November 2010
Journal Club Handout Template
Name: David J. Dries, MSE, MD
Assistant Medical Director for Surgical Care
HealthPartners Medical Group
Professor of Surgery & Anesthesiology
John F. Perry, Jr. Chair of Trauma Surgery
University of Minnesota
Article Title/Citation:
Results of the CONTROL Trial: Efficacy and Safety of Recombinant Activated Factor VII in the Management of Refractory Traumatic Hemorrhage.
J Trauma 2010; 69:489-500
Study objectives/purpose
To evaluate impact of recombinant Factor VIIa on blood product usage and mortality in a population of patients sustaining penetrating and blunt trauma.
Brief Background
Traumatic hemorrhage is the most common case of early mortality after injury. If blood loss and tissue injury are of sufficient magnitude, a coagulopathy after injury is also identified which is independently associated with increased morbidity and mortality. Traumatic coagulopathy may cause massive bleeding and death after shock. This coagulopathy presents even before resuscitation has been initiated.
Management of traumatic coagulopathy begins with administration of blood products. Agents such as recombinant Factor VIIa are under investigation to enhance clot formation in the presence of injured or ischemic tissue. Recombinant Factor VIIa has been approved for use in hemophilia but has been widely used off-label as part of management protocols for traumatic coagulopathy.
Funding Sources: Novo Nordisk A/S, Bagsvaerd, Denmark.
Methods
Study design and Methodology
Prospective, randomized double-blind multicenter (150 hospital in 26 countries) placebo controlled trial conducted from August 2005 to September 2008.
Patient Selection and Enrollment
This trial was designed to evaluate safety and efficacy of recombinant Factor VIIa in patients with active hemorrhage due to trauma who had already received 4 units of packed red blood cells but had not yet received an 8th unit.
Interventions
Patients were randomized 1:1 to receive three doses of recombinant Factor VIIa (200 mcg/kg at time zero, 100 mcg/kg at 1 hr and 100 mcg/kg at 3 hr) or placebo. Placebo contained the same formulation as the trial drug except for the recombinant Factor VIIa component.
Outcome Measures
Endpoints:
The primary endpoint was 30-day mortality. Secondary outcomes included blood product use in blunt and penetrating trauma. Safety screens, primarily for thrombotic events, were followed through 90 days.
Statistical Analysis:
Sample size calculations were based on comparisons of mortality for the intent to treat population using one-sided X2 tests (significance level 2.5%). The aim was to detect a 16.7% mortality reduction with recombinant Factor VIIa, assuming 30% mortality in placebo patients. These estimates were based on outcomes of patients in a prior Phase II trail. The probability of demonstrating efficacy at the primary endpoint (mortality) was estimated at >80% for a sample size of 1,276 blunt trauma patients.
Mortality, multiple organ failure and single organ failure rates through day 30 were compared using logistic regression and baseline covariates including age, Injury Severity Score, Glasgow Coma Score, INR and Acute Lung Injury (based on PaO2/FiO2 ratio <300). Days alive and free of multiple organ failure, single organ failure, mechanical ventilation, renal replacement therapy, ICU and hospitalization through day 30 were also evaluated using analysis of variance with treatment as a factor and relevant baseline factors as potential covariates.
Number of transfused units of red blood cells, fresh frozen plasma, platelets, cryoprecipitate or fibrinogen concentrates and allogeneic units were recorded and compared.
Results
Enrollment & Baseline Characteristics:
Five hundred and seventy-three patients (481 blunt, 92 penetrating trauma) were enrolled and randomized with 560 patients dosed with recombinant Factor VIIa or placebo. Ten patients (5 blunt, 5 penetrating) were randomized but withdrawn from the study before study solution was administered because they were found to be ineligible.
Populations were young and predominately male with baseline characteristics of the treatment groups similar for blunt and penetrating trauma. There were no relevant differences in baseline Injury Severity Score, Glasgow Coma Score, blood pressure, hemoglobin, markers of acidosis or coagulopathy between groups receiving recombinant Factor VIIa and placebo. Mean red blood cell transfusion requirement before enrollment was 5.6 units in both blunt trauma groups and 5.5 versus 5.4 units of red blood cells in penetrating trauma patients receiving recombinant Factor VIIa versus placebo.
Summary of Primary & Secondary outcomes
Interim analysis of mortality from 447 blunt trauma patients showed lower than expected mortality rates. The power to demonstrate superiority of recombinant Factor VIIa versus placebo was 11.2% versus the predefined threshold of 50%. The trial was stopped early with 573 of 1,502 patients enrolled because of the high likelihood of futility in demonstrating the primary endpoint of mortality reduction in the blunt trauma population.
Blunt Trauma Population
There was no difference in ventilator-free days, renal replacement therapy-free days or durable morbidity rates at day 30 between the two groups.
Major secondary endpoint differences were related to blood product use. Recombinant Factor VIIa treated blunt trauma groups showed significant reductions in red blood cell, fresh frozen plasma and total allogeneic transfusions.
Units transfused from Factor VIIa dosing to 24 hours were 6.9 versus 8.1 for red blood cells (p=0.04), 4.7 versus 6.9 for fresh frozen plasma (p<0.001), and 17.1 versus 20.7 for total allogeneic products (p=0.03) in the recombinant Factor VIIa group compared with the placebo group.
No significant difference was seen in safety profile of recombinant Factor VIIa compared with placebo after blunt trauma.
Penetrating Trauma Population
Patients with penetrating trauma were younger, predominately male and had a lower ISS than patients with blunt trauma. The recombinant Factor VIIa group was slightly older than the placebo group but the penetrating trauma groups were otherwise comparable.
As in blunt trauma, recombinant Factor VIIa reduced transfusion requirements. The recombinant Factor VIIa group showed consistent trends toward reduction in allogeneic blood product use from dosing to 24 hours and 48 hours. Because of small sample size, many of these results did not achieve statistical significance. The decrease in fresh frozen plasma use in the recombinant Factor VIIa group was significant. In the recombinant Factor VIIa group, 3.8 units of fresh frozen plasma were administered versus 5.7 units of fresh frozen plasma in the placebo group (p=0.04) from dosing to 24 hours and 4.0 units versus 6.5 units (p=0.02) from dosing to 48 hours.
As in blunt trauma, no difference was seen in overall safety profile of recombinant Factor VIIa compared with placebo after penetrating trauma. In fact, venous thrombotic events occurred in significantly higher numbers in placebo-treated patients following penetrating trauma.
Author’s Discussion and Conclusions
Brief Summary of Authors’ Main Discussion Points:
Recombinant Factor VIIa reduced blood product requirements in bleeding trauma patients. This is consistent with previous studies.
Thrombotic complications are frequent after major injury. Any pro-coagulant therapy may be expected to increase thrombotic risk. Although not powered for safety, this trial demonstrated no increase in thrombotic events where patients received recombinant Factor VIIa rather than placebo.
No prevention of death and only a trend toward less frequent multiple organ failure could be identified at the present trial size.
Author’s Conclusions:
It is difficult to demonstrate incremental improvement in trauma outcome with a single agent. Because its hemostatic effect is clear, the search for trauma patient subsets where recombinant Factor VIIa may have significant benefit should continue.
Discussion and Conclusions
Study Strengths:
This is a rigorously designed multi-center trial with excellent prospective organization and study design based on good administrative trauma data.
Study Limits, Weakness, Potentials for Bias, etc.:
Obviously, this study, being industry sponsored, was not carried to completion due to concern for futility. As with any industry work, there is a potential for bias. It is important that this negative study was published given the cost and potential risk associated with recombinant Factor VIIa use.
Applicability & Impact On Healthcare Providers:
Several other studies of factor VII use in trauma are cited below. None of these studies indicates a benefit of recombinant Factor VIIa on outcome. There is some data to suggest that blood product use may be reduced.
- Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: Two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005; 59:8-18.
- Raobaikady R, Redman J, Ball JA, et al. Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: A double-blind, randomized, placebo-controlled trial. Br J Anaesth 2005; 94:586-591.
- Wade CE, Eastridge BJ, Jones JA, et al. Use of recombinant factor VIIa in US military casualties for a five-year period. J Trauma 2010; 69:353-359
Additional Thoughts/Comments:
I have spoken with the lead investigator on recombinant Factor VIIa in the United States military. Consistent with the military data (reference above), the military has moved away from the use of recombinant Factor VIIa as a prominent part of trauma resuscitation.
Conclusions and Recommendations:
Broad use of recombinant Factor VIIa in the management of the injured patient with bleeding cannot be recommended at this time. I agree that additional study regarding the role for this expensive therapy is warranted. However, I believe that this should not take place outside of carefully designed clinical trials.
