JACC: Double clopidogrel loading dose begets better platelet inhibition

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A clopidogrel 600-mg double loading dose (first dose given more than 15 hours before and second dose given the morning of an interventional procedure) achieves greater platelet inhibition than conventional single loading doses, according to a March 18 issue of the Journal of American College of Cardiology.

Philippe L. L’Allier, MD, of the department of medicine at the Montreal Heart Institute in Montreal, and colleagues, said that this is the largest study to date comparing clopidogrel loading regimens and the first to report the effects of a double bolus loading strategy before an interventional procedure. The study’s objective was to compare the level of platelet inhibition achieved by three different clopidogrel loading regimens in patients undergoing elective angiography and PCI when appropriate, the authors wrote.

Allier and colleagues designed the study so patients were randomly assigned to one of three loading dose regimens according to an automated randomization list provided by the Montreal Heart Institute in sealed envelopes:

  • Group A, clopidogrel 300 mg the day before (≥15 h) + 75 mg the morning of the interventional procedure;
  • Group B, clopidogrel 600 mg the morning of (≥2 h before) the interventional procedure; and
  • Group C, clopidogrel 600 mg the day before (≥15 h) and 600 mg the morning of (≥2 h before) the interventional procedure.

The primary assumption was that Group C regimen (600-mg double loading dose) would increase inhibition of platelet aggregation by at least 15 percent over that of Groups A and B, according to the investigators.

The researchers found that inhibition of platelet aggregation was consistently better in the clopidogrel 600 mg double bolus group as compared with the other two regimens. Percent inhibition of Agg peak was 31.4 percent in Group A, 29 percent in Group B, and 49.5 percent in Group C when platelets were stimulated with 5 µmol/l ADP and 22.4 percent, 22.3 percent and 39.8 percent, respectively, with 20 µmol/l ADP.

The Agg peak values did not differ at baseline, but were significantly different on treatment. Comparisons between Group C and other groups were highly significant, and those between Groups A and B were not, the authors wrote.

The researchers also reported that there was no death, rehospitalization for MI, or repeat target vessel revascularization up to 30 days. 

The authors suggested that the most likely explanation for the better platelet inhibition achieved with a double bolus of clopidogrel lies in the higher plasma concentrations of clopidogrel and its active metabolite.

Interestingly, authors said that their results highlight a time-dependent catch-up phenomenon after a 300-mg loading dose as compared with the 600-mg loading dose.

Finally, the researchers concluded that clopidogrel administered as a 300-mg single bolus given more than 15 hours prior to — plus 75 mg on the morning of — an intervention achieves equivalent platelet inhibition as a 600-mg single bolus loading dose given on the morning of the procedure.