Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose

Abstract

Background-Clopidogrel loading has mostly been studied in clopidogrel-naïve patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation. Methods and Results-Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 mol ADP and the point-of-care assay VerifyNow P2Y 12 . The primary objective of the study was to evaluate the inhibition (relative change) of residual platelet aggregation (percentage of IRPA) between 600-and 900-mg first loading at 4 hours. IRPA at 24 hours also was evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as IRPA Ͻ10%. We included 166 consecutive patients with acute coronary syndromes (nϭ80, 48%) or stable coronary artery disease (nϭ86, 52%). Baseline characteristics were similar in the 3 dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively; Pϭ0.0024). The difference in percentage IRPA at 4 hours was not significant between 300 and 600 mg but was significant between 600 and 900 mg and between 300 and 900 mg. Percentage IRPA assessed at 24 hours when all patients had received 900 mg did not differ between the 3 loading regimens. The rates of suboptimal response (IRPA Ͻ10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively (Pϭ0.02 for all). Conclusions-In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor and/or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.

Can We Override Clopidogrel Resistance?

“…5 Aspirin and clopidogrel pharmacodynamic responses were evaluated with light transmission aggregometry (arachidonic acid 1.25 mol/L and ADP 20 mol/L; results expressed in percent residual platelet aggregation [RPA]) and with the VerifyNow assay (results expressed in aspirin reaction units with the aspirin cartridge and P2Y 12 reaction units and percent inhibition with the P2Y 12 cartridge). Aspirin resistance was defined either by an RPA Ͼ20% with arachidonic acid or by an aspirin reaction unit Ն550.…”

Pharmacotherapy During Percutaneous Coronary Interventions

“…The RELOAD and ARMYDA-4 RELOAD trials attempted to address the question of whether an additional loading dose of clopidogrel was required prior to PCI in stable and ACS patients who were already receiving chronic clopidogrel therapy (51)(52). The trials found that although clopidogrel reloading produced significantly greater levels of platelet inhibition, there was no difference in the primary endpoint of MACE.…”

What to Do With Patients Receiving Long-Term Clopidogrel

“…Collet and colleagues report the findings of a randomized clinical trial that evaluated residual platelet aggregation (RPA) after administration of 900 mg of clopidogrel provided in 3 dosing strategies. 12 Clopidogrel reloading was accomplished by either a single 900-mg dose followed 4 hours later with a placebo dose, or by split dosing with an initial bolus of 600 or 300 mg, followed 4 hours later by a second dose of 300 or 600 mg, respectively. Each patient had been treated with clopidogrel long term, the majority for a duration of Ͼ30 days.…”

“…12 We can achieve a greater level of inhibition of platelet aggregation by reloading patients on long-term clopidogrel therapy with a 600-to 900-mg LD. In low-risk patients or those known to have adequate IPA on long-term therapy, we can probably relax and not become too concerned about additional clopidogrel reloading, although it is unlikely to be harmful.…”