately. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Dose' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Dose'.)

We then introduce low-dose aspirin (using the approach described here) once the patient is stabilized. This can often be performed prior to discharge from the hospital.

●For aspirin-sensitive patients undergoing elective arterial revascularization, we usually refer the patient to an allergist in advance for evaluation.

Safety — In one author's (RS) experience, low-dose aspirin therapy can be safely introduced to any appropriate patient using this approach (see 'Protocol for aspirin introduction' below). Factors that contribute to the safety of this approach include the following:

●The aspirin doses given in this protocol are too low to induce symptoms in many patients with true hypersensitivity to aspirin.

●Many patients reporting past reactions to NSAIDs are not currently sensitive to these medications. In particular, hypersensitivity types 1, 2, and 3 are variable and episodic, such that symptoms often do not occur with each NSAID exposure.

●Aspirin has never been convincingly shown to cause IgE-mediated anaphylaxis.

Protocol for aspirin introduction — Our preferred approach is shown in the algorithm (algorithm 1) [3]. Most patients complete the protocol in three to five hours. Informed consent should be obtained, and it should be explained to patients with possible AERD that they may develop respiratory reactions during the procedure. Prior to initiating the protocol, patients with contraindications need to be identified. (See 'Contraindications to aspirin' above.)

Setting and precautions — This protocol can be performed in both the hospitalized and ambulatory patients.

●Hospitalized patients – It is important that patients with possible AERD are observed closely during the procedure for the development of respiratory symptoms and treated without delay. Bronchospasm may present as dry, repetitive coughing; chest tightness; or wheezing. Albuterol should be immediately available. (See 'Treating symptoms during the protocol' below.)

●Ambulatory patients – Introduction of aspirin to patients with possible AERD in the ambulatory setting should be done by allergy specialists in a setting equipped with spirometry and personnel trained to detect and treat reactions. Outpatient aspirin desensitization is discussed in more detail separately. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Safety'.)

Premedication agents and doses — Premedications are given to patients with respiratory reactions, including patients with reactions resembling anaphylaxis to aspirin, to reduce the severity of a potential reaction. All such patients should receive montelukast (or an equivalent leukotriene-modifying drug [LTMD]). Premedication with an LTMD blunts the asthmatic component of the reaction, making the protocol safer to perform. In contrast, LTMDs typically have minimal effect on the nasal or other symptoms, although these symptoms are rarely dangerous.

Patients with past respiratory reactions

●Montelukast, 10 mg orally (or an equivalent LTMD, such as zafirlukast) should be administered at least one hour prior to the first dose of aspirin. If the patient is already taking an LTMD, then it is simply continued.

●If the patient's asthma is not well controlled on their outpatient regimen, oral glucocorticoids should be administered, preferably for several days prior to the procedure, in addition to a combination inhaled corticosteroid/long-acting bronchodilator (ICS/LABA). If a more urgent introduction of aspirin is desired, prednisone (40 mg orally) or methylprednisolone (40 mg intravenously) should be given at least two hours before the first dose of aspirin. The latter would likely not have sufficient time to bring the patient's asthma under control, but would provide some degree of protection against severe bronchospasm. We also obtain spirometry in this situation, to assure that forced expiratory volume in one second (FEV₁) is at least ≥1.5 liters. The clinician should weigh risks and benefits in such situations.

●A combination ICS/LABA is also given to patients with poorly controlled asthma because the LABA component is helpful in preventing bronchospasm during the protocol, which should be avoided in patients with acute coronary syndrome (ACS). A long-acting antimuscarinic agent could also be used if the patient did not tolerate LABAs in the past.

Patients with past cutaneous reactions — These individuals do not require premedication. However, if they are taking daily H1 antihistamines for any reason, these should be continued because stopping antihistamines suddenly may result in reappearance of urticaria. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

Patients with past anaphylaxis — If a patient reporting past anaphylaxis (or suspected anaphylaxis) to an NSAID has any of the component disorders of AERD (asthma or chronic sinus problems), then premedication should be given. If not, the procedure can be done without premedication.

Reactions to aspirin specifically (as opposed to another NSAID) that resemble anaphylaxis are usually severe respiratory reactions with extra respiratory symptoms in patients with AERD. These patients should be premedicated. (See 'Premedication agents and doses' above.)

Algorithm for target dose of 81 to 100 mg — Our preferred protocol for introducing low-dose aspirin requires 2 to 3.5 hours to complete and uses doses of aspirin that are easily prepared by cutting standard tablets in half (algorithm 1) [3]. This protocol has been successfully performed in >300 patients at one author's (RS) institution [4]. Alternative protocols are discussed below. (See 'Alternative protocols' below.)

Note that the protocols described here are intended only for the administration of aspirin (and not other NSAIDs), because there is extensive clinical experience with aspirin, and, compared with other NSAIDs, aspirin carries a negligible risk of IgE-mediated anaphylaxis. Also, only aspirin has proven benefit for cardiovascular prevention or treatment. (See 'Other reactions (including anaphylaxis)' above.)

Treating symptoms during the protocol — Patients may manifest either respiratory or cutaneous reactions during the protocol. The protocol should not be aborted if these occur. Instead, the symptoms should be treated as described below. As soon as the symptoms have subsided, the dose that caused the reaction is repeated until the patient no longer reacts (usually, the AERD patient does not react when the same dose is given a second time). We usually wait a minimum of 60 minutes after the last dose and longer, if necessary. The protocol is then continued until complete. If the reaction was limited to a few hives, we usually treat the symptoms but do not repeat the triggering dose and just continue with the protocol until complete.

●Bronchospasm (repetitive, dry cough; chest tightness; or wheezing) can be treated with inhaled levalbuterol (preferred in patients with cardiac disease, one to two inhalations of a metered dose inhaler or 0.63 mg nebulized) or albuterol or another short-acting bronchodilator.

●Urticaria can be treated with H1 antihistamines (eg, cetirizine 10 mg orally or diphenhydramine 25 to 50 mg orally or intravenously). A few scattered urticaria is a relatively common reaction and usually responds to a single dose of antihistamines.

●Extreme nasal congestion/blockage, which usually only occurs in patients with AERD and severe nasal polyposis, can be relieved with topical oxymetazoline nasal spray. Nasal obstruction during the procedure can lead to retention of secretions and headache, which is very uncomfortable for the patient but not dangerous.

Algorithm for higher target dose — Uncommonly, a patient may require a higher single (loading) dose of aspirin, such as 300 or 325 mg. The most common situation in which this might occur is in an inpatient scheduled to undergo PCI within the next five or so days. In this case, the procedure can be extended another three to four hours using a second protocol (algorithm 2). If the second protocol is performed on the same day as the first, patients with past respiratory reactions do not need repeat premedications. However, if the second protocol is performed more than 24 hours later, premedications should be given again. Most patients with AERD will react during desensitization to this higher dose. (See 'Treating symptoms during the protocol' above.)

Patients who can wait for more than five days for their procedure can be treated with five consecutive days of aspirin 75 to 80 mg daily, and this dose is less likely to elicit symptoms. Alternatively, the procedure for reaching the higher dose can be performed later by an allergist as an outpatient.

Alternative protocols — A different protocol has been published, which does not attempt to distinguish among the different types of NSAID reactions [2]. It was studied in a multicenter trial that included 330 consecutive patients with self-reported histories of aspirin hypersensitivity. Patients' past reactions were reported to be urticaria or angioedema (74 percent), rhinitis/asthma/bronchospasm (20 percent), and anaphylactic shock (6 percent). An aspirin provocation/desensitization procedure consisting of six increasing doses (highest dose 100 mg) given over 5.5 hours was performed in all patients, either prior to cardiac catheterization (76 percent) or after primary PCI (24 percent). No premedications were administered. If the patient reacted, the symptoms were treated, and the procedure was aborted. The challenge procedure was uneventful in 95 percent of the patients, all of whom were discharged on 100 mg of aspirin daily. Aspirin therapy was discontinued in 18 percent during the first year of treatment, although this was not due to hypersensitivity in any case.

An important limitation of this protocol is the recommendation to abort the procedure if symptoms develop because patients with AERD may develop symptoms during desensitization but can be successfully treated through these symptoms. Most AERD patients react to doses between 60 and 120 mg, so not all patients will react to low-dose aspirin, but those who do can still tolerate aspirin if the symptoms are treated and the procedure is continued. For this reason, the authors and editors of this topic prefer the protocol outlined previously (algorithm 1). (See "Aspirin-exacerbated respiratory disease" and "Diagnostic challenge and desensitization protocols for NSAID reactions", section on 'Type 1 (respiratory reactions to multiple NSAIDs)'.)

OUTCOMES AND FOLLOW-UP

Success rates — A meta-analysis of various aspirin provocation/desensitization protocols, which included 15 studies and 480 patients with acute coronary syndrome (ACS), reported a pooled success rate of 98 percent for the primary endpoint of completion of the protocol and sustained aspirin therapy until discharge without symptoms of hypersensitivity [5]. The included studies were a mix of retrospective reviews, prospective studies, and case series. At 1 to 46 months of follow-up, there were no aspirin-related adverse effects, and no patients had discontinued aspirin for recurrent hypersensitivity symptoms. Although the success rates were slightly higher with protocols involving more than six dose-escalation steps, the authors concluded that a best approach could not be identified with the available data.

Follow-up — Patients who are successfully started on low-dose aspirin should continue the same daily dose indefinitely, unless they develop new symptoms of intolerance (eg, gastric pain, dark stools, tinnitus). Occasionally, patients with chronic spontaneous urticaria (CSU) find their urticaria more difficult to control on even very low doses of aspirin. Such patients should be referred to an allergy or dermatology specialist for further management.

Patient education — Patients with severe reactions to higher-dose aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) should be counseled that those sensitivities have not been altered by the introduction of low-dose (<100 mg) aspirin. For example, a patient who had anaphylaxis specifically to ibuprofen but has been started on low-dose aspirin must still avoid ibuprofen. These patients should also be referred to an allergy expert, if feasible, for further education and discussion of treatment options.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Patients who need an urgent or emergency cardiac or neurologic procedure, such as stenting of a coronary or carotid artery, and who would benefit from low-dose aspirin but report some form of hypersensitivity to aspirin can present a management challenge. However, low-dose aspirin (ie, 75 to 100 mg) can be safely introduced to most patients in this situation using a simple protocol. (See 'Indications for urgent aspirin therapy' above.)

●There are multiple types of nonsteroidal antiinflammatory drug (NSAID) hypersensitivity (table 1), and patients with any of these reactions can be treated with the approach presented in this topic. Of note, there are other rare forms of NSAID hypersensitivity that are contraindications to any future use of aspirin. (See 'Overview of aspirin hypersensitivity' above and 'Contraindications to aspirin' above.)

●The clinician should take a detailed history of the patient's past reaction to aspirin and other NSAIDs to categorize the type of hypersensitivity reaction. It is important to identify patients with past respiratory reactions (types 1 and 4) because they may have underlying aspirin-exacerbated respiratory disease (AERD). Patients with AERD can have severe respiratory reactions to aspirin and should be premedicated before aspirin is introduced. (See 'Determining the type of reaction' above and 'Premedication agents and doses' above.)

●The protocol can be done as an outpatient or inpatient, depending on the acuity of the situation. If the patient requires an immediate stenting procedure, other antiplatelet agents can be given instead, and low-dose aspirin can be introduced once the patient is stabilized. (See 'Our approach' above.)

●The protocol described here, although it is usually carried out by allergists, can also be administered by clinicians who are not allergy specialists. However, consultation with an allergist is strongly advised if the patient's past reaction to NSAIDs was life threatening or the clinician is not sure how to categorize the past reaction. (See 'Referral' above.)

●The protocol for introducing low-dose aspirin is shown in the algorithm (algorithm 1). It generally takes three to five hours to complete. Patients may require treatment for either respiratory or cutaneous reactions during the protocol. The protocol should not be aborted if they occur. Instead, the symptoms should be treated with bronchodilators or antihistamines, and the dose that caused the reaction is repeated until the patient no longer reacts. The protocol is then continued until complete. (See 'Protocol for aspirin introduction' above and 'Treating symptoms during the protocol' above.)

●This and other protocols are highly successful. Patients who are successfully started on low-dose aspirin should continue the same daily dose indefinitely. Patients with severe reactions to higher-dose aspirin or other NSAIDs should be counseled that those sensitivities have not been altered by the introduction of low-dose (≤100 mg) aspirin. For example, a patient who had anaphylaxis to ibuprofen but has been started on low-dose aspirin must still avoid ibuprofen. (See 'Outcomes and follow-up' above.)