Boffard KD, Rious 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 Inj Infect Crit Care. 2005;59(1):8-18.

The purpose of the study was to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as an adjunctive therapy to control bleeding in trauma patients. The study supported the use of rFVIIa in traumatic patients and also demonstrated clinical benefits in this patient population when compared with those who were limited to receiving only blood products, to correct coagulopathies.

The researchers wanted to evaluate the impact of rFVIIa on bleeding in traumatic patients. A gap in literature was reported relating to the fact that most data supporting the use of rFVIIa in trauma patients were limited to case studies and anecdotal reports. This provided a rationale to generate data that could support the use of rFVIIa in other patients as opposed to the traditional patient populations who are diagnosed with acquired hemophilia and FVIIa deficiency.

HYPOTHESIS

The researchers proposed that a 60% reduction in the postdose 48-hour red blood cells (RBC) requirement from 4.4 to 1.8 units would be clinically significant, and they calculated that 140 patients would be required in each trauma trial to detect the difference with an 80% power and 5% type 1 error.

METHODOLOGY

The study designs were 2 parallel randomized, placebo-controlled, double-blind clinical trials (one in blunt trauma and the other in penetrating trauma) which were conducted simultaneously at 32 hospitals in various parts of the world. The variables in the trials were operationally defined and this allowed for a better understanding of the data.

SAMPLE

The randomized double-blind sampling provided credibility to the findings. The research participants (N = 301) were described demographically by age, sex, health acuity status, and mode of injury (penetrating trauma (N = 158) vs blunt trauma (N = 143)). The research participants were categorized taking into account the time from injury to hospitalization and the time of injury from hospitalization to trial product dosing. One research participant was reported to have both blunt and penetrating trauma and was assigned to the blunt trauma group.

All the research participants were consented and the study protocols had the approval of the ethics committees from the participating hospitals. Because of the critical nature of the trauma diagnosis, it is often debatable if human subjects' rights to confidentiality and freedom from coercion can be safeguarded in such instances. The stressful conditions could have made it difficult for the research participants or their family members to express wishes for withdrawal.

DATA ANALYSIS

The authors used a nonparametric level of measurement to report the results. Prominent among the tests used was the one-sided Wilcoxon-Mann-Whitney rank test, which compared the total number of RBC units transfused within 48 hours from the start of the trial product treatment between the study groups. The test was also used to analyze ventilator-free and intensive care unit-free days within the 30 days of trial product treatment. The Hodges-Lehmann estimate was used to estimate the difference in red blood cell transfusions, and the Fisher exact test was used to compare the number of patients requiring massive transfusions and those experiencing critical complications or death within the follow-up trial period. Chi-square testing was used to analyze the effects on 48-hour mortality.

RESULTS

rFVIIa significantly reduced 48-hour RBC requirement by 2.6 units compared with placebo in the patients with blunt trauma. In the penetrating trauma group, no significant effect of rFVIIa was observed within the 48-hour RBC requirement. Statistical significance was not reached in both study groups when assigning patients who died to the worst outcome. There was no significant difference between the treatment groups with respect to the administration of fresh frozen plasma, platelets, or cryoprecipitates, and data were not shown in the publication.

LIMITATIONS

The data on thromboembolic complications were collected through adverse reporting events only and underreporting of asymptomatic thromboembolic events could have accounted for the low overall incidence and complications. The researchers had a tight inclusion and exclusion criterion, thereby creating a subgroup of trauma patients, which could lead to sampling bias. Routine monitoring of the prothrombin levels could have potentially revealed whether a patient received rFVIIa or placebo, creating limitations on the double-blind design.

Another limitation of the study was on the effect of treatment on days of ventilator dependency and hospitalization due to the 30-day cutoff period for follow-up. Hospitalization requirements could have been studied optimally if there would have been an extension of the follow-up period because a majority of the patients were reported to be hospitalized after 30 days.

Although the various trauma sites had to follow the study protocol, there were differences in patient management. No restrictions were imposed on procedures deemed necessary by the attending physicians; thus, other extrinsic factors could have influenced the study and clinical outcomes.

CONCLUSION

The authors established the safe use of rFVIIa in the trauma population. Bleeding control in blunt trauma patients was significantly improved with rFVIIa as evidenced by a decrease in the RBC transfusion requirements and the number of patients requiring transfusion. Trends in improved clinical outcomes were also observed as positive results of the study.

Although the authors did not make recommendations for future studies, the study has implications for future research and practice. More research could be done to evaluate the influence of the limitation factors on the outcomes of rFVIIa. This could play a pivotal role in reducing the morbidity and mortality of trauma patients. The study results have implications for nurses and researchers because it will generate a platform for discussions in establishing other options in managing coagulopathies in trauma patients.