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A comprehensive meta-analysis was performed to investigate whether the combination of high-/low-dose of aspirin and various intensities of warfarin (W) offer greater benefit than aspirin (ASA) alone. A total of 14 randomized clinical trials (RCTs) having 26,916 patients with acute coronary syndrome (ACS) met inclusion criteria. The efficacy and safety of all outcomes which included myocardial infarction (MI), all-cause death, stroke, and bleeding were calculated. The overall outcomes analysis showed there was no significant difference in the risk of MI (relative ratio [RR] 0.959, 95 % confidence interval [CI] 0.78–1.04, P = 0.308), stroke (RR 0.789, 95 % CI 0.57–1.09, P = 0.145), and all-cause death (RR 1.007, 95 % CI 0.93–1.09, P = 0.87) between the combination group and ASA group. The subgroup analysis suggested that ASA (≤100 mg/day) plus W (mean international normalized ratio [INR] 2.0–3.0) decreased the risk rate of stroke (RR 0.660, 95 % CI 0.50–0.87, P = 0.003). There was a lower risk of MI (RR 0.605, 95 % CI 0.47–0.77, P < 0.0001) as well as stroke (RR 0.594, 95 % CI 0.45–0.79, P < 0.0001) between W (INR 2.0–3.0) combined with ASA (mean dose ≥100 mg/day) and ASA. However, the risk of major bleeding (RR 1.738, 95 % CI 1.45–2.08, P < 0.0001) and minor bleeding (RR 2.767, 95 % CI 2.12–3.61, P < 0.0001) was almost doubled in the combined groups. Compared with ASA, high-dose aspirin with moderate-intensity warfarin (INR 2.0–3.0) may better reduce the risk of MI and stroke but confer an increased risk of bleeding.

Numerous studies have indicated that the expression of matrix metalloproteinase-9 (MMP-9) contributes to the atherosclerotic plaque hemorrhage and rupture. Aspirin, a non-steroidal anti-inflammation drug, has been known for its anti-platelet effect in the prevention of the vascular complications of atherosclerosis. The present study aimed to investigate the pharmacological effects of aspirin on tumor necrosis factor-α (TNF-α)-induced MMP-9 expression and the underlying molecular mechanisms in murine macrophage RAW264.7 cells. Western blot analysis indicated that the protein level of MMP-9 was reduced by aspirin in a dose-dependent manner. In addition, downregulation of MMP-9 mRNA and activity were detected in aspirin-treated cells using quantitative polymerase chain reaction and a gelatin zymography assay separately. It was also observed that aspirin has a suppressive effect on the activation of nuclear factor (NF)-κB and inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases 1/2, p38 and c-Jun N-terminal kinase. Furthermore, subsequent to inhibition of the MAPK pathway by specific inhibitors (PD98059, SB203580 and SP600125), the expression of MMP-9 was reduced, indicating that the inhibitory effect of aspirin on MMP-9 in TNF-α-treated RAW264.7 cells may be, at least in part, through suppression of NF-κB activation and the MAPK pathway. These findings support the notion that aspirin has therapeutic potential application in the prevention and treatment of atherosclerosis disease.

Clopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied.401 acute coronary syndrome (ACS) patients received either a 300 mg loading dose following 75 mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P0.05 vs. non-carriers) and thus decreased platelet inhibition (P0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel.CYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.