Darell Heiselman

Recovery of Platelet Function After Discontinuation of Prasugrel or Clopidogrel Maintenance Dosing in Aspirin-Treated Patients With Stable Coronary Disease : The Recovery Trial

OBJECTIVES The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel. BACKGROUND Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited. METHODS Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation. RESULTS A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment. CONCLUSIONS Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

Troponin-I as a prognosticator of mortality in severe sepsis patients ☆ ☆☆ ★

PURPOSE The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients. METHODS Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [>or=0.06 ng/mL], n = 451). RESULTS Cardiac troponin-I-positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65). CONCLUSION This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.

Rehospitalization following percutaneous coronary intervention for commercially insured patients with acute coronary syndrome: a retrospective analysis.

BackgroundWhile prior research has provided important information about readmission rates following percutaneous coronary intervention, reports regarding charges and length of stay for readmission beyond 30 days post-discharge for patients in a large cohort are limited. The objective of this study was to characterize the rehospitalization of patients with acute coronary syndrome receiving percutaneous coronary intervention in a U.S. health benefit plan.MethodsThis study retrospectively analyzed administrative claims data from a large US managed care plan at index hospitalization, 30-days, and 31-days to 15-months rehospitalization. A valid Diagnosis Related Group code (version 24) associated with a PCI claim (codes 00.66, 36.0X, 929.73, 929.75, 929.78–929.82, 929.84, 929.95/6, and G0290/1) was required to be included in the study. Patients were also required to have an ACS diagnosis on the day of admission or within 30 days prior to the index PCI. ACS diagnoses were classified by the International Statistical Classification of Disease 9 (ICD-9-CM) codes 410.xx or 411.11. Patients with a history of transient ischemic attack or stroke were excluded from the study because of the focus only on ACS-PCI patients. A clopidogrel prescription claim was required within 60 days after hospitalization.ResultsOf the 6,687 ACS-PCI patients included in the study, 5,174 (77.4%) were male, 5,587 (83.6%) were <65 years old, 4,821 (72.1%) had hypertension, 5,176 (77.4%) had hyperlipidemia, and 1,777 (26.6%) had diabetes. At index hospitalization drug-eluting stents were the most frequently used: 5,534 (82.8%). Of the 4,384 patients who completed the 15-month follow-up, a total of 1,367 (31.2%) patients were rehospitalized for cardiovascular (CV)-related events, of which 811 (59.3%) were revascularization procedures: 13 (1.0%) for coronary artery bypass graft and 798 (58.4%) for PCI. In general, rehospitalizations associated with revascularization procedures cost more than other CV-related rehospitalizations. Patients rehospitalized for revascularization procedures had the shortest median time from post-index PCI to rehospitalization when compared to the patients who were rehospitalized for other CV-related events.ConclusionsFor ACS patients who underwent PCI, revascularization procedures represented a large portion of rehospitalizations. Revascularization procedures appear to be the most frequent, most costly, and earliest cause for rehospitalization after ACS-PCI.

Prasugrel in children with sickle cell disease: Pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study

Introduction: This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel’s active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. Safety: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. Conclusions: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.

Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated).

IntroductionSerial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.MethodsThis was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy.ResultsOf 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration.ConclusionsThe study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies.Trial registrationClinicalTrials.gov identifier: NCT00386425.

Detecting a thienopyridine effect by platelet reactivity assessment and its implications for risk stratification

On‐treatment platelet reactivity (OTR) is a predictor of clinical outcomes in patients receiving thienopyridine therapy.

Psychometric testing of two new patient‐reported outcome instruments for the evaluation of treatment for hypogonadism

The aim of this study was to perform psychometric testing and estimate minimal important change (MIC) of two new patient‐reported outcome (PRO) instruments – Sexual Arousal, Interest and Drive Scale (SAID) and Hypogonadism Energy Diary (HED).