We included 14 RCTs on the prophylactic use (n
= 1137) and 12 on the therapeutic use (n
= 2538) of recombinant factor VIIa in patients without hemophilia in our review. This number of trials might be considered to be sufficient for an informative result. However, the results indicated continuing uncertainty about the magnitude of benefits and harms. In the prophylactic studies, only modest benefits favouring recombinant factor VIIa were seen in the outcomes of blood loss, requirements of red blood cell transfusion (equivalent to less than one unit of red blood cells saved) and number of patients receiving transfusions. In the therapeutic studies, there was no clear advantage of recombinant factor VIIa over placebo for the outcomes of mortality, control of bleeding and transfusion requirements. However, for mortality, the 95% CI was close to significance and may be considered clinically important (RR 0.90; 95% CI 0.76 to 1.06). In both groups of trials, there was a trend toward increased thromboembolic events, although most RCTs excluded patients with a history of thromboembolic events. Promising results in earlier therapeutic studies were not replicated in larger trials,3,30,38
and the risk of bias assessment highlighted frequent problems in randomization, blinding and sample size.
Continued lack of clarity about the overall clinical effectiveness certainly stems from recombinant factor VIIa being genuinely less effective than was originally predicted. The trials in our review were undertaken across diverse clinical settings where different complex hemostatic pathways operate, and the expectation that recombinant factor VIIa would reverse all coagulopathy is inappropriate.12
The findings of our review are similar to those of a recent appraisal by Hsia and colleagues.4
However, we grouped the RCTs by how recombinant factor VIIa was used (prophylactic or therapeutic), because the expectations of benefit and acceptance of risk in these two situations are different. This separation and greater attention to the risk of bias in the included studies has emphasized the degree of uncertainty about effectiveness of off-label use of recombinant factor VIIa.
Our review raises challenges for future research assessing hemostatic agents, particularly concerning the choice of outcomes. Blood loss and control of bleeding are difficult to record in a standardized manner. Transfusion protocols should be supplied. The presence of a protocol was shown to decrease the effect of an intervention, as measured by reduction in use of allogeneic blood, compared with studies that had no transfusion protocol.39–41
In the studies included in our review, transfusion protocols were not always provided, and even less frequently were protocols reported for hemostatically active co-interventions such as plasma and platelet products ( and ). Mortality is the key outcome for therapeutic trials. However, in our review, we found that the baseline risk of death in the control groups ranged from 0% to 30%, with a mean of 20%. If we assumed a baseline risk of 20% and designed a superiority trial with an α level of 0.05 and β level of 0.20 and an expected RR of 0.90 (equivalent to a mortality of 18% in the treatment group), the trial would require about 12 000 patients to detect this difference. The cumulative number of participants evaluated to date in therapeutic trials is less than a quarter of this number.
We were not able to obtain additional outcome data from some studies to allow them to be included in the pooled analyses. These studies generally showed no difference between recombinant factor VIIa and placebo; therefore, their inclusion might be expected to move values further toward a no-difference summary estimate. In addition, we included only published full-text articles. Although publication bias was investigated and has been previously explored,7
it is impossible to completely exclude it.
Clinically significant benefits of recombinant factor VIIa as a general hemostatic agent in patients without hemophilia remain unproven. Our systematic review did not show a consistent benefit of off-label use of recombinant factor VIIa in the therapeutic setting and at best only modest benefits in the prophylactic setting. Given its potential risks, off-label use of this hemostatic agent cannot be recommended, and in most instances, it should be restricted to clinical trials.