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__NOTOC__ | |||
{{SI}} | {{SI}} | ||
{{CMG}}; '''Associate Editor-In-Chief:''' Keri Shafer, M.D. | |||
{{CMG}}; Keri Shafer, M.D. | |||
==Overview== | ==Overview== | ||
In the general population, 0.6% to 2.5% of patients will develop a [ | In the general population, 0.6% to 2.5% of patients will develop a [[hypersensitivity]] reaction to [[aspirin]] and that number is increased to 4.3% to 11.0% among patients with asthma<ref name="pmid16670507">{{cite journal |author=Pfaar O, Klimek L |title=Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements |journal=[[Current Opinion in Allergy and Clinical Immunology]] |volume=6 |issue=3 |pages=161–6 |year=2006 |month=June |pmid=16670507 |doi=10.1097/01.all.0000225153.45027.6a |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1528-4050&volume=6&issue=3&spage=161 |issn= |accessdate=2010-07-01}}</ref><ref>Kasper, S|adek K, Duplaga M, et al.: Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland. Allergy 2003</ref><ref>Vally H, Taylor ML, Thompson PJ: The prevalence of aspirin-intolerant asthma (AIA) in Australian asthmatic patients. Thorax 2002, 57:569-574.</ref><ref> Szczeklik A, Nizankowska E, Duplaga M, et al.: Natural history of aspirin-induced asthma. Eur Respir J 2000, 16:432-436.</ref>. Dual antiplatelet therapy with both [[aspirin]] and [[clopidogrel]] has been associated with improved clinical outcomes in the management of patients with [[acute coronary syndromes]]. Although there is a lack of supporting data, patients with aspirin hypersensitivity are sometimes managed with clopidogrel monotherapy. Indeed, aspirin hypersensitivity has been associated with stent thrombosis in some case reports<ref name="pmid17913265">{{cite journal |author=Patanè S, Marte F, Di Bella G |title=Catastrophic early drug eluting stents thrombosis and aspirin hypersensitivity |journal=[[International Journal of Cardiology]] |volume=131 |issue=1 |pages=e25–7 |year=2008 |month=December |pmid=17913265 |doi=10.1016/j.ijcard.2007.07.053 |url=http://linkinghub.elsevier.com/retrieve/pii/S0167-5273(07)01545-8 |issn= |accessdate=2010-07-01}}</ref>. Aspirin desensitization is required when continued [[aspirin]] administration is essential (e.g. management of an [[acute coronary syndrome]] with stent placement). A rapid protocol can be used as described below.<ref name="pmid17200429">{{cite journal |author=Page NA, Schroeder WS |title=Rapid desensitization protocols for patients with cardiovascular disease and aspirin hypersensitivity in an era of dual antiplatelet therapy |journal=[[The Annals of Pharmacotherapy]] |volume=41 |issue=1 |pages=61–7 |year=2007 |month=January |pmid=17200429 |doi=10.1345/aph.1H437 |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=17200429 |issn= |accessdate=2010-07-01}}</ref> While this protocol can be implemented over the course of several hours, it is not applicable to those patients who must proceed to the cardiac catheterization laboratory such as the patient with [[ST segment elevation myocardial infarction]] where "time is muscle"<ref name="pmid18328841">{{cite journal |author=Rossini R, Angiolillo DJ, Musumeci G, Scuri P, Invernizzi P, Bass TA, Mihalcsik L, Gavazzi A |title=Aspirin desensitization in patients undergoing percutaneous coronary interventions with stent implantation |journal=[[The American Journal of Cardiology]] |volume=101 |issue=6 |pages=786–9 |year=2008 |month=March |pmid=18328841 |doi=10.1016/j.amjcard.2007.10.045 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9149(07)02228-X |issn= |accessdate=2010-07-01}}</ref>. | ||
Kasper, S|adek K, Duplaga M, et al.: Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland. Allergy 2003</ref><ref>Vally H, Taylor ML, Thompson PJ: The prevalence of aspirin-intolerant asthma (AIA) in Australian asthmatic patients. Thorax 2002, 57:569-574.</ref><ref> Szczeklik A, Nizankowska E, Duplaga M, et al.: Natural history of aspirin-induced asthma. Eur Respir J 2000, 16:432-436.</ref>. | ==Pathophysiology== | ||
The pathophysiology aspirin hypersensitivity involves both excess [[leukotriene]] production as well as the development of IgE antibodies directed toward aspirin. The goal of a desensitization protocol is to deplete the leukotrienes (as well as other mediators) and to down-regulate the leukotriene receptors. | |||
Aspirin desensitization is required when continued [ | |||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
The management of aspirin hypersensitivity is especially critical in patients with [ | The management of aspirin hypersensitivity is especially critical in patients with [[acute coronary syndromes]]. In one single center study, 26 of 1,014 patients admitted for cardiac catheterization had a history of aspirin sensitivity. Of these 26 patients, 61.5% presented with an acute coronary syndrome. While many patients could be desensitized, those with ST elevation MI could not be sensitized before the procedure.<ref name="pmid18328841">{{cite journal |author=Rossini R, Angiolillo DJ, Musumeci G, Scuri P, Invernizzi P, Bass TA, Mihalcsik L, Gavazzi A |title=Aspirin desensitization in patients undergoing percutaneous coronary interventions with stent implantation |journal=[[The American Journal of Cardiology]] |volume=101 |issue=6 |pages=786–9 |year=2008 |month=March |pmid=18328841 |doi=10.1016/j.amjcard.2007.10.045 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9149(07)02228-X |issn= |accessdate=2010-07-01}}</ref> | ||
==Diagnosis== | ==Diagnosis== | ||
The signs and symptoms of hypersensitivity include [[rhinorrhea]], exacerbation of [[asthma]], [[urticaria]], [[angioedema]], and [[anaphylaxis]]. The majority of patients develop asthma, asthma exacerbation or rhinitis.<ref name="pmid15613671">{{cite journal |author=Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA |title=Aspirin sensitivity: implications for patients with coronary artery disease |journal=[[JAMA : the Journal of the American Medical Association]] |volume=292 |issue=24 |pages=3017–23 |year=2004 |month=December |pmid=15613671 |doi=10.1001/jama.292.24.3017 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15613671 |issn= |accessdate=2010-07-01}}</ref> While aspirin is often the culprit, the reaction can also be induced by cross reaction with cycloxygenase 1 inhibitors (COX 1) such as ibuprofin (Motrin) and naproxen<ref name="pmid15613671">{{cite journal |author=Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA |title=Aspirin sensitivity: implications for patients with coronary artery disease |journal=[[JAMA : the Journal of the American Medical Association]] |volume=292 |issue=24 |pages=3017–23 |year=2004 |month=December |pmid=15613671 |doi=10.1001/jama.292.24.3017 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15613671 |issn= |accessdate=2010-07-01}}</ref>. There is also cross reactivity in patients who take acetaminophen (a weak COX 1 inhbitor), and these patients should not take more than 1000 mg as a single dose<ref name="pmid17609236">{{cite journal |author=Knowles SR, Drucker AM, Weber EA, Shear NH |title=Management options for patients with aspirin and nonsteroidal antiinflammatory drug sensitivity |journal=[[The Annals of Pharmacotherapy]] |volume=41 |issue=7 |pages=1191–200 |year=2007 |month=July |pmid=17609236 |doi=10.1345/aph.1K023 |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=17609236 |issn= |accessdate=2010-07-01}}</ref>. Even 4% of patients with aspirin hypersensitivity will cross-react and sustain a cutaneous reaction to a COX-2 selective NSAID <ref name="pmid17609236">{{cite journal |author=Knowles SR, Drucker AM, Weber EA, Shear NH |title=Management options for patients with aspirin and nonsteroidal antiinflammatory drug sensitivity |journal=[[The Annals of Pharmacotherapy]] |volume=41 |issue=7 |pages=1191–200 |year=2007 |month=July |pmid=17609236 |doi=10.1345/aph.1K023 |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=17609236 |issn= |accessdate=2010-07-01}}</ref>. | |||
The signs and symptoms of hypersensitivity include [ | ==Treatment== | ||
===Protocol for Aspirin Desensitization=== | |||
In the Wong protocol, the dose of aspirin is increased every 15 minutes until the maximum dose of aspirin is administered: | |||
While aspirin is often the culprit, the reaction can also be induced by cross reaction with cycloxygenase 1 inhibitors ( | |||
== | |||
== Protocol for Aspirin Desensitization | |||
In | |||
'''Dose''' | '''Dose''' | ||
0 minutes: 0.1 mg | 0 minutes: 0.1 mg | ||
| Line 49: | Line 35: | ||
135 minutes: 325 mg | 135 minutes: 325 mg | ||
===Success of Therapy=== | |||
==Success of | Data regarding the success of aspirin desensitization is based upon small observational studies. Patients with [[chronic idiopathic urticaria]] often cannot be desensitized<ref name="pmid15613671">{{cite journal |author=Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA |title=Aspirin sensitivity: implications for patients with coronary artery disease |journal=[[JAMA : the Journal of the American Medical Association]] |volume=292 |issue=24 |pages=3017–23 |year=2004 |month=December |pmid=15613671 |doi=10.1001/jama.292.24.3017 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15613671 |issn= |accessdate=2010-07-01}}</ref>. In one single center experience, 23/26 patients (88.5%) could be desensitized<ref name="pmid18328841">{{cite journal |author=Rossini R, Angiolillo DJ, Musumeci G, Scuri P, Invernizzi P, Bass TA, Mihalcsik L, Gavazzi A |title=Aspirin desensitization in patients undergoing percutaneous coronary interventions with stent implantation |journal=[[The American Journal of Cardiology]] |volume=101 |issue=6 |pages=786–9 |year=2008 |month=March |pmid=18328841 |doi=10.1016/j.amjcard.2007.10.045 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9149(07)02228-X |issn= |accessdate=2010-07-01}}</ref>. In another small singel center experience, 14/16 patients could be desensitized<ref name="pmid15695141">{{cite journal |author=Silberman S, Neukirch-Stoop C, Steg PG |title=Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting |journal=[[The American Journal of Cardiology]] |volume=95 |issue=4 |pages=509–10 |year=2005 |month=February |pmid=15695141 |doi=10.1016/j.amjcard.2004.10.022 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9149(04)01700-X |issn= |accessdate=2010-07-01}}</ref>. | ||
Data regarding the success of aspirin desensitization is based upon small observational studies. Patients with [ | ===Resensitization as a Complication of Therapy=== | ||
If patients are not treated with aspirin chronically after desensitization, they can develop resensitization. A 300 mg daily dose of aspirin was superior to a 100 mg daily dose in preventing resensitization<ref name="pmid18699939">{{cite journal |author=Rozsasi A, Polzehl D, Deutschle T, Smith E, Wiesmiller K, Riechelmann H, Keck T |title=Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily |journal=[[Allergy]] |volume=63 |issue=9 |pages=1228–34 |year=2008 |month=September |pmid=18699939 |doi=10.1111/j.1398-9995.2008.01658.x |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0105-4538&date=2008&volume=63&issue=9&spage=1228 |issn= |accessdate=2010-07-01}}</ref>. | |||
==Resensitization as a Complication of | ===Cost-Effectiveness of Therapy=== | ||
If patients are not treated with aspirin chronically after desensitization, they can develop resensitization. A 300 mg daily dose of aspirin was superior to a 100 mg daily dose in preventing resensitization <ref name="pmid18699939">{{cite journal |author=Rozsasi A, Polzehl D, Deutschle T, Smith E, Wiesmiller K, Riechelmann H, Keck T |title=Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily |journal=[ | Aspirin desensitization is much more cost effective than clopidogrel monotherapy. Clopidogrel was associated with a cost $106,453 per incremental Quality Adjusted Life Year saved when compared with aspirin desensitization<ref name="pmid17716716">{{cite journal |author=Shaker M, Lobb A, Jenkins P, O'Rourke D, Takemoto SK, Sheth S, Burroughs T, Dykewicz MS |title=An economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease |journal=[[The Journal of Allergy and Clinical Immunology]] |volume=121 |issue=1 |pages=81–7 |year=2008 |month=January |pmid=17716716 |doi=10.1016/j.jaci.2007.06.047 |url=http://linkinghub.elsevier.com/retrieve/pii/S0091-6749(07)01386-3 |issn= |accessdate=2010-07-01}}</ref>. | ||
== | |||
Aspirin desensitization is much more cost effective than clopidogrel monotherapy. Clopidogrel was associated with a cost $106,453 per incremental Quality Adjusted Life Year saved when compared with aspirin desensitization<ref name="pmid17716716">{{cite journal |author=Shaker M, Lobb A, Jenkins P, O'Rourke D, Takemoto SK, Sheth S, Burroughs T, Dykewicz MS |title=An economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease |journal=[ | |||
==Guidelines Recommendations Regarding the Reduction in GI Risks Associated with Antiplatelet and NSAID Use== | ==Guidelines Recommendations Regarding the Reduction in GI Risks Associated with Antiplatelet and NSAID Use== | ||
NSAID based GI adverse events are common and are associated with a 2 to 4 fold increase in the risk of adverse events. <blockquote>Recommendation: The use of low-dose ASA for cardioprophylaxis is associated with a 2- to 4-fold increase in UGIE risk. Enteric-coated or buffered preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with ASA dose escalation; thus, for the chronic phase of therapy, doses greater than 81 mg should not be routinely prescribed.<ref> | NSAID based GI adverse events are common and are associated with a 2 to 4 fold increase in the risk of adverse events. <blockquote>Recommendation: The use of low-dose ASA for cardioprophylaxis is associated with a 2- to 4-fold increase in UGIE risk. Enteric-coated or buffered preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with ASA dose escalation; thus, for the chronic phase of therapy, doses greater than 81 mg should not be routinely prescribed.<ref> | ||
Bhatt et al, ACCF/ACG/AHA Expert Consensus Document: Antiplatelets, NSAIDs, and GI Risk. Circulation 2008;118;1894-1909</ref></blockquote> | Bhatt et al, ACCF/ACG/AHA Expert Consensus Document: Antiplatelets, NSAIDs, and GI Risk. Circulation 2008;118;1894-1909</ref></blockquote> | ||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
{{WH}} | |||
{{WS}} | |||
[[CME Category::Cardiology]] | |||
[[Category:Disease]] | |||
[[Category:Cardiology]] | [[Category:Cardiology]] | ||
[[Category:Allergology]] | [[Category:Allergology]] | ||
[[Category:Immunology]] | |||
[[Category:Pulmonology]] | |||
[[Category:Emergency medicine]] | |||
[[Category:Intensive care medicine]] | |||
[[Category:Asthma]] | |||
[[Category:Up-To-Date]] | |||
[[Category:Up-To-Date pulmonology]] | |||
Latest revision as of 00:38, 15 March 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Keri Shafer, M.D.
Overview
In the general population, 0.6% to 2.5% of patients will develop a hypersensitivity reaction to aspirin and that number is increased to 4.3% to 11.0% among patients with asthma[1][2][3][4]. Dual antiplatelet therapy with both aspirin and clopidogrel has been associated with improved clinical outcomes in the management of patients with acute coronary syndromes. Although there is a lack of supporting data, patients with aspirin hypersensitivity are sometimes managed with clopidogrel monotherapy. Indeed, aspirin hypersensitivity has been associated with stent thrombosis in some case reports[5]. Aspirin desensitization is required when continued aspirin administration is essential (e.g. management of an acute coronary syndrome with stent placement). A rapid protocol can be used as described below.[6] While this protocol can be implemented over the course of several hours, it is not applicable to those patients who must proceed to the cardiac catheterization laboratory such as the patient with ST segment elevation myocardial infarction where "time is muscle"[7].
Pathophysiology
The pathophysiology aspirin hypersensitivity involves both excess leukotriene production as well as the development of IgE antibodies directed toward aspirin. The goal of a desensitization protocol is to deplete the leukotrienes (as well as other mediators) and to down-regulate the leukotriene receptors.
Epidemiology and Demographics
The management of aspirin hypersensitivity is especially critical in patients with acute coronary syndromes. In one single center study, 26 of 1,014 patients admitted for cardiac catheterization had a history of aspirin sensitivity. Of these 26 patients, 61.5% presented with an acute coronary syndrome. While many patients could be desensitized, those with ST elevation MI could not be sensitized before the procedure.[7]
Diagnosis
The signs and symptoms of hypersensitivity include rhinorrhea, exacerbation of asthma, urticaria, angioedema, and anaphylaxis. The majority of patients develop asthma, asthma exacerbation or rhinitis.[8] While aspirin is often the culprit, the reaction can also be induced by cross reaction with cycloxygenase 1 inhibitors (COX 1) such as ibuprofin (Motrin) and naproxen[8]. There is also cross reactivity in patients who take acetaminophen (a weak COX 1 inhbitor), and these patients should not take more than 1000 mg as a single dose[9]. Even 4% of patients with aspirin hypersensitivity will cross-react and sustain a cutaneous reaction to a COX-2 selective NSAID [9].
Treatment
Protocol for Aspirin Desensitization
In the Wong protocol, the dose of aspirin is increased every 15 minutes until the maximum dose of aspirin is administered: Dose 0 minutes: 0.1 mg
15 minutes: 0.3 mg
30 minutes: 1 mg
45 minutes: 3 mg
60 minutes: 10 mg
75 minutes: 20 mg
90 minutes: 40 mg
105 minutes: 81 mg
120 minutes: 162 mg
135 minutes: 325 mg
Success of Therapy
Data regarding the success of aspirin desensitization is based upon small observational studies. Patients with chronic idiopathic urticaria often cannot be desensitized[8]. In one single center experience, 23/26 patients (88.5%) could be desensitized[7]. In another small singel center experience, 14/16 patients could be desensitized[10].
Resensitization as a Complication of Therapy
If patients are not treated with aspirin chronically after desensitization, they can develop resensitization. A 300 mg daily dose of aspirin was superior to a 100 mg daily dose in preventing resensitization[11].
Cost-Effectiveness of Therapy
Aspirin desensitization is much more cost effective than clopidogrel monotherapy. Clopidogrel was associated with a cost $106,453 per incremental Quality Adjusted Life Year saved when compared with aspirin desensitization[12].
Guidelines Recommendations Regarding the Reduction in GI Risks Associated with Antiplatelet and NSAID Use
NSAID based GI adverse events are common and are associated with a 2 to 4 fold increase in the risk of adverse events.
Recommendation: The use of low-dose ASA for cardioprophylaxis is associated with a 2- to 4-fold increase in UGIE risk. Enteric-coated or buffered preparations do not reduce the risk of bleeding. For patients at risk of adverse events, gastroprotection should be prescribed. The risk of UGIE increases with ASA dose escalation; thus, for the chronic phase of therapy, doses greater than 81 mg should not be routinely prescribed.[13]
References
- ↑ Pfaar O, Klimek L (2006). "Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements". Current Opinion in Allergy and Clinical Immunology. 6 (3): 161–6. doi:10.1097/01.all.0000225153.45027.6a. PMID 16670507. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Kasper, S|adek K, Duplaga M, et al.: Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland. Allergy 2003
- ↑ Vally H, Taylor ML, Thompson PJ: The prevalence of aspirin-intolerant asthma (AIA) in Australian asthmatic patients. Thorax 2002, 57:569-574.
- ↑ Szczeklik A, Nizankowska E, Duplaga M, et al.: Natural history of aspirin-induced asthma. Eur Respir J 2000, 16:432-436.
- ↑ Patanè S, Marte F, Di Bella G (2008). "Catastrophic early drug eluting stents thrombosis and aspirin hypersensitivity". International Journal of Cardiology. 131 (1): e25–7. doi:10.1016/j.ijcard.2007.07.053. PMID 17913265. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Page NA, Schroeder WS (2007). "Rapid desensitization protocols for patients with cardiovascular disease and aspirin hypersensitivity in an era of dual antiplatelet therapy". The Annals of Pharmacotherapy. 41 (1): 61–7. doi:10.1345/aph.1H437. PMID 17200429. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ 7.0 7.1 7.2 Rossini R, Angiolillo DJ, Musumeci G, Scuri P, Invernizzi P, Bass TA, Mihalcsik L, Gavazzi A (2008). "Aspirin desensitization in patients undergoing percutaneous coronary interventions with stent implantation". The American Journal of Cardiology. 101 (6): 786–9. doi:10.1016/j.amjcard.2007.10.045. PMID 18328841. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ 8.0 8.1 8.2 Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA (2004). "Aspirin sensitivity: implications for patients with coronary artery disease". JAMA : the Journal of the American Medical Association. 292 (24): 3017–23. doi:10.1001/jama.292.24.3017. PMID 15613671. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ 9.0 9.1 Knowles SR, Drucker AM, Weber EA, Shear NH (2007). "Management options for patients with aspirin and nonsteroidal antiinflammatory drug sensitivity". The Annals of Pharmacotherapy. 41 (7): 1191–200. doi:10.1345/aph.1K023. PMID 17609236. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Silberman S, Neukirch-Stoop C, Steg PG (2005). "Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting". The American Journal of Cardiology. 95 (4): 509–10. doi:10.1016/j.amjcard.2004.10.022. PMID 15695141. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Rozsasi A, Polzehl D, Deutschle T, Smith E, Wiesmiller K, Riechelmann H, Keck T (2008). "Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily". Allergy. 63 (9): 1228–34. doi:10.1111/j.1398-9995.2008.01658.x. PMID 18699939. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Shaker M, Lobb A, Jenkins P, O'Rourke D, Takemoto SK, Sheth S, Burroughs T, Dykewicz MS (2008). "An economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease". The Journal of Allergy and Clinical Immunology. 121 (1): 81–7. doi:10.1016/j.jaci.2007.06.047. PMID 17716716. Retrieved 2010-07-01. Unknown parameter
|month=ignored (help) - ↑ Bhatt et al, ACCF/ACG/AHA Expert Consensus Document: Antiplatelets, NSAIDs, and GI Risk. Circulation 2008;118;1894-1909