prasugrel-hydrochloride and Kidney-Failure--Chronic

Chronic kidney disease has been identified as an independent cardiovascular risk factor. The morbidity and mortality due to cardiovascular disease are higher among chronic kidney disease patients when compared with patients with normal kidney function. Although P2Y12 inhibitors (eg. clopidogrel) are associated with increased survival rates after a myocardial infarction, most of the clinical trials excluded End-Stage Renal Disease (ESRD) patients. Besides, non-responders to P2Y12 inhibitors have been identified as at risk of cardiovascular adverse events and non-responder prevalence is higher among ESRD than in any other population. Recent data questioned the benefits from P2Y12 inhibitors among chronic kidney disease patients. This systematic review aimed to describe pharmacokinetics (PK) and pharmacodynamics (PD) evidence data among 3 widely prescribed P2Y12 inhibitors. Clopidogrel and prasugrel are bioactivated by the cytochromes P450 (CYP) while ticagrelor is already active. PD data used different assays among which the VerifyNow® which showed intravariability before and after dialysis. The potential explanation of modulated PK/PD parameters among ESRD patients will be addressed. Absorption as well as metabolism is diminished in ESRD patients. It could potentially lead to absence of clopidogrel or prasugrel bioactivation or ticagrelor accumulation. Evidence-based recommendation regarding the best option for antiaggregation secondary to percutaneous intervention in this high risk population is still lacking.

Topics: Adenosine; Animals; Cardiovascular Diseases; Clopidogrel; Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Ticagrelor; Ticlopidine

Topics: Adenosine; Angina, Unstable; Anticoagulants; Blood Glucose; Guideline Adherence; Humans; Kidney Failure, Chronic; Myocardial Infarction; Patient Education as Topic; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Practice Guidelines as Topic; Prasugrel Hydrochloride; Proton Pump Inhibitors; Purinergic P2Y Receptor Antagonists; Thiophenes; Ticagrelor

Novel adenosine diphosphate (ADP) P2Y(12) antagonists, including prasugrel, ticagrelor, cangrelor and elinogrel, are in various phases of clinical development. These ADP P2Y(12) antagonists have advantages over clopidogrel ranging from faster onset to greater and less variable inhibition of platelet function. Novel ADP P2Y(12) antagonists are under investigation to determine whether their use can result in improved antiplatelet activity, faster onset of action, and/or greater antithrombotic effects than clopidogrel, without an unacceptable increase in hemorrhagic or other side effects. Prasugrel (CS-747; LY-640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet ADP P2Y(12) receptor. Preclinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared to clopidogrel. Recent findings from large-scale phase III testing showed prasugrel to be more efficacious in preventing ischemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI); however, this is achieved at the expense of an increased risk of bleeding. Prasugrel provides more rapid and consistent platelet inhibition than clopidogrel.

Topics: Acute Coronary Syndrome; Angioplasty, Balloon, Coronary; Aspirin; Clinical Trials, Phase III as Topic; Clopidogrel; Drug Evaluation, Preclinical; Drug Therapy, Combination; Hemorrhage; Humans; Ischemia; Kidney Failure, Chronic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Thiophenes; Ticlopidine

Novel adenosine diphosphate (ADP) P2Y(12) antagonists such as prasugrel, ticagrelor, cangrelor, and elinogrel are in various phases of clinical development. These ADP P2Y(12) antagonists have advantages over clopidogrel ranging from faster onset to greater and less variable inhibition of platelet function. Novel ADP P2Y(12) antagonists are under investigation to determine whether their use can result in improved antiplatelet activity, faster onset of action, and/or greater antithrombotic effects than clopidogrel without an unacceptable increase in hemorrhagic or other side effects. Prasugrel (CS-747; LY-640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet ADP P2Y(12) receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower inter-individual variability in platelet response, and faster onset of activity compared to clopidogrel. Recent findings from large-scale phase-III testing show prasugrel to be more efficacious in preventing ischemic events in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI); however, this is achieved at the expense of an increased risk of bleeding. Prasugrel provides more rapid and consistent platelet inhibition than clopidogrel.

Topics: Clinical Trials as Topic; Humans; Kidney Failure, Chronic; Piperazines; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Thiophenes

Topics: Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Renal Dialysis; Sepsis; Ticagrelor

Individuals aged ≥75 years are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y. In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time to first bleed and the interactions between age and P2Y12-I type on modifying the effects of a bleed.. Twenty percent of the cohort were aged ≥75 years. There were 3096 (8%) gastrointestinal (GI) and 1298 (3%) intracranial (IC) bleeding events during a median follow-up of 1 year. Annual incidence rates for IC bleeds were 2% in those aged <55 years and 3% in those aged ≥75 years. Rates for GI bleeds were 4% in those aged <55 years and 9% in those aged ≥75 years. On clopidogrel, prasugrel, and ticagrelor, for every decade increase in age of the cohort members, the risk of IC bleed increased by 9%, 55%, and 59%, and the risk of GI bleed increased by 21%, 28%, and 39%, respectively. At age ≥75 years, prasugrel was associated with a greater risk of IC bleed than clopidogrel. At age ≥60 years, ticagrelor was associated with a greater risk of GI bleed than clopidogrel.. More potent P2Y12-Is (prasugrel and ticagrelor) were associated with a disproportionately higher risk of IC bleed with increasing age compared with that of clopidogrel-prasugrel was much worse than clopidogrel at age ≥75 years. All three drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age-ticagrelor was much worse than clopidogrel at ≥60 years of age. These results highlight the need for head-to-head clinical trials for the use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention.

Topics: Aged; Clopidogrel; Gastrointestinal Hemorrhage; Humans; Kidney Failure, Chronic; Middle Aged; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Renal Dialysis; Retrospective Studies; Ticagrelor

Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD).. From 2011-2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed.. Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P<0.05). Patients receiving hemodialysis versus peritoneal dialysis were less likely to receive prasugrel over clopidogrel, adjusted odds ratio (aOR) 0.67 (0.55-0.82). Each additional year of dialysis decreased the odds of receiving prasugrel over clopidogrel, aOR 0.91 (0.85-0.98). History of atrial fibrillation reduced the odds of receiving ticagrelor or prasugrel over clopidogrel, aOR 0.69 (0.54-0.89) and 0.73 (0.60-0.89), respectively. Concomitant oral anticoagulant use was not associated with choice of P2Y12-I. Occurrence of non-ST segment elevation myocardial infarction or percutaneous coronary intervention within the 6-month period prior to the index date favored ticagrelor over prasugrel, aOR 1.31 (1.06-1.62) and 1.29 (1.01-1.66), respectively. However, prescribing trends favoring ticagrelor over prasugrel were not observed for deployment of drug-eluting, or multiple coronary stents.. Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cardiovascular Diseases; Clinical Decision-Making; Clopidogrel; Drug Prescriptions; Drug Utilization; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Selection; Peritoneal Dialysis; Platelet Aggregation Inhibitors; Practice Patterns, Physicians'; Prasugrel Hydrochloride; Prevalence; Purinergic P2Y Receptor Antagonists; Registries; Renal Dialysis; Retrospective Studies; Risk Assessment; Risk Factors; Ticagrelor; Time Factors; Treatment Outcome; United States; Young Adult

High on-treatment platelet reactivity (HPR) under clopidogrel treatment is frequently observed in hemodialysis (HD) patients. In such patients, 10mg of prasugrel has reportedly inhibited platelet reactivity more adequately compared with 75mg of clopidogrel. However, the efficacy of 3.75mg prasugrel in Japanese HD patients is largely unknown.. A total of 41 Japanese coronary artery disease patients under HD who received aspirin and clopidogrel were enrolled. Clopidogrel was switched to 3.75mg prasugrel. At day 14, prasugrel was switched to clopidogrel. Platelet reactivity was measured using VerifyNow assay (Accumetrics, San Diego, CA, USA) at baseline, day 14, and day 28. VerifyNow P2Y12 reaction units (PRU) >208 was defined as HPR.. The PRU level on prasugrel therapy was significantly lower than that on clopidogrel therapy before switching (219.1±62.3 PRU vs. 238.2±68.0 PRU, p=0.02). Although the prevalence of HPR was numerically lower on prasugrel therapy compared with clopidogrel therapy before and after switching, the differences did not reach a statistical significance (57.6% vs. 75.7% vs. 74.2%, p=0.13). Even under prasugrel treatment, more than half of patients showed HPR.. Although low-dose prasugrel had somewhat better antiplatelet effect than clopidogrel, it could not significantly improve the prevalence of HPR in Japanese HD patients. Higher doses of prasugrel might be needed to achieve adequate platelet inhibition in this high thrombotic risk population.

Topics: Aged; Aspirin; Blood Platelets; Clopidogrel; Coronary Artery Disease; Drug Substitution; Female; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Prospective Studies; Renal Dialysis

Topics: Acute Coronary Syndrome; Clopidogrel; Humans; Kidney Failure, Chronic; Percutaneous Coronary Intervention; Prasugrel Hydrochloride; Renal Insufficiency, Chronic

We describe a case of a 34-year-old woman with chronic renal failure under haemodialysis. The patient exhibited high on-treatment platelet reactivity to gradually stronger thienopyridine regimens, including standard and high maintenance doses of prasugrel. Platelet function was monitored by VerifyNow assay and genotyping for various single-nucleotide polymorphisms was performed. Treatment with ticagrelor 180 mg/day was effective in reducing the platelet reactivity.

Topics: Adenosine; Adult; Drug Resistance; Female; Humans; Kidney Failure, Chronic; Piperazines; Platelet Activation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y; Renal Dialysis; Thiophenes; Ticagrelor

We compared platelet function results obtained with the VerifyNow P2Y12 (VN-P2Y12) point-of-care device and the light transmission aggregometry (5 and 20 microM adenosine diphosphate) method using an integrated database of eight clinical trials with a total of 591 subjects. The study was performed in healthy subjects, patients with coronary artery disease, patients with end-stage renal disease, and patients with acute coronary syndrome after treatment with prasugrel or clopidogrel. Analyses focused on loading doses of 60 mg prasugrel or 600 mg clopidogrel and daily maintenance doses of 10 mg prasugrel or 75 or 150 mg clopidogrel. Similar patterns of platelet inhibition were observed for light transmission aggregometry versus VN-P2Y12 and assay results were well correlated (r approximately 0.7), although a sigmoidal model may more accurately represent the relationship between light transmission aggregometry and VN-P2Y12, because VN-P2Y12 was relatively less sensitive to low and high levels of inhibition. The percentage of poor responders was less with prasugrel compared with clopidogrel by both assays, but the percentages tended to differ between the assays. The VN-P2Y12 "BASE" channel appeared to be susceptible to high levels of P2Y12 blockade, which would underestimate the VN-P2Y12-reported percent inhibition in individuals who respond well to loading doses of thienopyridines. This integrated analysis supports the findings of earlier individual studies comparing these methodologies that assess platelet function.

Topics: Acute Coronary Syndrome; Adenosine Diphosphate; Adult; Aged; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Databases, Factual; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Platelet Function Tests; Point-of-Care Systems; Prasugrel Hydrochloride; Thiophenes; Ticlopidine

The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment.. Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n = 12) or moderate renal impairment (n = 10) and matched healthy subjects with normal renal function (n = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD (n = 16) and matched healthy subjects with normal renal function (n = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 mum adenosine diphosphate as agonist.. Across all studies, prasugrel's C(max) and AUC(0-t) were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC(0-t) did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects.. There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.

Topics: Adult; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Protein Binding; Thiophenes