Coadministration Of Clopidogrel Research Articles

TCT-163: Accelerated Platelet Inhibition after Switching with Hydrophilic Statin in Patients with Increased Platelet Reactivity During Atorvastatin and Clopidogrel Coadministration (ACCEL-STATIN) study: a randomized, parallel-group trial

TCT-163: Accelerated Platelet Inhibition after Switching with Hydrophilic Statin in Patients with Increased Platelet Reactivity During Atorvastatin and Clopidogrel Coadministration (ACCEL-STATIN) study: a randomized, parallel-group trial

A Meta‐Analysis of Impact of Proton Pump Inhibitors on Antiplatelet Effect of Clopidogrel

Previous mechanistic studies have suggested a possible interaction between proton pump inhibitor (PPIs) and clopidogrel. However, the results of clinical trials about the effects of PPIs on safety and efficacy of clopidogrel are controversial. The study sought to estimate the impact of PPIs on antiplatelet effect of clopidogrel. The study performed a meta-analysis of comparative concomitant use of clopidogrel with PPIs versus clopidogrel without PPIs studies published or presented to October 2010. Cardiovascular death, readmission for myocardial infarction/readmission for acute coronary syndrome, and nonfatal stroke were set as clinical endpoints. In randomized control trials (RCTs), the clinical endpoints risk ratio for clopidogrel with PPIs versus clopidogrel without PPIs was 1.20 (P= 0.34) in the random-effects model and 1.03 (P= 0.63) in the fixed-effects model. In observational studies, the risk ratio for the clinical endpoints for clopidogrel with PPI versus clopidogrel without PPI was 1.40 (P < 0.001) in the random-effects model and 1.49 (P < 0.001) in the fixed-effects model. Different assay methods showed that coadministration of clopidogrel with PPIs was associated with attenuation of clopidogrel's antiplatelet effect in vitro. This meta-analysis indicated an obvious discrepancy between RCTs and observational studies with respect to the interaction between PPIs and clopidogrel.

In reply: Coadministration of clopidogrel and proton pump inhibitors (January 2011)

In reply: Coadministration of clopidogrel and proton pump inhibitors (January 2011)

Coadministration of clopidogrel and proton pump inhibitors (January 2011)

A reader comments on the interaction between clopidogrel (Plavix) and proton pump inhibitors (January 2011).

Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided.

Combination Antithrombotic Therapies

Atherothrombosis is the major pathophysiological process responsible for the occurrence of severe ischemic events in patients with cardiovascular diseases. In the United States, atherothrombosis strongly influenced mortality in 2004: One in 2.8 deaths was due to CVD, 1 in 5 deaths to coronary heart disease, and 1 in 17 deaths to stroke.1 Because cardiovascular disease is a progressive and systemic disease, long-term antithrombotic therapies that effectively target the entire arterial vasculature and modulate the key components responsible for thrombus generation are essential to improve patient outcomes. Because platelet activation is determined by multiple receptor-mediated signaling pathways, clinical studies have evaluated the efficacy of multidrug administration in the prevention of atherothrombotic complications.2,3 The major concern with these therapies is the critical balance between anti-ischemic effect and bleeding risk. This review summarizes our understanding of the role of combination antiplatelet therapies in the treatment and prevention of atherothrombosis. Platelet activation and aggregation play a pivotal role in the generation of occlusive thrombus at the site of coronary arterial plaque rupture. In addition, platelets influence various endothelial and inflammatory responses during the initiation and progression of atherosclerosis. Under normal conditions, anucleate circulating platelets are in a quiescent state. Healthy vascular endothelium prevents adhesion and activation of platelets by producing antithrombotic factors such as CD39 (ectoADPase), prostaglandin I2, nitric oxide, heparin, matrix metalloproteinase-9, protein S, and thrombomodulin.3,4 Endothelial activation and denudation and frank atherosclerotic plaque rupture expose the subendothelial matrix and release prothrombotic factors during acute coronary syndromes (ACS) and percutaneous interventions. These processes result in localized platelet adhesion and platelet activation. After adhesion to the exposed subendothelial matrix, platelets are activated by shear and the soluble agonists thromboxane A2 (TxA2), ADP, and thrombin. TxA2 is produced from arachidonic acid, which originates from membrane phospholipids and …

Assessment of clopidogrel non-response by the PFA-100® system using the new test cartridge INNOVANCE® PFA P2Y

Until now, the PFA-100 system has been considered unsuitable for monitoring clopidogrel efficacy. The authors evaluated platelet function in peripheral arterial occlusive disease (PAOD) patients using a new PFA-100(R) test cartridge (product name: INNOVANCE PFA P2Y*) specifically designed for this purpose. Twenty-two stable PAOD patients on antithrombotic therapy with clopidogrel alone (n = 22) and 18 patients undergoing a peripheral catheter intervention, preliminarily treated with 100 mg/day of aspirin followed by co-administration of clopidogrel (loading dose 300 mg, maintenance dose 75 mg/day), were enrolled in this study. Defining non-responsiveness to clopidogrel as an aggregation response within the reference range (90% central interval), four (18.2%) non-responders using light transmittance aggregometry (LTA) induced by 5 microM adenosine diphosphate (ADP) and six (27.3%) non-responders using LTA induced by 2 microM ADP (LateAggr >72.1% and >42.9%, respectively) were identified. INNOVANCE PFA P2Y* determined six (27.3%) non-responders (CT < 87 s). Agreement between the two aggregometry assays and INNOVANCE PFA P2Y* on the definition of clopidogrel response and non-response exceeded 70%. Only three patients were uniformly identified as clopidogrel non-responders by all three assays. When clopidogrel was co-administered with aspirin, two (11.1%) non-responders to clopidogrel were detected with INNOVANCE PFA P2Y*, whereas ADP-induced LTA found all patients to be responsive. INNOVANCE PFA P2Y* appears to be suitable for monitoring the effect of clopidogrel on platelet function. Its sensitivity in detecting responsiveness or non-responsiveness to clopidogrel is comparable to ADP-induced LTA. Additional prospective studies are needed to clarify the clinical relevance of the test results and classification obtained with INNOVANCE PFA P2Y*.

Absence of Pharmacodynamic or Pharmacokinetic Interactions When TAK-442, An Oral, Direct Factor Xa Inhibitor, Is Coadministered with Aspirin or Clopidogrel.

Abstract 4175 IntroductionTAK-442 is a novel orally active, direct Factor Xa (fXa) inhibitor in clinical development for the prevention of venous and arterial thrombotic disorders. Currently, aspirin and clopidogrel are widely used for platelet inhibition in patients with an increased risk of atherothrombotic events, and it is highly likely that TAK-442 may provide incremental anti-thrombotic benefit when used in conjunction with either of these agents. The primary aim of this study was to evaluate the effect of TAK-442 on inhibition of platelet aggregation by aspirin or clopidogrel. MethodsHealthy male and female (n=77), subjects were randomly assigned to 1 of 2 treatments groups and received either TAK-442 60 mg or placebo twice daily (BID) for 11 days, with the addition of aspirin 162 mg or clopidogrel 75 mg once daily (QD) from days 5 to 11. Pharmacokinetics were assessed for TAK-442 (days 4 and 11), aspirin/salicylic acid (day 11) and clopidogrel/carboxylic acid metabolite (day 11. Inhibition of fXa (Coatest®) was assessed on day 1 and two hours post dose on days 4 and 11. Platelet aggregation (arachidonic acid-induced for the aspirin group or ADP-induced for the clopidogrel group) was assessed on day -1 and 2 hours post dose on days 4 and 11; bleeding time was assessed on day -1 and 2 hours post dose on day 11. ResultsInhibition of arachidonic acid-induced platelet aggregation by aspirin was not affected by TAK-442 (71% for aspirin + TAK-442 and 74% for aspirin + placebo) nor was there any clinically significant effect of TAK-442 treatment on the inhibition of ADP-induced platelet aggregation by clopidogrel (56% for clopidogrel + TAK-442 and 67% for clopidogrel + placebo) at 2 hours post dose on day 11. Likewise, co-administration of TAK-442 did not have a clinically significant effect on the pharmacokinetic profiles of aspirin or clopidogrel. AUC0-24 and Cmax values were increased ≤16% for clopidogrel and ≤13% for the carboxylic acid metabolite. Although aspirin AUC0-24 and Cmax were increased 2- to 3-fold with coadministration (90% confidence intervals were: 76.2% to 741.8% and 90.1% to 825.1%, respectively), the proportional exposure was very low and the variability was high; the values for the active metabolite, salicylic acid, were increased less than 20% with coadministration. TAK-442-mediated inhibition of fXa activity and prolongation of PT, and the PK profile of TAK-442, were unaffected by co-administration with aspirin or clopidogrel. Coadministration of TAK-442 resulted in modest increases in mean bleeding time compared to aspirin with placebo (aspirin + TAK-442: 558 sec vs. aspirin + placebo: 392 sec) and to clopidogrel with placebo (clopidogrel + TAK-442: 893 sec vs. clopidogrel + placebo: 829 sec). TAK-442 was well tolerated, with a low and similar frequency of mild bleeding events with or without aspirin or clopidogrel coadministration. ConclusionThis study demonstrated that no clinically meaningful pharmacodynamic or pharmacokinetic interactions were observed when TAK-442 was co-administered with aspirin or clopidogrel. Disclosures:Stringer:Takeda Global Research & Development, Inc.: Employment. Scott:Takeda Global Research & Development, Inc.: Employment. Kupfer:Takeda Global Research & Development, Inc.: Employment. Cao:Takeda Global Research & Development, Inc.: Employment. Kawamura:Takeda Global Research & Development, Inc.: Employment.

Lack of Evidence of a Clopidogrel–Statin Interaction in the CHARISMA Trial

The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up. There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy. The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non-CYP3A4-MET). Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non-CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non-CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates. Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.

Comparison of the effects of medium and long chain triglyceride containing liquid meals on gall bladder and small intestinal function in normal man.

We investigated the effects of medium (MCT) and long (LCT) chain triglyceride test meals on gall bladder contraction (using ultrasonography) and small intestinal bile acid concentrations and ileal flow rates (using intubation techniques) in normal individuals. Comparing the effects of ingesting medium chain triglyceride and long chain triglyceride meals, the gall bladder volume was reduced by 23.4 +/- 33.6% and 59.0 +/- 17.1% respectively (mean +/- SD, p less than 0.01, n = 13), the jejunal bile acid concentrations increased significantly only after the ingestion of long chain triglyceride (p less than 0.05, n = 5), while the volume of the postprandial jejunal contents was not significantly different (540 +/- 150, 522 +/- 169 ml, medium chain triglyceride vs long chain triglyceride, p = 0.2, n = 5). The postprandial colonic inflow was 48.5 +/- 12.5 and 123.4 +/- 35.2 ml/h (medium chain triglyceride vs long chain triglyceride, p less than 0.01, n = 5). Thus medium chain triglyceride, compared with long chain triglyceride, produces a smaller input of bile acids into the small intestine and a smaller volume of fluid delivered to the colon. These observations may be relevant to the beneficial effects of medium chain triglyceride substitution for long chain triglyceride in the treatment of diarrhoea in patients with small intestinal disease.