doi: 10.1161/01.CIR.0000134306.28561.2A
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(Circulation. 2004;110:e1-e4.)
© 2004 American Heart Association, Inc.
Clinician Update |
Approach to "Aspirin Allergy" in Cardiovascular Patients
From the Krannert Institute of Cardiology, Clarian Cardiovascular Center, Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind.
Correspondence to Vijay G. Kalaria, MD, FACC, FSCAI, Associate Director, Catheterization Laboratories and Interventional Cardiology, Krannert Institute of Cardiology, Indiana University School of Medicine, Clarian Cardiovascular Center, E404, 1800 North Capitol Ave, Indianapolis, IN 46202. E-mail vkalaria{at}iupui.edu
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Introduction |
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 Top Introduction Adverse Reactions to ASAConclusionReferences |
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Aspirin (ASA), by irreversibly inhibiting platelet cyclooxygenase-1 enzyme (COX-1), prevents platelet aggregation and is the mainstay of pharmacotherapy of patients with coronary artery disease (CAD). Long-term ASA therapy reduces mortality in CAD patients after an initial coronary event. Periprocedural ASA therapy significantly reduces major adverse cardiovascular events (MACE) after percutaneous coronary interventions.1,2 Despite a plethora of clinical data showing marked efficacy of ASA therapy in cardiovascular patients, ASA use continues to be less than optimal in real-world registries.3,4 A history of adverse reactions to ASA may prevent long-term use in a cardiovascular patient, thereby reducing optimal event protection. Most adverse reactions to ASA, such as gastrointestinal intolerance, are predictable and are dose and host related.5 However, ASA can also cause a hypersensitivity reaction, of which there are 3 types: respiratory sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria and/or angioedema), and systemic sensitivity (anaphylactoid reaction).6 Various terms have been used to describe the hypersensitivity reactions to ASA, including ASA intolerance, ASA idiosyncrasy, pseudoallergic reactions, and ASA sensitivity.7 The prevalence of ASA sensitivity in cardiovascular patients is not well known. Besides substitution with an alternative class of antiplatelet agents such as thienopyridines, ASA desensitization is an option for ASA-allergic patients who require long-term therapy for cardiovascular diseases.7
In this article, we review various hypersensitivity reactions to ASA and discuss desensitization protocols to allow ASA therapy in ASA-sensitive cardiovascular patients.
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Adverse Reactions to ASA |
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TopIntroductionAdverse Reactions to ASAConclusionReferences |
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ASA-Exacerbated Respiratory Disease
ASA-exacerbated respiratory disease (AERD) is a triad of asthma, ASA sensitivity, and rhinitis/nasal polyps. Patients with AERD have aggressive mucosal inflammation and suffer from precipitation of asthma and rhinitis after ingestion of ASA and nonsteroidal antiinflammatory drugs (NSAIDs).8 AERD is also commonly referred to as ASA-sensitive, ASA-induced, or ASA-intolerant asthma. AERD is the cause of 10% to 15% of all cases of asthma,8 is usually seen in adulthood, and has a higher prevalence in females. Determination of patients who are at the highest risk for AERD presents a clinical challenge. Most patients with AERD have moderate or severe persistent asthma and suffer from nasal polyposis and recurrent sinus infections.9 Thus, the presence of underlying moderate or severe persistent asthma can be considered a significant risk factor for AERD. There has been a case report of AERD in multiple members of one family10; however, familial occurrence is rare, and thus a family history is not necessarily a risk factor for AERD.
Inhibition of the COX-1 enzyme by ASA and NSAIDs decreases the production of prostaglandins (PGs), most importantly PGE2. PGE2, an inhibitor of 5-lipoxygenase enzyme, has a modulating effect on mast cells. Decreased availability of PGE2 preferentially stimulates the 5-lipoxygenase pathway, leading to an increase in leukotrienes (LTs).7 Several LTs (especially LTC4, LTD4, and LTE4) mediate eosinophil chemotaxis, increase vascular permeability and mucus gland secretion, and precipitate bronchoconstriction.7 Those LTs have also been shown to elicit a wheal and flare reaction when administered subcutaneously to patients.11 At this time, it is not completely understood why the interruption of PGE2 by ASA and NSAIDs causes respiratory reactions in some humans but not others. Alternate modulators of the prostaglandins–leukotrienes pathway or differences in structure or susceptibility of COX enzymes may account for varied susceptibility of patients to ASA.8
NSAIDs (ASA)-Induced Cutaneous Disease
Cutaneous reactions to NSAIDs consist of urticaria, which can occur separately or simultaneously with angioedema. These reactions also tend to occur more in adulthood and in young females.12 Cutaneous reactions to ASA have been documented to occur more frequently in atopic individuals (persons with a hereditary predisposition toward developing certain hypersensitivity reactions such as hay fever, asthma, or urticaria).13 Additionally, NSAIDs exacerbate urticaria in one third to two thirds of patients with chronic idiopathic urticaria.14
The postulated mechanism for cutaneous reactions, just as for the respiratory reactions, is the increased production of leukotrienes resulting from COX-1 inhibition.14 One support of this "cyclooxygenase theory" is the demonstration that pretreatment with leukotriene-receptor antagonists can block NSAID-induced urticaria and angioedema reactions.14
In addition to NSAIDs class-related urticaria and angioedema, Stevenson et al15 describe single-drug anaphylaxis and blended reactions. In single-drug anaphylaxis, after the initial drug exposure and sensitization, subsequent drug exposure leads to cutaneous reactions plus respiratory symptoms. Single-drug anaphylactic reactions are presumed to be immunoglobulin E mediated and lack cross-reactivity with other NSAIDs. Blended reactions consist of a mixed clinical picture of urticaria and/or angioedema, cough, dyspnea, hoarseness, wheezing, rhinorrhea, and/or tearing.
ASA-Induced Anaphylactoid Reactions
Anaphylactoid reactions occur within minutes of ingesting ASA and are characterized by hypotension, swelling, laryngeal edema, generalized pruritus, tachypnea, and lapses in consciousness.6 Angioedema with hypotension is generally considered an anaphylactoid reaction rather than a cutaneous reaction to ASA. Because specific immunoglobulin E against ASA has not been found, these reactions are called anaphylactoid and are clinically indistinguishable from anaphylactic reactions.7 The treatment for anaphylactoid reactions is the same as that for anaphylactic reactions.
ASA Challenge and Desensitization Protocols
No in vitro test exists that can identify patients with ASA hypersensitivity; the only way to definitively make the diagnosis is through provocative ASA challenge, namely oral, bronchial or nasal routes (only oral ASA challenges are available in the United States).7 Even cutaneous tests have failed to consistently elicit wheal and flare responses.6
Several successful desensitization protocols are available that involve oral challenge and dosing intervals of up to 24 hours. ASA challenge should not be performed purely for diagnostic purpose, as some of the reactions can be quite severe. In unstable patients with CAD and recent stent placement, it becomes necessary to devise protocols that would allow ASA therapy to be administered safely within a few hours.16
Desensitization Protocols for Patients With AERD
Szcezeklik and Stevenson8 described a strategy for desensitizing patients with AERD. This protocol, also referred to as "Scripps Clinic Protocol," involves small incremental oral doses of ASA administered over the course of 2 to 3 days, until 400 to 650 mg of ASA is tolerated (Table 1). They recommend that ASA desensitization, followed by daily ASA treatment, be considered a therapeutic option for the following groups of patients with AERD: those whose disease can be controlled only with unacceptably high doses of systemic corticosteroids; those who require repeated nasal polypectomies and/or sinus surgery, even if they are not taking systemic corticosteroids; and those who need ASA/NSAIDs for the treatment of other diseases, such as CAD, arthritis, or thromboembolism.
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Schaefer and Gore5 reported a 45-year-old female patient with a history of mild asthma and allergic rhinitis and ASA sensitivity. She was hospitalized for a myocardial infarction, treated with coronary stenting, and discharged with ticlodipine 250 mg twice-daily therapy. She underwent the oral ASA challenge test and desensitization in an outpatient setting using a protocol similar to the Scripps Clinic protocol by Szcezeklik and Stevenson,8 described in Table 1. The first day of placebo challenges is done to ensure airway stability with vital signs and pulmonary function measured hourly.1
Desensitization Protocols for Patients With ASA/NSAID-Induced Cutaneous Reactions
Wong et al16 performed challenge-desensitization studies on 11 patients with history of ASA- or NSAID-induced urticaria or angioedema, 9 of whom had CAD. Ten patients were pretreated with an antihistamine agent and 1 patient received prednisone (60 mg) the night before and the morning of the study. Nine out of 11 patients tolerated the procedure without adverse effects and continued ASA therapy from 1 to 24 months without developing urticaria or angioedema. This protocol (Table 2) is particularly useful in patients with unstable CAD, as it can be completed within a few hours, thus allowing for rapid desensitization.
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Another protocol described by Schaefer and Gore5 was used on a 40-year-old woman with an anterior myocardial infarction treated with 2-vessel coronary artery bypass surgery. Five years before her infarction she had urticarial facial rash attributed to ASA. A 1-day protocol for the evaluation of ASA-sensitive urticaria was performed (Table 3). She tolerated the challenge well without any dermatologic, respiratory, or systemic reaction and was maintained on ASA 81 mg daily. This protocol is to be used only if there is zero-to-minimum risk of a respiratory/anaphylactoid reaction.1
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At present, ASA desensitization protocols are highly variable without a universally accepted methodology. Any of the aforementioned published ASA challenge/densensitization protocols may be performed based on the preference of the consulting allergist. It is important to optimize overall clinical status of the patient with oral and inhaled corticosteroids, intra-nasal corticosteroids, theophylline, and long-acting bronchodilators before oral ASA challenges, if time permits.7 Antileukotriene modifiers such as zileuton and montelukast can block bronchospastic responses during oral ASA challenges, but often do not inhibit AERD reactions. However, anticholinergics, antihistamines, cromolyn, and short-acting inhaled ß-agonists should be discontinued 24 hours before challenge. In patients with chronic idiopathic urticaria, discontinuing antihistamine a day or two before the oral challenge often results in a flare of urticaria, which may coincide with but be unrelated to the drug challenge. As those with active urticaria (at the time of challenge) have a much higher prevalence of ASA sensitivity, antihistamines should be tapered to the lowest effective dose.7 Thus, we recommend discontinuing antihistamines before ASA challenge in a patient with AERD, but continuing antihistamines when doing a challenge in a patient with urticaria. ASA challenge should be attempted when the patient’s baseline forced expiratory volume in first minute (FEV1) value is equal to or greater than 70% of best predicted FEV1 value and above an absolute value of 1.5 L.17
A classic positive ASA challenge reaction is described as a 20% or greater decrease in FEV1 combined with naso-ocular symptoms (chemosis, tearing, periorbital swelling, nasal congestion, rhinorrhea). Isolated asthmatic (FEV1 decline) or naso-ocular symptoms can also occur.5,7,17 If positive reactions occur during the ASA challenge/desensitization protocol, vigorous symptomatic treatment should be promptly started. After a positive reaction during the desensitization process, subsequent ASA doses will be dependent on the desensitization protocol used.5,8,16,17 Once desensitized, it is prudent to maintain regular ASA therapy to prevent breakthrough ASA allergic reactions.
There are no published protocols involving ASA desensitization in individuals known to have an anaphylactoid response to ASA; rather, it seems more practical to use an alternative agent such as thienopyridines.7 Selective COX-2 inhibitors and low-dose acetaminophen are generally safe in patients with ASA sensitivity. The current recommendations from the American College of Cardiology and the American Heart Association regarding ASA desensitization in cardiovascular patients is that if true ASA allergy is present, other antiplatelet agents such as dipyridamole, ticlopidine, or clopidogrel may be substituted. The diagnostic and management approach to cardiovascular patients with a reported history of "ASA allergy" is outlined in the Figure.
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Conclusion |
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TopIntroductionAdverse Reactions to ASAConclusionReferences |
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ASA therapy has been shown to be of extreme benefit for cardiovascular patients, both in primary and secondary prevention of CAD. As described above, allergic reactions to ASA form a clinical spectrum, and not all patients with a reported ASA allergy have ASA-induced anaphylactoid reaction. Avoiding ASA in the patient subsets with AERD and ASA-induced cutaneous reactions would be a significant disadvantage from a long-term pharmacotherapy standpoint for the majority of these patients. Proper classification of "ASA-allergic" patients and early referral to allergy services for potential ASA desensitization will allow use of this highly cost-effective therapy in cardiovascular patients. Population-based studies are needed to better document prevalence of ASA allergy and clinical subtypes in cardiovascular patients. Standardization of an ASA challenge/desensitization protocol will also facilitate optimal management of the cardiovascular patient with ASA allergy.
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References |
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TopIntroductionAdverse Reactions to ASAConclusionReferences |
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1. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998; 339: 1665–1671.
2. Schwartz L, Bourassa MG, Lesperance J, et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med. 1988; 318: 1714–1719.[Abstract]
3. Hoekstra JW, Pollack CV Jr, Roe MT, et al. Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: the CRUSADE initiative. Acad Emerg Med. 2002; 9: 1146–1155.[CrossRef][Medline] [Order article via Infotrieve]
4. Rogers WJ, Canto JG, Lambrew CT, et al. Temporal trends in the treatment of over 15 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol. 2000; 36: 2056–2063.
5. Schaefer OP, Gore JM. Aspirin sensitivity: the role for aspirin challenge and desensitization in postmyocardial infarction patients. Cardiology. 1999; 91: 8–13.[Medline] [Order article via Infotrieve]
6. Manning ME, Stevenson DD, Mathison DA. Reactions to aspirin and other nonsteroidal anti-inflammatory drugs. Immunol Allergy Clin North Am. 1992; 12: 611–631.
7. Namazy JA, Simon RA. Sensitivity to nonsteroidal anti-inflammatory drugs. Ann Allergy Asthma Immunol. 2002; 89: 542–550.[Medline] [Order article via Infotrieve]
8. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol. 1999; 104: 5–13.[CrossRef][Medline] [Order article via Infotrieve]
9. Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2003; 111: 180–186.[CrossRef][Medline] [Order article via Infotrieve]
10. Miller FF. Aspirin-induced bronchial asthma in sisters. Ann Allergy. 1971; 29: 263–265.[Medline] [Order article via Infotrieve]
11. Settipane GA. Aspirin sensitivity and allergy. Biomed Pharmacother. 1988; 42: 493–498.[Medline] [Order article via Infotrieve]
12. Strom BL, Carson JL, Lee Morse M, et al. The effect of indication on hypersensitivity reactions associated with Zomepirac sodium and other nonsteroidal anti-inflammatory drugs. Arthritis Rheum. 1987; 30: 1142–1148.[Medline] [Order article via Infotrieve]
13. Sanchez-Borges M, Capriles-Hulett A. Atopy is a risk factor for non-steroidal anti-inflammatory drug sensitivity. Ann Allergy Asthma Immunol. 2000; 84: 101–106.[Medline] [Order article via Infotrieve]
14. Sanchez-Borges M, Capriles-Hulett A, Caballero-Fonseca F. Cutaneous reactions to aspirin and nonsteroidal anti-inflammatory drugs. Clin Rev Allergy Immunol. 2003; 24: 125–135.[CrossRef][Medline] [Order article via Infotrieve]
15. Stevenson DD, Sanchez-Borges M, Szczeklik A. Classification of allergic and pseudo-allergic reactions to drugs that inhibit cyclo-oxygenase enzymes. Ann Allergy Asthma Immunol. 2001; 87: 1–4.
16. Wong JT, Nagy CS, Krinzman SJ, et al. Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema. J Allergy Clin Immunol. 2000; 105: 997–1001.[CrossRef][Medline] [Order article via Infotrieve]
17. Pleskow WW, Stevenson DD, Mathison DA, et al. Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol. 1982; 69 (1 Pt 1): 11–19.[Medline] [Order article via Infotrieve]
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