Reversal of clopidogrel-induced bleeding with rFVIIa in healthy subjects: a randomized, placebo-controlled, double-blind, exploratory study.

BACKGROUND: Clopidogrel (Plavix®) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven®) induces hemostasis in hemophilia patients with inhibitors (alloantibodies) and has been proposed as potential treatment for mitigating clopidogrel therapy-mediated bleeding. METHODS: In this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrel-enhanced bleeding in an experimentally induced punch biopsy in healthy subjects. Efficacy assessments included the reversal of bleeding characteristics (bleed duration [BD], the primary end point and blood loss volume [BV] induced by punch biopsy, and thromboelastograph [TEG®] parameters) with rFVIIa or placebo after clopidogrel treatment. RESULTS: A significant number of subjects (56%) had limited response to clopidogrel (defined as ≤30% platelet aggregation inhibition) and were discontinued from study. The remaining subjects continued and had 4 biopsies. Of 40 subjects randomized, 37 were evaluated for efficacy. Clopidogrel treatment increased BD and BV compared with the baseline biopsy. Recombinant FVIIa (10 and 20 µg/kg) significantly mitigated the clopidogrel-induced effects on BV (P = 0.007 and P = 0.001, respectively). Early trial termination limited the evaluation of effects of higher rFVIIa doses. Subgroup analyses of subjects biopsied by the same physician demonstrated significant reduction of clopidogrel-induced BD with 20 µg/kg rFVIIa (P = 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG®-R) and clot angle (TEG®-A) (P < 0.005). CONCLUSIONS: In this clinical study, rFVIIa (10 and 20 µg/kg) reversed the effect of clopidogrel on blood loss.

Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects.

The use of warfarin has a well-known bleeding risk. Recombinant activated factor VII (rFVIIa) is a non-plasma-derived, rapid-acting, and rapidly infused potential treatment. This randomized, single-center, placebo-controlled, double-blinded, dose-escalation, exploratory phase 1 trial assessed safety and effects of rFVIIa in reversing warfarin-induced changes in bleeding and coagulation parameters, using a punch biopsy-induced bleeding model in healthy subjects. The effects of warfarin (experiment 1) and rFVIIa (5-80 microg/kg; experiment 2) were evaluated. Outcomes were bleeding duration, blood loss, coagulation parameters, and safety. Warfarin treatment significantly increased bleeding duration and blood loss from pretreatment (experiment 1, 12 subjects). However, these parameters after rFVIIa treatment were not significantly different from placebo (experiment 2, 85 subjects). Mean activated partial thromboplastin time, prothrombin time, and international normalized ratio were reduced from warfarin-elevated levels. rFVIIa (80 microg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared with placebo (P < .05), and returned the thrombin generation speed to baseline. There were no thromboembolic or serious adverse events. In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation, and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated in the punch biopsy model. Trial registration is exempt (phase 1).

Accuracy and precision of the NovoPen 3 insulin delivery device after mechanical and temperature stresses.

OBJECTIVE: To evaluate the precision, accuracy, and durability of an insulin pen injection device (NovoPen 3) at three preset doses (2 IU, 35 IU, and 70 IU) after exposure to various stress and durability tests that were intended to simulate daily use by patients. METHODS: Twenty-nine reusable NovoPen 3 insulin delivery devices were tested. The precision and accuracy of 10 insulin pen devices were evaluated after they were subjected to multiple thermal and vibration stress tests. Another 10 pen devices were subjected to a free-fall test. Nine other insulin pens were subjected to endurance testing that simulated 5 years of injections. RESULTS: The accuracy (as measured by the relative error of the delivered dose of insulin) of the insulin pen injection devices was within 1% of the preset dose after all stress or endurance tests. A free-fall test produced no indication of damage except for broken clips and snap catches on the caps, which did not affect the integrity or performance of the insulin pens. The precision of the pen devices (as measured by relative standard deviations of delivered volumes of insulin) was likewise high after thermal stress, vibration stress, free-fall testing, or 5-year endurance testing. CONCLUSION: Overall, this study showed that the insulin pen injection devices tested were durable under conditions of stress likely to be encountered in daily patient use. Neither a wide variety of repetitive stresses nor insulin injection cycles corresponding to 5 years of use affected the accuracy or precision enough to have clinical significance for reliable insulin delivery.