The present study was designed to determine the effects of puerarin pre-treatment on the pharmacokinetics of the oral anticoagulant agent warfarin and the antiplatelet agent clopidogrel in rats. In the treatment group, rats was gavaged with warfarin or clopidogrel after repeated treatment with puerarin at intraperitoneal doses of 20, 60, or 200 mg·kg(-1) for 7 days, while rats in the control group were administrated only with the same dose warfarin or clopidogrel. Plasma samples were obtained at the prescribed times and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that rats treated with puerarin at all the test doses of 20, 60 and 200 mg·kg(-1) were found to affect the pharmacokinetics of warfarin, but not clopidogrel, suggesting a potential herb-drug interaction between puerarin and warfarin.
Animals ; Anticoagulants ; pharmacokinetics ; Chromatography, Liquid ; Clopidogrel ; Drug Administration Schedule ; Herb-Drug Interactions ; Injections, Intraperitoneal ; Isoflavones ; administration & dosage ; pharmacology ; Male ; Platelet Aggregation Inhibitors ; pharmacokinetics ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; Ticlopidine ; analogs & derivatives ; pharmacokinetics ; Vasodilator Agents ; administration & dosage ; pharmacology ; Warfarin ; pharmacokinetics

BACKGROUND/AIMS: Combination single-pill therapy can improve cost-effectiveness in a typical medical therapy. However, there is a little evidence about the efficacy and tolerability of combination single-pill antiplatelet therapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). METHODS: From June to November 2012, in total, 142 patients who met the following criteria were enrolled: at least 18 years old; successful PCI with DES at least 3 months earlier; and regular medication of aspirin and clopidogrel with no side effects. After VerifyNow P2Y12 and aspirin assays, the combination single pill of aspirin and clopidogrel was given and laboratory tests were repeated 6 weeks later. RESULTS: At baseline, the incidence of aspirin resistance, defined as aspirin reaction unit (ARU) > or = 550, was 9.2%, that of clopidogrel resistance, defined as P2Y12 reaction unit (PRU) > or = 230, was 46.5%, and that of percent inhibition of PRU < 20% was 32.4%. At follow-up, the incidence of resistance by ARU value was 7.0%, 50.0% by PRU value, and 35.9% by percentage inhibition of PRU, respectively. The mean values of ARU (431.5 +/- 63.6 vs. 439.8 +/- 55.2; p = 0.216) and PRU (227.5 +/- 71.4 vs. 223.3 +/- 76.0; p = 0.350) were not significantly different before versus after antiplatelet-combination single-pill therapy. Five adverse events (3.5%) were observed during the study period. CONCLUSIONS: Combination single-pill antiplatelet therapy, which may reduce daily pill burden for patients after PCI with DES, demonstrated similar efficacy to separate dual-pill antiplatelet therapy.
Aged ; Antiplatyhelmintic Agents/*administration & dosage/adverse effects ; Aspirin/*administration & dosage/adverse effects ; Drug Combinations ; Drug Resistance ; *Drug-Eluting Stents ; Female ; Humans ; Intention to Treat Analysis ; Male ; Middle Aged ; Myocardial Ischemia/blood/diagnosis/*therapy ; Percutaneous Coronary Intervention/adverse effects/*instrumentation ; Platelet Function Tests ; Prospective Studies ; Tablets ; Ticlopidine/administration & dosage/adverse effects/*analogs & derivatives ; Time Factors ; Treatment Outcome

PURPOSE: Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown. MATERIALS AND METHODS: We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35). RESULTS: Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0+/-10.2% versus 11.8+/-9.7%, p=0.61, and 286.3+/-54.7 versus 295.7+/-53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5+/-17.9% versus 28.3+/-16.6%, p=0.02, and 207.3+/-68.2 versus 241.3+/-76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7+/-8.7% to 15.8+/-18.4%, p=0.08, and from -18.6+/-58.0 to -61.9+/-84.3, p=0.08). CONCLUSION: Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.
Adult ; Aged ; Blood Platelets/drug effects ; Cross-Over Studies ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Platelet Aggregation Inhibitors/*administration & dosage ; Prospective Studies ; Receptors, Purinergic P2Y12/metabolism ; Tetrazoles/*administration & dosage ; Thrombosis/drug therapy ; Ticlopidine/administration & dosage/*analogs & derivatives ; Time Factors ; Treatment Outcome

PURPOSE: The aim of this study was to find an optimal range of activated clotting time (ACT) during off-pump coronary artery bypass surgery (OPCAB) yielding ischemic protection without the risk of hemorrhagic complications in patients with recent exposure to dual antiplatelet therapy. MATERIALS AND METHODS: Three hundred and five patients who received aspirin and clopidogrel within 7 days of isolated multi-vessel OPCAB were retrospectively studied. Combined hemorrhagic and ischemic outcome was defined as the occurrence of 1 of the following: significant perioperative bleeding (>30% of estimated blood volume), transfusion of packed red blood cell (pRBC) > or =2 U, or myocardial infarction (MI). This was compared in relation to the tertile distribution of the time-weighted average ACT-212-291 sec (first tertile), 292-334 sec (second tertile), 335-485 sec (third tertile). RESULTS: The amount of perioperative blood loss was 937+/-313 mL, 1014+/-340 mL, and 1076+/-383 mL, respectively (p=0.022). Significantly more patients in the third tertile developed MI (4%, 4%, and 12%, respectively, p=0.034). The incidence of significant perioperative blood loss and transfusion of pRBC > or =2 U were lower in the first tertile than those of other tertiles without statistical significance. In the multivariate analysis, the first tertile was associated with a 52% risk reduction of combined hemorrhagic and ischemic outcomes (95% confidence interval: 0.25-0.92, p=0.027). CONCLUSION: A lower degree of anticoagulation with a reduced initial heparin loading dose should be carefully considered for patients undergoing OPCAB who have recently been exposed to clopidogrel.
Age Factors ; Aged ; Anastomosis, Surgical ; Blood Loss, Surgical/prevention & control ; Blood Transfusion ; *Coronary Artery Bypass, Off-Pump ; Female ; Heparin/administration & dosage/therapeutic use ; Humans ; Intraoperative Complications ; Male ; Middle Aged ; Multivariate Analysis ; Myocardial Infarction/etiology/prevention & control ; Perioperative Period ; Platelet Aggregation Inhibitors/administration & dosage/*therapeutic use ; Premedication ; Reference Values ; Retrospective Studies ; Sex Factors ; Ticlopidine/administration & dosage/*analogs & derivatives/therapeutic use ; Whole Blood Coagulation Time

BACKGROUNDThe combination of cilostazol, aspirin and clopidogrel (triple antiplatelet therapy, TAT) after a percutaneous coronary intervention has been used as an alternative therapy. We performed a meta-analysis to evaluate the efficacy and safety of TAT for patients after percutaneous coronary intervention (PCI).

METHODSWe systematically searched Pubmed, Embase and Web of Science databases to identify all randomized controlled trials (RCTs) that compared dual antiplatelet therapy (DAT) with and without cilostazol after PCI. All analyses were conducted using Review Manager 5.0.

RESULTSThe final analysis consisted of 4474 patients from ten studies. The combined results suggested that there was a lower risk of cardiac death (relative risk (RR) = 0.55, 95% confidence interval (CI): 0.31 - 0.98, P < 0.05) and major adverse cardiac events (MACEs) (RR = 0.63, 95% CI: 0.54 - 0.74, P < 0.05) in patients treated with TAT as compared to those with DAT follow-ups after six months to one year; no significant difference was observed in bleeding and non-fatal myocardial infarction (MI) (RR = 1.14, 95% CI: 0.80 - 1.64, P > 0.05; RR = 0.87, 95% CI: 0.42 - 1.83, P > 0.05). However, the rate of adverse drug reaction was higher in patients receiving TAT than in patients receiving DAT (RR = 2.21, 95% CI: 1.84 - 2.66, P < 0.05). Moreover, there was a lower risk of stent thrombosis in patients treated with TAT as compared to those treated with DAT (RR = 0.44, 95% CI: 0.21 - 0.94, P < 0.05). The TAT group had a reduced risk of target lesion revascularization (TLR) (RR = 0.60, 95% CI: 0.43 - 0.82, P = 0.001) and target vessel revascularization (TVR) than the DAT group (RR = 0.56, 95% CI: 0.45 - 0.71, P < 0.05). The number of MACEs was lower for patients in the TAT group than in the DAT group with diabetes mellitus sub-analysis (RR = 0.41, 95% CI: 0.28 - 0.61, P < 0.05). But no significant difference was observed between the two groups regarding MACEs in patients with drug-eluting stent implantations (RR = 0.82, 95% CI: 0.65 - 1.03, P > 0.05).

CONCLUSIONTAT could significantly reduce the rates of MACEs and cardiac death in comparison to DAT, but more attention should be paid to adverse side effects of the drugs.

Aspirin ; administration & dosage ; Drug Therapy, Combination ; Humans ; Percutaneous Coronary Intervention ; Platelet Aggregation Inhibitors ; administration & dosage ; adverse effects ; Publication Bias ; Stents ; adverse effects ; Tetrazoles ; administration & dosage ; Ticlopidine ; administration & dosage ; analogs & derivatives

INTRODUCTIONTicagrelor is a novel antiplatelet drug developed to reduce atherothrombosis. The PLATO trial compared ticagrelor and aspirin to clopidogrel and aspirin in patients with acute coronary syndromes (ACS). Ticagrelor was found to be superior in the primary composite endpoint of cardiovascular death, myocardial infarction or stroke, without increasing major bleeding events. The current study estimates the lifetime cost-effectiveness of ticagrelor relative to generic clopidogrel from a Singapore public healthcare perspective.

METHODSThis study used a two-part cost-effectiveness model. The first part was a 12-month decision tree (using PLATO trial data) to estimate the rates of major cardiovascular events, healthcare costs and health-related quality of life. The second part was a Markov model estimating lifetime quality-adjusted survival and costs conditional on events during the initial 12 months. Daily drug costs applied were SGD 1.05 (generic clopidogrel) and SGD 6.00 (ticagrelor). Cost per quality-adjusted life years (QALY) was estimated from a Singapore public healthcare perspective using life tables and short-term costs from Singapore, and long-term costs from South Korea. Deterministic and probabilistic sensitivity analyses were performed.

RESULTSTicagrelor was associated with a lifetime QALY gain of 0.13, primarily driven by lower mortality. The resulting incremental cost per QALY gained was SGD 10,136.00. Probabilistic sensitivity analysis indicated that ticagrelor had a > 99% probability of being cost-effective, given the lower recommended WHO willingness-to-pay threshold of one GDP/capita per QALY.

CONCLUSIONBased on PLATO trial data, one-year treatment with ticagrelor versus generic clopidogrel in patients with ACS, relative to WHO reference standards, is cost-effective from a Singapore public healthcare perspective.

Acute Coronary Syndrome ; drug therapy ; economics ; Adenosine ; analogs & derivatives ; economics ; therapeutic use ; Aspirin ; administration & dosage ; Clinical Trials as Topic ; Cost-Benefit Analysis ; Decision Trees ; Drug Costs ; Humans ; Markov Chains ; Platelet Aggregation Inhibitors ; administration & dosage ; economics ; Purinergic P2Y Receptor Antagonists ; administration & dosage ; economics ; Quality-Adjusted Life Years ; Republic of Korea ; Singapore ; Ticlopidine ; administration & dosage ; analogs & derivatives

The combined use of batifiban, a synthetic platelet GPII b/ IIIa receptor antagonist, and antithrombin agents is an attractive option for the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention. To observe whether antithrombin agents affect the pharmacokinetic and pharmacodynamic properties of batifiban in combination therapy and optimize clinical administration dosage of batifiban, an open-label and parallel study was conducted. Thirty healthy subjects were randomly divided into three groups, which were sequentially treated with batifiban alone, or oral coadministration of clopidogrel, aspirin and UFH, or batifiban coadministered with these antithrombin agents. Blood samples were collected at pre-specified time points. The evaluation index included the inhibition of platelet aggregation and pharmacokinetic parameters. The pharmacokinetic parameters of batifiban and batifiban coadministered with antithrombin agents showed no significant differences. The mean inhibition rate of platelet aggregation (%) suggested that neither batifiban alone nor antithrombin agents alone could provide such potent inhibition rate (>80%) to obtain the best clinical efficacy, but they had a synergistic effect on platelet inhibition. No serious adverse effects were observed. The results in these healthy subjects suggest that batifiban coadministrated with antithrombin agents could achieve optimum clinical treatment effect for patients with NSTE ACS, and also those scheduled for percutaneous coronary intervention.
Administration, Oral ; Adolescent ; Adult ; Area Under Curve ; Aspirin ; administration & dosage ; pharmacology ; China ; Drug Administration Schedule ; Female ; Fibrinolytic Agents ; administration & dosage ; pharmacology ; Heparin ; administration & dosage ; pharmacology ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Male ; Metabolic Clearance Rate ; drug effects ; Peptides, Cyclic ; administration & dosage ; pharmacokinetics ; Platelet Aggregation Inhibitors ; administration & dosage ; pharmacokinetics ; Ticlopidine ; administration & dosage ; analogs & derivatives ; pharmacology ; Time Factors ; Young Adult

OBJECTIVEBased on real world research the circumstances of the clinical use of usual drugs combined with salvianolate injection are surveyed.

METHODDescriptive statistics on the use of salvianolate injection in 18 general hospitals in China.

RESULTIn 1 605 patients with coronary heart disease (CHD), salvianolate injection was most frequently (51%) combined with clopidogrel and isosorbide dinitrate. In addition this combination showed a higher clinical effectiveness as compared with other drug combinations.

CONCLUSIONIn the real world, salvianolate injection combined with usual treatment was found to be more effective than other treatment combinations. In addition practice conformed to the clinical treatment of coronary heart disease (CHD) guidelines for drug use. However, liver and kidney function, routine blood tests and the blood's coagulation function require ongoing monitoring.

Aged ; Aged, 80 and over ; Coronary Disease ; drug therapy ; mortality ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Hospital Information Systems ; statistics & numerical data ; Humans ; Isosorbide Dinitrate ; therapeutic use ; Male ; Middle Aged ; Plant Extracts ; administration & dosage ; Pragmatic Clinical Trials as Topic ; Propensity Score ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Treatment Outcome

In order to understand the treatment of coronary heart disease with parenterally administered Shenmai and the efficacy of combination therapies, the study selected 18 hospitals for analysis. Data from each hospital's hospital injection system (HIS) was collected. Data of in-patients receiving parenterally administered Shenmai for a diagnosis of coronary heart disease was analyzed using; the Apriori algorithm to model use, Clementine 12.0 linkage analysis to find correlations between various drugs, and chi-square test for commonly used combination therapies to ascertain the cure rate. In 5 583 patients with coronary heart disease, it was found that Shenmai was commonly used with isosorbide mononitrate, aspirin, clopidogrel hydrogen and common combinations of combination therapy, and that the cure rate was better in these combinations than for other treatment regimes. When Shenmai is used with combination therapies for coronary heart disease, treatment guidelines should be complied with. In clinical application, the types of concomitant medications and their interactions, should be observed so as to prevent of adverse reactions.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aspirin ; therapeutic use ; Coronary Disease ; drug therapy ; Drug Combinations ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Hospital Information Systems ; statistics & numerical data ; Humans ; Infusions, Parenteral ; Logistic Models ; Male ; Middle Aged ; Outcome Assessment (Health Care) ; Pragmatic Clinical Trials as Topic ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Treatment Outcome ; Young Adult

INTRODUCTIONEverolimus eluting stents (EES) have demonstrated excellent re-stenosis and thrombosis rates in a number of randomised controlled trials. This study reported the real world experience in a single tertiary centre with EES in predominantly acute coronary syndrome (ACS) patients and compared the outcomes in small and large vessels. We measured the medium to long-term major adverse cardiovascular events (MACE) defined as all-cause mortality, myocardial infarction (MI) and target vessel revascularisation (TVR) and stent thrombosis.

MATERIALS AND METHODSAll consecutive patients underwent percutaneous coronary intervention (PCI) with EES (PROMUSTM, Boston Scientific, Natick USA; XIENCE VTM, Abbott Vascular, Santa Clara USA) between March 2007 and September 2009 recorded in our coronary intervention registry were included in this study. All patients were advised to stay on dual antiplatelet therapy with Aspirin 100 mg/day and Clopidogrel 75 mg/day. All patients had at least 6 months of clopidogrel, government funded and a further 6 months required self funding.

RESULTSFour hundred and six consecutive patients received EES during the study period; 403 were included in this study and 3 were lost to follow-up. Indications for PCI were stable angina in 11% of the patients, unstable angina in 38%, non-ST elevation myocardial infarction in 43%, and ST-elevation myocardial infarction in 8%. Procedural success was achieved in 99.5% of the cases. During a median follow-up of 23 months, 3% of the patients had an MI, 3% underwent TVR, 5% all-cause mortality and 2 (0.5%) cases of definite or probable stent thrombosis. The Kaplan Meier 2-year survival and MACE free survival were 95% and 89% respectively. A subgroup analysis comparing MACE in patients who were treated with a single small (≤ 2.75 mm; n = 91) or large (≥ 3 mm; n = 118). EES did not show significant difference during the 2-year follow-up (12% vs 9%; P = 0.34).

CONCLUSIONEverolimus eluting stent appears to be safe in a real world setting with satisfactory median-term outcomes which include low rates of TVR and other adverse events. EES appear to be equally effective in both small and large vessels.

Adult ; Aged ; Aged, 80 and over ; Angioplasty, Balloon, Coronary ; methods ; Aspirin ; therapeutic use ; Coronary Artery Disease ; drug therapy ; mortality ; therapy ; Drug-Eluting Stents ; Everolimus ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; New Zealand ; Platelet Aggregation Inhibitors ; therapeutic use ; Registries ; Retrospective Studies ; Sirolimus ; administration & dosage ; analogs & derivatives ; therapeutic use ; Survival Analysis ; Ticlopidine ; analogs & derivatives ; therapeutic use ; Time Factors ; Treatment Outcome