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1.
Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients
Russell JA, Vincent JL, Kjolbye AL, Olsson H, Blemings A, Spapen H, Carl P, Laterre PF, Grundemar L
Critical Care (London, England). 2017;21((1)):213.
Abstract
BACKGROUND Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. METHODS This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. RESULTS A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 mug/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 mug/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. CONCLUSIONS In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation. TRIAL REGISTRATION ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.
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2.
Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial
Dutton RP, Parr M, Tortella BJ, Champion HR, Bernard GR, Boffard K, Bouillon B, Croce MA, Dimsits J, Holcomb JB, et al
The Journal of Trauma. 2011;71((1):):12-9.
Abstract
BACKGROUND Safety data on recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsværd, Denmark) in actively hemorrhaging trauma patients are limited. We present detailed safety data from a large multicenter, randomized, placebo-controlled phase III study (the CONTROL trial). METHODS Data from 560 patients were analyzed. Subjects were monitored for adverse events (AEs) after rFVIIa or placebo administration. Incidences, timing, and presence of risk factors were reported by site investigators, supported by external study monitors and overseen by an independent Data Monitoring Committee. RESULTS There were no differences in overall mortality, organ system failure, or AEs, serious AEs, or medical events of special interest. Arterial and venous thromboembolic (TE) events and their risk factors were similar in both groups. The greatest risk factor for TE events was a chest injury requiring mechanical ventilation >3 days (86%). There were four site investigator-reported myocardial infarctions in the rFVIIa group of which only one met diagnostic criteria preestablished by the Data Monitoring Committee. There were no reported myocardial infarctions in the placebo group. Troponins were increased in 30% of all patients. The rate of acute respiratory distress syndrome was lower in the rFVIIa (3.0%) than in the placebo (7.2%) group (p = 0.022). CONCLUSIONS This represents the largest placebo-controlled dataset of rFVIIa use in trauma patients to date. In this prospective study of critically bleeding trauma patients, rFVIIa use was associated with an imbalance of investigator-reported Acute myocardial infarction/non-ST segment elevation myocardial infarction (AMI/NSTEMI), but was not associated with an increased risk for other AEs, including TE complications.
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3.
Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage
Hauser CJ, Boffard K, Dutton R, Bernard GR, Croce MA, Holcomb JB, Leppaniemi A, Parr M, Vincent JL, Tortella BJ, et al
The Journal of Trauma. 2010;69((3):):489-500.
Abstract
BACKGROUND Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. METHODS We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma bundleswith formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. RESULTS Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10. 8% vs. 27. 5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11. 0% (rFVIIa) versus 10. 7% (placebo) (p = 0. 93, blunt) and 18. 2% (rFVIIa) versus 13. 2% (placebo) (p = 0. 40, penetrating). Blunt trauma rFVIIa patients received (mean +/- SD) 7. 8 +/- 10. 6 RBC units and 19. 0 +/- 27. 1 total allogeneic units through 48 hours, and placebo patients received 9. 1 +/- 11. 3 RBC units (p = 0. 04) and 23. 5 +/- 28. 0 total allogeneic units (p = 0. 04). Thrombotic adverse events were similar across study cohorts. CONCLUSIONS rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.
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4.
Efficacy and safety of recombinant activated factor vii in the management of hemorrhagic shock due to trauma
Hauser CJ, Boffard KD, Dutton RP, Bernard GR, Croce MA, Holcomb JB, Leppaniemi AK, Parr MJA, Vincent JL, Tortella BJ, et al
ISTH Congress. 2009;: Abstract No. OC-TH-069.
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5.
A multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome
Vincent JL, Artigas A, Petersen LC, Meyer C
Critical Care Medicine. 2009;37((6):):1874-80.
Abstract
OBJECTIVE To evaluate the safety and efficacy of active site inactivated recombinant factor VIIa (FFR-rFVIIa) in patients with acute respiratory distress syndrome. DESIGN Phase II, randomized, double-blind, placebo-controlled, dose-escalation trial. SETTING Forty-six intensive care units (ICU) in ten countries. PATIENTS All adult (>or=18 years), mechanically ventilated patients with acute onset (within 48 hour) of acute lung injury/acute respiratory distress syndrome were included. INTERVENTIONS Four sequential (in ascending order) treatment groups (cohorts) in single and multiple dosing strategies. Subjects were randomized in a 2:1 ratio to either FFR-rFVIIa or placebo within each cohort. MEASUREMENTS AND RESULTS Data were collected daily for 7 days and on days 14 and 28 for efficacy variables including hematology and coagulation parameters, plasma d-dimer levels, plasma interleukin-6 levels, vital signs, ventilator parameters, lung injury score, and Sequential Organ Failure Assessment score. The study was discontinued prematurely by the Safety Committee based on statistical analysis of the mortality in cohort 3 (4 x 400 microg/kg), which suggested that, after adjusting for prognostic covariates, 28-day mortality was significantly higher in this cohort than in the placebo group and time to death was significantly shorter. A total of 214 patients (147 male) were included in the trial, mean age 59 years (range, 24-85 years). Overall, there were no significant differences in mortality rates in treated and placebo patients (36/144 deaths FFR-rFVIIa, 15/70 placebo). There was no treatment effect of FFR-rFVIIa on vital signs, blood chemistry parameters, hematology parameters, or amount of transfusion products required. There was a trend to increased bleeding with increasing FFR-rFVIIa dose. CONCLUSION In this randomized double-blind, placebo- controlled, dose-escalation trial, FFR-rFVIIa had no beneficial effects on morbidity or outcome overall. The cohort of patients receiving 4 x 400 g/kg of FFR-rFVIIa had increased mortality rates compared with placebo-treated patients, and there was a trend to increased risk of serious bleeding with increasing doses.
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6.
Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding - A European perspective
Vincent JL, Rossaint R, Riou B, Ozier Y, Zideman D, Spahn DR
Critical Care. 2006;10((4):):R120, E.
Abstract
Introduction: Our aim was to develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage. Methods: A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A to E (with A being the highest) according to the strength of evidence available. Consensus was sought among the committee members for each recommendation. Results: A recommendation for the use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E), and bleeding after cardiac surgery (grade D). r FVIIa could not be recommended for use in the following: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child-Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child-Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team. Conclusion: There is a rationale for using rFVIIa to treat massive bleeding in certain indications, but only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.
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7.
Pharmacokinetics and pharmacodynamics of once-weekly subcutaneous epoetin alfa in critically ill patients: results of a randomized, double-blind, placebo-controlled trial
Vincent JL, Spapen HD, Creteur J, Piagnerelli M, Hubloue I, Diltoer M, Roman A, Stevens E, Vercammen E, Beaver JS
Critical Care Medicine. 2006;34((6):):1661-7.
Abstract
OBJECTIVE To describe the erythropoietin pharmacokinetic profile after once-weekly epoetin alfa treatment in critically ill patients. Secondary objectives were to compare pharmacodynamic and safety profiles between active treatment and placebo in these patients. DESIGN Randomized, double-blind, placebo-controlled study. SETTING Medical, surgical, or mixed medical/surgical intensive care units. PATIENTS A total of 73 anemic critically ill adults with an expected stay of >3 days and a hematocrit value of <38%. INTERVENTIONS Patients were randomized 2:1 to epoetin alfa, 40,000 IU, administered subcutaneously once weekly (n=48) or matching placebo (n=25) for up to 4 wks. MEASUREMENTS AND MAIN RESULTS Serum erythropoietin concentration and hematologic variables (percentage reticulocytes [RETI], hemoglobin [Hb], and total red blood cell [RBC] counts) were measured, and area under the serum concentration-time curve from time 0 to the last blood sampling time at time t (t: 120, 144, or 168 hrs) postdose (AUC0-Tlast) for these three variables was determined. Mean serum erythropoietin concentrations in placebo patients were slightly higher than typical physiologic levels of erythropoietin in healthy subjects, although not appropriate for the degree of anemia in these patients. Overall, exposure of endogenous erythropoietin in the placebo group (in terms of AUC0-Tlast) was only about 20% of exposure to exogenous erythropoietin in the epoetin alfa group. Baseline hemoglobin levels were the same in both groups (9. 9 g/dL). Mean change in hemoglobin level from baseline through day 29 was 1. 9 g/dL and 1. 6 g/dL in the epoetin alfa and placebo groups, respectively. Mean AUC(RETI)0-Tlast was higher with epoetin alfa than with placebo and was related to the AUC of erythropoietin. There were no apparent differences in AUC(Hb)0-Tlast and AUC(RBC)0-Tlast between epoetin alfa and placebo groups, which was most likely due to bleeding and transfusion events. Epoetin alfa was safe and well tolerated, with a rate of treatment-emergent complications similar to that seen with placebo. CONCLUSION Epoetin alfa, once weekly, augmented the erythropoietic response in critically ill patients as indicated by the increased erythropoietin levels and larger AUC(RETI)0-Tlast in treated patients.
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8.
Does aprotinin influence the inflammatory response to cardiopulmonary bypass in patients?
Schmartz D, Tabardel Y, Preiser JC, Barvais L, d'Hollander A, Duchateau J, Vincent JL
The Journal of Thoracic and Cardiovascular Surgery. 2003;125((1):):184-90.
Abstract
OBJECTIVES Aprotinin has been shown to have anti-inflammatory properties, but its effects on the inflammatory reaction to cardiopulmonary bypass remain controversial. This prospective, randomized, double-blind study evaluated the influence of aprotinin on various blood markers of inflammation during and after cardiopulmonary bypass. METHODS Sixty male patients underwent coronary artery bypass grafting. The patients were randomized into 3 groups: a placebo group, a second group receiving 2,000,000 KIU of aprotinin followed by an infusion of 500,000 KIU/h and 2,000,000 KIU in the pump prime, and a third group receiving half this dosage. Measurements of tumor necrosis factor, interleukin 6, interleukin 8, interleukin 10, endotoxin, histamine, complement factors, prekallikrein, and prostaglandin D(2) were obtained at baseline, 30 minutes after study drug loading, 10 minutes after the beginning of cardiopulmonary bypass, before the end of bypass, 4 hours after bypass, and on the first and second postoperative days. RESULTS Aprotinin had no significant effect on any of these parameters. As expected, aprotinin reduced early blood loss in both treated groups. CONCLUSIONS These results indicate that aprotinin at doses currently used to reduce blood loss has no significant influence on the systemic inflammatory response during moderate hypothermic cardiopulmonary bypass in human subjects, as assessed by the mediators measured in this study.