This review concluded that recombinant activated factor VII (rFVIIa) reduced bleeding in approximately three-quarters of patients treated for serious bleeding in abdominal, vascular or urological surgery, and that response to treatment significantly improved the probability of survival. Given the unclear reporting of the review and the uncertain quality of included studies, the validity of these conclusions is unclear.

To determine the role of recombinant activated factor VII (rFVIIa) in the treatment of serious bleeding in abdominal, vascular, and urological surgery.

MEDLINE, BIOSIS Previews, EMBASE, and Current Contents were searched for articles published between 1980 and March 2006. Key search terms were reported. References lists of retrieved articles were searched for further relevant publications. The manufacturer of rFVIIa was also asked to recommend articles. Both studies published in full and those available as abstracts were eligible for inclusion.

Eligible for inclusion were case reports or case series of patients undergoing abdominal or vascular surgery without pre-existing coagulation disorder that were treated with rFVIIa. Case series were defined as those involving at least three patients treated with rFVIIa for acute publication, with at least one having surgery in abdominal region. Eligible studies had to report outcomes including cessation of bleeding, reduction of blood loss, mortality, or occurrence of thromboembolic complications. Trauma patients and patients with abdominal trauma were excluded.

For included case reports (publication dates 1999 to 2005), approximately two-thirds of patients were male; most patients were adults in their forties and fifties (although some were infants); doses and indications were variable. For included case series (publication dates ranged from 2004 to 2006), indications, doses and patient characteristics were variable (where reported).

The authors did not state how reviewers selected studies for the review.

The review did not report any study quality assessment.

Based on whether there was a cessation or reduction in blood loss following rFVIIa administration, patients were classified as either 'responders' or 'non-responders' to the treatment. Data were also extracted on the following clinical outcomes: reduction or cessation of bleeding, mortality, and thromboembolism.

The authors did not state how many reviewers performed the data extraction.

For case reports, a range of basic descriptive statistics was reported for each outcome. For case series, random-effects meta-analyses were conducted for each outcome. It also appeared a meta-analysis was performed of placebo-controlled trials, although the review did not state that such data were searched for.

Ten case series (n=50 patients) and 15 case reports (n=17 patients) were included in the review. Additionally, it appeared that eight placebo controlled trials (n=840 patients) were reported as considered for a meta-analysis, of which five trials (n=717 patients) were included in the meta-analysis (the other three trials reported zero events).

Bleeding and mortality: The meta-analyses of the case series data indicated that after recombinant activated factor VII (rFVIIa) administration, bleeding was stopped or reduced in 73.2% (95% CI 51.0 to 95.4; 39 out of 50 patients) of cases and survival rates were 53.0% (95% CI 26.4 to 79.7; 20 out of 39 patients). For 10 patients in the case series, bleeding was not reduced or stopped after rFVIIa administration; only one patient survived. Of the 29 patients who did experienced a reduction or cessation of bleeding, 19 survived. In the case reports, all 17 patients experienced a reduction or cessation of bleeding after rFVIIa administration. Eight patients received a single dose of rFVIIa; others received two or more doses.

Thromboembolic complications: A meta-analysis of placebo-controlled trials (n=840 patients) indicated that the odds of thromboembolism were higher after receiving rFVIIa than with placebo, but the difference was not statistically significant. Of case series reporting side effects, six of the 36 patients showed signs of thromboembolic complications. Two of the 13 case reports containing information on side effects, reported thromboembolic events after renal transplantation.

A meta-analysis of case series showed a reduction of bleeding in 73.2% of patients undergoing abdominal surgery. Patients who responded to treatment with recombinant activated factor VII (where bleeding had stopped or was reduced) had a significantly higher probability of survival. Recombinant activated factor VII was not associated with an increased risk of thromboembolism compared with placebo.

This review addressed a clear review question, but the study selection criteria were unclear. Appropriate databases were searched, but neither the fact that placebo-controlled trials were eligible for inclusion, nor what measures were taken to identify conference abstracts, was reported. Few details were provided of the review process, so the risk of reviewer errors and/or bias affecting study selection, assessment of study quality and data extraction was unclear.

No quality assessment was reported, and most included studies were case reports or case series (generally considered lower quality evidence than large scale observational data or randomised controlled trials). Sufficient primary study details were reported for case reports and case series, but not for placebo-controlled trials. The method of synthesis generally appeared appropriate, although the stated assumption that the studies identified within the case series were a random sample may not be reliable; the intention to perform a meta-analysis of placebo-controlled studies was not stated at this stage. The results were adequately reported.

Overall, as much of the review was unclearly reported and most of the included studies were of uncertain quality, the validity of the conclusions based on these results is unclear.

Several of the authors disclosed financial links Novo Nordisk Pharma (manufacturers of rFVIIa drugs and one of the sponsors of the review).

Practice: The authors stated that, if there are not pre-existing coagulation disorders, there are no indications for the prophylactic administration of rFVIIa, but rFVIIa can be considered as an additional therapeutic option if serious bleeding was refractory to conventional treatment.

Research: The authors stated that prospective randomised studies are needed to investigate the efficacy and cost-effectiveness of rFVIIa in patients in whom serious bleeding was refractory to conventional treatment, in order to allow a final assessment of the importance of this treatment to be made.

Charite-University Medicine Berlin; Novo Nordisk Pharma GmbH, Mainz, Germany (manufacturers of recombinant activated factor VII drugs).

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.