Abstract

BACKGROUND Rapid replacement of blood loss is critical in patients suffering from traumatic hemorrhage. When the availability of blood products is limited, certain interventions have shown promise in conserving blood supplies. Recombinant factor (rF) VIIa has been administered, as an off-label use, to assist in controlling hemorrhage in trauma patients. Although rFVIIa has a tendency to remain localized to areas of vascular insult, there may be an increase in thromboembolism formation when patients suffer multiple sites of injury as seen in blunt force trauma. OBJECTIVES This review aimed to synthesize the best available evidence regarding the incidence of thromboembolism formation after receiving rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of packed red blood cells [PRBCs], fresh frozen plasma [FFP], platelets and crystalloid solutions) in patients suffering from traumatic injuries (blunt force and penetrating trauma). INCLUSION CRITERIA TYPES OF PARTICIPANTS Civilian and combat trauma patients who were 15 years and older suffering from blunt force and penetrating traumatic injuries. TYPES OF INTERVENTION(S)/PHENOMENA OF INTEREST Use of rFVIIa as an adjunct to hemorrhage control measures (standard resuscitation efforts consisting of varying amounts of PRBCs, FFP, platelets and crystalloid solutions). TYPES OF STUDIES This review considered both experimental and epidemiological study designs. TYPES OF OUTCOMES Confirmed formation of thromboembolism (confirmation based on specific diagnostic tests such as ultrasound, ventilation-perfusion scan or angiography). SEARCH STRATEGY The databases searched included CINAHL, Ovid MEDLINE, Web of Science, EMBASE and the Cochrane Control Register of Clinical Trials. Studies published after June 1986 were considered for inclusion in this review. Search for unpublished studies was performed. METHODOLOGICAL QUALITY Studies selected for inclusion were critically appraised by two independent reviewers using standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). DATA EXTRACTION Data was extracted from articles using standardized data extraction instruments from the JBI. DATA SYNTHESIS Quantitative results were pooled in statistical meta-analysis using the Joanna Briggs software for meta-analysis. RESULTS Two studies with a total of 831 participants were included. Both the studies were randomized, placebo-controlled, double-blind trials. No studies of combat trauma patients met the inclusion criteria for this review. A meta-analysis was performed. In blunt force trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 1.17 with a 95% confidence interval (CI) from 0.77 to 1.79; results not statistically significant (P = 0.4594); large CI and imprecise estimate. In penetrating trauma patients, the incidence of thromboembolism formation on administering rFVIIa revealed an overall relative risk of 0.77 with a 95% CI from 0.27 to 2.20; results not statistically significant (P = 0.6242); very large CI and imprecise estimate. CONCLUSIONS The estimates of the effects are imprecise, results are compatible with effects in opposite directions, increase or decrease of thromboembolism formation, and an increase of thromboembolism formation cannot be excluded. IMPLICATIONS FOR PRACTICE When rFVIIa is administered to trauma patients, there does not appear to be an increased risk of thromboembolism formation favoring one type of injury over the other (blunt force versus penetrating trauma). Owing to large CIs and imprecise estimates, the overall risk of thromboembolism cannot be excluded. The use of rFVIIa does appear to decrease the overall need for blood products in trauma patients with no statistically significant improvement in survival rates. With the high cost of rFVIIa, its use is limited to those facilities that can afford it. In situations wherein blood supply is limited, rFVIIa could conserve limited supplies of

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.

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.

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.

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.

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.

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.

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.

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.

Abstract

STUDY OBJECTIVE The use of recombinant activated factor VII (rFVIIa) in severe trauma is controversial. This evidence-based emergency medicine review evaluates the existing evidence about the efficacy and safety of rFVIIa for the management of severe trauma. METHODS We searched MEDLINE, EMBASE, the Cochrane Library, and other databases. We limited our review to prospective, controlled trials that involved the therapeutic use of rFVIIa in the emergency department phase of care. We included studies with blunt and penetrating severe trauma. The primary outcome measure of interest was mortality. Secondary patient-important outcome measures included neurologic outcome, delayed surgical intervention, and adverse effects. Standard criteria were used to evaluate the quality of published trials. RESULTS One randomized, blinded trial met the inclusion criteria. There was no significant difference in mortality or adverse effects between rFVIIa and placebo. Our other selected secondary outcome measures of interest were not reported. CONCLUSION Existing evidence suggests that there is no significant difference in mortality between rFVIIa and placebo. Further research is needed to better understand the efficacy and safety of rFVIIa in patients with severe trauma.