Circulation: CAD patients RESPOND to clopidogrel after treatment with ticagrelor

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The reversible anti-clotting medication ticagrelor can overcome a patient's nonresponsiveness to clopidogrel, according to results of the RESPOND trial published online March 1 in Circulation.

Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research in Baltimore, and colleagues enrolled 144 patients with CAD between May 19, 2008, and March 25, 2009, into the randomized, double-blind, double-dummy cross-over trial. Patients who were between the ages of 45 and 85 were split into two cohorts: 34 nonresponders (83 percent) and 54 responders (95 percent).

“Before the present study, there were no investigations designed to examine the effect of ticagrelor in clopidogrel nonresponders and the effect of changing therapy from clopidogrel to ticagrelor and vice versa,” the authors wrote.

Two to four weeks prior to the study, researchers assessed a patient’s responsiveness to clopidogrel by administering a 300 mg dose to determine ADP-induced platelet aggregation (IPA) prior to the dose, and six to eight hours after. Patients were classified as nonresponders if they had a change in platelet aggregation that was greater than or equal to 10 percent.

During the first period of the trial, both cohorts were randomly treated with a 600 mg dose of clopidogrel followed by either a 75 mg daily maintenance therapy or a 180 mg ticagrelor load followed by a 90 mg twice daily maintenance therapy. During the second period, all nonresponders switched treatment, half of responders remained on the same treatment and all other responders switched treatments.

Results showed that within the nonresponder patient cohort, the number of patients who responded to ticagrelor was higher than those administered clopidogrel. Additionally, those patients treated with ticagrelor showed a greater change in platelet aggregation.

After patients being treated with clopidogrel switched to ticagrelor, platelet aggregation fell from an average of 59 percent to an average of 35 percent. Patients who switched from clopidogrel to ticagrelor showed a rapid enhancement in platelet inhibition in both responders and nonresponders of clopidogrel: 36 to 56 percent.

“The higher and more consistent IPA and lower platelet reactivity upon switching to ticagrelor demonstrate that the latter may be a reasonable strategy for clopidogrel nonresponders,” the authors wrote.

Additionally, the researchers found that platelet reactivity for patients administered ticagrelor therapy was below cut points associated with ischemic risk.

During the study, four patients treated with ticagrelor experienced serious adverse events including MI, hypotension, atrial fibrillation and bradycardia. According to the authors, one major and three minor bleeding events occurred during treatment with ticagrelor, while no bleeding events took place in patients treated with clopidogrel.

In addition, 13 cases of dyspnea were reported in patients receiving ticagrelor compared with four cases in patients administered clopidogrel.

“The definition of clopidogrel nonresponsiveness remains controversial and is dependent on the time, dose and method of assessment,” concluded the authors.