First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers.

BACKGROUND: ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes. METHODS AND RESULTS: This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was approximately 2 hours, and mean residence time was approximately 3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from approximately 10% to approximately 21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC(90) value of 2.0 mug/mL (151 nmol/L) and of platelet function with an EC(90) value of 2.6 mug/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related. CONCLUSIONS: This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose- and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.

Analysis of diagnostic error in paid malpractice claims with substandard care in a large healthcare system.

OBJECTIVE: Although claims databases are not representative of all care delivery, their predisposition toward serious unintended injury can complement resource-intensive chart reviews and guide patient safety initiatives. MATERIALS AND METHODS: Non-Veterans Health Administration (VA) practitioners reviewed 1,949 VA malpractice claims paid during fiscal years 1998 through 2003. The portion associated with substandard care, the severity of harm, and types of negligence were identified. RESULTS: Negligent adverse events occurred in 37% (n = 723) of paid VA malpractice claims. These had high proportions of serious injury (55%) and morbidity (37%). Diagnostic negligent adverse events were most frequent (45%) and with 41% associated morbidity. The annual incidence of diagnosis-related paid VA malpractice claims was 1.95 per 100,000 patients and predicts that 122 of every 100,000 patients may have diagnostic negligent adverse events. Comparisons against non-VA data suggest this to be a healthcare industry problem. CONCLUSIONS: Diagnosis-related negligent adverse events are a serious problem in the healthcare industry.