ORIGINAL R ESEARCH AR TICLE
Calcium-Channel Blockers Attenuate the Antiplatelet Effect of Clopidogrel Thomas Gremmel,1 Markus Durstberger,1 Beate Eichelberger,2 Renate Koppensteiner1 & Simon Panzer2 1 Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria 2 Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
Keywords Calcium-channel blockers; Clopidogrel; Flow cytometry. Correspondence Prof. Dr. Thomas Gremmel, M.D., Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: +431-40400-4671; Fax: +431-40400-4665; E-mail: [email protected]
doi: 10.1111/1755-5922.12138
SUMMARY Aims: Dihydropyridine calcium-channel blockers (CCBs) inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form. The impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to adenosine diphosphate (ADP), so far. We therefore sought to investigate platelet activation in response to ADP by flow cytometry in clopidogrel-treated patients without and with CCBs. Methods: Platelet surface P-selectin expression and activated glycoprotein (GP) IIb/IIIa in response to ADP were determined by flow cytometry in 302 patients on dual antiplatelet therapy with aspirin and clopidogrel after successful angioplasty with stent implantation. Results: Ninety-two patients (30.5%) received CCBs. Patients with concomitant CCB therapy showed significantly higher platelet surface expressions of P-selectin and activated GPIIb/IIIa in response to ADP than patients without CCBs (both P ≤ 0.03). Moreover, the fold increase of P-selectin and activated GPIIb/IIIa in response to ADP was significantly more pronounced in patients taking CCBs (both P ≤ 0.03). The associations of ADP-inducible activated GPIIb/IIIa and fold increase of activated GPIIb/IIIa after the addition of ADP with CCB therapy remained significant after adjustment for differences in patient characteristics and factors that were previously associated with clopidogrel response by multivariate regression analyses (both P < 0.05). High levels of ADP-inducible P-selectin and activated GPIIb/IIIa were seen significantly more frequent in patients with CCBs than in patients without CCB therapy (both P ≤ 0.01). Conclusion: Dihydropyridine CCBs attenuate the effect of clopidogrel on ADP-inducible platelet activation in patients undergoing angioplasty and stenting for cardiovascular disease.
Introduction Despite the emergence of the new P2Y12 inhibitors prasugrel and ticagrelor, clopidogrel remains the most frequently prescribed adenosine diphosphate (ADP) receptor antagonist in patients with atherosclerotic cardiovascular disease. The addition of clopidogrel to aspirin reduces adverse ischemic events in patients with acute coronary syndromes by 20% [1]. However, clopidogrel is a prodrug and requires biotransformation to its active metabolite by the hepatic cytochrome P450 enzyme system to finally exert its antiplatelet effect [2]. Previous studies have shown that exogenous and endogenous factors impairing the hepatic metabolism of clopidogrel reduce its antiplatelet effect. [3] In detail, loss-of-function polymorphisms of cytochrome 2C9 and 2C19 [4–7], demographical patient characteristics [8], various comorbidities [9–12], and comedication [13–15] have been associated with increased on-treatment residual platelet reactivity to ADP during clopidogrel therapy. Furthermore, high on-treatment residual platelet reactivity (HRPR) to ADP was linked to the occurrence of adverse ischemic events in
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patients undergoing percutaneous coronary angioplasty and stenting [16]. One of the most intensely discussed influencing factors for clopidogrel-mediated platelet inhibition is the potential interaction of clopidogrel metabolism with calcium-channel blockers (CCBs). Dihydropyridine CCBs inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form [17,18]. Indeed, several studies reported increased on-treatment residual platelet reactivity to ADP by different platelet aggregation tests in clopidogrel-treated patients, who concomitantly received CCBs [14,19,20]. In contrast to these observations, a large study found no significant association between CCB therapy and clopidogrel-mediated platelet inhibition as assessed by multiple electrode platelet aggregometry [21]. Moreover, the impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to ADP, so far. We therefore sought to investigate platelet activation in response to ADP by whole-blood flow cytometry in clopidogrel-treated patients without and with CCB therapy following angioplasty and stenting for cardiovascular disease.
ª 2015 John Wiley & Sons Ltd
T. Gremmel et al.
Methods Study Population The study population consisted of 302 patients on dual antiplatelet therapy after percutaneous intervention with endovascular stent implantation. All patients received daily aspirin (100 mg/day) and clopidogrel therapy (75 mg/day). Exclusion criteria were a known aspirin or clopidogrel intolerance (allergic reactions, gastrointestinal bleeding), a therapy with vitamin K antagonists (warfarin, phenprocoumon, acenocoumarol) or novel oral anticoagulants (rivaroxaban, apixaban, dabigatran, edoxaban), treatment with ticlopidine, dipyridamole, or nonsteroidal anti-inflammatory drugs, a family or personal history of bleeding disorders, malignant paraproteinemias, myeloproliferative disorders or heparin-induced thrombocytopenia, severe hepatic failure, known qualitative defects in thrombocyte function, a major surgical procedure within 1 week before enrollment, a platelet count 450,000/lL, and a hematocrit
Calcium-Channel Blockers Attenuate the Antiplatelet Effect of Clopidogrel Thomas Gremmel,1 Markus Durstberger,1 Beate Eichelberger,2 Renate Koppensteiner1 & Simon Panzer2 1 Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria 2 Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
Keywords Calcium-channel blockers; Clopidogrel; Flow cytometry. Correspondence Prof. Dr. Thomas Gremmel, M.D., Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Tel.: +431-40400-4671; Fax: +431-40400-4665; E-mail: [email protected]
doi: 10.1111/1755-5922.12138
SUMMARY Aims: Dihydropyridine calcium-channel blockers (CCBs) inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form. The impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to adenosine diphosphate (ADP), so far. We therefore sought to investigate platelet activation in response to ADP by flow cytometry in clopidogrel-treated patients without and with CCBs. Methods: Platelet surface P-selectin expression and activated glycoprotein (GP) IIb/IIIa in response to ADP were determined by flow cytometry in 302 patients on dual antiplatelet therapy with aspirin and clopidogrel after successful angioplasty with stent implantation. Results: Ninety-two patients (30.5%) received CCBs. Patients with concomitant CCB therapy showed significantly higher platelet surface expressions of P-selectin and activated GPIIb/IIIa in response to ADP than patients without CCBs (both P ≤ 0.03). Moreover, the fold increase of P-selectin and activated GPIIb/IIIa in response to ADP was significantly more pronounced in patients taking CCBs (both P ≤ 0.03). The associations of ADP-inducible activated GPIIb/IIIa and fold increase of activated GPIIb/IIIa after the addition of ADP with CCB therapy remained significant after adjustment for differences in patient characteristics and factors that were previously associated with clopidogrel response by multivariate regression analyses (both P < 0.05). High levels of ADP-inducible P-selectin and activated GPIIb/IIIa were seen significantly more frequent in patients with CCBs than in patients without CCB therapy (both P ≤ 0.01). Conclusion: Dihydropyridine CCBs attenuate the effect of clopidogrel on ADP-inducible platelet activation in patients undergoing angioplasty and stenting for cardiovascular disease.
Introduction Despite the emergence of the new P2Y12 inhibitors prasugrel and ticagrelor, clopidogrel remains the most frequently prescribed adenosine diphosphate (ADP) receptor antagonist in patients with atherosclerotic cardiovascular disease. The addition of clopidogrel to aspirin reduces adverse ischemic events in patients with acute coronary syndromes by 20% [1]. However, clopidogrel is a prodrug and requires biotransformation to its active metabolite by the hepatic cytochrome P450 enzyme system to finally exert its antiplatelet effect [2]. Previous studies have shown that exogenous and endogenous factors impairing the hepatic metabolism of clopidogrel reduce its antiplatelet effect. [3] In detail, loss-of-function polymorphisms of cytochrome 2C9 and 2C19 [4–7], demographical patient characteristics [8], various comorbidities [9–12], and comedication [13–15] have been associated with increased on-treatment residual platelet reactivity to ADP during clopidogrel therapy. Furthermore, high on-treatment residual platelet reactivity (HRPR) to ADP was linked to the occurrence of adverse ischemic events in
264
Cardiovascular Therapeutics 33 (2015) 264–269
patients undergoing percutaneous coronary angioplasty and stenting [16]. One of the most intensely discussed influencing factors for clopidogrel-mediated platelet inhibition is the potential interaction of clopidogrel metabolism with calcium-channel blockers (CCBs). Dihydropyridine CCBs inhibit cytochrome 3A4 and could therefore interfere with the conversion of clopidogrel to its active form [17,18]. Indeed, several studies reported increased on-treatment residual platelet reactivity to ADP by different platelet aggregation tests in clopidogrel-treated patients, who concomitantly received CCBs [14,19,20]. In contrast to these observations, a large study found no significant association between CCB therapy and clopidogrel-mediated platelet inhibition as assessed by multiple electrode platelet aggregometry [21]. Moreover, the impact of CCBs on the antiplatelet effect of clopidogrel has not been studied with assays directly capturing platelet activation to ADP, so far. We therefore sought to investigate platelet activation in response to ADP by whole-blood flow cytometry in clopidogrel-treated patients without and with CCB therapy following angioplasty and stenting for cardiovascular disease.
ª 2015 John Wiley & Sons Ltd
T. Gremmel et al.
Methods Study Population The study population consisted of 302 patients on dual antiplatelet therapy after percutaneous intervention with endovascular stent implantation. All patients received daily aspirin (100 mg/day) and clopidogrel therapy (75 mg/day). Exclusion criteria were a known aspirin or clopidogrel intolerance (allergic reactions, gastrointestinal bleeding), a therapy with vitamin K antagonists (warfarin, phenprocoumon, acenocoumarol) or novel oral anticoagulants (rivaroxaban, apixaban, dabigatran, edoxaban), treatment with ticlopidine, dipyridamole, or nonsteroidal anti-inflammatory drugs, a family or personal history of bleeding disorders, malignant paraproteinemias, myeloproliferative disorders or heparin-induced thrombocytopenia, severe hepatic failure, known qualitative defects in thrombocyte function, a major surgical procedure within 1 week before enrollment, a platelet count 450,000/lL, and a hematocrit
