High Dose Clopidogrel In Patients With High On-treatment Platelet Reactivity: A Meta–analysis

Objective 1. To explore the efficacy and safety of high maintenance dose clopidogrel in patients with high on-treatment platelet reactivity(HTPR) after percutaneous coronary intervention(PCI). 2. To explore the effect of CYP2C19*2 gene polymorphism in patients using high dose clopidogrel. Methods We set the search strategy according to the PICOS. The search strategy combined the key words and mesh word. We searched Pub Med(from 1966 to May 2014), EMBASE(from 1974 to May 2014), the Cochrane Library(May2, 2014), CNKI(May 2014), Wangfang database(May 2014), VIP database(May 2014) and identified trials with the inclusive criteria. Risk of bias was assessed using the criteria of the Cochrane back review group. Then the character and the data of all included trials were extracted, the meta-analysis of included randomized controlled trials(RCTs) was performed to assess the efficacy and safety of high maintenance dose clopidogrel for HTPR patients in MACE/MACCE, ST, TVR CV death and platelet agglutination rate. Meanwhile, to explore whether the CYP2C19*2 gene polymorphism could influence the effect of high loading dose clopidogrel, the meta-analysis to compared patients with CYP2C19*2/*1 or *2/*2 to patients with CYP2C19*1/*1was also performed. Results 19 RCTs with11616 patients were included. 12 RCTs emphasized clinical outcomes of the high maintenance dose clopidogrel. And 7 RCTs explored the relationship of CYP2C19*2 and high dose clopidogrel. 1. In HTPR patients, high maintenance-dose clopidogrel compared with standard maintenance-dose clopidogrel could significantly reduce the risk of MACE/MACCE(RR 0.48;95%CI: 0.34, 0.67; P<0.0001), ST(RR 0.34; 95%CI: 0.18,0.64; P=0.0008), TVR(RR0.40;95%CI: 0.18,0.89; P=0.03), and CVD(RR 0.31;95%CI:0.12, 0.85; P=0.02) without reducing MI(RR 0.67;95%CI:0.42,1.07;P=0.09). 2. This was similar that high-maintenance dose clopidogrel reducing the event of MACE/MACCE compared with the effect of 75 mg working in normal patients. 3. High-maintenance dose clopidogrel increased the events of minor bleeding(RR 1.28;95%CI:1.02,1.62;P=0.04) but not major bleeding(RR 0.79;95%CI: 0.46,1.36;P=0.4). Regardless of platelet assays, high maintenance dose clopidogrel can lower the platelet aggregate rate Verify Now-P2Y12:MD-76,95%CI(-99.82,-52.18),P<0.00001; VASP :MD-19.36, 95%CI(-27.32,-11.40); P<0.00001; LTA-IPA: MD-11.80,95%CI(-12.88,-10.72), P<0.00001;LTA-PAR:MD-9.68, 95%CI(-11.19,-8.17), P<0.00001. 4. Clopidogrel in patients with CYP2C19 *2/*1 or *2/*2 could not work as well as in patients with CYP2C19*1/*1 in reducing the incidence of MACE/MACCE(RR 1.68; 95%CI: 1.19, 2.37; P=0.003) or ST(RR 1.67; 95%CI: 1.25, 2.23; P=0.0005). Last, the funnel plot suggested the report bias existed. Conclusion 1. A high maintenance dose of clopidogrel may be a feasible and available treatment measure to lower the risk of recurrent cardiovascular events for patients having HTPR after PCI. 2. High maintenance dose clopidogrel was a safety method which did not bring more remarkable bleeding events than standard maintenance dose clopidogrel. 3. High maintenance dose clopidogrel can reduce the platelet aggressiveness. 4. Patients with CYP2C19 *2 would influence the effect of high loading dose clopidogrel.