Clopidogrel bisulfate is a thienopyridine oral antiplatelet agent that acts via irreversible inhibition of adenosine diphosphate-mediated platelet activation and aggregation.1 It is widely used in the treatment and secondary prevention of a variety of cardiovascular diseases. Clopidogrel has been shown to decrease death and ischemic events in patients with recent myocardial infarction, ischemic stroke or symptomatic peripheral arterial disease,2 patients with non-ST-segment elevation acute coronary syndromes,3 and patients undergoing percutaneous coronary interventions.4,5 More recently, clopidogrel was shown to improve outcomes in patients with ST-segment elevation myocardial infarction who received thrombolytic therapy.6 Clopidogrel is well tolerated by the majority of patients. However, rare, serious hypersensitivity reactions have been reported including spontaneous reports during post-marketing surveillance.7 Recently, case reports of clopidogrel hypersensitivity reactions have also been published.8–13 Given the large number of patients with indications for the use of clopidogrel, it is likely that most practitioners will face the dilemma of managing patients with clopidogrel hypersensitivity. In this study, we present our initial clinical experience with clopidogrel desensitization in patients with thienopyridine hypersensitivity. Methods Our institution has instituted a protocol for desensitizing patients with cutaneous hypersensitivity to clopidogrel and an indication for dual antiplatelet therapy (Table 1). Our Allergy-Immunology department developed this protocol as a modification of a previously presented desensitization procedure.12 Desensitization is performed in the intensive care unit (ICU) under the direction of specialists in Allergy-Immunology and Cardiology. Prior to desensitization, patients are taken off antihistamines and steroid medications for 3 days and beta-blockers are held, preferably for 4 days. Solutions of oral clopidogrel are prepared by a pharmacist in the form of aliquots of escalating doses of clopidogrel powder that are then suspended in water. These are administered at 15-minute intervals over a period of 2 hours while the patient is monitored for acute hypersensitivity symptoms and hemodynamic instability (Table 2). The patient is monitored in the ICU for 1 hour after the final dose of the protocol and then is monitored overnight on a cardiology ward after completion of the protocol. Successfully desensitized patients are discharged on a daily dose of 75 mg of clopidogrel. Planned percutaneous interventions are delayed for a few weeks, if possible, to ensure that no late hypersensitivity symptoms develop. Between October 2004 and December 2005, this protocol was used to desensitize 8 patients with a history of cutaneous hypersensitivity reactions to clopidogrel and an indication for continued or renewed clopidogrel therapy. Results To date, all 8 patients have successfully completed desensitization and were able to tolerate a 75 mg dose of clopidogrel prior to discharge. All patients have been followed for 3 to 12 months post-desensitization. Clinical characteristics of the patients are presented in Table 3. Patient 1 was placed on clopidogrel after drug-eluting stent implantation and developed generalized pruritus the following day. A maculopapular rash developed on day 3 of therapy. These symptoms resolved after discontinuation of clopidogrel. The patient was managed with coumadin and aspirin prior to desensitization. After desensitization, the patient had a planned second percutaneous coronary intervention (PCI) with drug-eluting stent placement. Patient 2 was placed on clopidogrel following drug-eluting stent placement and developed a pruritic maculopapular rash after 2 to 3 weeks of clopidogrel therapy. This rash resolved after discontinuation of clopidogrel. The patient underwent desensitization prior to a second PCI. Patient 3 had a history of multiple prior PCIs. Clopidogrel was tolerated following the first procedure. Generalized pruritus developed after restarting clopidogrel following the second PCI, persisted throughout the 6 months of therapy and resolved immediately upon discontinuing the clopidogrel. Pruritus recurred following resumption of clopidogrel therapy following the third PCI and continued for 1–2 months. At this point, clopidogrel was discontinued and dipyridamole was used in its place. The pruritus resolved upon discontinuation of the clopidogrel. No clopidogrel was used following the fourth PCI, and no pruritus developed. Desensitization was performed prior to cardiac catheterization, with probable PCI due to continued angina on maximal medical therapy. Patient 4 had two drug-eluting stents placed and developed urticaria 8 days after beginning clopidogrel and lisinopril. Lisinopril was discontinued but the urticaria worsened and the patient developed angioedema. Symptoms were attributed to clopidogrel by the Allergy consultants. At this point, clopidogrel was discontinued and the patient was treated with steroids and anti-histamines until clopidogrel desensitization was performed. Patient 5 was started on clopidogrel in 2000 following coronary stent placement and developed a maculopapular rash that resolved with discontinuation of the medication. In September 2005, the patient received a drug-eluting stent and was started on ticlopidine due to her previous clopidogrel reaction. After 5 days, the patient developed rash, urticaria and fever, and ticlopidine was discontinued. The symptoms resolved after 6 days of treatment with prednisone and antihistamines. Desensitization to clopidogrel was performed to allow the use of dual antiplatelet therapy. Patient 6 had 3 drug-eluting stents placed after a non-ST-elevation myocardial infarction. After taking clopidogrel for 10 days, the patient developed nausea, vomiting and generalized pruritus followed the next day by urticaria and angioedema. The patient was admitted for clopidogrel desensitization. Given her recent drug-eluting stent implantation, the patient was placed on intravenous (IV) heparin while off clopidogrel. Patient 7 had a history of erythematous, pruritic maculopapular rash after clopidogrel exposure in 2002 following bare metal stent placement in a saphenous vein graft. The rash resolved with discontinuation of the clopidogrel. The patient presented recently with unstable angina and was found to have in-stent restenosis. Clopidogrel desensitization was performed to allow drug-eluting stent placement. Patient 8 was placed on clopidogrel after placement of 4 drug-eluting stents during primary PCI for an anterior ST-elevation myocardial infarction. A pruritic, maculopapular rash began 4 days after the initiation of clopidogrel. The rash improved promptly with cessation of clopidogrel therapy. Clopidogrel desensitization was performed to allow dual antiplatelet therapy, given the recent drug-eluting stent placement. Of the 8 patients desensitized, there were no major and 2 minor hypersensitivity reactions during desensitization. Patient 3 had mild pruritus after the third dose of the protocol that responded to a single dose of oral hydroxyzine. The protocol was then completed without further events. Patient 6 developed urticaria and pruritus following the final dose of the standard desensitization protocol. This patient received oral cimetidine and prednisone plus intravenous diphenhydramine with resolution of the symptoms. Since the reaction was an isolated cutaneous reaction, the decision was made to repeat the desensitization attempt the following day. A modified desensitization protocol using lower initial doses of clopidogrel and 30-minute spacing between doses as well as premedication with cimetidine, prednisone and diphenhydramine was employed and well tolerated by the patient. A three-dose graded challenge to clopidogrel, following premedication, was performed on the third day and was well tolerated. The patient was then given a standard 75 mg dose without premedication on the fourth day without evidence of recurrent hypersensitivity reaction. The 1st, 2nd and 7th patients underwent planned drug-eluting stent placement after desensitization. The 3rd had subcritical stenoses and no intervention was performed. This patient remained on clopidogrel after angiography for secondary prevention given her prior myocardial infarction, multiple prior PCIs and large burden of nonobstructive CAD. The 4th, 5th, 6th and 8th patients had drug-eluting stents placed prior to clopidogrel desensitization. All 8 of these patients have remained on clopidogrel therapy and been followed without recurrence of hypersensitivity symptoms or major adverse cardiac events for a median duration of 7.5 months. Discussion Hypersensitivity reactions are immunologically-mediated reactions caused by exposure to an antigen. Reported clinical presentations of clopidogrel hypersensitivity include urticaria,8 skin rashes9,11–13 and angioedema.10 While the precise immunologic mechanism of clopidogrel hypersensitivity has not been elucidated, the report of a patient with positive intradermal skin testing12 would support an IgE-mediated process. Other potential mechanisms for the hypersensitivity reactions would include direct mast cell activation, complement activation, immune complex formation, T-cell activation or other unknown mechanism(s). It is also possible that the hypersensitivity reactions may be caused by a metabolite of clopidogrel rather than directly by clopidogrel itself. Clinical management of patients with clopidogrel hypersensitivity can be challenging, as alternatives are limited. Another available thienopyridine, ticlopidine, has been supplanted by clopidogrel due to clopidogrel’s lower incidence of adverse hematologic effects, including neutropenia14,15 and thrombotic thrombocytopenic purpura.16,17 There is also concern regarding potential cross-sensitivity between clopidogrel and ticlopidine given their similar chemical structure, differing only by the addition of a carboxymethyl side group to clopidogrel.18,19 This is supported by the experience of patient 5 in our series, who had hypersensitivity reactions to both drugs. Warfarin, in addition to aspirin, has been used following bare metal stent placement, but has been shown to have only marginal benefit over aspirin alone and to be inferior to a regimen of aspirin and thienopyridine.20 In addition, there is no published experience to support the use of warfarin after drug-eluting stent placement. In selected cases, coronary artery bypass surgery could be performed rather than coronary artery stenting to avoid the need for clopidogrel after revascularization, but this approach may expose patients to increased procedural morbidity. Additionally, this option is not available for patients who have hypersensitivity reactions after stent implantation. An alternative approach to management would be to desensitize the patient to clopidogrel and thus allow it to be used safely. In general, desensitization is the process of inducing tolerance to a sensitizing agent via repeated exposure to the agent. This is accomplished by exposing the patient to initially low and then escalating doses of a drug in a monitored setting until a therapeutic dose can be tolerated without reaction. The precise immunologic mechanism by which rapid oral desensitization procedures work is both complex and incompletely defined, but the fundamental effect is the induction of antigen-specific mast cell tolerance.21–23 This process has been successfully used in patients with hypersensitivity reactions to numerous antibiotics.24–27 Desensitization protocols have also been used safely in patients with hypersensitivity reactions to aspirin28,29 including patients with coronary artery disease.30,31 To our knowledge, this is the largest published experience regarding desensitization of patients with clopidogrel hypersensitivity. A previously published case series by Camara et al13 contained 3 patients with skin rashes after exposure to clopidogrel. The desensitization protocols differ slightly in their initial doses and dose escalation schedules. While Camara used both inpatient and outpatient settings for desensitization, we chose to mandate ICU admission to facilitate close monitoring of the patients and allow for rapid response in the event of an adverse reaction. The Camara protocol takes approximately 8 hours to complete, while our protocol can be completed in 3 hours. The successful desensitization of 2 patients with angioedema is unique to our current study. Our series also showed that desensitization prior to PCI can allow for the safe use of clopidogrel after drug-eluting stent placement in patients with a history of prior hypersensitivity reactions. The major limitations of our experience are the small number of patients treated to date and the moderate follow-up times. While the initial results of this desensitization protocol have been encouraging, the observed safety and efficacy should be validated in a larger cohort of patients. Additionally the hypersensitivity reactions in the majority of the patients desensitized to date have included cutaneous symptoms of rash and pruritus. This protocol has been tested in 2 patients with a history of clopidogrel-associated angioedema, but in no patients with respiratory symptoms or anaphylaxis. It also has not been used in patients with severe exfoliative dermatitis reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, as desensitization is contraindicated in patients with these types of reactions. We recommend that patients who have undergone clopidogrel desensitization should be followed by an allergist while they remain on clopidogrel to monitor for the recurrence of hypersensitivity reactions. Finally, based on experience with desensitization to other drugs, the patient must remain on clopidogrel therapy without interruption to insure the maintenance of tolerance. While there is experience regarding the safety and efficacy of repeat desensitization to drugs such as penicillin after interruption of therapy, we have no such experience with clopidogrel. Our experience suggests that it is possible to safely desensitize patients with a history of isolated cutaneous hypersensitivity reactions, including angioedema, to clopidogrel. Desensitization may allow for the use of clopidogrel as part of dual antiplatelet therapy in hypersensitive patients with recent or planned coronary stent implantation or for secondary prevention of cardiovascular events.
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