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1.
Deviations from evidence-based clinical management guidelines increase mortality in critically injured trauma patients*
Rice TW, Morris S, Tortella BJ, Wheeler AP, Christensen MC
Critical Care Medicine. 2012;40((3):):778-86.
Abstract
OBJECTIVES The effect of treatment guidelines on clinical outcomes in general and specifically for trauma patients has not been well-studied. We hypothesized that better compliance with guidelines would be associated with improved clinical outcomes. DESIGN Prospective, randomized, double-blinded, multicentered, placebo-controlled study of recombinant factor VII in severe trauma that utilized guidelines for damage control, transfusions, and mechanical ventilation. Vanderbilt Coordinating Center reviewed compliance in near real-time and reported deviations classified as minor, moderate, or major to investigators. Multivariate regression analysis measured the association between outcomes (30-day and 90-day mortality, development of multiple organ failure, ventilator-free days, renal failure-free days, and blood products transfused) and compliance with each guideline, as well as a composite assessment of overall compliance. SETTING One hundred hospitals in 26 countries. PATIENTS Blunt and/or penetrating trauma patients aged 18-70 yrs who had received 4-8 units of red blood cells for active torso and/or proximal lower extremity bleeding despite standard interventions. MEASUREMENTS AND MAIN RESULTS When assessed as composite end point, major deviations from guidelines were associated with significantly higher mortality at 30 and 90 days after injury and fewer renal failure-free days. Moderate deviations were associated with a significantly higher risk of multiple organ failure and fewer ventilator-free days. Moderate and major deviations from damage control and ventilation guidelines were also significantly associated with higher risk of death at days 30 and 90. Within the ventilation protocol, noncompliance with tidal volume and plateau pressure targets was associated with significantly higher mortality at days 30 and 90 and fewer ventilator-free days, whereas noncompliance with weaning guideline was only associated with significantly fewer ventilator-free days. CONCLUSIONS In a clinical trial of trauma patients, higher compliance with guidelines for damage control, transfusion, and ventilation management is associated with lower mortality and improved outcomes.
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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.
Global differences in causes, management, and survival after severe trauma: the recombinant activated factor VII phase 3 trauma trial
Christensen MC, Parr M, Tortella BJ, Malmgren J, Morris S, Rice T, Holcomb JB, CONTROL Study Group
The Journal of Trauma. 2010;69((2):):344-52.
Abstract
BACKGROUND Little is known about international variation in mortality after severe trauma. This study examines variation in mortality, injury severity, and case management among countries from a recent prospective multinational trauma trial. METHODS This trauma trial was a prospective, randomized, double-blinded, multicenter comparison of recombinant activated factor VII versus placebo in severely injured bleeding trauma patients. Differences in baseline patient characteristics, case management, and clinical outcomes were examined for the 11 countries recruiting most patients. Between-country differences in mortality were examined using regression analysis adjusting for case mix and case management differences. Global predictors of mortality were also identified using multivariate regression analysis. RESULTS Significant differences were observed between countries in unadjusted mortality rates at 24 hours (p = 0. 025) and 90 days (p < 0. 0001). When adjusting for differences in case mix and case management, the between country differences in mortality at 24 hours and 90 days remained significant. Consistent independent predictors of 24-hour, 24-hour to 90-day, and 90-day mortality were admission lactate >or=5 mmol/L (odds ratio: 9. 06, 3. 56, and 5. 39, respectively) and adherence to clinical management guidelines (odds ratio: 4. 92, 5. 90, and 3. 26, respectively). On average, the damage control surgery guideline was less well adhered to than the RBC transfusion and ventilator guidelines. There was statistically significant variation between countries with respect to adherence to the RBC transfusion guideline. CONCLUSIONS Considering international variation in mortality when designing or interpreting results from multinational trauma studies is important. Significant differences in mortality persisted between patients from different countries after case mix and case management adjustment. Adherence to clinical guidelines was associated with improved survival. Stratification, case mix adjustment, and use of guidelines on damage control surgery, transfusion, and ventilation may mitigate country-driven variation in mortality.
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4.
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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5.
Prolonged prothrombin time after recombinant activated factor VII therapy in critically bleeding trauma patients is associated with adverse outcomes
McMullin NR, Wade CE, Holcomb JB, Nielsen TG, Rossaint R, Riou B, Rizoli SB, Kluger Y, Choong PI, Warren B, et al
The Journal of Trauma. 2010;69((1):):60-9.
Abstract
BACKGROUND In trauma patients with significant hemorrhage, it is hypothesized that failure to normalize prothrombin time (PT) after recombinant activated factor VII (rFVIIa) treatment predicts poor clinical outcomes and potentially indicates a need for additional therapeutic interventions. METHODS To assess the value of PT to predict outcomes after rFVIIa or placebo therapy, we performed a post hoc analysis of data from 169 severely injured, critically bleeding trauma patients who had 1-hour postdose PT measurements from two randomized clinical trials. Baseline characteristics and outcome parameters were compared between subjects with 1-hour postdose PT >or=18 seconds and PT <18 seconds. RESULTS In rFVIIa-treated subjects, prolonged postdose PT values >or=18 seconds were associated with significantly higher 24-hour mortality (60% vs. 3%; p < 0. 001) and 30-day mortality, increased incidence of massive transfusion, and fewer intensive care unit-free days compared with postdose PT values <18 seconds. Recombinant rFVIIa-treated subjects with postdose PT >or=18 seconds had significantly lower baseline hemoglobin levels, fibrinogen levels, and platelet counts than subjects with postdose PT values <18 seconds even though they received similar amounts of blood products before rFVIIa dosing. Placebo-treated subjects with postdose PT >or=18 seconds had significantly increased incidence of massive transfusion, significantly decreased intensive care unit-free days, and significantly lower levels of fibrinogen and platelets at baseline compared with subjects with postdose PT values <18 seconds. CONCLUSIONS The presence of prolonged PT after rFVIIa or placebo therapy was associated with poor clinical outcomes. Because subjects with postdosing PT >or=18 seconds had low levels of hemoglobin, fibrinogen, and platelets, this group may benefit from additional blood component therapy.
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6.
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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7.
The treatment of bleeding is to stop the bleeding! Treatment of trauma-related hemorrhage
Boffard KD, Choong PI, Kluger Y, Riou B, Rizoli SB, Rossaint R, Warren B, NovoSeven Trauma Study Group
Transfusion. 2009;49((Suppl 5):):240S-7S.
Abstract
BACKGROUND The secret with any alternative to transfusion is to minimize the need for transfusion in the first place. This can be done by reducing the volume of blood loss. The volume of blood being lost can be reduced by direct methods where possible (i. e. , hemostasis at the point of bleeding), or by improving the coagulation profile of the patient, thereby improving the extrinsic coagulation. Recombinant activated factor VII (rFVIIa) offers theoretical possibilities of improving the coagulation profile. STUDY DESIGN AND METHODS The efficacy and safety of rFVIIa for the treatment of bleeding in patients with severe blunt and penetrating trauma has been investigated in two double-blind, placebo-controlled studies within a single trial-one on patients with blunt injury and the other in similar patients with penetrating injury. RESULTS In patients with blunt trauma alive at 48 hours, treatment with rFVIIa effected a significant reduction in the primary endpoint of 48-hour red blood cell (RBC) transfusion requirement (p = 0. 02), and the safety of the dosing regimen was established. Similar trends were observed in patients with penetrating injuries. Across both studies and treatment arms, the 48-hour mortality rate ranged from 16 to 19 percent. In the blunt trauma study, this equated to 13 patients from each arm who died before the benefits of treatment could be adequately assessed. Analysis of data for the 117 blunt trauma patients who survived at least 48 hours after receiving study treatment shows that, in addition to reducing RBC requirement, rFVIIa significantly reduced the need for massive transfusion over 48 hours (>20 RBC units) (relative risk reduction of 56% [95% confidence interval: 9%-79%]; p = 0. 03), and the fresh-frozen plasma (p = 0. 036), platelet (p = 0. 023), and cryoprecipitate (p = 0. 053) requirements within 48 hours, and was associated with a significant reduction in the 30-day risk of acute respiratory distress syndrome (ARDS) (p = 0. 05) and multiple organ failure and/or ARDS (p = 0. 05). CONCLUSION Treatment with adjunctive rFVIIa significantly reduces transfusion requirements in the 48 hours after severe injury and these procoagulant effects may improve clinical outcome at 30 days.
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8.
Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding
Dutton R, Hauser C, Boffard K, Dimsitts J, Bernard G, Holcomb J, Leppaniemi A, Tortella B, Bouillon B
Clinical Trials. 2009;6((5):):467-79.
Abstract
BACKGROUND Clinical research in trauma patients poses multiple challenges in study design. These reflect the heterogeneity of injury and treatment, the paucity of acceptable study endpoints aside from mortality, and the difficulties inherent in obtaining informed consent in acutely ill populations. A current example of this problem is the study of recombinant factor VIIa (rFVIIa), which has attracted considerable interest as a systemic procoagulant agent for use in trauma patients with exsanguinating hemorrhage. PURPOSE To report on the implementation of an international trial - CONTROL - intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience. METHODS The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in an acutely injured population with altered levels of consciousness, (3) avoiding futile care, while recruiting subjects with incompletely diagnosed injuries, (4) standardizing trauma intensive care across different investigating sites and countries, and (5) establishing study endpoints that were both clinically relevant and convincing to regulatory authorities. The resulting study methodology is reported. RESULTS The CONTROL trial began active recruitment in October 2005, and was halted on June 11, 2008 because the observed mortality in the 576 enrolled patients was so far below expectations that the study would lack sufficient statistical power at the planned number of subjects to demonstrate a benefit. The utility of the endpoints selected for study will not be known until completion of data analysis. LIMITATIONS Any clinical trial in trauma patients must cope with the urgency of care required, issues of patient heterogeneity, standardization of care across multiple centers, and the difficulties of obtaining informed consent. CONCLUSION Research in acutely hemorrhaging trauma patients presents numerous scientific and ethical challenges. The methodology of the CONTROL study is presented as an example of how some of these challenges can be approached and managed, and of the pitfalls that may arise.
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9.
Safety of rFVIIa in hemodynamically unstable polytrauma patients with traumatic brain injury: post hoc analysis of 30 patients from a prospective, randomized, placebo-controlled, double-blind clinical trial
Kluger Y, Riou B, Rossaint R, Rizoli SB, Boffard KD, Choong PI, Warren B, Tillinger M
Critical Care (London, England). 2007;11((4):):R85.
Abstract
BACKGROUND Trauma is a leading cause of mortality and morbidity, with traumatic brain injury (TBI) and uncontrolled hemorrhage responsible for the majority of these deaths. Recombinant activated factor VIIa (rFVIIa) is being investigated as an adjunctive hemostatic treatment for bleeding refractory to conventional replacement therapy in trauma patients. TBI is a common component of polytrauma injuries. However, the combination of TBI with polytrauma injuries is associated with specific risk factors and treatment modalities somewhat different from those of polytrauma without TBI. Although rFVIIa treatment may offer added potential benefit for patients with combined TBI and polytrauma, its safety in this population has not yet been assessed. We conducted a post hoc sub analysis of patients with TBI and severe blunt polytrauma enrolled into a prospective, international, double-blind, randomized, placebo-controlled study. METHODS A post hoc analysis of study data was performed for 143 patients with severe blunt trauma enrolled in a prospective, randomized, placebo-controlled study, evaluating the safety and efficacy of intravenous rFVIIa (200 + 100 + 100 microg/kg) or placebo, to identify patients with a computed tomography (CT) diagnosis of TBI. The incidences of ventilator-free days, intensive care unit-free days, and thromboembolic, serious, and adverse events within the 30-day study period were assessed in this cohort. RESULTS Thirty polytrauma patients (placebo, n = 13; rFVIIa, n = 17) were identified as having TBI on CT. No significant differences in rates of mortality (placebo, n = 6, 46%, 90% confidence interval (CI): 22% to 71%; rFVIIa, n = 5, 29%, 90% CI: 12% to 56%; P = 0. 19), in median numbers of intensive care unit-free days (placebo = 0, rFVIIa = 3; P = 0. 26) or ventilator-free days (placebo = 0, rFVIIa = 10; P = 0. 19), or in rates of thromboembolic adverse events (placebo, 15%, 90% CI: 3% to 51%; rFVIIa, 0%, 90% CI: 0% to 53%; P = 0. 18) or serious adverse events (placebo, 92%, 90% CI: 68% to 98%; rFVIIa, 82%, 90% CI: 60% to 92%; P = 0. 61) were observed between treatment groups. CONCLUSION The use of a total dose of 400 (200 + 100 + 100) microg/kg rFVIIa in this group of hemodynamically unstable polytrauma patients with TBI was not associated with an increased risk of mortality or with thromboembolic or adverse events.
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10.
Pharmacokinetics of recombinant activated factor VII in trauma patients with severe bleeding
Klitgaard T, Tabanera y Palacios R, Boffard KD, Iau PT, Warren B, Rizoli S, Rossaint R, Kluger Y, Riou B, NovoSeven Trauma Study Group
Critical Care (London, England). 2006;10((4):):R104.
Abstract
INTRODUCTION Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown. METHODS In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 microg x kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 microg x kg-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)). RESULTS Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml x kg-1 x h-1; central volume of distribution 89 (32% CV) ml x kg-1; inter-compartmental clearance 24 ml x kg-1 x h-1; and peripheral compartment volume 31 ml x kg-1. Baseline FVII coagulant activity was estimated at 0. 29 (39% CV) U x ml-1, initial half-life was 0. 6 (34% CV) hours, and terminal half-life 2. 4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters. CONCLUSION A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.