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- Supporting Information
Aspirin (ASA) has been shown to be effective at reducing cardiovascular events; unless otherwise contraindicated, it is recommended for both primary prevention in those at risk of cardiovascular disease and secondary prevention for those who already have cardiovascular disease.1 In the general population, 0.5% to 1.9% experience ASA hypersensitivity2; urticarial reactions are reported in about 0.07% to 0.2% and respiratory reactions in up to 10% of asthmatics.3 Thus, despite the clear benefit of ASA therapy, without some intervention, patients reporting ASA hypersensitivity cannot receive this treatment.
Aspirin hypersensitivity manifests in different clinical patterns. Patients may have ASA-exacerbated respiratory disease (AERD) consisting of asthma (generally severe), chronic rhinosinusitis with nasal polyposis, and respiratory reaction to ASA. Other syndromes include urticaria/ angioedema exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs), multiple NSAID-induced urticaria/ angioedema, single NSAID-induced reactions, mixed reactions, or delayed reactions to NSAIDs.2,4 Because these reactions are not typically related to immunoglobulin E (IgE) production, oral challenge is the only way to objectively prove ASA hypersensitivity; in vitro or in vivo testing is not available.5,6 In some instances, such as AERD, the introduction of ASA invariably leads to a pulmonary reaction. Thus, in cardiac patients with a convincing history of ASA hypersensitivity (AERD or other), a temporary induction of drug tolerance (oral desensitization) may be preferable to the risk of a reaction to an oral challenge. This temporary induction of tolerance by giving small, incremental doses of medication is referred to in this article as desensitization (DS).
Because of frequent requests for evaluation of patients with reported ASA hypersensitivity and a cardiac indication for ASA, we conducted a retrospective chart review to confirm our clinical experience that DS can be safely carried out in this subset of patients. A secondary objective was to evaluate a 7-step rapid desensitization protocol (7SP) utilized by our clinic in both the inpatient and outpatient settings (Table 1). We compared our 7SP to our other DS procedures to confirm the safety and efficacy of this specific protocol. Our final objective was to evaluate whether any routine historical information was associated with reaction during an ASA DS protocol.
Table 1. 7-Step Rapid Desensitization Protocol
|Volume (mL)a||Dosage (mg)b||Cumulative Dosage (mg) |
| ||End test|| |
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We identified 309 individual patients as needing evaluation for ASA allergy. The distribution of these patients is shown in the Supporting Figure 1. One hundred and fifty patients required ASA for a cardiac indication and were included in our study. Due to overlap, 160 separate patient visits were included in the study. These visits included 133 inpatient and 27 outpatient visits. Diagnostic oral challenge, performed in 34 patients (22.67%), and no procedure in 27 (18%) left 81 patients for whom DS was necessary. Eight of the 150 patients (5.33%) did not have enough information recorded to determine which procedure was chosen. Reasons that no procedure was elected included risk determined to be greater than benefit (9), history not consistent with ASA allergy (9), patient refusal (6), previously unsuccessful DS (1), no need for daily ASA (1), and patient having just received ASA from primary team with no reaction (1).
Eighty-one patients required DS procedures. Seventy-four patients received 1 DS; 6 patients received 2 DS; 1 patient received 3 DS. Demographic information and key characteristics of the DS patients are listed in Table 2. Only 16 patients (19.7%) had a DS reaction. Eleven of these were instructed to continue ASA. Four of the 16 elected not to continue ASA; 1 patient does not have enough documentation to determine if ASA was continued. Characteristics of the patients who had reactions are shown in Table 3.
Table 2. Demographic and Key Baseline Characteristics of Patients Undergoing Any Desensitization and the 7SP
|Characteristic||All Desensitization Patients, N = 81 (% or SD)||7SP Patients, n = 23 (% or SD) |
|Sex|| || |
| M||31 (38.3)||10 (43.5)|
| F||50 (61.7)||13 (56.5)|
|Age||63.85 ± 12.324||62.57 ± 14.148|
|Race|| || |
| White||62 (76.5)||19 (82.6)|
| Black||17 (21)||3 (13)|
| Other||1 (1.2)||0 (0) |
|Asthma||22 (27.2)||6 (26.1)|
|Polyps||7 (8.6)||1 (4.3)|
|Allergic rhinitis||13 (16)||9 (39.1)|
|Chronic urticaria||2 (2.5)||1 (4.3)|
|Chronic angioedema||1 (1.2)||1 (4.3)|
|Reported allergy to other medications||54 (66.7)||10 (43.5)|
|Type of drug initially reacted to:|| || |
| ASA||66 (81.5)||17 (73.9)|
| NSAIDa||4 (4.9)||2 (8.7)|
|Initial reaction to ASA involving:b|| || |
| Rash or hives||41 (50.6)||11 (47.8)|
| Angioedema||42 (51.9)||11 (47.8)|
| SOB or wheeze||18 (22.2)||5 (21.7)|
|Time since last reaction, y|| || |
| <1||6 (7.4)||3 (13)|
| 2–5||9 (11.1)||2 (8.7)|
| 6–10||12 (14.8)||2 (8.7)|
| 11–20||15 (18.5)||5 (21.7)|
| >20||23 (28.4)||6 (26.1)|
Table 3. Characteristics of Patients Having Reactions During Desensitization
|Characteristic||No. of Patients, N = 16 (% or SD) |
| M||10 (62.5)|
| F||6 (37.5)|
|Age||62.69 ± 12.213|
| White||13 (81.3)|
| Black||3 (18.8)|
|Allergic rhinitis||2 (12.5)|
|Chronic urticaria||1 (6.3)|
|Chronic angioedema||1 (6.3)|
|Reported allergy to other medications||13 (81.3)|
|Initial reaction to ASA involving:|| |
| Rash or hives||11 (68.8)|
| Angioedema||12 (75)|
| SOB or wheeze||2 (12.5)|
|Time since last reaction, y|| |
| <1||5 (31.3)|
| 2–5||2 (12.5)|
| 6–10||3 (18.8)|
| 11–20||1 (6.3)|
| >20||2 (12.5)|
|DS performed inpatient||11 (68.8)|
|DS performed outpatienta||5 (31.2)|
|On antihistamines, LTRAs, or systemic steroids at time of procedure||8 (50)|
|On β-blocker at time of procedure||7 (43.8)|
|Reaction time after previous dose, h||9.8 ± 1.2|
|Reaction before next dose (<20 min)||5 (31.25)|
|Reaction after protocol complete||7 (43.75)|
|Reaction at dose <105 mg||7 (43.75)|
|Protocol require adjustment||6 (37.5)|
|Discharged on ASA||11 (68.8)|
|Still on ASA||6 (37.5)|
|Stop ASA later because of reaction||1 (6.3)|
Of the 81 DS patients, 45 (55.6%) were still on ASA at the time of their most recent clinical evaluation. Only 2 patients (2.2%) had documentation of stopping ASA because of later reactions. One had cough, the other had cutaneous symptoms.
As noted above, 7 patients required ≥1 DS. The reasons for repeat DS were discontinuation of ASA for surgery (3) or colonoscopy (1), reaction to ASA (1), unclear discharge instructions (1), and unclear reasons (2). Hence, there are 89 DS procedures, of which 67 were performed on inpatients and 22 on outpatients. One procedure was aborted in the outpatient clinic and restarted as an inpatient; it is included among the inpatient procedures.
Twenty-six of the 89 (29.2%) procedures used the 7SP. These procedures were performed on 23 patients. Baseline characteristics of these patients are outlined in Table 2. Reactions occurred in 3 patients (13% 7SP patients). Twelve of these patients were still on ASA at the time of their most recent clinical documentation.
Analysis evaluating whether factors were likely to be associated with reaction during DS (Table 4) yielded 2 factors significantly more likely to be associated: time since last reaction if within the past year (P = 0.006), and angioedema as an initial reaction to ASA (P = 0.025). The use of 7SP did not have increased association with reaction when compared with other DS protocols (P = 0.102).
Table 4. Characteristics Evaluated for Increased Association With Reaction During Desensitization
|Characteristic||P Value |
|Initial reaction to ASA involving:|| |
| Rash or hives||0.262|
| SOB or wheeze||0.501|
|Time since last reaction <1 year||0.006|
|Setting where DS performed||0.132|
|On antihistamines, LTRAs, or systemic steroids at time of procedure||0.438|
|On β-blocker at time of procedure||1|
|7SP used as protocol||0.102|
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- Supporting Information
Aspirin and NSAID hypersensitivity to multiple members of this class is most often thought to be mediated by inhibition of cyclooxygenase-1 with increased release of leukotrienes; thus, cross-reactivity exists among cyclooxygenase-1 inhibitors. In single-drug reactors, it is possible to have an IgE-mediated reaction to a single agent.5 Unlike immunotherapy, which induces immunologic tolerance, DS does not alter immune reactivity. Rather, it is thought to render the immune system unable to react; this state is lost quickly if the drug is stopped. Healthcare providers with previous experience performing DS should supervise these procedures.4 In patients with cutaneous single-drug or cross-reacting multiple-drug reactions needing ASA, DS can generally be completed in 1 day, but patients with AERD typically have reactions during the course of the protocol, necessitating multiday protocols for DS.7
There have previously been several small case series demonstrating ASA desensitization in patients with CAD. Most protocols were carried out in an inpatient setting,8–15 and 1 group used a multiday protocol in an outpatient setting.16 It is not clear if Christou et al performed desensitization on inpatients or outpatients.17 The majority of these case series consisted of <20 patients, though 1 European group had 42 patients15 and another had 26.10 These protocols have had good outcomes. Wong et al have published a rapid protocol with dosing intervals of 10 to 30 minutes, which is similar to that presented here, but it was used only in the inpatient setting for patients with CAD.9
In our patient population, diagnoses for which ASA was required were cardiac in nature and ranged from primary CAD prevention to placement of a drug-eluting stent. As mentioned in Table 2, there were 7 patients with nasal polyps, 22 with asthma, and 18 initial reactions that included shortness of breath or wheezing. Because oral challenges were not conducted for unequivocal diagnosis of ASA allergy, it is possible that some patients actually did have undiagnosed AERD. However, only 5 of the patients with polyps also had asthma and a history of a respiratory reaction to ASA; all tolerated DS without reaction.
When evaluating our DS outcomes, we classified patients as having a reaction if there were any problems during the DS, regardless of whether or not they were felt to be a direct result of ASA. These reactions are characterized in Table 5. The majority of the reactions were mild and cutaneous or gastrointestinal in nature. Eleven of the 16 patients (68.7%) were discharged from either the hospital or clinic with instructions to continue ASA. Five of the 16 reactions (31.2%) occurred in patients receiving DS as an outpatient. No patients died, 1 had his hospitalization prolonged by a few hours, and patient 44 went to the emergency department. Four patients had symptoms that were considered severe. Three of these reactions were not clearly linked to ASA (patients 44, 111, and 131), and patient 125 was noted to be wheezing prior to beginning DS, though it is likely ASA was involved in the reaction. Six of the patients having reactions were documented to still be on ASA during their most recent clinical evaluation. Only 1 patient with a reaction during the protocol later chose to discontinue daily ASA due to a subsequent reaction.
Table 5. Summary of Reactions and Ability to Tolerate ASA
|Patient||Symptoms||Cumulative Dose (mg)||Tolerate Daily ASA? |
|9||Angioedema of fingers||636||Yes|
|10||Angioedema of lip, itch||31||No|
|88||Angioedema of lip||27||Yes|
|111||Pulmonary edema, wheeze||101.5||Yes|
|125||Epigastric burning, CP, wheeze||325||Not documentedc|
|131||CP, diaphoresis, bradycardia||30||No|
Previously, the only protocol that has been published for outpatient ASA DS requires 3 days.16 The 7SP presented here was used in the clinic 16 times and in 10 inpatient procedures. Of the 3 reactions with 7SP, 2 occurred in the outpatient setting; all 3 patients had angioedema. Two of the 3 reactions occurred within 24 hours of completing the protocol, and these 2 patients continued ASA therapy. The third elected alternative antiplatelet therapy. When compared with all DS procedures, the use of the 7SP was not significantly more associated with reaction (P = 0.102). To our knowledge, this is the first rapid protocol that has been shown to be both safe and effective in the outpatient setting.
Factors that may affect the outcome of desensitization to ASA in cardiac patients have not been previously evaluated. Urticaria and angioedema are typically documented together in discussions of symptoms upon ASA ingestion, as they relate to oral challenge or DS.3,8 Our data suggest that angioedema alone, with or without urticaria, is more likely to be associated with a reaction during DS (P = 0.025) but does not preclude successful DS. Patients who had their last reaction to ASA within the past year also had significantly more reactions during DS (P = 0.006). Knowledge of these 2 factors may allow the allergist to better individualize DS protocols.
Our study does have several limitations. As a retrospective chart review, documentation was at times missing, such as reaction history to other NSAIDs. The study is also subject to recall bias. Reactions were historical and not witnessed, and diagnostic oral challenges were not performed in DS patients due to safety concerns, so it is possible that some of our patients may not have had true ASA hypersensitivity. Follow-up appointments were not routinely scheduled for all patients undergoing DS to ASA for cardiac indications, which decreases the information available. We also recognize the need for future, prospective analysis to determine whether or not angioedema and the length of time since a reaction to ASA can truly be used as predictors for reaction during DS. The patient population presented here does not include patients with diagnosed AERD. Although we do desensitize AERD patients to treat their respiratory disease, none of our AERD population needed ASA for a cardiac indication. Therefore, the 7SP as presented does not apply to this subset of patients. For further reading on ASA DS in patients with AERD, the reader is directed to a review by Lee and Stevenson.18 Nevertheless, our clinical experience with 81 patients and 89 DS procedures adds to the literature on the safety of ASA DS in non-AERD patients with a cardiac requirement for ASA.