An Observational Study of the Relationship Between Outcome and Platelet Reactivity in Chinese Patients Undergoing PCI Loading with 600 mg Clopidogrel

Objectives:We sought to determine whether high posttreatment platelet reactivity(HPPR)to a 600 mg loading dose of clopidogrel affects outcomes in Chinese patients with acute coronary syndrome(ACS)following percutaneous coronary intervention(PCI)and to investigate whether there is a relationship between the number of platelet reactivity units(PRUs)and the characteristics of the patients.Background:Although impaired platelet response to clopidogrel is a strong predictor of unfavorable outcome after PCI,the impact of HPPR to a 600 mg loading dose of clopidogrel in Chinese patients with ACS undergoing PCI is still unknown.Methods:We performed observational research on 134 unselected patients with ACS undergoing urgent or planned PCI with a 600 mg loading dose of clopidogrel.Platelet activation was expressed as the PRU value measured by the VerifyNow assay.Results:Among the 134 patients(mean age 60.62 years[standard deviation 9.13 years],60.4%male),there were 46 patients with HPPR(34.3%)and 88 patients without HPPR(65.7%).At a mean follow-up of 6 months(standard deviation 1 month),the rates of cardiac death,unstable angina,and rehospitalization for target lesion revascularization were higher in the HPPR group(19.6%vs.6.8%,P=0.029).Multivariate analysis identifi ed hemoglobin level and sex as independent predictors of the PRU value(y=456.355−1.736 x 1−31.880 x 2,P<0.05).On receiver operating characteristic curve analysis,PRU values could signifi cantly discriminate between patients with and patients without cardiac death,unstable angina,and rehospitalization for target lesion revascularization(area under the curve 0.758,95%confi dence interval 0.62–0.85,P=0.001,P<0.05).Conclusion:In patients with ACS,HPPR to a 600 mg loading dose of clopidogrel is associated with worse outcomes after PCI.There is some relationship between the PRU value and the hemoglobin level and sex.PRU values can predict the prognosis.

Platelet reactivity in patients with atrial fibrillation

We read the article entitled ＇Gender and tachycardia： independent modulation of platelet reactivity in patients with atrial fibrillation＇ with great interest. In this article Procter, et al.reported that gender and heart rate are independent determinants ofplatelet function in patients with acute atrial fibrillation （AF）.

The correlation and consistency of light transmission aggregometry and thrombelastography in identifying high clopidogrel on-treatment platelet reactivity in patients with acute coronary syndrome

Various platelet function tests are currently used to identify responsiveness to antiplatelet therapy. 176 ACS patients were enrolled and Linear regression and Kappa consistency analysis showed there was a significant but moderate correlation between platelet inhibition rate and a significant but fair agreement between high clopidogrel on-treatment platelet reactivity tested by light transmission aggregometry and thrombelastography.

Obstructive Sleep Apnea Affecting Platelet Reactivity in Patients Undergoing Percutaneous Coronary Intervention

Background：The relationship between obstructive sleep apnea （OSA） and platelet reactivity in patients undergoing percutaneous coronary intervention （PCI） has not been defined.The present prospective,single-center study explored the relationship between platelet reactivity and OSA in patients with PCI.Methods：A total of 242 patients were finally included in the study.OSA was screened overnight by polysomnography.Platelet reactivity was assessed with a sequential platelet counting method,and the platelet maximum aggregation ratio （MAR） and average aggregation ratio were calculated.All patients were assigned per apnea-hypopnea index （AHI） to non-OSA （n =128） and OSA （n =l 14） groups.The receiver operating characteristic curve analysis was used to evaluate the accuracy of AHI for high platelet reactivity （HPR） on aspirin and clopidogrel,and multivariable logistic regression was used to determine the independent predictors of HPR on aspirin and clopidogrel.Results：Median AHI was significantly higher in the OSA group than in the non-OSA group （34.5 events/h vs.8.1 events/h,Z =-13.422,P 〈 0.001）.Likewise,median arachidonic acid-and adenosine diphosphate-induced maximum aggregation rate （MAR） in the OSA group was significantly higher than those in the non-OSA group （21.1% vs.17.7%,Z=-3.525,P 〈 0.001 and 45.8% vs.32.2%,Z =-5.708,P 〈 0.001,respectively）.Multivariable logistic regression showed that OSA was the only independent predictor for HPR on aspirin （odds ratio [OR]：1.055,95% confidence interval [CI]：1.033-1.077,P 〈 0.001） and clopidogrel （OR：1.036,95% CI：1.017-1.056,P 〈 0.001）.The cutoffvalue of AHI for HPR on aspirin was 45.2 events/h （sensitivity 47.1% and specificity 91.3%）,whereas cutoffvalue of AHI for HPR on clopidogrel was 21.3 events/h （sensitivity 68.3% and specificity 67.7%）.

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 ofticagrelor 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.

Clopidogrel and proton pump inhibitors-where do we stand in 2012?

Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events.Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines.Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19(CYP2C19) and proton pump inhibitors(PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well.Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole,but not for pantoprazole.Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events,when under clopidogrel and PPI treatment at the same time.These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI(especially omeprazole) in the same year.In contrast,more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel.Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality,with high and moderate quality studies not reporting any association,rising concern about unmeasured confounders biasing the low quality studies.Thus,no definite evidence exists for an effect on mortality.Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding,combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.

CYP2C19＊2 and Other Allelic Variants Affecting Platelet Response to Clopidogrel Tested by Thrombelastography in Patients with Acute Coronary Syndrome

Background：To investigate the contributions ofCYP2C 19 polymorphisms to the various clopidogrel responses tested by thrombelastography （TEG） in Chinese patients with the acute coronary syndrome （ACS）.Methods：Patients were screened prospectively with ACS diagnose and were treated with clopidogrel and aspirin dual antiplatelet therapy.CYP2C 19 loss of function （LOF） and gain of function （GOF） genotype,adenosine 5＇-diphosphate （ADP）-channel platelet inhibition rate （PIR） tested by TEG and the occurrence of 3-month major adverse cardiovascular events and ischemic events were assessed in 116 patients.Results：High on-treatment platelet reactivity （HTPR） prevalence defined by PIR 〈30% by TEG in ADP-channel was 32.76% （38/116）.With respect to the normal wild type,CYP2C 19＊2,and ＊3 LOF alleles,and ＊ 17 GOF alleles,patients were classified into three metabolism phenotypes：41.38% were extensive metabolizers （EMs）,56.90% were intermediate metabolizers （IMs）,and 1.72% were poor metabolizers （PMs）.Of the enrolled patients,31.47%,5.17%,and 0.43%,respectively,were carriers of ＊2,＊3,and ＊ 17 alleles.The HTPR incidence differed significantly according to CYP2C 19 genotypes,accounting for 18.75%,41.54%,and 100.00% in EMs,IMs,and PMs,respectively.Eighteen （17.24%） ischemic events occurred during the 3-month follow-up,and there was a significant difference in ischemic events between HTPR group and nonhigh on-treatment platelet reactivity group.Conclusions：Genetic CYP2C 19 polymorphisms are relative to the inferior,the antiplatelet activity after clopidogrel admission and may increase the incidence of ischemic events in patients with ACS.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention:A randomized controlled trial

Background:High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2 C19,the enzyme that converts clopidogrel into its active form.Shexiang Tongxin Dropping Pill(STDP)is a traditional Chinese medicine to treat angina pectoris.STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice.However,whether STDP can affect platelet function remains unknown.Objective:The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention(PCI)for unstable angina.The interaction between the effects of STDP with polymorphisms of CYP2 C19 was also investigated.Design,participants and intervention:This was a single-center,randomized controlled trial in patients undergoing elective PCI for unstable angina.Eligible subjects were randomized to receive STDP(210 mg per day)plus dual antiplatelet therapy(DAPT)with clopidogrel and aspirin or DAPT alone.Main outcome measures:The primary outcome was platelet function,reflected by adenosine diphosphate(ADP)-induced platelet aggregation and platelet microparticles(PMPs).The secondary outcomes were major adverse cardiovascular events(MACEs)including recurrent ischemia or myocardial infarction,repeat PCI and cardiac death;blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme(CK-MB)and high-sensitive troponin I(hs Tn I);and biomarkers for inflammation including intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),monocyte chemoattractant protein-1(MCP-1)and galectin-3.Results:A total of 118 subjects(mean age:[66.8±8.9]years;male:59.8%)were included into analysis:58 in the control group and 60 in the STDP group.CYP2 C19 genotype distribution was comparable between the 2 groups.In comparison to the control group,the STDP group had significantly lower CKMB(P<0.05)but similar hs Tn I(P>0.05)at 24 h after PCI,lower ICAM-1,VCAM-1,MCP-1 and galectin-3 at 3 months(all P<0.05)but not at 7 days after PCI(P>0.05).At 3 months,the STDP group had lower PMP number([42.9±37.3]vs.[67.8±53.1]counts/μL in the control group,P=0.05).Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers(66.0%±20.8%in STDP group vs.36.0%±28.1%in the control group,P<0.05),but not in intermediate or fast metabolizers.The rate of MACEs during the 3-month follow-up did not differ between the two groups.Conclusion:STDP produced antiplatelet,anti-inflammatory and cardioprotective effects.Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.

Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention

Background The CYP2C19 G681A single polymorphism has been proven to affect clopidogrel responsiveness. However, the effect of coexisting polymorphisms of other genes has not yet been reported in the Chinese population. This study investigated the effect of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and adverse clinical events in Chinese patients. Methods In 577 Han Chinese patients undergoing stent placement because of acute coronary syndrome had platelet reactivity assessed by thromboelastography, and the CYP2C19 G681A and P2Y12 C34T polymorphisms were detected by the ligase detection reaction. Primary clinical endpoints included cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis. The secondary clinical endpoints were thrombolysis in myocardial infarction bleeding. The follow-up period was 12 months. Results Genotyping revealed 194 carriers of the wild type GG genotype of CYP2C19 and the wild type CC genotype of P2Y12 （group 1）, 102 carriers of the wild type GG genotype of CYP2C19 and the mutational T allele of P2Y12 （group 2）, 163 carriers of the mutational A allele of CYP2C19 and the wild type CC genotype of P2Y12 （group 3）, and 118 carriers of the mutational A allele of CYP2C19 and the mutational T allele of P2Y12 （group 4）. Group 4 had the lowest ADP-inhibition （49.74＋32.61） and the highest prevalence of clopidogrel low response （29.7%） of the four groups. The rate of the composite of primary clinical endpoints increased more in group 4 （8.5%） than in the other three groups; the rate of composite primary endpoints in group 2 （2.9%） and group 3 （3.7%） were not significantly different than that of group 1 （1.5%）. Conclusion Coexisting polymorphisms of different genes affected clopidogrel responsiveness and clinical outcome more than single polymorphism in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention.