Clopidogrel Desensitization: Background and Recommendations for Use of a Rapid (4 Hour) Protocol.

The purpose of this section is to educate the reader on how to successfully manage patients with a hypersensitivity reaction to clopidogrel using desensitization protocol based on various published protocols. Additionally, we will define drug desensitization, and describe the possible mechanism of how desensitization may function as alternative medication. The indications/contraindications for desensitization will be reviewed. The different published clopidogrel desensitization protocols will be discussed. Based on those protocols, we recommend a protocol we feel is safe and efficacious. Clopidogrel is a thienopyridine antiplatelet drug widely used for treatment and also employed for secondary prevention regarding a range of cardiovascular diseases. However, it has been reported to cause hypersensitivity reactions. Ticlopidine is an alternative medication that can be considered when patients have an allergic reaction to clopidogrel. Additionally, ticlopidine is associated with increased risk causing potentially life-threatening adverse reactions to include: Aplastic anemia, reversible neutropenia, and thrombotic thrombocytopenia purpura vs. clopidogrel. Thus, clopidogrel desensitization offers an attractive alternative. Drug desensitization is defined as causing a temporary state of tolerance to a specific medication responsible for a hypersensitivity reaction. Furthermore, drug desensitization can only be maintained by continuous administration of this drug. Discussion: The exact immunologically mediated mechanism of how rapid oral desensitization works is not fully understood and yet to be defined. Ultimately desensitization results in causing antigen-specific mast cell tolerance. Various protocols have been published. The length of desensitization ranged from 2 h using 9 doses to 7 h using 15 doses. Recommendations: Taking the above into account, we recommend using a modification to the protocol that has the largest number of patients to undergo a standardized clopidogrel desensitization. This approach is shorter, as time has immense importance for these patients. Dosing starts at 10 mg dose and with 60 min intervals between doses, this now becomes a 4 h desensitization protocol.

Use of a composite symptom score during challenge in patients with suspected aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease is characterized by asthma, chronic rhinosinusitis, nasal polyposis, and sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. Confirmation of the diagnosis requires provocation challenge with resulting upper and/or lower airways reactivity. Currently, determination of a positive challenge result is based solely on clinical judgment that synthesizes subjective symptoms and objective measures, as a concomitant increase in nasal or bronchial airways resistance is measured in only half of patients. OBJECTIVE: To describe a quantitative scoring system, based on symptoms typically reported during provocation challenge, used to identify a positive challenge result. METHODS: A total of 115 patients were asked to record 10 symptoms, rated on a scale from 1 (mild) to 10 (most severe), at regular intervals during intranasal ketorolac with modified oral aspirin challenge performed in our office. Composite scores, a simple sum of all individual scores, were calculated at each time point and compared with baseline, prechallenge values. RESULTS: One hundred of the 115 patients were determined to have a positive challenge result. A statistically significant difference in composite scores was observed in reactors vs nonreactors. All nonreactors recorded an increase in composite score of less than 5, whereas 69% of reactors recorded an increase of 5 or more. CONCLUSION: Our 10-symptom composite score provides a quantitative and comparable measure of symptoms that typically present during a challenge with a positive result. Although an external validation is needed to confirm its diagnostic performance characteristics, a change in composite score of 5 or more appears to be specific to reactors.

Performing Aspirin Desensitization in Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic rhinosinusitis with nasal polyps, asthma, and reactions to cyclooxygenase-1-inhibiting drugs. This condition is often refractory to standard medical treatments and results in aggressive nasal polyposis that often requires multiple sinus surgeries. Aspirin desensitization followed by daily aspirin therapy is an important treatment option, and its efficacy has been validated in multiple research studies. Aspirin desensitization is not without risk, but specific protocols and recommendations exist to mitigate the risk. Most patients with AERD can undergo aspirin desensitization in an outpatient setting under the supervision of an allergist.

Aspirin-exacerbated respiratory disease: characteristics and management strategies.

Aspirin-exacerbated respiratory disease is a clinical entity comprising chronic rhinosinusitis with nasal polyposis, asthma and intolerance to COX-1 inhibiting drugs. The pathogenesis is not completely understood at this point, but abnormal arachidonic acid metabolism is a key feature in this syndrome. The diagnosis is confirmed only by direct drug challenge. Aspirin desensitization followed by daily aspirin therapy is a useful treatment option in these patients. In this review article are discussed the important characteristics and treatment of aspirin-exacerbated respiratory disease.

Update on aspirin desensitization for chronic rhinosinusitis with polyps in aspirin-exacerbated respiratory disease (AERD).

Aspirin-exacerbated respiratory disease (AERD) is a clinical condition which results in adverse upper and lower respiratory symptoms, particularly rhinitis, conjunctivitis, bronchospasm, and/or laryngospasm, following exposure to cyclooxygenase-1 (COX-1) inhibiting drugs, namely aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs). A provocative aspirin challenge is the gold standard for diagnosis of AERD. Aspirin desensitization and continuous aspirin therapy has been highly efficacious in those patients with suboptimal control of their disease on current available pharmacotherapy or those with other underlying conditions (i.e., cardiovascular disease) who may require frequent treatment with aspirin or NSAIDs. This review article focuses on aspirin desensitization and the management of patients with AERD with a particular emphasis on outcomes in those patients with chronic rhinosinusitis and nasal polyposis.

Supraesophageal reflux disease: a review of the literature.

Supraesophageal reflux disease (SERD), defined as reflux proximal to the upper esophageal sphincter, is a common cause of morbidity of the upper aerodigestive tract, including rhinitis, laryngitis, cough, postnasal drip, and throat clearing. Although SERD has a high prevalence, the ideal means of diagnosing and treating the disease remain poorly defined. Evolving pH monitoring technology and a body of literature with conflicting reports regarding the best means for measuring and interpreting supraesophageal acidic reflux complicates the diagnosis of SERD. Treatment options include empiric acid suppression therapy, lifestyle modification, and surgery. However, limited data regarding the effectiveness of these strategies vary between studies and patient populations. It is the goal of this article to summarize the presentation and pathogenesis of SERD and to integrate the evolving body of literature pertaining to diagnostic and treatment strategies.

Aspirin-exacerbated respiratory disease: burden of disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by adult onset of asthma, chronic rhinosinusitis (CRS), nasal polyposis, and aspirin sensitivity. In this syndrome, each disease component has deleterious effects on the patient's health and quality of life. Latest figures from the Centers for Disease Control indicate 8.2% of the U.S. population has asthma and among adult asthmatic patients, up to 9% have AERD. Approximately 13% of the population suffers from CRS and 15% of patients with CRS with nasal polyposis have AERD. A review of the impact that each component of AERD has on patients will delineate the considerable burden of AERD, especially when considering the cumulative effects of the tetrad.

Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis.

BACKGROUND: A definitive diagnosis of aspirin-exacerbated respiratory disease (AERD) requires a positive oral aspirin challenge (OAC), but predicting which patients will have positive challenges is often difficult. OBJECTIVE: To analyze information about historical aspirin- and nonsteroidal anti-inflammatory drug (NSAID)-associated respiratory reactions and clinical characteristics as potential markers to predict positive OACs. METHODS: A total of 243 patients underwent OACs. Data related to previous reactions and clinical characteristics of patients were correlated with the result of the OACs. RESULTS: Without prior exposure to aspirin or NSAIDs, the chance of a positive OAC was 5 in 12 (42%) but was 198 in 231 (86%) for those with a history of aspirin- and NSAID-associated asthma attacks. Sex, atopy, number of sinus infections per year, and number of sinus surgical procedures were not associated with positive OACs. Patients with 2 or more prior aspirin- and NSAID-associated respiratory reactions had an 89% chance of having a positive OAC vs single reactors (80%; P = .04). Mild or moderate prior reactions were associated with 84% or 80% positive OACs, whereas 100% of the 45 patients with severe prior reactions had positive OACs (P = .007). Except for hospitalizations, treatment locations of prior reactions (home or emergency department) did not seem to make any difference. Logistic regression identified age, sense of smell, and multiple prior reactions as independent risk factors associated with positive OACs. CONCLUSIONS: Age younger than 40 years, poor sense of smell, multiple prior respiratory reactions, and severe prior asthmatic reactions associated with aspirin and NSAIDs significantly increased the chances of a positive OAC.

Clopidogrel desensitization after drug-eluting stent placement.

OBJECTIVES: We hypothesized that a standardized outpatient clopidogrel desensitization protocol would be safe and effective. BACKGROUND: Adverse reactions to clopidogrel are not uncommon, and affected patients must switch to ticlopidine after drug-eluting stent placement, despite its more malignant side-effect profile, because of the risk of ischemic events associated with premature discontinuation of dual antiplatelet therapy. METHODS: Patients with suspected clopidogrel sensitivity were treated with escalating doses of clopidogrel administered orally in solution until either a clinically significant reaction occurred or the full 75-mg tablet of clopidogrel was tolerated. Desensitization was performed on an outpatient basis except in cases in which the subjects were inpatients at the time of enrollment. Follow-up was performed at 2 to 4 weeks and 6 months after treatment. Successful desensitization was defined as the ability to take clopidogrel 75 mg daily without a mucocutaneous, bronchial, or anaphylactic response. RESULTS: We enrolled 24 consecutive patients with suspected reactions to clopidogrel after DES implantation, 20 of whom were outpatients. During desensitization, allergic-type reactions occurred in 4 patients and angina occurred in 1 patient. Desensitization was acutely successful in all 24 patients, and by 6-month follow-up, 1 patient had persistent but improved pruritus controlled with oral antihistamines and 23 remained asymptomatic, with only 2 patients requiring repeat desensitization. CONCLUSIONS: Clopidogrel desensitization is safe and effective, induces a sustained remission, and could be advantageous in treating outpatients who are at-risk for premature discontinuation of dual antiplatelet therapy.

The blocking effect of essential controller medications during aspirin challenges in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: The blocking effect of controller medications for asthma could have an effect on the outcome of aspirin challenges in patients suspected of having aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: To evaluate whether there was any blocking effect of long-acting beta2-agonists, systemic corticosteroids, and/or inhaled corticosteroids alone or as co-therapy with leukotriene modifier drugs (LTMDs). METHODS: Between 1981 and 2004, 678 patients with suspected AERD were admitted for aspirin challenge and desensitization. All patients had asthma, chronic sinusitis, nasal polyposis, and at least 1 historical reaction to a nonsteroidal anti-inflammatory drug. Asthma controller medications taken during aspirin challenge were recorded and analyzed with respect to their potential effects on 4 possible outcomes of aspirin challenge, namely, naso-ocular reaction, lower airway reaction, classic upper and lower airway reaction, or a negative challenge result. RESULTS: When compared with AERD patients who received no controller medications, the combined use of LTMDs, inhaled corticosteroids, and long-acting beta2-agonists led to a statistically significant change in aspirin challenge outcomes (P = .009), mainly shifting the reaction from a classic upper and lower respiratory tract reaction to naso-ocular reactions only. LTMDs appeared to have the strongest effect (P < .001) in blocking lower respiratory tract reactions. Systemic corticosteroids did not have the same effects. Blocking of both upper and lower respiratory tract reactions to aspirin as a result of taking controller medications did not occur. CONCLUSION: Controller medications are frequently needed to stabilize airways of patients with AERD. LTMDs alone or in combination with other controllers blocked lower respiratory tract reactions during aspirin challenge in some patients with AERD but did not change the overall rate of positive aspirin challenge results and did not lead to false-negative challenges.

Failure of tacrolimus to prevent aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions. OBJECTIVE: A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization. METHODS: Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences. RESULTS: Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences. CONCLUSIONS: Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.

Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by progressive sinusitis, nasal polyposis, and asthma that begins and continues in the absence of exposure to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Cross-sensitivity to all NSAIDs that inhibit cyclooxygenase-1 (COX-1) occurs in these individuals. Reactions to aspirin and NSAIDs in patients with AERD are largely due to inhibition of COX-1. Despite accumulating data on the safety of COX-2 selective inhibitors in AERD, concern still remains that high doses of a COX-2 inhibitor may be sufficient to induce a cross-reaction. OBJECTIVE: To determine whether high-dose rofecoxib cross-reacts in patients with AERD and asthma. METHODS: Sixty asthmatic patients underwent blinded placebo-controlled oral challenges with 50 mg of rofecoxib. Aspirin sensitivity was subsequently confirmed in all patients with the use of single-blinded aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination results, or declines in lung function during rofecoxib challenge. All 60 patients experienced respiratory reactions to aspirin challenge, with a mean provoking dose of 57 mg. The exact 1-sided 95% confidence interval for the underlying probability of 50 mg of rofecoxib inducing respiratory cross-reactions in patients with AERD is 0 to 0.05, or 0% to 5%. CONCLUSIONS: These results confirm the lack of cross-reactivity of aspirin and the highly selective COX-2 inhibitors in AERD. We suggest that it is time for the labeling of highly selective COX-2 inhibitors to reflect these data and for the warning that patients with AERD in particular and asthmatic patients in general avoid selective COX-2 inhibitors to be removed.

Treatment of patients with respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs.

Aspirin exacerbated respiratory disease (AERD) is an adult onset condition manifested as asthma, rhinosinusitis/nasal polyps, and sensitivity to aspirin and other cyclooxygenase-1 (Cox-1)-inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs). There is no cross-sensitivity to highly selective Cox-2 inhibitors.

Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs.

Aspirin-exacerbated respiratory disease (AERD) is an adult-onset condition that manifests as asthma, rhinosinusitis/nasal polyps, and sensitivity to aspirin and other cyclooxygenase-1 (COX-1)-inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs). There is no cross-sensitivity to highly selective COX-2 inhibitors. AERD is chronic and does not improve with avoidance of COX-1 inhibitors. The diagnosis of AERD is made through provocative challenge testing. Following a positive aspirin challenge, patients can be desensitized to aspirin and NSAIDs. The desensitized state can be maintained indefinitely with continued daily administration. After desensitization, there is an approximately 48-hour refractory period to adverse effects from aspirin. The pathogenesis of AERD remains unknown, but these patients have been shown to have multiple abnormalities in arachidonic acid metabolism and in cysteinyl leukotriene 1 receptors. AERD patients can take up to 650 mg of acetaminophen for analgesic or antipyretic relief. Patients can also use weak COX-1 inhibitors, such as sodium salicylate or choline magnesium trisalicylate. Treatment of AERD patients with antileukotriene medications has been helpful but not preferential when compared with non-AERD patients. An alternative treatment for many AERD patients is aspirin desensitization. This is particularly effective in reducing upper-airway mucosal congestion, nasal polyp formation, and systemic steroids.

Prevention and treatment of reactions to NSAIDs.

Avoidance of ASA and other NSAIDs prevents the reactions and careful attention to clinical history along with patient education are important. However, blanket advice to avoid all NSAIDs is no longer reasonable. Except for AERD and chronic urticaria, cross-reactivity with other NSAIDs does not occur. A physician can definitively prove this by giving the patient another NSAID in their office and observing no reaction. Furthermore, for patients with AERD and chronic urticaria, they can be given the new selective COX-2 inhibitors (rofecoxib and celecoxib) without any cross-reactivity. All AERD patients can be desensitized to ASA and treated with ASA indefinitely. However, ASA desensitization in chronic urticaria is not possible. Underlying mild and moderate AERD responds well to topical and systemic corticosteroids and leukotriene modifiers. However, the severe forms of the disease should be desensitized to ASA and treated with this drug on a long term basis. In the future, new drugs that prevent eosinophil activation and chemotaxis or enhance eosinophil apoptosis are likely to be useful. Specific blockers of the second cystLT receptor would also be useful. Ultimately as the genetics of these heterogeneous disorders are unraveled, gene substitution therapy may be the ultimate answer.

Sensitivity to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Aspirin can provoke reactions ranging from respiratory to cutaneous in susceptible individuals. There has been particular attention looking at the role of cyclo-oxygenase enzymes 1 and 2 and their role in aspirin-exacerbated respiratory disease. OBJECTIVE: Patients who present with a spectrum of allergic and pseudoallergic reactions to aspirin pose a special challenge for the physician. This article discusses proposed classification system, clinical manifestations, pathogenesis of disease, and current treatment options of aspirin-related disease. DATA SOURCES: Relevant articles in the medical literature were derived from searching the MEDLINE database with key terms aspirin-sensitive asthma, cyclo-oxygenase enzymes 1 and 2. Sources also include review articles, randomized control trials, and standard textbooks of allergy and immunology. RESULTS: Aspirin-exacerbated respiratory disease remains a complex, heterogenous disease with varied clinical presentations. There have been many advances in trying to elucidate the pathogenesis of this disease. The classification system presented will provide greater ease when reading the literature and communicating with one another. Oral aspirin challenge remains the diagnostic test of choice for both respiratory and cutaneous reactions. Aspirin desensitization is an option for those with refractory respiratory disease or who require aspirin for other medical conditions. CONCLUSIONS: This review discusses the challenges in classification, diagnosis, and treatment of those patients with a sensitivity to aspirin. Special attention is made to the possible mechanisms mediating disease progression and how specific therapies, such as leukotriene modifiers, may be helpful.

The natural history and clinical characteristics of aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinitis, nasal polyps, asthma, and precipitation of asthma and rhinitis attacks after ingestion of aspirin (ASA) and most nonsteroidal anti-inflammatory drugs (NSAIDs). Most information about the disease in the United States has come from small samples of patients. OBJECTIVE: The purpose of this study was to examine the natural history and clinical characteristics of 300 AERD patients, referred to our institution for aspirin desensitization. METHODS: All potential AERD patients were evaluated using a standard questionnaire that included information about clinical characteristics and natural progression of their disease, previous history of reactions to ASA and other NSAIDs, current use of medications, and ethnic backgrounds. All patients underwent oral ASA challenges to prove they had AERD. RESULTS: From patients' history we found that the average age at onset of AERD was 34 years, and that 57% were female. Counting ASA as an NSAID, 33% had previously reacted on two occasions to NSAIDs and 36% on more than three occasions to NSAIDs, whereas only 27% had reacted to one NSAID before they came to us for evaluation. Our patients had averaged 5.5 episodes of sinusitis per year. There were no significant differences in the clinical characteristics or use of medications between genders. Ethnicity was heterogeneous in most participants. CONCLUSIONS: AERD begins in the third decade of life and in both sexes. The disease progressed over the 13 years between historical onset and current evaluation, with more sinusitis and need for controller medications over time. There was no ethnic or familial distribution of AERD.