Thienopyridine Antiplatelet Agent Research Articles

Comparison of the Degree of Gastric Mucosal Injury between Patients Who Are Receiving Dual Antiplatelet Therapy or Single Antiplatelet Therapy.

Background: Patients taking low-dose aspirin have a higher incidence of gastroduodenal ulcers and higher risk of upper gastrointestinal bleeding than patients who do not. Thienopyridine antiplatelet agents may similarly cause bleeding gastroduodenal erosions and ulcers. The incidence of gastrointestinal bleeding is reported to be higher when these antithrombotic drugs are used in combination. Until now, most studies have focused on bleeding, and no study has compared the degree of gastric mucosal injury between patients receiving dual antiplatelet therapy (DAPT) and those receiving single antiplatelet therapy (SAPT) in real-world clinical practice. Aim: Our objective was to compare the degree of gastric mucosal injury in patients taking low-dose aspirin in combination with clopidogrel (one of the thienopyridine antiplatelet agents) with that of patients who were taking aspirin or clopidogrel as a single agent. Methods: Patients who were taking aspirin and/or clopidogrel and who underwent scheduled esophagogastroduodenoscopy between April 2015 and March 2020 were enrolled in this study. Endoscopic images were reviewed retrospectively, and the degree of gastric mucosal injury was assessed with the modified Lanza score (m-Lanza score). The m-Lanza score was compared between DAPT patients taking aspirin and clopidogrel and SAPT patients taking either aspirin alone or clopidogrel alone. Results: The m-Lanza scores of the DAPT group, the aspirin group, and the clopidogrel group were 1.67 ± 1.81 (mean ± standard deviation), 0.95 ± 1.61, and 0.72 ± 1.29, respectively. The m-Lanza score of the DAPT group tended to be higher than that of the aspirin group (p = 0.06) and was significantly higher than that of the clopidogrel group (p = 0.03). Conclusion: The degree of gastric mucosal injury in DAPT patients was significantly higher than that in patients using clopidogrel alone and tended to be higher than that in patients using aspirin alone in real-world clinical practice.

Comparative Effectiveness of Machine Learning Approaches for Predicting Gastrointestinal Bleeds in Patients Receiving Antithrombotic Treatment

Anticipating the risk of gastrointestinal bleeding (GIB) when initiating antithrombotic treatment (oral antiplatelets or anticoagulants) is limited by existing risk prediction models. Machine learning algorithms may result in superior predictive models to aid in clinical decision-making. To compare the performance of 3 machine learning approaches with the commonly used HAS-BLED (hypertension, abnormal kidney and liver function, stroke, bleeding, labile international normalized ratio, older age, and drug or alcohol use) risk score in predicting antithrombotic-related GIB. This retrospective cross-sectional study used data from the OptumLabs Data Warehouse, which contains medical and pharmacy claims on privately insured patients and Medicare Advantage enrollees in the US. The study cohort included patients 18 years or older with a history of atrial fibrillation, ischemic heart disease, or venous thromboembolism who were prescribed oral anticoagulant and/or thienopyridine antiplatelet agents between January 1, 2016, and December 31, 2019. A cohort of patients prescribed oral anticoagulant and thienopyridine antiplatelet agents was divided into development and validation cohorts based on date of index prescription. The development cohort was used to train 3 machine learning models to predict GIB at 6 and 12 months: regularized Cox proportional hazards regression (RegCox), random survival forests (RSF), and extreme gradient boosting (XGBoost). The performance of the models for predicting GIB in the validation cohort, evaluated using the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, and prediction density plots. Relative importance scores were used to identify the variables that were most influential in the top-performing machine learning model. In the entire study cohort of 306 463 patients, 166 177 (54.2%) were male, 193 648 (63.2%) were White, the mean (SD) age was 69.0 (12.6) years, and 12 322 (4.0%) had experienced a GIB. In the validation data set, the HAS-BLED model had an AUC of 0.60 for predicting GIB at 6 months and 0.59 at 12 months. The RegCox model performed the best in the validation set, with an AUC of 0.67 at 6 months and 0.66 at 12 months. XGBoost was similar, with AUCs of 0.67 at 6 months and 0.66 at 12 months, whereas for RSF, AUCs were 0.62 at 6 months and 0.60 at 12 months. The variables with the highest importance scores in the RegCox model were prior GI bleed (importance score, 0.72); atrial fibrillation, ischemic heart disease, and venous thromboembolism combined (importance score, 0.38); and use of gastroprotective agents (importance score, 0.32). In this cross-sectional study, the machine learning models examined showed similar performance in identifying patients at high risk for GIB after being prescribed antithrombotic agents. Two models (RegCox and XGBoost) performed modestly better than the HAS-BLED score. A prospective evaluation of the RegCox model compared with HAS-BLED may provide a better understanding of the clinical impact of improved performance.

Risk of hypoglycemia associated with repaglinide combined with clopidogrel, a retrospective cohort study

BackgroundRepaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-β-D-glucuronide inhibits CYP2C8 activity. In this study, we retrospectively investigated the effect of clopidogrel with repaglinide on plasma glucose and the risk of hypoglycemia associated with the combination of both drugs.MethodPatients were taking clopidogrel (75 mg/day) and started taking glinide (1.5 mg/day repaglinide or 30 mg/day mitiglinide) for the first time from April 2012 to March 2017. We targeted subjects who were hospitalized at the start of glinide and whose preprandial plasma glucose was measured by a nurse. The glucose levels were collected for up to 5 days before and after the glinide start date.ResultsAverage fasting plasma glucose levels (before breakfast) in the repaglinide and clopidogrel group before and after starting repaglinide were 180.1±35.5 and 136.5 ± 44.1 mg/dL, with a mean decrease of 43.6 ± 33.6 mg/dL. In contrast, there was only a moderate decrease of 11.6 ± 30.0 mg/dL in the mitiglinide and clopidogrel group. Minimum plasma glucose levels in the repaglinide and clopidogrel group before and after starting repaglinide were 145.2 ± 42.9 and 93.3 ± 36.3 mg/dL, respectively. Decrease in minimum levels after starting glinide in the repaglinide and clopidogrel group (51.9 ± 47.5 mg/dL) was more significant than those in the mitiglinide and clopidogrel group (only 2.1 ± 29.1 mg/dL), and the repaglinide group (without clopidogrel, 15.5 ± 20.0 mg/dL). Hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, but only 1 of 15 patients in the mitiglinide and clopidogrel group, and no patients in the repaglinide group.ConclusionThese findings indicate that minimum plasma glucose levels were significantly decreased in patients taking repaglinide and clopidogrel. Considering the risk of hypoglycemia associated with taking repaglinide and clopidogrel, when a glinide is required in patients taking clopidogrel, mitiglinide may be a better choice.

Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing

Background and objectivesVicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel. MethodsStudy A was a single-ascending-dose study of vicagrel (5–75 mg) compared with clopidogrel (75 mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20 mg compared with clopidogrel 300 mg in 12 healthy subjects. Plasma concentrations of three common metabolites of vicagrel and clopidogrel, the active thiol metabolite H4, the inactive thiol metabolite H3, and the S-methylated form of H3 (SM3, the major metabolite of vicagrel), were determined using a validated UHPLC–MS/MS method. The relationship between the AUC0−t of active H4 and the P2Y12 reaction units at 4 h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25 mg to two healthy Chinese subjects. ResultsIn the single-ascending-dose study, vicagrel was metabolized rapidly with the median tmax for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25–1.75 h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5–75 mg, with the mean Cmax and AUCs for H4 and H3 increasing in an approximately 1:1 dose-proportional manner and for SM3 increasing in a <1:1 dose-proportional manner. The median tmax for active H4 in the vicagrel 5 mg group was slightly shorter than that in the clopidogrel 75 mg group (0.50 versus 0.75 h). The mean AUC0−t for H4 in the vicagrel 5 mg group was similar to that in the clopidogrel 75 mg group (11.7 versus 11.8 ng∙h/mL). The AUC0−t of active H4 was apparently associated with the P2Y12 reaction units at 4 h for vicagrel. In the loading-dose study, for active H4, the median tmax was slightly shorter (0.50 versus 0.75 h) and the mean AUC0−t was 29% higher in the vicagrel 20 mg group than those in the clopidogrel 300 mg group. After a single oral administration of vicagrel 25 mg to 2 subjects, vicagrel was detected in blood but in very low concentrations. ConclusionsVicagrel was rapidly and extensively metabolized, and the levels of the parent drug in circulation were very low. The pharmacokinetics of the three metabolites of vicagrel were linear and predictable across the dose range of 5–75 mg. The AUC of active H4 was apparently associated with the P2Y12 reaction units for vicagrel. For active H4, vicagrel 5 mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75 mg, and vicagrel 20 mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300 mg in humans.Trial Registration: CTR20150346, CTR20160379.

Study on antiplatelet effect of a new thiophenopyridine platelets P2Y12 receptor antagonist DV-127

P2Y12 receptor antagonists are a class of drugs that act on platelet P2Y12 receptors and inhibit adenosine diphosphate-induced platelet aggregation. As a thienopyridine antiplatelet agent which is approved by the US Food and Drug Administration for the treatment of cardiovascular diseases, currently, clopidogrel was once considered to be the most safe and effective antiplatelet drug in the P2Y12 receptor antagonists, however, it has become increasingly clear that clopidogrel does not satisfactorily inhibit the platelets of approximately one-third of patients. This is in part due to clopidogrel is a prodrug and reliance on multiple cytochrome P450 enzymes for conversion into its active metabolite. Prasugrel and ticagrelor reduces the risk of adverse cardiovascular events compared to clopidogrel in acute coronary syndromes patients, however, the cardiovascular benefit of both drugs is counter-balanced by increased rates of spontaneous bleeding. Unlike clopidogrel, which is a prodrug, cangrelor is an active drug not requiring metabolic conversion, despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness.DV-127 was synthesized by using three generations of thienopyridine P2Y12 receptor antagonists as research models, using high resolution mass spectrometry, selective deuteration, and 2,7-position replacement groups technologies in order to maximize cardiovascular benefit while minimizing adverse effects on hemostasis. Our results show that although the dose of DV-127 is greatly reduced, it can achieve similar anticoagulant and antiplatelet effects as clopidogrel, and DV-127 can more strongly inhibit the release of α-granules even though the inhibitory effect of dense granules is similar to clopidogrel.

Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans.

Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel.

Ticagrelor Cessation Rates and Risk Factors Post Acute Coronary Syndrome

Aim: Ticagrelor is the first line thienopyridine antiplatelet agent for the acute coronary syndrome (ACS). Side effects of ticagrelor include bleeding and dyspnoea with cessation rates of approximately 7.4% in randomised controlled trials. This retrospective study aimed to identify the rate of ticagrelor cessation and risk factors that predicted cessation in Tasmania. Methods: Patients prescribed ticagrelor for ACS between January 1 and August 31, 2016 were included in the analysis. Patients undergoing surgical revascularisation were excluded. Follow-up period was a minimum of five months. Baseline demographics, risk factors and angiographic characteristics were identified and cessation factors assessed. Results: Of the 116 patients prescribed ticagrelor during the study period, 27 (23%) ceased the medication. Average time to cessation was 58.5 days (range 3-257 days, SD: 49.4 days). Females were more likely to cease ticagrelor compared to males (36.7% vs. 18.6%, p = 0.044), as were smokers compared to non-smokers (37.2% vs. 15.1%, p = 0.006) and patients with chronic obstructive airways disease (64.3% vs. 17.6%, p < 0.001). Patients on an anticoagulant were more likely to cease (66.7% vs. 13.7%, p < 0.001), in the absence of significant bleeding. Patients with stage IV-V chronic renal disease more frequently ceased compared to those without (54.5% vs. 20.0%, p = 0.010). Conclusion: Ticagrelor cessation in Tasmania is higher than the quoted average. In the presence of confounders, risk factors for ticagrelor cessation in a Tasmanian population include females, active smokers, patients with COPD and those with chronic renal failure. Anticoagulated patients have high rates of cessation in the absence of significant bleeding events.

Dual antiplatelet therapy is associated with prolonged survival after lower extremity revascularization

BackgroundDual antiplatelet therapy (DAPT) after coronary stenting prolongs survival by preventing both in-stent thrombosis and other cardiovascular atherothrombotic events. Patients with peripheral artery disease (PAD) typically have a heavy burden of unrevascularized coronary artery disease and also stand to benefit from increased atherothrombotic protection with DAPT. The potential benefit of DAPT compared with aspirin alone in patients with PAD is not well described. MethodsWe identified all patients undergoing an initial elective lower extremity revascularization (bypass or endovascular) from 2003 to 2016 in the Vascular Quality Initiative registry discharged on aspirin or aspirin plus a thienopyridine antiplatelet agent (DAPT). We first estimated models predicting the likelihood of receiving DAPT and then used inverse probability weighting to account for baseline differences in the likelihood of receiving DAPT and compared late survival. For sensitivity analysis, we also performed Cox proportion hazard modeling on the unweighted cohorts and generated adjusted survival curves. ResultsWe identified 57,041 patients undergoing lower extremity revascularization (28% bypass). Of 15,985 bypasses (69% for critical limb ischemia [CLI]), 38% were discharged on DAPT. Of 41,056 endovascular interventions (39% for CLI), 69% were discharged on DAPT. Analyses using inverse probability weighting demonstrated a small survival benefit to DAPT at 1 year for bypass (93% vs 92% [P = .001]) and endovascular interventions (93% vs 92% [P = .005]) that was sustained through 5 years of follow-up (bypass, 80% vs 78% [P = .004]; endovascular, 76% vs 73% [P = .002]). When stratified by severity of PAD, DAPT had a survival benefit for patients with CLI undergoing bypass (5 years, 70% vs 66% [P = .04]) and endovascular intervention (5 years, 71% vs 67% [P = .01]) but not for patients with claudication (bypass, 89% vs 88% [P = .36]; endovascular, 87% vs 85% [P = .46]). The protective effect of DAPT was similar when using Cox proportional hazard models after bypass (hazard ratio, 0.81 [95% confidence interval, 0.72-0.90]) and endovascular intervention (hazard ratio, 0.89 [95% confidence interval, 0.83-0.95]). ConclusionsDAPT at time of discharge was associated with prolonged survival for patients with CLI undergoing lower extremity revascularization but not for those with claudication. Further research is needed to quantify the risks associated with DAPT and to identify subgroups at increased risk of thrombotic and bleeding complications to guide medical management of patients with PAD.

Reduction of in-stent thrombus immediately after percutaneous coronary intervention by pretreatment with prasugrel compared with clopidogrel: An optical coherence tomography study

BackgroundPrasugrel is a new-generation thienopyridine antiplatelet agent that provides more consistent and prompt platelet inhibition than clopidogrel. The aim of this study was to compare in-stent thrombus inhibition effect of pretreatment with prasugrel and clopidogrel by using optical coherence tomography (OCT) immediately after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). MethodsWe performed OCT immediately after PCI in 108 ACS patients pretreated with either prasugrel (n=51) or clopidogrel (n=57). OCT detected thrombus/plaque protrusion in all stented segments. ResultsAlthough stent volume (190.4±119.1mm3 vs. 189.4±95.8mm3, p=0.961), mean stent area (6.9±2.9mm2 vs. 7.1±2.0mm2, p=0.772), and minimum stent area (5.6±2.7mm2 vs. 5.4±1.7mm2, p=0.554) were not different between the two groups, in-stent thrombus/plaque protrusion volume (1.8±2.9mm3 vs. 4.5±5.3mm3, p=0.002), mean in-stent thrombus/plaque protrusion area (0.1±0.1mm2 vs. 0.2±0.2mm2, p=0.005), and maximum in-stent thrombus/plaque protrusion area (0.5±0.7mm2 vs. 0.8±0.6mm2, p=0.007) were significantly smaller in the prasugrel group compared with the clopidogrel group. ConclusionsPretreatment with prasugrel was associated with significantly reduced in-stent thrombus/plaque protrusion immediately after PCI for ACS compared with that with clopidogrel.

COMPARISON OF IN-STENT THROMBUS IMMEDIATELY AFTER PERCUTANEOUS CORONARY INTERVENTION FOR ACUTE CORONARY SYNDROME BETWEEN PATIENTS PRETREATED WITH PRASUGREL VERSUS CLOPIDOGREL BY USING OPTICAL COHERENCE TOMOGRAPHY

Prasugrel is a new-generation thienopyridine antiplatelet agent that provides more consistent and prompt platelet inhibition than clopidogrel. The aim of this study was to compare in-stent thrombus inhibition effect of pretreatment with prasugrel and clopidogrel by optical coherence tomography (OCT

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog.

Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 ± 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 ± 0.1 and 6.6 ± 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.

Bone marrow toxicity induced by clopidogrel

The use of thienopyridine antiplatelet agents (ticlopidine, clopidogrel or prasugrel), along with aspirin, reduces mortality in acute coronary syndromes and in patients with coronary stents. The first drug of this type was ticlopidine, but its use was associated with a high rate of neutropenia. Clopidogrel, on the other hand, has a more favorable safety profile, and is rarely a cause of neutropenia or bone marrow toxicity.

Designing analogs of ticlopidine, a wall teichoic acid inhibitor, to avoid formation of its oxidative metabolites

The thienopyridine antiplatelet agent, ticlopidine and its analog, clopidogrel, have been shown to potentiate the action of β-lactam antibiotics, reversing the methicillin-resistance phenotype of methicillin-resistant Staphylococcus aureus (MRSA), in vitro. Interestingly, these thienopyridines inhibit the action of TarO, the first enzyme in the synthesis of wall teichoic acid, an important cell wall polymer in Gram-positive bacteria. In the human body, both ticlopidine and clopidogrel undergo a rapid P450-dependent oxidation into their respective antiplatelet-active metabolites, resulting in very low plasma concentrations of intact drug. Herein, a series of analogs of ticlopidine and clopidogrel that would avoid oxidative metabolism were designed, prepared and evaluated as inhibitors of TarO. Specifically, we replaced the P450-labile thiophene ring of ticlopidine and clopidogrel to a more stable phenyl group to generate 2-(2-chlorobenzyl)-1,2,3,4-tetrahydro-isoquinoline) (6) and (2-chloro-phenyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid methyl ester (22), respectively. The latter molecules displayed inhibitory activity against TarO and formed the basis of a library of analogs. Most synthesized compounds exhibited comparable efficacy to ticlopidine and clopidogrel. So far, it was introduction of a trifluoromethyl group to compound 6, to generate 2-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-isoquinoline (13) that exhibited enhanced activity against TarO. Compound 13 represents a novel stable inhibitor of TarO with synergistic impact on β-lactam antibiotics against MRSA and low potential for P-450 metabolism.

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

BackgroundPlatelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study.MethodsThe primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients.ResultsThere were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events.ConclusionsDespite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Allergic diseases of the skin and drug allergies – 2036. Exanthematous drug eruption to prasugrel: a case report

Prasugrel is a thienopyridine anti-platelet agent used for managing cardiac patients under going percutaneous coronary intervention (PCI) or stent placement to reduce thrombotic event rate. Prasugrel has multiple side effects, however, only one case of an allergic reaction has been reported to the drug before.

Glutaredoxin Is Involved in the Formation of the Pharmacologically Active Metabolite of Clopidogrel from Its GSH Conjugate

Clopidogrel is a thienopyridine antiplatelet agent that is converted to the active metabolite, R-361015, in vivo. Clopidogrel is first oxidized to a thiolactone intermediate R-115991. R-115991 is thought to be metabolized to a GSH conjugate of R-361015 (R-361015-SG) and then is reduced to R-361015 in the presence of GSH. In this study, we investigated the enzyme-mediated formation of R-361015 from R-361015-SG in human liver microsomes and cytosols. After incubation of R-115991 in human liver microsomes, the formation of R-361015-SG, and subsequently of R-361015, was observed. The apparent formation rate of R-361015-SG was markedly decreased when human liver cytosols were added. Fitting the data to the kinetic model showed that the rate constant of R-361015-SG reduction to R-361015 in human liver microsomes was approximately 20-fold higher in the presence of human liver cytosols (6.56 min⁻¹) than in the absence of cytosols (0.326 min⁻¹). In addition, the formation rate of R-361015 from R-361015-SG was higher in human liver cytosols (2843 ± 1176 pmol · min⁻¹ · mg⁻¹) compared with in human liver microsomes (508 ± 396 pmol · min⁻¹ · mg⁻¹). The formation of R-361015 from R-361015-SG in human liver microsomes or cytosols was inhibited by anti-human glutaredoxin antibody in a concentration-dependent manner. Recombinant human glutaredoxin mediated the formation of R-361015 from R-361015-SG with the K(m) and V(max) values of 30.0 ± 1.3 μM and 381.6 ± 209.8 pmol · min⁻¹ · μg⁻¹, respectively. The intrinsic clearance value (V(max)/K(m)) was 12.9 ± 7.5 μl · min⁻¹ · μg⁻¹. In conclusion, we found that human glutaredoxin is a main contributor to the formation of the pharmacologically active metabolite of clopidogrel from its GSH conjugate in human liver.

Absorption enhancement studies of clopidogrel hydrogen sulphate in rat everted gut sacs

Clopidogrel, a thienopyridine antiplatelet agent, is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These two factors are responsible for its incomplete intestinal absorption. In this study, we have attempted to enhance the absorption of clopidogrel by improving its solubility and by inhibiting intestinal P-gp activity. Solubility enhancement was achieved by preparing solid dispersions. Quinidine and naringin were selected as P-gp inhibitors, whilst tartaric acid was selected as the intestinal absorption enhancer. Absorption studies were performed using the everted gut sac model prepared from rat jejunum. The determination of clopidogrel was performed by high performance liquid chromatography. We noticed an enhancement of clopidogrel absorption by improving its solubility or by inhibiting the P-gp activity. The greatest results were obtained for solid dispersions in the presence of P-gp inhibitors at their highest concentrations, with an absorption improvement of 3.41- and 3.91-fold for naringin (15mg/kg) and quinidine (200µm), respectively. However, no clopidogrel absorption enhancement occurred in the presence of tartaric acid. Naringin, a natural compound which has no undesirable side effects as compared with quinidine, could be used as a pharmaceutical excipient in the presence of clopidogrel solid dispersions to increase clopidogrel intestinal absorption and therefore its oral bioavailability.

Biomarkers of Hemostatic Activation in a Randomized, Double-Blind, Phase 2 Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract 2127 Introduction:Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods:This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results:Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions:As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. [Display omitted] Disclosures:Wun:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Abstract 847▪FN2▪This icon denotes a clinically relevant abstract Introduction:Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods:This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results:Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). [Display omitted] [Display omitted] Conclusions:Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures:Wun:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.