Authors' objectives:

The objectives of this special report were to review the clinical, methodologic and cost issues associated with rFVIIa use. This report also reviews the RCT evidence that is available on the safety and efficacy of rFVIIa for specific off-label indications.

Authors' results and conclusions: There are numerous reports of off-label use of rFVIIa for a wide variety of indications. Eleven RCTs were identified that met the inclusion criteria, including the indications of intracranial hemorrhage (ICH), trauma, GI bleeding, and a number of elective surgical procedure. The data on efficacy is most compelling for ICH, for which one high-quality RCT of 399 patients reported significant benefits associated with rFVIIa treatment. These benefits included a relative decrease in mortality of 38% (absolute risk reduction 11%; number needed to treat [NNT]=9), and substantial improvements on a variety of stroke-related and general quality of life and functional status measurements. This trial also reported an increased risk of arterial thrombotic events (5% versus 1%, p=0.01), but it was felt unlikely that this increase in adverse events offset the reported benefits. One trial of trauma suggested potential benefits for rFVIIa treatment in blunt trauma patients, including a decrease in the number of patients requiring massive transfusion and a decrease in critical organ complications (defined as acute respiratory distress syndrome and/or multi-organ failure). This study did not meet the criteria for a high-quality trial, did not report any differences in mortality, and did not find statistically significant benefits for patients with penetrating trauma. The other available RCTs do not report benefits in morbidity or mortality outcomes. Some of the studies, e.g., GI bleeding in patients with cirrhosis, report no group differences. For the elective surgery studies, some studies report decreased total blood loss and/or decreased transfusion requirements. However, this finding is not consistent across studies and some studies of elective surgery report no differences in blood loss or transfusion requirements. Most of the available RCTs do not report a significant increase in adverse events. The rate of thrombotic events aggregated across all eleven RCTs was 6.4% for rFVIIa vs. 5.0% for placebo, a difference that was not statistically significant when calculated by chi-square.

Authors' recommendations: The potential off-label indications for rFVIIa use in uncontrolled bleeding are numerous. Case reports and case series exist for treatment of inherited coagulopathies, platelet disorders, hepatic dysfunction, intracranial hemorrhage, acute trauma, GI bleeding, neonatal and pediatric coagulopathies, reversal of anticoagulation, and perioperative blood loss. For some of the rarer conditions, such as inherited factor deficiencies, the decision to use rFVIIa may need to be made on an individual basis in consultation with experts, given that RCTs in these conditions may not be feasible. For more common conditions, the results of RCTs can be expected to guide optimal rFVIIa use. The available RCTs have begun to define the potential benefits of rFVIIa in terms of morbidity and mortality, as well as blood loss and transfusion requirements. While there is only limited evidence for each indication, some studies report significant health outcome benefits. In the larger ICH trial, the mortality reduction and the improvement in quality of life and functional status is impressive, suggesting a potential major treatment advance for this condition in patients who meet eligibility requirements. For trauma, one trial also suggests benefits for rFVIIa in terms of avoiding critical organ complications, but this trial has some methodologic limitations, and the magnitude of benefit appears to be less compared with the ICH trial. Some of these trials, particularly those on elective surgical procedures, report only on outcomes related to blood loss and/or transfusion requirements. These benefits are more difficult to put into clinical perspective, given the very small risks associated with blood transfusion today. In the absence of morbidity and mortality benefits, blood loss outcomes need to weigh the small risks of allogeneic transfusion against the risks of adverse events from rFVIIa and the costs of this agent. At present, the adverse event rate is poorly defined for off-label indications; therefore, it is not possible to estimate the risk/benefit ratio of using rFVIIa to reduce perioperative blood loss. The costs of rFVIIa are substantial and vary widely depending on the dose used and whether repeated doses are given. The costs for treatment of individual bleeding episodes may range from several thousand dollars to over US$50,000. Future studies that better define the optimal dosing and repeated administration would be helpful in reducing this variability. Formal cost-effectiveness analyses may be helpful in the future to evaluate the trade-off between costs of this agent, savings due to prevention of morbidity and mortality, and savings due to avoidance of the need for other blood products.

Authors' methods: Review

Project Status: Completed

URL for project: http://www.bcbs.com/blueresources/tec/contact-tec.html

Year Published: 2006

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: BlueCross BlueShield Association

Contact Address: BlueCross BlueShield Association, Technology Evaluation Center, 225 North Michigan Ave, Chicago, Illinois, USA. Tel: 888 832 4321

Contact Name: tec@bcbsa.com

Contact Email: tec@bcbsa.com

Copyright: BlueCross BlueShield Association (BCBS)