Background Dual antiplatelet therapy with aspirin and clopidogrel is the standard treatment regimen in both acute coronary syndromes and following coronary artery stent implantation. Clopidogrel is a pro-drug that is converted by liver enzymes to an active metabolite that acts selectively on P2Y12 receptors. The response to clopidogrel is widely variable between individuals and poor responders are at greater risk of ischaemic events. Preliminary data from another group suggest that rifampicin may enhance the inhibitory effect of clopidogrel by inducing the hepatic cytochromes responsible for the generation of the active metabolite. We assessed in healthy volunteers whether rifampicin increases the extent of platelet inhibition by clopidogrel through greater P2Y12 receptor blockade.
Methods 12 eligible healthy volunteers were consented and recruited into the study. The study involved five visits over a 4-week time period. Clopidogrel 600 mg was given as a loading dose (visit 1) followed by 75 mg daily for 1 week before visit 2. After a washout period of 1 week, subjects were commenced on rifampicin 300 mg twice daily for one week and then received a further 600 mg loading dose of clopidogrel (visit 4), after which they received clopidogrel 75 mg daily and rifampicin 300 mg twice daily for the final week of the study before visit 5. A 13C-erythromycin breath test was performed before each clopidogrel loading dose (visits 1 and 4). Platelet aggregation was assessed by optical aggregometry in response to ADP 20 μmol before and after each of the clopidogrel loading doses (visits 1 and 4) and at the end of each week of treatment with clopidogrel (visits 2 and 5). P2Y12 receptor blockade was assessed concurrently by using a 33P-2MeSADP radioligand binding assay in the presence of a P2Y1 receptor antagonist to determine the number of unblocked P2Y12 receptors.
Results ADP-induced platelet aggregation and 33P-2MeSADP binding were inhibited in all subjects following 600 mg of clopidogrel and 7 days of maintenance therapy. Rifampicin significantly increased the degree of inhibition of ADP-induced platelet aggregation (p<0.05) associated with a significant increase in the inhibition of 33P-2MeSADP binding to P2Y12 receptors (p<0.05, see figs 1 and 2). There was a non-significant trend towards enhanced erythromycin metabolism after 1 week of rifampicin (p = 0.066).
Conclusion Rifampicin increases the extent of inhibition of platelet aggregation achieved by clopidogrel therapy by increasing the extent of P2Y12 receptor blockade.