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Tapering clopidogrel before cessation did not lower platelet aggregation
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Published data did not support the theory that rebounding blood platelets account for clusters of thrombotic events previously reported after clopidogrel cessation, nor did it confirm any benefit from tapering the drug before discontinuation.
“The hypothesis of a rebound phenomenon of blood platelets has been declared causative, but its existence in the context of clopidogrel withdrawal has never been addressed by specifically designed studies,” researchers wrote.
They enrolled 69 patients with coronary artery disease who had drug-eluting stents implanted and were assigned to long-term (≥6 months) dual antiplatelet therapy with aspirin (100 mg twice daily) and clopidogrel (75 mg daily) in a double blind study. The researchers randomly assigned patients to either a prespecified tapering clopidogrel regimen during a 28-day period (n=35) or continued daily treatment with clopidogrel and abrupt discontinuation after an additional 28 days (n=34). Patients assigned the tapering regimen were assigned a medication blister that alternated between clopidogrel (75 mg) and placebo during the first week and then clopidogrel (75 mg daily) twice a week with placebo dispersed at varying intervals during the following three weeks.
The researchers measured platelet function using two methods — light transmission aggregometry (LTA) using platelet-rich plasma, and multiple electrode platelet aggregometry (MEA) using whole blood — first at study inclusion and again two to eight weeks after assignment.
They observed no significant differences using LTA between the highest value of adenosine diphosphate–induced platelet aggregation in either group during weeks five to eight (5 mcmol/L in percentage; 73% in the off group vs. 69.3% in the tapering group).
Additionally, the researchers observed no significant differences between the groups in mean thrombin receptor–activating peptide- or collagen-induced platelet aggregation values after complete clopidogrel cessation at weeks five, six, seven and eight.
Similarly, there were no differences between the two study groups as measured by MEA (925 AU × minute in the off group vs. 890 AU × minute in the tapering group; P=.055).
“For all agonists used and regardless of the concentration that was used for [adenosine diphosphate], evidence for the existence of a rebound phenomenon or for a possible benefit of tapering clopidogrel was not provided by any of our investigations,” the researchers wrote.
Sibbing D. J Am Coll Cardiol. 2010; 6:558-565.
This is a well-done study that puts to rest the theoretical concerns that had been raised about the existence of clopidogrel ‘rebound.’ The likely explanation for the increase in ischemic events upon clopidogrel cessation that has been noted in some studies is most probably withdrawal of a protective effect, as may be seen upon cessation of any protective medication such as aspirin or statins, as opposed to a biological rebound in platelet activation.
– Deepak L. Bhatt, MD
Director, Integrated Cardiovascular Program Brigham and Women’s Hospital, Boston