The efficiency and safety of recombinant factor VIIa for bleeding in patients without haemophilia: a meta-analysis of 12 randomized controlled trials

Background: Despite widely use of recombinant factor VIIa (rFVIIa) for bleeding in patients without haemophilia, its efficiency and safety remain unclear. Therefore, we carried out a meta-analysis on this topic. Methods: We searched Cochrane Library, Web of Science, PubMed and Embase, from January 2008 to July 2019 for randomized controlled trials on the topic. The results of this work are synthesized and reported in accordance with the PRISMA statement. Results: Twelve trials met our inclusion criteria. rFVIIa over 200ug/kg reduced red blood cell (RBC) transfusions within 24 h by 232.34ml (95% confidence interval CI; -410.31 to -54.37). rFVIIa did not significantly reduce 30-day mortality (relative risk RR, 1.00; 95%CI, 0.82-1.21), total thromboembolic events (RR, 1.13; 95%CI, 0.94-1.36), myocardial infarction (RR, 1.37; 95%CI, 0.92-2.05), deep vein thrombosis (RR, 0.83; 95%CI, 0.52–1.33), ICU staying (RR, 0.40; 95%CI, -1.28 to 2.07) and number of patients transfused RBC (RR, 0.94; 95%CI, 0.83-1.08). However, rFVIIa may increase the incidence of arterial thrombotic events (RR, 1.38; 95%CI, 1.08–1.77). Conclusion: rFVIIa over 200ug/kg reduced RBC transfusions for bleeding in patients without haemophilia. However, it may increase the risk of arterial thrombotic events.

However, it may increase the risk of arterial thrombotic events.

Background
Major bleeding is an usually perioperative complication, which not only increases the incidence of homologous blood transfusion but also increases mortality [1,2].Recombinant activated factor VII (rFVIIa), a potent procoagulant that promotes hemostasis at sites of vascular injury [3].It is licensed for the treatment of patients with haemophilia A and B, acquired haemophilia, factor VII deficiency, or Glanzmann thrombasthenia, but it has been successfully used off-label in a very large number of patients with major bleeding [4]. Offlabel used of rFVIIa has been reported in severe trauma, liver transplantation, cardiac surgery, spontaneous intracerebral haemorrhage (ICH), and postpartum haemorrhage (PPH) [6][7][8][9][10][11][12][13][14][15][16]. A clinical trial published recently in patients with spontaneous intracerebral hemorrhage (ICH) that the administration of rFVIIa limits hematoma expansion [17].
However, concerns about extending the use of rFVIIa is the potential for adverse effects, in particular the risk of thromboembolism [5]. Mayer SA et al. [18] has reported that rFVIIa used to treatment of acute intracerebral hemorrhage increased thromboembolic. But studies could not show a clear benefit and harmful. Studies considering other systems focused on selected groups of participants or were conducted before many randomized controlled trials (RCT) publications. Therefore, more quality and statistically significant data are needed to guide the off-label applications, new trails are needed to update guidelines to adjust clinical practice. This review will critically evaluate the results of different identification trials and extend the early Cochrane findings for systematic review by including as many additional trials as possible.

Literature Search and Selection
Four trained investigators independently searched for comprehensive systematic literature in PubMed, Cochrane Library, Embase and Web of Science from January 2008 to July 2019.
The search strategy included the following terms: factor VIIa, recombinant activated factor VII, recombinant factor VIIa, NovoSeven, rFVIIa, Factor 7A, Factor Seven A, hemorrhage, bleeding, blood loss, haemorrhage. Moreover, we reviewed the references of included studies and the included research of related reviews to identify additional studies.
This study followed the statement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [21]. This study analyzed the efficiency and safety of rFVIIa in adult non-haemophiliac hemorrhage in randomized controlled trials. The inclusion criteria were as follows: Patients older than 18 years who require hemostatic treatment for hemorrhage. Patients with haemophilia or other haemostatic defects (for example, Glanzmann's thrombasthenia, inherited factorVII deficiency) were excluded; intervention: rFVIIa versus (Vs) placebo; study design: randomized controlled trials.
We excluded non-RCT trials and RCT studies in underage patients on this topic. In addition, studies with fewer than 10 patients were excluded, and we think would affect the accuracy and reliability of the analysis results.

Statistical Analysis
The risk ratio (RR) with 95% confidence intervals (95% CIs) was calculated for categorical varies and the mean difference (MD) was estimated by numeric varies. Heterogeneity among studies was tested using the Cochran Chi-square test and Inconsistency index (I 2 ), in which I 2 > 50% suggested significant heterogeneity. And when I 2 >50%, a random-effects model was chosen to pool the results, while the fixed-effects model was used when I 2 < 50%. Publication bias was detected using the Funnel plots tests, and the Egger test was recommended for enumeration data [23].Two-tailed P-values < 0.05 were considered statistical significance. The effect of publication bias on study results was analysis with the trim and fill method. In order to evaluate the effect of dose on red blood cell transfusions, we added a subgroup analysis to observe whether using a higher dose of rFVIIa can reduce RBC transfusions and improve the hemostatic effect. We performed sensitivity analyses of primary outcome events and heterogeneous significant outcomes.

Results of search
According to the previous search strategy, 617 studies were obtained from the four databases and 2 studies were found by searching the reference lists and reviewed articles. After removing the duplicates, 416 publications remained in total and 401 records were excluded by browsing title and abstract. Among the remaining 15 records, 4 citations were removed according to our inclusion and exclusion criteria. Finally, 11 full-text studies (12 trials, a study consisted of 2 parallel randomized controlled trials) were suitable for this meta-analysis. (Fig. 1). The characteristics, type of haemorrhageand intervention methods of included studies were summarized in Table 1.

Risk of bias within studies
Bias risk of twelve trials was assessed in Fig.2. Two experiments did not provide a detailed method of random processes. The blinding process was at high risk of bias in two studies and unclear risk of bias in one study. No study had unclear or incomplete descriptions of their outcome data. Five trials did not provide a satisfactory description of reporting bias and nine studies did not indicate the other bias in the article. [MD=-232.34(-410.31--54.37), P for effect =0.01, P for heterogeneity=0.77, I2 = 0%].

Arterial thrombotic events
Compared with the control group, rFVIIa significantly increased the incidence of arterial thrombotic events, and there was no significant heterogeneity.  (Fig. 4c).  (Fig.5a).

Publication Bias and Sensitivity Analysis
Funnel plots showed that there was asymmetric distribution of included studies. Egger

Discussion
The main results in this meta-analyzed show that high dose rFVIIa would significantly reduce RBC transfusions, increase arterial thrombotic events, but did not increase patiences mortality, ICU-stay, total thromboembolic events, deep vein thrombosis and myocardial infarction.
Besides, there were no heterogeneity among studies on most outcomes and sensitivity analysis also suggested the results were not affected by individual research.

Availability of data and materials
All data generated or analysed during this study are included in this published article and its supplementary information files.

Competing interests
The authors declare that they have no competing interests.