Acute coronary syndrome antiplatelet alternatives in clopidogrel allergy

Design

Case presentation 1

A 65-year-old woman with an extensive past medical history presented with intermittent substernal chest pain. Her previous medication allergies included sulfa (unknown reaction), lisinopril (cough), intravenous contrast media (lip swelling), tetracycline analogs (unknown reaction), milnacipran (rash, lip swelling), and amiodarone (rash). After an electrocardiogram (ECG) revealed ST-segment elevation and elevated cardiac troponin, the patient was diagnosed with critical two-vessel coronary artery disease and was treated with percutaneous coronary intervention (PCI) with implantation of bare metal stents to both lesions. The patient was loaded with aspirin 325 mg orally and clopidogrel 300 mg orally, then initiated with aspirin 81 mg daily and clopidogrel 150 mg/daily, orally, along with previous home medications, including warfarin. Clopidogrel dosage was decreased to 75 mg/daily after 7 days, to continue for 6 months. After 9 months, the patient again presented with chest pain, and underwent similar treatment, and was loaded with 600 mg clopidogrel followed by 75 mg daily for 28 days. She continued aspirin 81 mg/day and warfarin. 

After 16 days, the patient complained of a severe itch over various parts of her body, despite no visible rash. Clopidogrel was thought to be the most likely cause of urticaria. Still, the final 12 days of treatment regimen were continued, with addition of hydroxyzine and the continuation of hydrocortisone 0.05% topical cream twice daily as needed and prednisone 5 mg/day orally. One year later, the patient again presented with chest pain, fever, and change in mental status, again determined to be due to myocardial infarction (MI). After catheterization, the patient was loaded with a single dose of ticagrelor 180 mg followed by 90 mg orally twice daily, instead of clopidogrel. Five days after catheterization, the patient was discharged on ticagrelor 90 mg orally twice daily and aspirin 81 mg daily. No further incidents were reported. 

Case presentation 2

A 38-year-old man presented after 1 day of experiencing nausea, lightheadedness, dyspnea and sharp, left-sided, non-radiating chest pressure/pain that had increased in severity throughout the day. The patient reported no known allergies at the time. Home medications consisted of duloxetine (unknown dose). The patient's ECG revealed ST-segment elevation as well as an elevated cardiac troponin T level of 0.52 ng/mL. The patient was diagnosed with critical two-vessel coronary artery disease. In the cardiac catheterization lab, the patient was loaded with clopidogrel 600 mg and aspirin 325 mg orally, followed by initiation of clopidogrel 75 mg/day and aspirin 325 mg/day. The patient was discharged in 4 days, with additional medications including atorvastatin, lisinopril, metoprolol succinate, and nitroglycerin. 

At an 8-month follow-up, the patient was observed by a cardiologist to have a chronic rash on the arm and torso. Rash had appeared shortly after PCI and was thought to be a result of clopidogrel allergy. In 4 months' time, the rash had spread diffusely and was increased in severity, requiring treatment with topical steroids. The patient's clopidogrel was discontinued, and the rash soon resolved. At a future date, the patient presented again with a recurrent MI. Instead of clopidogrel, the patient was loaded with aspirin 325 mg and ticagrelor 180 mg orally, followed by initiation of ticagrelor 90 mg orally twice daily and aspirin 81 mg once daily. Four days later, the patient was discharged home without further reported incidents. 

Study Author Conclusions

Clopidogrel lymphocyte-mediated delayed hypersensitivity reaction carries a 27% cross-reactivity with prasugrel and ticlopidine that may be avoided with ticagrelor. The unique structure of ticagrelor compared with other available oral ADP antagonists seems to make it a viable alternative in patients requiring dual antiplatelet therapy who have a clopidogrel allergy.

Oral antiplatelet agent hypersensitivity and cross-reactivity managed by successful desensitisation

Design

Case presentation

A 57-year-old man with significant history of ischemic heart disease underwent elective percutaneous coronary intervention (PCI) with insertion of two drug-eluting stents in February 2014. The patient was initiated on dual antiplatelet therapy with clopidogrel in addition to his regular aspirin. No previous drug allergies were reported at this time. However, 11 days after initiation of clopidogrel, the patient reported with a generalized urticarial rash, including on his scalp and palms, accompanied with peripheral paresthesia. The patient was treated with antihistamines, and his clopidogrel was changed to ticagrelor. However, 36-hours later, he again presented with facial angioedema and left sided chest pain and dysphagia. Subsequently, ticagrelor was stopped, and symptoms resolved with intramuscular adrenaline and intravenous corticosteroids. 

Further cardiology consultation recommended a trial of prasugrel, under close supervision. Within 2 hours, the patient developed a urticarial reaction involving the hands, feet, and groin. The effects subsided with antihistamine treatment. After a third dose of prasugrel, the patient experienced chest, left arm, and abdominal discomfort, along with periorbital and lip angioedema. Additionally, the patient was diaphoretic and required oxygen therapy, but improved with intramuscular adrenaline, intravenous fluids, and oral and intravenous antihistamines. Trial of ticlopidine was considered, but ultimately avoided due to concern for similar and more severe and rapid-onset hypersensitivity due to similar molecular structures of clopidogrel, ticlopidine, and prasugrel. Eventually, the patient underwent successful clopidogrel desensitization with prednisolone cover without complication and was maintained on strict daily dose afterwards. The patient was continued on clopidogrel without adverse events for 4 months post-desensitization. 

Study Author Conclusions

Oral platelet aggregation inhibitors used in combination with aspirin to prevent in-stent thrombosis following percutaneous coronary intervention are not uncommonly associated with hypersensitivity reactions. This case of cross-reactive hypersensitivity between thienopyridines (clopidogrel and prasugrel) and the structurally dissimilar cyclopentyl-triazolo-pyrimidine (ticagrelor) suggests the mechanism may be their common chemical action rather than immunological recognition. Nevertheless, desensitization is a therapeutic option irrespective of the underlying mechanism.

Ticagrelor Use in a Patient With a Documented Clopidogrel Hypersensitivity

Design

Case presentation

A 64-year-old woman with an extensive past medical history and numerous drug allergies, including clopidogrel, ticlopidine, amoxicillin/clavulanate, penicillin, sulfa drugs, and iodinated radiocontrast dyes presented to the emergency department with chest pain. Previously, the patient had presented with a positive cardiac stress test and had undergone percutaneous transluminal coronary angioplasty and stenting. After this clopidogrel had been initiated with subsequent development of full-body maculopapular rash approximately 2 weeks later. Discontinuation of clopidogrel and corticosteroid treatment resulted in resolution of rash. A similar reaction was observed with ticlopidine challenge, which was also discontinued and not reinitiated. In 2008, the patient was again admitted with angina. After testing, the patient underwent clopidogrel desensitization as an outpatient, prior to percutaneous transluminal coronary angioplasty. 

The protocol for the outpatient desensitization consisted of escalating doses of clopidogrel, from 0.1 to 75 mg over a period of 3 days. The process was successful, and the patient was continued on clopidogrel after the procedure for approximately 2 years. At the current time, however, the patient again presented with retrosternal chest discomfort radiating to both shoulders, shortness of breath, and diaphoresis. The patient was ultimately treated for a non-ST segment elevated myocardial infarction (NSTEMI). It was discussed by clinicians if the patient should be desensitized to clopidogrel a second time or if ticagrelor should be attempted instead. On day 2 of hospitalization, the patient was initiated on ticagrelor for at least 12 months, along with aspirin 81 mg daily, as well as various other medications. Ticagrelor was administered with a loading dose of 180 mg and a maintenance dose of 90 mg twice daily. No adverse reactions or evidence of hypersensitivity were reported during the hospital stay or at 2 and 4 weeks after discharge. 

Study Author Conclusions

The current case report describes the successful use of ticagrelor in a patient with a documented hypersensitivity to clopidogrel and ticlopidine. Ticagrelor was tolerated throughout the hospital stay as well as at 2 and 4 weeks following discharge. Prasugrel use was not considered based on the need for conservative medical management of NSTEMI in this patient, and clopidogrel desensitization was also regarded as less ideal, given the need for ICU care. The authors recommend cautious use of ticagrelor in this setting until further data become available but suggest that it may be a reasonable option when an alternative P2Y12 inhibitor is required for ACS treatment.