Xuyun Wang

Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials

BACKGROUND Pharmacogenetic (PG) algorithms were proposed to predict warfarin therapeutic dose more accurately. However, the clinical efficacy of the strategy over the standard treatment was not consistently proven. METHODS We conducted a meta-analysis of the published randomized controlled trials (RCTs) comparing PG algorithm-based warfarin dosing (PG group) with clinical or standard protocols (STD group). The PUBMED, EMBASE, Cochrane Library and Web of Science databases were searched up to June 2014. RESULTS A total of 10 RCTs were retrieved for the meta-analysis with the inclusion of 2,601 participants. Primary analysis showed both major bleeding (2.65% versus 4.75%; RR: 0.57, 95% CI: 0.37- 0.90, P=0.02) and thromboembolic events (0.59% versus 1.88%; RR: 0.38, 95% CI: 0.17-0.85, P=0.02) were significantly lower in PG than in STD group. There was a trend towards increased percentage of time in therapeutic range (%TTR) [mean difference (MD): 4.65, 95% CI: 0.01- 9.29, P=0.05] in PG group, but no difference was observed for over-anticoagulation (INR>4). Subgroup analyses showed significant reduction of both major bleeding and thromboembolic events in PG group when the follow-up time was more than 1 month. After stratified by different PG algorithms, significant major bleeding reduction could be found in PG group when warfarin indication or co-medication of amiodarone was integrated in the algorithms. CONCLUSION PG algorithm-guided warfarin anticoagulation is beneficial for the reduction of both major bleeding and thromboembolic events compared with standard dosing strategy. The benefits may be prominent in patients with longer follow-up time, or guided by refined PG algorithms.

Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention– a systematic review and meta-analysis

INTRODUCTION High-dose clopidogrel has been recommended to overcome clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention (PCI), especially those with CYP2C19 loss-of-function genotypes. However, there is controversy over the pharmacodynamics and clinical effects of the strategy. This meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel according to CYP2C19*2 alleles in patients undergoing PCI. METHODS Based on PubMed, Cochrane, and EMBASE prior to June 1st, 2014, a systematic review and meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel on platelet reactivity and clinical outcomes in PCI treated patients according to CYP2C19*2 genotypes. The reported outcomes including on-treatment platelet reactivity (OTPR), high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events (MACE), stent thrombosis and composite cardiovascular events. RESULTS Nineteen studies involving 10,960 patients were included. After high-dose clopidogrel administration (600/900 mg loading dose and/or 150 mg/day maintenance dose), compared with non-carriers, carriers of CYP2C19*2 genotype had significantly increased OTPR (SMD for VASP assay: 0.69, 95% CI: 0.48-0.90, p = 4 × 10(-4); for VerifyNow P2Y12 assay: 0.70, 95% CI: 0.54-0.85, p < 10(-5); for LTA assay:0.58, 95% CI: 0.48-0.69, p = 4 × 10(-4)). The incidence rate of HTPR was higher in CYP2C19*2 carriers after high-dose clopidogrel treatment (RR: 1.21, 95% CI:1.05-1.39, p = 0.008 for cutoff PRI > 50% by VASP assay; RR: 1.69, 95% CI: 1.44-1.98, p < 1 × 10(-4) for cutoff PRU > 230 by VerifyNow P2Y12 assay). As for clinical outcomes, CYP2C19*2 was associated with higher risk for MACE (RR: 1.68, 95% CI: 1.19- 2.37, p = 0.003), stent thrombosis (RR: 1.75, 95% CI: 1.31-2.34, p = 0.0001), as well as composite cardiovascular events (RR: 1.82, 95% CI: 1.42- 2.34, p < 10(-5)) after treated by high-dose clopidogrel. CONCLUSION High-dose clopidogrel could not overcome the variability of clopidogrel antiplatelet effects between the CYP2C19 *2 carriers and non-carriers in patients treated with PCI.

The Performance of CRUSADE and ACUITY Bleeding Risk Scores in Ticagrelor-Treated ACS Patients Who Underwent PCI

The performance of the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) and ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) risk scores for the prediction of major bleeding in ticagrelor-treated acute coronary syndrome (ACS) patients who underwent percutaneous coronary intervention (PCI) is unknown. The aim of the present study is to validate the performance of both scores in a contemporary Chinese cohort of ACS patients hospitalized for PCI and administrated with ticagrelor. From January 2013 to December 2014, a total of 629 ticagrelor-treated ACS patients who underwent PCI were recruited consecutively. The overall rate of major bleeding defined by the BARC (Bleeding Academic Research Consortium) criteria was 1.7%. This incidence increased with the risk category of both the CRUSADE (very low, 0.6%; low, 1.3%; moderate, 1.1%; high, 7.0%; and very high, 13.0%; p = 0.001) and the ACUITY score (low, 0.6%; moderate, 1.4%; high, 4.9%; and very high, 7.0%; p = 0.003). The CRUSADE score demonstrated adequate calibration and discriminatory capacity for the patients as a whole (HL-p [Hosmer-Lemeshow goodness-of-fit test p-value] >0.3; AUC [area under the curve]: 0.78), with the excellent performance in the subgroups of acute myocardial infarction, men, diabetes and those implanted with more than two DESs (AUC: 0.85, 0.80, 0.93 and 0.93, respectively). For the ACUITY score, adequate calibration and discriminatory capacity could be observed for the whole patients (HL-p > 0.3; AUC: 0.78), with excellent performance for the patients with diabetes or those implanted with more than two DESs (AUC: 0.90 and 0.97, respectively). In conclusion, both CRUSADE and ACUITY risk scores performed adequate discriminatory power for the prediction of major bleeding within 30 days in ticagrelor-treated ACS patients who underwent PCI.

Relationship between ADP-induced platelet-fibrin clot strength and anti-platelet responsiveness in ticagrelor treated ACS patients

Background Ticagrelor provides enhanced antiplatelet efficacy but increased risk of bleeding and dyspnea. This study aimed to display the relationship between ADP-induced platelet-fibrin clot strength (MAADP) and clinical outcomes in acute coronary syndrome (ACS) patients treated by ticagrelor. Methods Consecutive Chinese-Han patients with ACS who received maintenance dose of ticagrelor on top of aspirin were recruited. After 5-day ticagrelor maintenance treatment, MAADP measured by thrombelastography (TEG) were recorded for the evaluation of ticagrelor anti-platelet reactivity. Pre-specified cutoffs of MAADP > 47 mm for high on-treatment platelet reactivity (HTPR) and MAADP < 31 mm for low on-treatment platelet reactivity (LTPR) were applied for evaluation. The occurrences of primary ischemic cardiovascular events (including a composite of cardiac death, non-fatal myocardial infarction and stroke), the Thrombolysis in Myocardial Infarction (TIMI) defined bleeding events, and ticagrelor related dyspnea were recorded after a follow-up of three months. Results Overall, 176 ACS patients (Male: 79.55%, Age: 59.91 ± 10.54 years) under ticagrelor maintenance treatment were recruited. The value of MAADP ranged from 4.80% to 72.90% (21.27% ± 12.07% on average), with the distribution higher skewed towards the lower values. Using the pre-specific cutoffs for HTPR and LTPR, seven patients (3.98%) were identified as HTPR and 144 patients (81.82%) as LTPR. After a follow-up of three months in 172 patients, major cardiovascular events occurred in no patient, but TIMI bleeding events in 81 (47.09%) with major bleedings in three patients. All patients with major bleedings were classified as LTPR. Ticagrelor related dyspnea occurred in 31 (18.02%) patients, with 30 (21.28%) classified as LTPR and no one as HTPR (P = 0.02). Conclusions In ticagrelor treated ACS patients, MAADP measured by TEG might be valuable for the prediction of major bleeding and ticagrelor related dyspnea. Due to the small number of patients with HTPR after ticagrelor maintenance treatment, larger scale study should be warranted to verify the relationship between MAADP defined HTPR and ticagrelor related ischemic events.