Long-term clinical efficacy and safety of adding cilostazol to dual antiplatelet therapy for patients undergoing PCI: A meta-analysis of randomized trials with adjusted indirect comparisons

Division of Cardiology, Xinhua Hospital School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Current Medical Research and Opinion (Impact Factor: 2.65). 10/2013; 30(1). DOI: 10.1185/03007995.2013.850067
Source: PubMed


To assess the long-term clinical efficacy and safety of adding cilostazol to aspirin plus clopidogrel (triple antiplatelet therapy, TAT) in patients undergoing percutaneous coronary intervention (PCI) and explore its role in the era of new generation adenosine diphosphate (ADP)-receptor antagonists.

PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) comparing TAT versus dual antiplatelet therapy (DAT), followed by a manual search. Then, a meta-analysis of RCTs comparing TAT versus standard DAT in patients undergoing PCI was performed. Furthermore, indirect comparisons of TAT versus new generation ADP-receptor antagonist based DAT (prasugrel or ticagrelor based DAT) were undertaken, with standard DAT as a common comparator. The included end-points were major adverse cardiovascular event (MACE), target lesion revascularization (TLR), target vessel revascularization (TVR), death, myocardial infarction (MI), stent thrombosis, bleeding and other drug adverse events.

Twelve RCTs with a total of 31,789 patients were included. Compared with standard DAT (n = 2551), TAT (n = 2545) significantly reduced the incidence of MACE (OR: 0.56, 95% CI: 0.47-0.68, P < 0.00001), TLR (OR: 0.51, 95% CI: 0.34-0.75, P = 0.0006) and TVR (OR: 0.59, 95% CI: 0.46-0.75, P < 0.0001), and did not change significantly in death (OR: 0.68, 95% CI: 0.44-1.05, P = 0.08), MI (OR: 0.80, 95% CI: 0.45-1.44, P = 0.46), stent thrombosis (OR: 0.61, 95% CI: 0.27-1.36, P = 0.23), major bleeding (OR: 1.42, 95% CI: 0.52-3.85, P = 0.49) and overall bleeding (OR: 1.16, 95% CI: 0.79-1.69, P = 0.45). Compared with prasugrel (n = 6813) or ticagrelor based DAT (n = 6732), TAT (n = 2545) further reduced the incidence of MACE (OR: 0.80, 95% CI: 0.72-0.90, P = 0.0012; OR: 0.83, 95% CI: 0.75-0.92, P = 0.0003, respectively).

Compared with standard DAT, the long-term use of TAT in patients with PCI gives more benefits in reducing the incidence of MACE, TLR and TVR without increasing bleeding. Furthermore, it might be superior to prasugrel or ticagrelor based DAT in term of MACE, which needs to be confirmed by future studies with direct comparisons.

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    • "Furthermore, the majority of the patients in both age groups were on ticlopidine and about a fifth was taking cilostazol. These drugs have been previously reported to reduce CV events [12] [13] and are more commonly prescribed in Asian populations. Therefore, the findings of this study should be interpreted with caution. "
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    • "[43] [44]. Because cilostazol is an inhibitor of agonist-induced platelet aggregation [43], as are aspirin and clopidogrel, the occurrence of stent thrombosis in patients on either TAT or DAT gives credence to our results that suggest shear-induced platelet activation due to stents is an important factor in stent thrombosis. "
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    ABSTRACT: Coronary stenting is one of the most commonly used approaches to open coronary arteries blocked due to atherosclerosis. However, stent struts can induce stent thrombosis due to altered hemodynamics and endothelial dysfunction, and the microscopic process is poorly understood. The objective of this study was to determine the microscale processes during the initiation of stent thrombosis.Methods We utilized a discrete element computational model to simulate the transport, collision, adhesion, and activation of thousands of individual platelets and red blood cells in thrombus formation around struts and dysfunctional endothelium.ResultsAs strut height increased, the area of endothelium activated by low shear stress increased, which increased the number of platelets in mural thrombi. These thrombi were generally outside regions of recirculation for shorter struts. For the tallest strut, wall shear stress was sufficiently low to activate the entire endothelium. With the entire endothelium activated by injury or denudation, the number of platelets in mural thrombi was largest for the shortest strut. The type of platelet activation (by high shear stress or contact with activated endothelium) did not greatly affect results.Conclusions During the initiation of stent thrombosis, platelets do not necessarily enter recirculation regions or deposit on endothelium near struts, as suggested by previous computational fluid dynamics simulations. Rather, platelets are more likely to deposit on activated endothelium outside recirculation regions and deposit directly on struts. Our study elucidated the effects of different mechanical factors on the roles of platelets and endothelium in stent thrombosis.
    Computers in Biology and Medicine 11/2014; 56. DOI:10.1016/j.compbiomed.2014.11.006 · 1.24 Impact Factor
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    ABSTRACT: Abstract Platelet activation plays a pivotal role in the pathogenesis of atherothrombosis and the development of ischaemic complications during an acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI) (1-4).Thromboxane A2 (TxA2) and ADP are two major platelet agonists that are released from activated platelets, thus enhancing platelet activation, and promoting the formation of stable thrombus at the site of vascular injury (1,5). Therefore, the pharmacologic management of coronary artery disease patients with high thrombotic risk consists of the inhibition of TxA2 synthesis with the cyclooxygenase-1 inhibitor aspirin, and blockade of the ADP-receptor P2Y12 with specific antagonists clopidogrel, prasugrel or ticagrelor (5). The combination of aspirin with one of the above ADP-receptor antagonists is known as dual antiplatelet therapy (DAT) (5). DAT with aspirin and clopidogrel became the gold standard treatment of ACS patients as well as in those undergoing PCI since its beneficial effect in reducing the incidence of stent thrombosis and major adverse cardiovascular events (MACEs) compared with aspirin alone is well established (6-8). Indeed, in the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events) trial, the combination of aspirin and clopidogrel produced additive effects in patients with non-ST-elevation ACS, by reducing the rate of the first primary outcome, a composite of cardiovascular death, non-fatal myocardial infarction (MI), or stroke, from 11.4 to 9.3% (RR, 0.80; 95% CI, 0.72-0.90, P<0.001) when compared with aspirin alone (6). Furthermore, the PCI-CURE study, a subgroup analysis of the CURE trial, demonstrated a 1.9% absolute risk reduction (P=0.03) in adverse cardiovascular events at 30 days and a 3.4% absolute risk reduction at 9 months in the clopidogrel loading arm, favoring long-term use of DAT (7). These results were further supported by the CREDO (Clopidogrel for the Reduction of Events During Observation) trial (8) in which long-term DAT in 2,116 patients with coronary artery disease undergoing elective PCI resulted in a 3% absolute risk reduction and a 26.9% relative risk reduction (P=0.02) in death, MI, or stroke (8).
    Current Medical Research and Opinion 10/2013; 30(1). DOI:10.1185/03007995.2013.850070 · 2.65 Impact Factor
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