La Jolla, CA - Patients who experience allergic reactions to clopidogrel appear to benefit from a desensitization protocol that enables them to continue taking the drug long term, which is particularly important after placement of a drug-eluting stent (DES) [1].

This is the conclusion of a new study, published in the November 20, 2007 issue of the Journal of the American College of Cardiology (published online November 5, 2007).

The authors, led by Dr Karl von Tiehl (Scripps Clinic, La Jolla, CA), say: "Clopidogrel desensitization appears safe and highly effective in inducing a sustained remission in clopidogrel-sensitive patients who require prolonged dual antiplatelet therapy after [placement of] drug-eluting stents. Our data support [the idea] that this approach should be considered in all stable outpatients with clopidogrel sensitivity who meet our inclusion and exclusion criteria to avoid the potential adverse effects of ticlopidine and to avoid the thrombotic risk of discontinuation of thienopyridine therapy."

Von Tiehl et al explain that long-term treatment with aspirin and clopidogrel is recommended after placement of a DES to prevent stent thrombosis and cardiac events but that potentially allergic reactions to clopidogrel have been reported in approximately 4% of patients, usually requiring drug discontinuation. They point out that the alternative thienopyridine, ticlopidine, is more expensive, dosed more often, and associated with a more frequent and serious adverse side-effect profile, including blood dyscrasias, limiting its clinical safety and utility.

They therefore investigated the possibility of desensitizing such patients to their allergic reactions to clopidogrel. Such desensitization protocols already exist for several medications, including aspirin, and involve introducing the drug in very small incremental amounts and gradually building up to the therapeutic dose.

The study was conducted in 24 consecutive patients with suspected allergic reactions to clopidogrel after DES implantation, 20 of whom were outpatients. When possible, clopidogrel was discontinued and patients were transitioned to ticlopidine 250 mg orally twice a daily for five days before desensitization for both drug elimination and symptom resolution. The clopidogrel desensitization protocol was administered by a dedicated drug-desensitization nurse and supervised by an allergist, who confirmed and treated any reactions during the protocol. The use of steroids, antihistamines, and antileukotrienes was stopped for seven days before desensitization if feasible. Beta blockers were held on the day of desensitization if possible.

The protocol involved oral administration of an aqueous solution containing increasing amounts of clopidogrel. The first dose given was solvent only, followed 30 minutes later by 0.005 mg of clopidogrel in solution. Thereafter, doubling doses of dilute clopidogrel were given every 30 minutes until a single 75-mg tablet was given. All patients were monitored for adverse reactions. If a potentially allergic reaction occurred, the patient was given diphenhydramine (oral or IV) or oral cetirizine for symptom control. Once symptoms subsided and 30 minutes had elapsed since the previous dose of clopidogrel had been given, the same dose was repeated. If no reaction occurred, then the protocol was continued. If a reaction reoccurred, the patient was given the same treatment as mentioned previously, then the next dose of clopidogrel given was half of the provoking dose.

Results showed that during desensitization, allergic-type reactions occurred in four patients and angina occurred in one patient. Desensitization was acutely successful in all 24 patients, and by six-month follow-up, one patient had persistent but improved pruritus controlled with oral antihistamines and 23 remained asymptomatic, with only two patients requiring repeat desensitization.

Von Tiehl et al note: "This study demonstrates that primarily outpatient-based clopidogrel desensitization is feasible, safe, and effective and induces a sustained remission for at least six months." They add, however, that a sustained response to desensitization requires excellent patient compliance, as even brief discontinuation of the offending drug can cause symptoms to recur once the drug is restarted. Therefore, the recurrence of clopidogrel sensitivity in patients who have been previously desensitized may serve as a warning of noncompliance.

The authors write: "Premature discontinuation of dual antiplatelet therapy has been clearly shown to be a strong, independent risk factor for stent thrombosis, which frequently results in MI and death. Therefore, efforts to reduce discontinuation of clopidogrel up to 12 months after DES implantation are crucial."

They further point out that the most common period for the onset of clopidogrel reactions is within the first 10 days after PCI, which coincides with the highest risk of stent thrombosis when not treated with a thienopyridine. "Clopidogrel desensitization may therefore be an important approach to prevent discontinuation and subsequent major adverse cardiac events in clopidogrel-sensitive patients after DES [implantation]," they say.