TY - JOUR
T1 - Antiplatelet profiles of the fixed-dose combination of extended-release dipyridamole and low-dose aspirin compared with clopidogrel with or without aspirin in patients with type 2 diabetes and a history of transient ischemic attack
T2 - A randomized, single-blind, 30-day trial
AU - Serebruany, Victor L.
AU - Malinin, Alex I.
AU - Pokov, Alex N.
AU - Hanley, Daniel F.
N1 - Funding Information:
This study was supported by Boehringer Ingelheim, Ingelheim am Rhein, Germany. The sponsor had no involvement in the design or conduct of the trial or in the writing of the manuscript. Dr. Serebruany has received grants, submitted patent applications, sat on advisory boards, and served on speakers' bureaus for Boehringer Ingelheim, Johnson & Johnson, Bayer Corporation, and the Sanofi-BMS Partnership. The other authors have no potential conflicts of interest to report.
PY - 2008/2
Y1 - 2008/2
N2 - Background: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens. Objective: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA). Methods: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States. Eligible patients were aged ≥40 years and had a diagnosis of type 2 diabetes and a history of TIA. Patients were allocated to receive ER-DP+ASA 200/25 mg BID, clopidogrel 75 mg/d, or clopidogrel 75 mg/d plus ASA 81 mg/d. Multiple platelet bio-markers were assessed at baseline, day 15, and day 30 using aggregometry, cartridge-based platelet function analyzers, and flow cytometry. The primary end point was the change in platelet receptor expression after 30 days of therapy. Compliance and tolerability were monitored by measuring plasma dipyridamole levels and recording all episodes of headache and vomiting. Results: The study enrolled 60 consecutive patients (20 per treatment arm), all of whom completed the study. There were no significant differences between treatment arms, although the ER-DP+ASA group had a numerically greater mean age, higher proportion of men, and a greater prevalence of vascular disease and smoking compared with the other groups. There were no deaths or serious adverse events during the study, including symptoms attributable to cerebral ischemia, worsening of diabetes, or cerebral or systemic bleeding. Three patients in the ER-DP+ASA group and 1 in the clopidogrel plus ASA group reported headache during the first several days of therapy; 1 patient in the clopidogrel monotherapy group experienced transitory nausea and vomiting. ER-DP+ASA was associated with a significantly delayed (day 30) reduction in expression of glyco-protein (GP) Ilb/IIIa activity (P = 0.02), platelet-endothelial cell adhesion molecule 1 (PECAM-1) (P = 0.03), GP Ib (P = 0.001), vitronectin (P = 0.001), P-selectin (P = 0.001), lysosome-associated membrane protein 1 (P = 0.001), and cluster of differentiation 40 ligand (P = 0.01), as well as significant inhibition of the intact (P = 0.01) and cleaved (P = 0.01) epitopes of protease-activated receptor 1. Clopidogrel monotherapy, on the other hand, was associated with significant inhibition of adenosine diphosphate-induced platelet aggregation (P = 0.001), closure-time prolongation (P = 0.01), and reduction in measurements on the rapid platelet function assay-ASA at day 15 (P = 0.001). Expression of PECAM-1 (P = 0.03) and GP IIb/IIIa activity (P = 0.01) was reduced at day 15 in clopidogrel-treated patients. The addition of ASA to clopidogrel was associated with significant inhibition of collagen-induced platelet aggregation (P = 0.001) and diminished formation of platelet-monocyte microparticles at days 15 (P = 0.02) and 30 (P = 0.03).
AB - Background: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens. Objective: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA). Methods: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States. Eligible patients were aged ≥40 years and had a diagnosis of type 2 diabetes and a history of TIA. Patients were allocated to receive ER-DP+ASA 200/25 mg BID, clopidogrel 75 mg/d, or clopidogrel 75 mg/d plus ASA 81 mg/d. Multiple platelet bio-markers were assessed at baseline, day 15, and day 30 using aggregometry, cartridge-based platelet function analyzers, and flow cytometry. The primary end point was the change in platelet receptor expression after 30 days of therapy. Compliance and tolerability were monitored by measuring plasma dipyridamole levels and recording all episodes of headache and vomiting. Results: The study enrolled 60 consecutive patients (20 per treatment arm), all of whom completed the study. There were no significant differences between treatment arms, although the ER-DP+ASA group had a numerically greater mean age, higher proportion of men, and a greater prevalence of vascular disease and smoking compared with the other groups. There were no deaths or serious adverse events during the study, including symptoms attributable to cerebral ischemia, worsening of diabetes, or cerebral or systemic bleeding. Three patients in the ER-DP+ASA group and 1 in the clopidogrel plus ASA group reported headache during the first several days of therapy; 1 patient in the clopidogrel monotherapy group experienced transitory nausea and vomiting. ER-DP+ASA was associated with a significantly delayed (day 30) reduction in expression of glyco-protein (GP) Ilb/IIIa activity (P = 0.02), platelet-endothelial cell adhesion molecule 1 (PECAM-1) (P = 0.03), GP Ib (P = 0.001), vitronectin (P = 0.001), P-selectin (P = 0.001), lysosome-associated membrane protein 1 (P = 0.001), and cluster of differentiation 40 ligand (P = 0.01), as well as significant inhibition of the intact (P = 0.01) and cleaved (P = 0.01) epitopes of protease-activated receptor 1. Clopidogrel monotherapy, on the other hand, was associated with significant inhibition of adenosine diphosphate-induced platelet aggregation (P = 0.001), closure-time prolongation (P = 0.01), and reduction in measurements on the rapid platelet function assay-ASA at day 15 (P = 0.001). Expression of PECAM-1 (P = 0.03) and GP IIb/IIIa activity (P = 0.01) was reduced at day 15 in clopidogrel-treated patients. The addition of ASA to clopidogrel was associated with significant inhibition of collagen-induced platelet aggregation (P = 0.001) and diminished formation of platelet-monocyte microparticles at days 15 (P = 0.02) and 30 (P = 0.03).
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U2 - 10.1016/j.clinthera.2008.02.006
DO - 10.1016/j.clinthera.2008.02.006
M3 - Article
C2 - 18343263
AN - SCOPUS:41549124477
SN - 0149-2918
VL - 30
SP - 249
EP - 259
JO - Clinical therapeutics
JF - Clinical therapeutics
IS - 2
ER -