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A Randomized Controlled Trial of Adjunctive Bunchang Naoxintong Capsule (步长脑心远胶囊) Versus Maintenance Dose Clopidogrel in Patients with CYP2C19会 Polymorphism*
作者:陈慧[1] 
单位:福建省立医院[1]  
文章号:W114542  
2016/8/20 10:32:47    
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ABSTRACT Objec伽e: To determine the impact of adjunctive Buchang Naoxintong Capsule (步长脑心通胶囊, NXT)on dual antiplatelet therapy in patients with cyt,∞hrome P450 2C19´2 (CYP2C1矿2) polymorphism undergoing percutaneous coronary intervention (PCI). Methods: Ninety patients with CYP2C1矿2 polymorphism were enrolled, 365医学网 转载请注明
and their genotypes were confirmed by polymerase chain reaction (PCR). 丁he patients were randomly assigned to 陪ceive either adjunctive NXT (triple group,45 cases) or dual antiplatelet therapy (dual group,45 臼.ses) using a computer-generated randomization sequence and sealed envelopes. Platelet function was assessed at baseline 365医学网 转载请注明
and 7 days after treatment with conventional aggregometry. Subsequent m司or adverse cardiovascular events (MACE,including sudden cardiac arrest and acute coronary syndrome) were rl orded during a 12-month follow? up. Resul怨: 8aseline platelet function measurements were similar in both groups. After 7 days,percent inhibitions of maximum platelet aggregation and late platelet aggregation were significantly greater in the triple versus dual 365医学网 转载请注明
group (42.3% 士 16.0% VS. 20.8% 士 15.2%,P<0.01,and 54.7% 主 18.3% VS. 21.5% :t29.2%,P<0.01,respectively). Du时ng the 12-month follow-up ,the rate of subsequent MACE (6/45) was significantly lower in the triple group compared with the dual group (14/45; P<0.05). Conclusion: Adjunctive NXT to maintenance dose clopidogrel (75 g) could enhance the antiplatelet e.何ect and decrease subsequent MACE in patients with the CYP2C19.2 365医学网 转载请注明
polymorphism undergoing PCI. 365医学网 转载请注明
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KEYWORDS P阳.1elet,CYP2C19.2 gene mutation,Buchang Nao刘ntong Capsule,maintenanωdose clopidogrel, clinical prognosis,Chinese medicine,randomized ∞ntrolled trial 365医学网 转载请注明
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Clopidogrel ,a thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist ,requires 365医学网 转载请注明
bioactivation to its active metabolite (R130964) to inhibit platelet aggregation. Cytochrome P450 2C19 (CYP2C19) plays an important role in the 365医学网 转载请注明
bioactivation of the prodrug clopidogre l. Once 365医学网 转载请注明
absorbed ,only approximately 15% of clopidogrel is bioactivated in the liver in a two-step process 365医学网 转载请注明
mediated by several CYP450 isoenzymes.(1) Among these ,CYP2C19 is responsible for approximately 365医学网 转载请注明
45% of the first step (2-oxo-clopidogrel formation) and approximately 20% of the final step (generation of the pharmacologically active thiol metabolite). There are genetic polymorphisms in several CYP450 365医学网 转载请注明
enzymes involved in the metabolism of clopidogrel , 365医学网 转载请注明
but variants in CYP2C19 ,particularly CYP2C19*2 (encoding a nonfunctional protein),are reproducibly 365医学网 转载请注明
associated with variability in clopidogrel active metabolite bioavailability ,antiplatelet effects ,and 365医学网 转载请注明
clinical outcomes.(2-4) There are ethnic differences in its distribution; approximately 50% of the Chinese population possesses at least one copy of the reduced function CYP2C1902 allele.币,6) Chinese data 365医学网 转载请注明
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have shown that 41%-52% patients with coronary atherosclerotic heart disease carry CYP2C19´2. (7,日) The number of reduced functional alleles is important; individuals with one variant allele (intermediate metabolizers) exhibit 26%-31 % reductions in the 365医学网 转载请注明
active metabolite of clopidogrel ,and those with 365医学网 转载请注明
two genetic polymorphisms (poor metabolizers) had 46%-55% lower levels compared with those with no CYP2C19 polymorphisms,(9) We previously demonstrated that the CYP2C19命 2 allele weakens the antiplatelet effect of clopidogrel and increases the 365医学网 转载请注明
risk of m刮or adverse cardiovascular events (MACEs) 365医学网 转载请注明
in patients undergoing percutaneous coronary 365医学网 转载请注明
。The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2014 ´Supported by the Provincial Natural Science Foundation of Fujian (No,2011J0133) and the National Natural Science Foundation of China (No. 81373838) 365医学网 转载请注明
Fujian Provincial Cardiovascular Disease Institute,Provincial 365医学网 转载请注明
Clinical College of Fujian Medical University,Fuzhou (350001) , 365医学网 转载请注明
China 365医学网 转载请注明
Correspondence to Prof ,CHEN Hui,Tel: 86-591-82217400 , 365医学网 转载请注明
F础: 86-591-82215016 ,E-mail: chenhuiwyd@sina_com 365医学网 转载请注明
DOI: 10.1007/s11655-014-2023-z 365医学网 转载请注明
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Chin J Intear Med 2014 Dec:20(12):894-902 365医学网 转载请注明
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intervention (PCI).(8) A meta-analysis revealed a higher odds ratio of adverse clinical events in the Asian population with loss-of-function CYP2C19 variants compared with Western populations.(10) 365医学网 转载请注明
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One approach to overcoming low clopidog陌r el r陪esponsiveness 陆is怕to increase the dose.(1忖仙忡乍1「….1… 365医学网 转载请注明
e副t 副aI口(14钊4) demonstrated that among p创ati陷e时nts with 创stab剧le 365医学网 转载请注明
cardiovascular disease ,tripling the maintenance dose (MD) of clopidogrel to 225 mg daily in CYP2C19´ 2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in 365医学网 转载请注明
noncarriers. In contrast ,doses as high as 300 mg daily 365医学网 转载请注明
did not result in comparable degrees of platelet inhibition in CYP2C19*2 homozygotes. Another strategy is to add a third drug (such as cilostazol) to aspirin and c1opidogrel 365医学网 转载请注明
to further enhance platelet inhibition.(15) A third altemative is to substitute a newer,more potent platelet inhibitor drug (e.g.,prasugrel or ticagretor) for clopidogre l.(16) However,these strategi臼that enhance responsiveness to c1opidogrel are often associated with a higher risk for 365医学网 转载请注明
bleeding that may be attributed to the inhibition of the thromboxane A2 (TXA2) and ADP platelet activation pathways that are essential for normal hemostasis.(17-19) These considerations underscore the need for agents that provide more comprehensive platelet inhibition without affecting hemostasis to offer greater protection against thrombotic events. 365医学网 转载请注明
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Chinese medicine (CM) seeks to regulate yin and yang balance(20) by applying holistic approaches to enhance systemic harmony ,a method called dual 365医学网 转载请注明
regulation. In a small prospective study,administration 365医学网 转载请注明
。,f St.‘John´s wo此 enhanced the platelet inhibitory e仔ect of clopidogrel in volunteers known to be unresponsive to the drug and in patients with stable coronary a此ery 365医学网 转载请注明
dìsease.(21) We previously reported that Buchang Naoxintong Capsule (步长脑心通胶囊, NXT) combined with dual antiplatelet therapy could inhibit platelet 365医学网 转载请注明
aggregation ,balance pro- and anti-inflammatory 365医学网 转载请注明
cytokines and serum endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) ,and decrease coronary microembolization (CME) in a rat model. 365医学网 转载请注明
This therapy also reduced the risk of intraoperative bleeding during dual antiplatelet therapy in a rat model 365医学网 转载请注明
of CME.(22,23) Jn V;VO,adjunctive NXT to clopidogrel can 365医学网 转载请注明
enhance the antiplatelet effect in volunteers with the CYP2C19空 polymorphism accompanied by qi 365医学网 转载请注明
deficiency and blood stasis constitution. (24) However, 365医学网 转载请注明
it is unknown whether adjunctive NXT to dual 365医学网 转载请注明
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antiplatelet therapy can improve the clinical prognosis in patients with CYP2C19*2 undergoing PCI. 365医学网 转载请注明
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The purpose of the present study was to determine the impact of adjunctive NXT to MD (75 mg daily) clopidogrel in patients with the CYP2C19*2 polymorphism 365医学网 转载请注明
undergoing PCI.We performed a prosp民tive,randomized 365医学网 转载请注明
study to compare the degree of platelet inhibition and subsequent MACEs by adjunctive 1.6 9 NXT th时ce daily versus dual antiplatelet therapy. 365医学网 转载请注明
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METHODS 365医学网 转载请注明
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Patient Population 365医学网 转载请注明
Patients were eligible for enrollment if they were older than 45 years ,undergoing successful elective PCI,and were confirmed to have a CYP2C19´2 polymorphism (CYP2C19寸户2 and CYP2C 19´2户2). 365医学网 转载请注明
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Major exclusion criteria included acute myocardial infarction (MI),hemodynamic instability ,active bleeding and bleeding diatheses ,oral anticoagulation therapy with warfarin ,use of periprocedural glycoprotein IIb/illa inhibitors,contraindication to antiplatelet therapy ,left ventricular ejection fraction <30%,leukocyte count 365医学网 转载请注明
<3,000/mm气 platelet count <100,000/mm气 aspartate aminotransferase or alanine aminotransferase levels 3 times the upper normal limit,serum creatinine 365医学网 转载请注明
level 注,2.5 mg/dL,stroke within 3 months,noncardiac disease with a life expectancy <1 year ,or inability to follow the protocol. 365医学网 转载请注明
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The Institutional Review Board of the Provincial Clinical College of F叫ian Medical University approved the study protocol,and the patients provided written informed consents for participation. The study was performed in the Clinical Pharmacological Base of 365医学网 转载请注明
Fujian Provincial Hospital. The Chinese clinical trial 365医学网 转载请注明
registration number was ChiCTR-TRC-13003596. CYP2C19´2 genotyping and ADP-induced platelet aggregation were finished in Cardiovascular Medicine Department as Fujian Provincial Clinical Key 365医学网 转载请注明
Specialties and Fujian Provincial Clinical Laboratory, 365医学网 转载请注明
respectively. Clinical data were also collected. Hypertension was defined as systolic blood pressure 365医学网 转载请注明
140 mm Hg,diastolic blood pressure 注90 mm 365医学网 转载请注明
Hg,and/or the use of antihypertensive medication. Diabetes was defined as having a fasting blood 365医学网 转载请注明
glucose level ;;;;´7.0 mmol/L ,blood glucose level 365医学网 转载请注明
11.1 mmol/L 2 h after a 75-g oral glucose load,and/ or self-repo时ed current treatment with antidiabetes 365医学网 转载请注明
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medication (insulin or oral hypoglycemic agents). Hypercholesterolemia was defined as total cholesterol (TC) >5.18 mmol/L (200 mg/dL). Drug intake was documented for participants who reported having 365医学网 转载请注明
taken antidiabetes ,antihypertensive ,or lipid-Iowering 365医学网 转载请注明
drugs during the previous 2 weeks. 365医学网 转载请注明
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Genotyping by Polymerase Chain Reaction Genomic DNA was extracted from 200μL 365医学网 转载请注明
peripheral potassium ethylenediaminetetraacetic acid­ anticoagulated blood with the TIANamp Blood DNA Kit 365医学网 转载请注明
(丁iangen Biotech Co.,Ltd.,Beijing,China) according to 365医学网 转载请注明
the manufacturer´s instruction. CYP2C19´2 (681G>A; rs4244285) was genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP). A MultiGene™ 365医学网 转载请注明
Gradient Thermal Cycler (TC9600-G-230V ,Labnet 365医学网 转载请注明
International,Inc.,Edison,NJ,USA) was used. PCR was performed in a 25μL reaction mixture containing 365医学网 转载请注明
1.0 J.L L DNA,0.8μL of each primer (fo附ard primer 365医学网 转载请注明
5´ -CAGAGCTTGGCATATTGTATC-3´ and reverse primer 5´- GTAAACACACAACTAGTCAATG -3´) , 365医学网 转载请注明
2.0μL each dNTPs ,2.5μL 10 >< reaction buffer, 365医学网 转载请注明
17.6μL sterilizing and 0.3μL Taq DNA polymerase (XiamenTagegeBiotechnologyCo.Ltd.,China).The 365医学网 转载请注明
PCR parameters were an initial denaturation for 5 min at 94 "C, followed by 35 cycles of 30 5 at 94 "C, 20 5 365医学网 转载请注明
at 56 "C, 20 5 at 72 "C, and a final extension for 5 min 365医学网 转载请注明
at 72 "C. The PCR product was then digested with Smal (Xiamen Tagege Biotechnology Co. Ltd.,China) for 5-6 h at 30 "C, yielding two fragments of 212 and 365医学网 转载请注明
109 bp in the case of the GG genotype. For the AA genotype ,a single band of 321 bp was observed. For the GA genotype ,3 fragments of 321,212,and 109 365医学网 转载请注明
bp were observed. Genotypes were directly observed with an ImageMaster VDS-CL (GE Healthcare Life Sciences ,Uppsala,Sweden) and were confirmed with 365医学网 转载请注明
an ABI 3700 Automated DNA Sequencer (Applied Biosystems ,Foster City,CA,USA). PCR-RFLP was performed to genotype CYP2C19´2 in 304 patients 365医学网 转载请注明
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Chin J Intear Med 2014 Dec:2DI12\:894-9D2 365医学网 转载请注明
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by 100 mg daily (300 mg daily for the first month) of aspirin and 75 mg daily clopidogrel therapy after PCI for 365医学网 转载请注明
1 year. Diagnostic and interventional procedures were 365医学网 转载请注明
performed according to standard techniques. If patients with a CYP2C19´2 polymorphism were identified,they 365医学网 转载请注明
were randomly assigned to receive adjunctive NXT (trial group) or dual antiplatelet therapy (dual group) using a computer-generated randomization sequence and sealed envelopes. Patients in the trial group (45 cases) received a 3.2 9 loading dose of NXT within 6 hrs after 365医学网 转载请注明
randomization ,followed by 1.6 9 NXT thrice daily at 365医学网 转载请注明
least for 3 months. NXT 0.4 g/capsule (Compilation of The National Standard of Chinese Traditional Medicine No. WS-10001 [ZD-0001]-2002; batch No. Z20025001) 365医学网 转载请注明
were produced by the Buchang Pharmaceutical Co., 365医学网 转载请注明
Ltd in Xianyang ,Shaanxi,China. Plavix (clopidogrel bisulfate) 75 mg tablets (batch No. J20080090) were 365医学网 转载请注明
produced by Sanofi-Winthrop Industriy. Aspirin enteric­ coated 100 mg tablets (batch No. H20080331) were produced by Bayer Health Care AG. Blood samples were obtained to measure ADP-induced platelet aggregation by turbidimetry at baseline and 7 days 365医学网 转载请注明
after treatment.AII patients had a normal diet and had 365医学网 转载请注明
quit smoking. They were assessed by reviewing the patient charts on readmission; in a special outpatient 365医学网 转载请注明
clinic; or by telephone interview at 1,3,6,and 12 365医学网 转载请注明
months after therapy. 365医学网 转载请注明
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before undergoing elective PCI successfully between 365医学网 转载请注明
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July 2009 and July 2010. There were 140,130, and 34 patients with the CYP2C19寸/寸 (681GG) , CYP2C19´1户2(681 GA) and CYP2C19´2户2(681AA) 365医学网 转载请注明
genotypes ,respectively. 365医学网 转载请注明
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Study Design 365医学网 转载请注明
The flow diagram of the study is depicted in Figure 1. AII patients received a 300-mg loading dose 365医学网 转载请注明
(LD) of clopidogrel and aspirin 6 h before PCI,followed 365医学网 转载请注明
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Notes: CTP2C19´2 = CYP2C19´2 gene mutation,Primary manifestations of Liver yang hyperactivity included headache or dizziness aggravated by mental upset,irritability,flushed face, tinnitus ,dry mouth with a bitter taste,dream-disturbed sleep , reddened tongue with yellow coating,and tachycardia 365医学网 转载请注明
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Chin J Intear Med 2014 Dec:20112\:894-902 365医学网 转载请注明
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ADP-Induced Platelet Aggregation 365医学网 转载请注明
Aggregation studies were performed within 2 h after blood collection at 37 "C using a previously described turbidimetric method(25) on a LBY-NJ4- 365医学网 转载请注明
channel platelet aggregation analyzer (Beijing Precil Instrument Co.,Ltd.,Beijing,China). Briefly,whole 365医学网 转载请注明
blood was centrifuged atγ00 r/min for 4 min to prepare platelet-rich plasma (PRP). The remaining blood was 365医学网 转载请注明
further centrifuged at 3,500 r/min for 10 min to prepare 365医学网 转载请注明
platelet-poor plasma (PPP). The PRP platelet counts were adjusted to 200 x 109 L. Results were recorded 365医学网 转载请注明
as light transmission at maximal aggregation (Aggmax) and 5-min aggregation (Agg1ate) after the addition of 365医学网 转载请注明
ADP (Sigma-Aldrich ,St. Louis , MO,USA) at final 365医学网 转载请注明
concentrations of 5μmol/L. Aggm副 is considered to reflect the activity of both P2Y1 and P2Y12 receptors , 365医学网 转载请注明
whereas Agg1ðt• is more reflective of P2Y12 receptor activity. Inhibition of platelet aggregation (IPA) was defined as the percent decrease of aggregation 365医学网 转载请注明
values (Aggmax and Agg 1at.) between baseline and after treatment and was calculated as follows: IPA (%)=[(intensity of aggregation at baseline­ 365医学网 转载请注明
intensity of aggregation after treatment)/(intensity of aggregation at baseline) ] x 100.(14) Percentage of platelet disaggregation between Aggmax and Agg1ate 365医学网 转载请注明
was defined as follows: disaggregation (%)=[(Aggm剧­ 365医学网 转载请注明
Agglate)/Aggmax] X 100.(14) 365医学网 转载请注明
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Follow-Up 365医学网 转载请注明
A 川 90 patients are followed for a 12-month period with follow-up visits at 1,3,6,and 12 months after treatment ,respectively. The MACEs included cardiac death,sudden cardiac arrest,and readmission 365医学网 转载请注明
due to acute coronary syndrome (ACS). ACS was diagnosed if one of the following criteria was fulfilled: unstable angina [clinical symptoms and new electrocardiogram (ECG) changes but no markers of myocardial necrosis] or acute MI with markers of myocardial necrosis [troponin or creatine kinase (CK)­ MB] including ST elevation MI (STEMI) and non-ST elevation MI (NSTEMI). Cardiac or sudden death was considered if death was correlated with documented MI,congestive heart failure ,or malignant ventricular arrhythmias. 365医学网 转载请注明
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Statistical Analysis 365医学网 转载请注明
Continuous variables are presented as mean ::!:: standard deviation and were compared using Student´s unpaired or pairwise t-tests. Categorical variables are presented as numbers or percentages and 365医学网 转载请注明
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were compared using chi-square tests. One-year cumulative incidence rates of MACEs were estimated by the Kaplar卜Meier method. A value of P<0.05 was 365医学网 转载请注明
considered statistically significant. AII analyses were 365医学网 转载请注明
pe斤。rmed using SPSS software (version 16.0,SPSS Inc.,Chicago,IL,USA). 365医学网 转载请注明
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RESULTS 365医学网 转载请注明
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Patient Characteristics and Follow-Up 365医学网 转载请注明
Baseline platelet function measurements and CYP2C19´2 genotype assessments were performed 365医学网 转载请注明
in a total of 304 patients. Of these ,164 patients 365医学网 转载请注明
(53.94%) had CYP2C19空 polymorphisms ,and 90 patients (62 CYP2C19´1户2 and 28 CYP2C19事 365医学网 转载请注明
2户2) were ultimately enrolled (Figure 1). Baseline characteristics were well matched between the study groups (Tables 1 and 2). Baseline platelet aggregation values (Aggm阻 and Agg1ate) with 5 mol/L 365医学网 转载请注明
ADP stimuli were similar in the triple group compared 365医学网 转载请注明
with the dual group (Table 3). Furthermore ,baseline percent platelet inhibition did not differ significantly between the groups (Figure 3). 365医学网 转载请注明
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Because both treatments were well tolerated and no subject discontinued the study drugs,platelet function could be assessed in all patients after 7 365医学网 转载请注明
days of therapy. For all patients ,the number of remaining tablets demonstrated complete compliance 365医学网 转载请注明
with the study protoco l. A 12-month follow-up was achieved for 90 patients. In the triple group ,there were 20 patients with NXT for 3 months , 15 with NXT for 6 months,and 10 with NXT for 12 months. Although there were 14 and 6 patients with MACEs in the dual and triple groups,respectively (P<0.05 , Table 4) ,there was no cardiac death and no m叫or or 365医学网 转载请注明
minor bleeding in either group. 365医学网 转载请注明
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ADP-Induced Platelet Aggregation 365医学网 转载请注明
Patients in both groups exhibited definite reductions in Aggmax and Agg1ate after 7 days of therapy compared with corresponding baseline measurements 365医学网 转载请注明
(all values P<0.01). Aggmax and Agg1ate values in the triple group were significantly lower than those in the dual group after 7 days of therapy (Table 3). IPAs of 365医学网 转载请注明
Aggmax and Agg1ate with 5μmol/L ADP stimuli were consistently greater in the triple group compared with the dual group (Figure 2). IPA of Agg max with 365医学网 转载请注明
5μmol/L ADP stimulus was 42.33% 士 15.99% in 365医学网 转载请注明
the triple group and 20.76%::!:: 15.18% in the dual group ,with a mean difference of 21.57% (95% 365医学网 转载请注明
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Table 1. Demographics of the Study Population Variables Dualgroup Triple grou P value 365医学网 转载请注明
(45cases) (45cases) 365医学网 转载请注明
Age (Year,x :ts) 64.00 :t 11.29 62.01 :t11.90 0.431 365医学网 转载请注明
Male [Case (%)] 35(万.8) 36(80.0) 0.796 365医学网 转载请注明
BMI (kg/m2,x :ts) 24.46 :t3.17 24.86 :t2.80 0.526 365医学网 转载请注明
Diabetes mellitus 16(旦6) 10 (:但 2) 0.163 365医学网 转载请注明
[Case(%)] 365医学网 转载请注明
Hype时:ension [Case (%)] 34(75.6) 36 (80.0) 0.612 365医学网 转载请注明
Hypercholesterolemia [Case 13 (28.9) 12 (26.7) 0.841 365医学网 转载请注明
(%)] 365医学网 转载请注明
Current smoking 16 (35.6) 12 (26.η 0.362 365医学网 转载请注明
[Case(%)] 365医学网 转载请注明
Concomitant medications 365医学网 转载请注明
Statin [Case (%)] 41 (91.1) 44(97.8) 0.203 365医学网 转载请注明
Be恒-blocker [Case (%)] 13 (28.9) 12 (26.7) 0.814 365医学网 转载请注明
ACEI [Case (%)] 31 (68.9) 36 (80.0) 0.227 365医学网 转载请注明
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Chin J Intear Med 2014 Dec:20(12):894-902 365医学网 转载请注明
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Table 3. Platelet Function Measurements by Light Transmittance Aggregomet 叩(%,支士 s) 365医学网 转载请注明
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Variables Dua|group Triple group p value (45 cases) (45 cases) 365医学网 转载请注明
Maximalagσegation with 5μmoVLADP 365医学网 转载请注明
Baseline 48.02:!: 12.79 48.59:!: 11.43 0.822 365医学网 转载请注明
7 days after randomization 37.45 :t 10.27 27.66:!: 8.62 <0.001 365医学网 转载请注明
Lateagg陪gation with 5μmoVLADP 365医学网 转载请注明
Baseline 38.92:!: 14.69 4ο.45 士 11.98 0.589 365医学网 转载请注明
7days after randomization 27.87 士 9.50 18.12 士 9.75 <0.001 Note: ADP: adenosine diphosphate 365医学网 转载请注明
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54.68% 士 18.26% and 21 .47% 士 29.18% in the triple and dual groups ,respectively ,with a mean difterence of 33.21% (95% CI: 23.02% to 43.41%; P<0.01). 365医学网 转载请注明
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Calcium-channel blocker 11 (24.4) 12 (26.7) 0.809 365医学网 转载请注明
[Case(%)] 365医学网 转载请注明
PPls [Case (%)] 39 (86.7) 40 (88.9) 0.612 365医学网 转载请注明
LV ejection fraction (%,x :ts) 58.2 :t6.4 57.2 :t 6.6 0.456 365医学网 转载请注明
Hb(g/dL,x 士 5) 12.9 :t1.3 13.0 :t 1.1 0.935 365医学网 转载请注明
Platelet ∞unt ( x 109/L,x :t5) 235.7 :t57.9 227.2 :t58.4 0.487 365医学网 转载请注明
TC(mmoVL ,x 士 5) 4.42 :t1.18 4.67 :t 1.14 0.306 365医学网 转载请注明
TG (mmoVL,x:t s) 1.55:!:0.80 1.44 :t 0.67 0.497 365医学网 转载请注明
HDL (mmoVL,x :t5) 2.80:!:1.04 2.92 士 0.98 0.604 365医学网 转载请注明
Cr(mg/dL,x 士 5) 0.98 :t 0.32 0.96 :t0.33 0.754 365医学网 转载请注明
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100 365医学网 转载请注明
90 365医学网 转载请注明
80 365医学网 转载请注明
70 365医学网 转载请注明
飞、 60 365医学网 转载请注明
且<( 50 365医学网 转载请注明
40 365医学网 转载请注明
30 365医学网 转载请注明
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Baseline 365医学网 转载请注明
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* 365医学网 转载请注明
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7th day 365医学网 转载请注明
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• Dual group 365医学网 转载请注明
口Triple group 365医学网 转载请注明
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CYP2C19*2!2 [Case (%)] 14 (31.1) 14 (31.1) 1.000 365医学网 转载请注明
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Notes: ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; Cr: creatinine; Hb: hemoglobin; HDL: high density cholesterol; LV: left ventricular; PPls: proton pump inhibitors; TC: total cholesterol; TG: triglyceride; current smoking was defined as smoking ;;;.10 cigarettes within 2 weeks 365医学网 转载请注明
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Table 2. Lesion and Procedural Characteristics of the Study Population [Case (%)] 365医学网 转载请注明
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Variables Target vessel 365医学网 转载请注明
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Figure 2. IPA at Baseline and after 7 Days of Antiplatelet Therapy 365医学网 转载请注明
Note: 节<0.05,compared with the dual group 365医学网 转载请注明
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The percentages of platelet disaggregation with 5μmol/L ADP stimuli did not difter between the groups at baseline (Figure 3). A significant increase of platelet disaggregation after 7 days of therapy was observed in the triple group compared with the dual group (P<0.05). 365医学网 转载请注明
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•Dual group 365医学网 转载请注明
口Triple group 365医学网 转载请注明
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斗¢ 365医学网 转载请注明
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F 365医学网 转载请注明
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Notes: ACC: American College of Cardiology; AHA: 365医学网 转载请注明
American Heart Association 365医学网 转载请注明
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confidence interval [CI]: 15.04% to 28.10% ,P<0.01). IPAs of Agg ´a´e with 5μmol/L ADP stimuli were 365医学网 转载请注明
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10 365医学网 转载请注明
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Baseline 7th day 365医学网 转载请注明
Figure 3. Platelet Disaggregation at Baseline and After 7 Days of Antiplatelet Therapy 365医学网 转载请注明
Note: 事P<0.05 ,compared with the dual group 365医学网 转载请注明
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Chin j Inte咽r Med 2014 Dec:20(12):894-902 365医学网 转载请注明
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Outcome of the Follow-up 365医学网 转载请注明
MACEs were more frequent in the dual group 365医学网 转载请注明
28.%) compared with the triple group (13.33%, P=0.043,odds ratio=0.341 ,95% CI 0.117 to 0.990; Table 4). Cumulative Kaplan-Meier analysis showed 365医学网 转载请注明
that the rate of MACEs in the dual group was higher than that in the triple group during the 12-month 365医学网 转载请注明
follow-up period (P=0.044,Figure 4). The MACEs 365医学网 转载请注明
were driven by the higher rate of readmission due to AC8. 365医学网 转载请注明
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-一- Green line: patients with NXT 365医学网 转载请注明
-- Blue line: patients without NX T 365医学网 转载请注明
1.0 365医学网 转载请注明
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0.8 365医学网 转载请注明
-。』》咀 365医学网 转载请注明
币2=U33 06 365医学网 转载请注明
GEFJ 04 365医学网 转载请注明
UCG〉HJ 02 365医学网 转载请注明
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o 2 4 6 8 10 12 365医学网 转载请注明
Time (Months) 365医学网 转载请注明
Figure 4. Cumulative Kaplan-Meier Estimates of MACE 365医学网 转载请注明
Note: Cumulative Kaplan-Meier estimates of MACE rates during the 12-month follow-up 365医学网 转载请注明
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DISCUSSION 365医学网 转载请注明
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The active metabolite (R-130964) of clopidogrel is a secondary metabolite ,and multiple CYPs , including CYP3A ,CYP2C19 ,CYP2C9 ,CYP2B6 ,and CYP1A2,contribute to the two sequential metabolic 365医学网 转载请注明
steps resulting in the formation of R-130964. Of these ,the CYP2C19 and 3A4 isoenzymes play 365医学网 转载请注明
major roles.(26-28) Besides genetic polymorphisms in several CYP enzymes ,another mechanism for 365医学网 转载请注明
clopidogrel resistance is competitive inhibition of CYP isoenzymes required for the metabolic 365医学网 转载请注明
activation of clopidogre l. Calcium-channel blockers 365医学网 转载请注明
are competitive inhibitors of the isoenzyme CYP3A4. 8mall observational studies of patients undergoing PCI have shown that this interaction 365医学网 转载请注明
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´899´ 365医学网 转载请注明
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has important effects on clopidogrel activity. (29) Proton pump inhibitors (PPls) are competitive 365医学网 转载请注明
inhibitors of CYP2C19 ,the other major isoenzyme 365医学网 转载请注明
involved in clopidogrel activation. PPls are often given concomitantly with clopidogrel to minimize the risk of gastrointestinal bleeding in patients with AC8 ,especially those undergoing PCls. Recently , 365医学网 转载请注明
attention has been placed on a potential interaction observed between clopidogrel and widely used PPls. 80me evidence suggests that omeprazole interacts with clopidogrel and reduces clopidogrel´s antiplatelet effects as measured by various laboratory tests.(30) Most data indicated that the interaction involves the competitive inhibition of the CYP2C19 isoenzyme. 365医学网 转载请注明
The interaction appears to be clinically significant , 365医学网 转载请注明
as several retrospective analyses have shown an increase in adverse cardiovascular outcomes when PPls and clopidogrel are used concomitantly.(31-34) 365医学网 转载请注明
365医学网 转载请注明
Conversely ,8t. John´s wort induces CYP2C19 activity ,and clinicians should pay great attention when 8t. John´s wort is added to or withdrawn from 365医学网 转载请注明
an existing drug regimen that includes substrates for such enzymes.(35) A study conducted in healthy 365医学网 转载请注明
volunteers showed that 8t. John´s wort amplified 365医学网 转载请注明
the effects of clopidogrel ,turning non-responders into responders. (36) Previous human investigations 365医学网 转载请注明
have shown that CYP2C19 activity is susceptible to induction by herbs and natural products,including 8t John´s wort ,Gingko biloba ,and the Chinese herbal 365医学网 转载请注明
mixture Yin Zhi Huang (also called Jaundiclear).(37 创) NXT is comprised of Buyang Huanwu Decoction (补 阳还五汤) plus 8corpio and Hirudo. Zhang ,et al(40) 365医学网 转载请注明
showed that the Buyang Huanwu decoction could ameliorate coronary heart disease in patients with qi deficiency and blood stasis syndrome by reducing levels or C-reactive protein and CD40 in rats. The present study demonstrated that adjunctive NXT enhanced the platelet inhibitory e仔ect of clopidogrel and decreased subsequent MACEs in patients undergoing PCI who carried the CYP2C19*2 polymorphism. This study showed that adjunctive 1.6 9 NXT thrice daily resulted in a 33% increase of Agg´ate and a 34% 365医学网 转载请注明
decrease in the risk of MACEs. 365医学网 转载请注明
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Table 4. MACEs during the 12-Month Follow-up Period (Case) 365医学网 转载请注明
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Risk 365医学网 转载请注明
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Dual group (45 cases) 365医学网 转载请注明
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Triple group (45 cases) 365医学网 转载请注明
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1 month 3 month 6 month 12 month Total 1 month 3 month 6 month 12 month Total P value 365医学网 转载请注明
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Sudden cardiac arrest 2 0 0 0 365医学网 转载请注明
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14 0 。 0 365医学网 转载请注明
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6 0.043 365医学网 转载请注明
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Readmission due to ACS 2 3 5 。 2 2 365医学网 转载请注明
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´900´ 365医学网 转载请注明
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Understanding drug interactions that impair therapeutic efficacy is important ,especially with multidrug treatment. Clopidogrel町based dual antiplatelet therapy is an important part of treatment after PCI. 365医学网 转载请注明
Drug treatment is influenced by many factors. Data from translational medicine and evidence-based medicine studies and the present work indicates that the CYP2C19 gene polymorphism is carried by more 365医学网 转载请注明
than 50% of the Chinese population,which is closely 365医学网 转载请注明
related to clopidogrel resistance. CM compounds have multiple components and multiple targets. Our data suggests that clopidogrel resistance in qi deficiency and blood stasis patients carrying this gene 365医学网 转载请注明
variant might be significantly improved by taking NXT. 365医学网 转载请注明
The mechanism of adjunctive NXT to clopidogrel on the prevention and treatment of coronary thrombosis 365医学网 转载请注明
might be related with multiple targets ,including 365医学网 转载请注明
increased CYP2C19 enzyme activity and inhibition of inflammatory cytokines.(41) Although our findings 365医学网 转载请注明
are provocative ,they should be confirmed in a large? 365医学网 转载请注明
scale,multicenter ,prospective clinical trial. Such work could lead to a new scheme of clopidogrel therapy for 365医学网 转载请注明
patients with CYP2C19 polymorphisms and provide new evidence for multiple target regulation based on 365医学网 转载请注明
an integrated medical model. 365医学网 转载请注明
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In conclusion ,adjunctive 1.6 9 NXT given thrice daily to MD 75 mg clopidogrel per day can enhance the antiplatelet effect and decrease the risk of subsequent MACEs in patients with the CYP2C19*2 365医学网 转载请注明
polymorphism undergoing PCI. 365医学网 转载请注明
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Con1lict 01 Interest 365医学网 转载请注明
This paper is our original review. The authors have no conflict of interest to . 365医学网 转载请注明
365医学网 转载请注明
Author Contribution 365医学网 转载请注明
AII authors contributed to designing the study protocol and drafting the manuscript. Chen H and Wang H conceived 365医学网 转载请注明
of the study. Wu XY and Wu HX were in charge of direct implementation and acquisitìon of data,as well as statistical analysis. 365医学网 转载请注明
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作者简介
陈慧
单位:福建省立医院
简介: 从医35年,福建省立医院.省心血管病研究所内科二级主任医师、高血压研究室主任、福建医科大学省立临
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