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Figure 1.
Study characteristics and selection.

Study characteristics and selection.

Figure 2.
Plot of allogeneic packed red blood cell transfusion rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Plot of allogeneic packed red blood cell transfusion rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Figure 3.
Plot of thromboembolic complication rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Plot of thromboembolic complication rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Figure 4.
Plot of mortality rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Plot of mortality rates in the selected studies. CI indicates confidence interval; rFVIIa, recombinant activated factor VII.

Table 1. 
Description of Studies Included in the Systematic Review
Description of Studies Included in the Systematic Review
Table 2. 
Number of Patients and Interventions in the 7 Selected Studies
Number of Patients and Interventions in the 7 Selected Studies
Table 3. 
Description of the 7 Full Studies Included in the Systematic Review
Description of the 7 Full Studies Included in the Systematic Review
1.
Monroe  DMHoffman  MOliver  JARoberts  HR Platelet activity of high dose factor VIIa is independent of tissue factor. Br J Haematol 1997;99 (3) 542- 547
PubMedArticle
2.
Hedner  UErhardtsen  E Potential role for rFVIIa in transfusion medicine. Transfusion 2002;42 (1) 114- 124
PubMedArticle
3.
Ahonen  JJokela  R Recombinant factor VIIa for life-threatening post-partum haemorrhage. Br J Anaesth 2005;94 (5) 592- 595
PubMedArticle
4.
Bouwmeester  FWJonkhoff  ARVerheijen  RHvan Geijn  HP Successful treatment of life-threatening postpartum hemorrhage with recombinant activated factor VII. Obstet Gynecol 2003;101 (6) 1174- 1176
PubMedArticle
5.
Daniloś  JGoral  APaluszkiewicz  PPrzesmycki  KKotarski  J Successful treatment with recombinant factor VIIa for intractable bleeding at pelvic surgery. Obstet Gynecol 2003;101 (6) 1172- 1173
PubMedArticle
6.
Dunkley  SMMackie  F Recombinant factor VIIa used to control massive haemorrhage during renal transplantation surgery; vascular graft remained patent. Hematology 2003;8 (4) 263- 264
PubMedArticle
7.
Flynn  JDPajoumand  MCamp  PC  JrJahania  MSRamaiah  CAkers  WS Recombinant factor VIIa for refractory bleeding following orthotopic heart transplantation. Ann Pharmacother 2004;38 (10) 1639- 1642
PubMedArticle
8.
Gerlach  RMarquardt  GWissing  HScharrer  IRaabe  ASeifert  V Application of recombinant activated factor VII during surgery for a giant skull base hemangiopericytoma to achieve safe hemostasis. J Neurosurg 2002;96 (5) 946- 948
PubMedArticle
9.
Gielen-Wijffels  SEvan Mook  WNvan der Geest  SRamsay  G Successful treatment of severe bleeding with recombinant factor VIIa after kidney transplantation. Intensive Care Med 2004;30 (6) 1232- 1234
PubMedArticle
10.
Heilmann  LWild  CHojnacki  BPollow  K Successful treatment of life-threatening bleeding after cesarean section with recombinant activated factor VII. Clin Appl Thromb Hemost 2006;12 (2) 227- 229
PubMedArticle
11.
Leibovitch  LKenet  GMazor  K  et al.  Recombinant activated factor VII for life-threatening pulmonary hemorrhage after pediatric cardiac surgery. Pediatr Crit Care Med 2003;4 (4) 444- 446
PubMedArticle
12.
Liem  AKBiesma  DHErnst  SMSchepens  AA Recombinant activated factor VII for false aneurysms in patients with normal haemostatic mechanisms. Thromb Haemost 1999;82 (1) 150- 151
PubMed
13.
Price  GKaplan  JSkowronski  G Use of recombinant factor VIIa to treat life-threatening non-surgical bleeding in a post-partum patient. Br J Anaesth 2004;93 (2) 298- 300
PubMedArticle
14.
Raux  MChiche  LVanhille  ERiou  B Recombinant activated factor VII to control massive postoperative bleeding after septic aortobifemoral grafting. Eur J Anaesthesiol 2005;22 (10) 805- 807
PubMedArticle
15.
Stratmann  GRussell  IAMerrick  SH Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair. Ann Thorac Surg 2003;76 (6) 2094- 2097
PubMedArticle
16.
Vidal  MASebastianes  CEizaga  RMartinez  ETorres  LM Activated recombinant factor VII for bleeding after a kidney transplant. Rev Esp Anestesiol Reanim 2005;52 (10) 638- 639
PubMed
17.
Weilbach  CScheinichen  DJuttner  BSchurholz  TPiepenbrock  S Excessive blood loss after abdominal hysterectomy: use of recombinant factor VIIa. Anasthesiol Intensivmed Notfallmed Schmerzther 2004;39 (11) 672- 675
PubMedArticle
18.
Aggarwal  AMalkovska  VCatlett  JPAlcorn  K Recombinant activated factor VII (rFVIIa) as salvage treatment for intractable hemorrhage. Thromb J 2004;2 (1) 9
PubMedArticle
19.
Al Douri  MShafi  TAl Khudairi  D  et al.  Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11 ((suppl 1)) S121- S127
PubMedArticle
20.
Benharash  PBongard  FPutnam  B Use of recombinant factor VIIa for adjunctive hemorrhage control in trauma and surgical patients. Am Surg 2005;71 (9) 776- 780
PubMed
21.
Carvalho  ALeitao  JLouro  E  et al.  Small dose of recombinant factor VIIa (rFVIIa) to perform percutaneous liver biopsies in cirrhotic patients. Rev Esp Enferm Dig 2002;94 (5) 280- 285
PubMed
22.
DiDomenico  RJMassad  MGKpodonu  JNavarro  RAGeha  AS Use of recombinant activated factor VII for bleeding following operations requiring cardiopulmonary bypass. Chest 2005;127 (5) 1828- 1835
PubMedArticle
23.
Egan  JRLammi  ASchell  DNGillis  JNunn  GR Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med 2004;30 (4) 682- 685
PubMedArticle
24.
Etxániz Alvarez  APita Zapata  ERama Maceiras  PDuro Tacon  JPose Cambeiro  P Recombinant activated factor VII in the postanesthetic recovery unit: review of 16 cases. Rev Esp Anestesiol Reanim 2006;53 (3) 159- 162
PubMed
25.
Gala  BQuintela  JAguirrezabalaga  J  et al.  Benefits of recombinant activated factor VII in complicated liver transplantation. Transplant Proc 2005;37 (9) 3919- 3921
PubMedArticle
26.
Heisel  MNagib  MMadsen  LAlshiekh  MBendel  A Use of recombinant factor VIIa (rFVIIa) to control intraoperative bleeding in pediatric brain tumor patients. Pediatr Blood Cancer 2004;43 (6) 703- 705
PubMedArticle
27.
Hyllner  MHoultz  EJeppsson  A Recombinant activated factor VII in the management of life-threatening bleeding in cardiac surgery. Eur J Cardiothorac Surg 2005;28 (2) 254- 258
PubMedArticle
28.
Kaw  LL  JrCoimbra  RPotenza  BMGarfin  SRHoyt  DB The use of recombinant factor VIIa for severe intractable bleeding during spine surgery. Spine 2004;29 (12) 1384- 1387
PubMedArticle
29.
Manning  BJHynes  NCourtney  DFSultan  S Recombinant factor VIIa in the treatment of intractable bleeding in vascular surgery. Eur J Vasc Endovasc Surg 2005;30 (5) 525- 527
PubMedArticle
30.
O’Connell  NMPerry  DJHodgson  AJO’Shaughnessy  DFLaffan  MASmith  OP Recombinant factor VIIa in the management of uncontrolled hemorrhage. Transfusion 2003;43 (12) 1711- 1716
PubMedArticle
31.
Park  PFewel  MEGarton  HJThompson  BGHoff  JT Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients. Neurosurgery 2003;53 (1) 34- 38
PubMedArticle
32.
Raivio  PSuojaranta-Ylinen  RKuitunen  AH Recombinant factor VIIa in the treatment of postoperative hemorrhage after cardiac surgery. Ann Thorac Surg 2005;80 (1) 66- 71
PubMedArticle
33.
Tawfick  WATawfik  SHynes  NMahendran  BSultan  S Critical bleeding in vascular surgery: expanding the indication of recombinant activated factor VII. Vascular 2006;14 (1) 32- 37
PubMedArticle
34.
Tobias  JDSimsic  JMWeinstein  SSchechter  WKartha  VMichler  R Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients. J Intensive Care Med 2004;19 (5) 270- 273
PubMedArticle
35.
Yan  QChang  AC Pharmacologic therapy for postoperative bleeding in children after cardiac surgery: when will the bleeding stop? Pediatr Crit Care Med 2004;5 (3) 297- 298
PubMedArticle
36.
Hendriks  HGMeijer  Kde Wolf  JT  et al.  Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001;71 (3) 402- 405
PubMedArticle
37.
Karkouti  KBeattie  WSWijeysundera  DN  et al.  Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005;45 (1) 26- 34
PubMedArticle
38.
Niemann  CUBehrends  MQuan  D  et al.  Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores. Transfus Med 2006;16 (2) 93- 100
PubMedArticle
39.
von Heymann  CRedlich  UJain  U  et al.  Recombinant activated factor VII for refractory bleeding after cardiac surgery: a retrospective analysis of safety and efficacy. Crit Care Med 2005;33 (10) 2241- 2246
PubMedArticle
40.
Friederich  PWGeerdink  MGSpataro  M  et al.  The effect of the administration of recombinant activated factor VII (NovoSeven) on perioperative blood loss in patients undergoing transabdominal retropubic prostatectomy: the PROSE study. Blood Coagul Fibrinolysis 2000;11 ((suppl 1)) S129- S132
PubMedArticle
41.
Pihusch  MBacigalupo  ASzer  J  et al.  Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation. J Thromb Haemost 2005;3 (9) 1935- 1944
PubMedArticle
42.
Jeffers  LChalasani  NBalart  LPyrsopoulos  NErhardtsen  E Safety and efficacy of recombinant factor VIIa in patients with liver disease undergoing laparoscopic liver biopsy. Gastroenterology 2002;123 (1) 118- 126
PubMedArticle
43.
Lodge  JPJonas  SJones  RM  et al.  Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11 (8) 973- 979
PubMedArticle
44.
Lodge  JPJonas  SOussoultzoglou  E  et al.  Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial. Anesthesiology 2005;102 (2) 269- 275
PubMedArticle
45.
Planinsic  RMvan der Meer  JTesta  G  et al.  Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005;11 (8) 895- 900
PubMedArticle
46.
Shao  YFYang  JMChau  GY  et al.  Safety and hemostatic effects of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Am J Surg 2006;191 (2) 245- 249
PubMedArticle
47.
Raobaikady  RRedman  JBall  JAMaloney  GGrounds  RM Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: a double-blind, randomized, placebo-controlled trial. Br J Anaesth 2005;94 (5) 586- 591
PubMedArticle
48.
Friederich  PWHenny  CPMesselink  EJ  et al.  Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet 2003;361 (9353) 201- 205
PubMedArticle
49.
Diprose  PHerbertson  MJO’ Shaughnessy  DGill  RS Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005;95 (5) 596- 602
PubMedArticle
50.
Siegel  LJGerigk  LTuettenberg  JDempfle  CEScharf  JFiedler  F Cerebral sinus thrombosis in a trauma patient after recombinant activated factor VII infusion. Anesthesiology 2004;100 (2) 441- 443
PubMedArticle
51.
Bui  JDDespotis  GDTrulock  EPPatterson  GAGoodnough  LT Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII. J Thorac Cardiovasc Surg 2002;124 (4) 852- 854
PubMedArticle
52.
Mayer  SABrun  NCBroderick  J  et al.  Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352 (8) 777- 785
PubMedArticle
53.
Biondi-Zoccai  GGLAgostoni  PAbbate  ATesta  LBurzotta  F A simple hint to improve Robinson and Dickersin's highly sensitive PubMed search strategy for controlled clinical trials. Int J Epidemiol 2005;34 (1) 224- 225
PubMedArticle
54.
Egger  MDavey-Smith  GPhillips  AN Meta-analysis: principles and procedures. BMJ 1997;315 (7121) 1533- 1537
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55.
Higgins  JPThompson  SGDeeks  JJAltman  DG Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414) 557- 560
PubMedArticle
56.
Egger  MDavey-Smith  GSchneider  MMinder  C Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315 (7109) 629- 634
PubMedArticle
57.
Duval  STweedie  R Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56 (2) 455- 463
PubMedArticle
58.
Klein  SSimes  JBlackburn  GL Total parenteral nutrition and cancer clinical trials. Cancer 1986;58 (6) 1378- 1386
PubMedArticle
59.
Moher  DCook  DJEastwood  SOlkin  IRennie  DStroup  DF Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses. Lancet 1999;354 (9193) 1896- 1900
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60.
Leandro  G Bias in the meta-analytical approach. Meta-analysis in Medical Research. Oxford, England Blackwell Publishing Ltd2005;39- 42
61.
Poon  MC Use of recombinant factor VIIa in hereditary bleeding disorders. Curr Opin Hematol 2001;8 (5) 312- 318
PubMedArticle
62.
Salomon  OZivelin  ALivnat  T  et al.  Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency. Blood 2003;101 (12) 4783- 4788
PubMedArticle
63.
Von Heymann  CKastrup  MRedlich  UKox  WJSpies  CD Experiences with recombinant activated factor VII (rFVIIa) for refractory bleeding after cardiac surgery [abstract]. Anesthesiology 2003;99A442
64.
Levi  MPeters  MBuller  HR Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005;33 (4) 883- 890
PubMedArticle
65.
Grounds  RMBolan  C Clinical experiences and current evidence for therapeutic recombinant factor VIIa treatment in nontrauma settings. Crit Care 2005;9 ((suppl 5)) S29- S36
PubMedArticle
66.
Vincent  J-LRossaint  RRiou  BOzier  YZideman  DSpahn  DR Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding: a European perspective. Crit Care 2006;10 (4) R120
PubMedArticle
67.
da Silva Viana  J Recombinant factor VIIa in major abdominal surgery and liver t ransplantation. Transplant Proc 2006;38 (3) 818- 819
PubMedArticle
68.
Hedner  UErhardtsen  E Potential role of recombinant factor VIIa as a hemostatic agent. Clin Adv Hematol Oncol 2003;1 (2) 112- 119
PubMed
69.
Herbertson  M Recombinant activated factor VII in cardiac surgery. Blood Coagul Fibrinolysis 2004;15 ((suppl 1)) S31- S32
PubMedArticle
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Waner  M Novel hemostatic alternatives in reconstructive surgery. Semin Hematol 2004;41 (1) ((suppl 1)) 163- 167
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Lawson  JHMurphy  MP Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol 2004;41 (1) ((suppl 1)) 55- 64
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Grounds  M Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review. Blood Rev 2003;17 ((suppl 1)) S11- S21
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Review
March 01, 2008

Efficacy and Safety of Recombinant Activated Factor VII in Major Surgical ProceduresSystematic Review and Meta-analysis of Randomized Clinical Trials

Author Affiliations

Author Affiliations: Department of Cardiovascular Anaesthesia, IRCCS Policlinico S. Donato, Milan, Italy.

Arch Surg. 2008;143(3):296-304. doi:10.1001/archsurg.2007.66
Abstract

Objective  To investigate the efficacy and safety of recombinant activated factor VII (rFVIIa) treatment in patients undergoing major surgical procedures.

Data Sources  Relevant studies were searched in BioMedCentral, CENTRAL, PubMed, and PubMed Central.

Study Selection  Only randomized controlled trials on humans undergoing major surgery were included. Efficacy was determined as the rate of patients receiving allogeneic packed red blood cells; safety was assessed in terms of thromboembolic complications and mortality rate.

Data Extraction  We followed the Cochrane Collaboration method for data extraction and internal validity procedures, as well as the Quality of Reporting of Meta-analyses statement.

Data Synthesis  Seven randomized controlled trials met the inclusion criteria. Treatment with rFVIIa is associated with a reduced risk of receiving allogeneic packed red blood cells (odds ratio, 0.29; 95% confidence interval, 0.10-0.80). In a subgroup analysis, only patients receiving at least 50 μg/kg of rFVIIa had a significant benefit (odds ratio, 0.43; 95% confidence interval, 0.23-0.78). No differences in thromboembolic complications and mortality rates were observed.

Conclusions  Treatment with rFVIIa is effective in reducing the rate of patients undergoing transfusion with allogeneic packed red blood cells. However, the cost-benefit ratio is favorable only in patients who need a huge number of packed red blood cell units. No safety concerns arise from the present study.

Recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk A/S, Bagsværd, Denmark) is a pharmacologic agent currently registered for perioperative prophylaxis and treatment of bleeding episodes in hemophilic patients with inhibitors against coagulation factors VIII and IX (United States) and for patients with acquired hemophilia, coagulation factor VII deficiency, and Glanzmann thrombasthenia who are refractory to platelets (European Union). Its pharmacologic action induces thrombin generation in locally activated platelets and contributes to the formation of a stabilized fibrin clot at the site of vessel injury.1,2

In recent years, a consistent and growing number of studies and scientific publications have suggested many “off-label” indications for rFVIIa in bleeding disorders associated with surgical procedures in patients without any known congenital hemostasis or coagulation defects. The existent literature is mainly composed of case reports317 and case series1835 apparently describing a positive experience. Some retrospective studies with historical controls3639 and randomized controlled trials (RCTs)4049 have been published, but at present, the results seem conflicting or biased by the underpower of many studies. Moreover, concerns about the safety of this drug, focused on its possible determinism for thromboembolic complications, have been raised by different case reports50,51 and RCTs in nonsurgical patients.52

To address the efficacy and safety of rFVIIa in major surgical procedures, we conducted a systematic review and meta-analysis of data pooled from existing RCTs.

METHODS
END POINTS AND DEFINITIONS

This study has efficacy and safety end points. Efficacy was defined in terms of the proportion of patients requiring homologous packed red blood cell (PRBC) transfusions in rFVIIa-treated patients vs controls. Safety was defined as the thromboembolic complication rate and the mortality rate in rFVIIa-treated patients vs controls. We accepted the authors' definitions of thromboembolic events in each selected study. This meant considering as thromboembolic events the occurrence of myocardial infarction, stroke, peripheral arterial or venous thromboembolism, mesenteric infarction, and pulmonary embolism. Subgroup analyses based on rFVIIa dose were planned.

SEARCH STRATEGY

Pertinent studies were independently searched by 2 trained investigators (M.R. and G.I.) in BioMedCentral, CENTRAL, PubMed, and PubMed Central (updated September 15, 2006). The following key words were used: rFVIIa, recombinant activated factor VII, NovoSeven, and surgery. To conduct the research, we followed the strategy suggested by Biondi-Zoccai and coworkers.53 Further searches, performed either manually or with computer assistance, involved the recent (since 2002) proceedings and abstracts from congresses of the following scientific associations: American Society of Anesthesia, European Society of Anaesthesiology, European Society of Intensive Care Medicine, Society of Cardiovascular Anesthesiologists, European Association of Cardiothoracic Anaesthesiologists, International Society on Thrombosis and Hemostasis, and American College of Chest Physicians. In addition, the references of retrieved articles and pertinent reviews were scanned, and international experts were contacted and interviewed. No ongoing trials were included. No language selection was applied.

STUDY SELECTION

A first selection of the references obtained by the previously described search was performed by 2 independent investigators (M.R. and G.S.) on the basis of the title and the abstract, with divergences resolved by consensus. If considered pertinent, the studies were retrieved as complete articles.

The following inclusion criteria were applied for selecting potentially relevant studies: (1) random allocation to treatment, (2) absence of known congenital hemostasis and coagulation defects, (3) comparison of rFVIIa vs placebo, and (4) study performed in patients undergoing major surgical procedures (procedures requiring open surgical access). The exclusion criteria were (1) duplicate publications (in this case only the article reporting the larger patient population was considered), (2) pediatric patients (<12 years), (3) nonhuman experiments, and (4) no outcome data. The selected studies were independently decided by 2 investigators (M.R. and G.S.), with divergences resolved by consensus (Table 1).

DATA ABSTRACTION AND STUDY CHARACTERISTICS

The baseline, procedural, and main outcome data in the selected studies were independently abstracted by 2 investigators (M.R. and B.D.T.), with divergences resolved by consensus (Table 2). Some studies included 2 rFVIIa treatment groups with different drug doses, and they are considered separately. In cases of missing data or when further information was required, at least 2 separate attempts at contacting the original authors were made.

INTERNAL VALIDITY

The internal validity of the selected trials was appraised by 2 independent researchers (M.R. and B.D.T.) according to the Cochrane Collaboration methods by assessing the risk of selection, performance, attrition, and detection biases, expressed as low (A), moderate (B), or severe (C) risk of bias or incomplete reporting leading to the inability to assess the underlying risk of bias (D). In addition, allocation concealment was distinguished as adequate (A), unclear (B), inadequate (C), or not used (D) (Table 3). Divergences between the reviewers were resolved by consensus.

DATA ANALYSIS, BIAS, AND HETEROGENEITY ASSESSMENT

The 3 binary outcomes were analyzed according to the Mantel-Haenszel model to compute an odds ratio (OR) with a pertinent 95% confidence interval (CI) for each selected study. Pooled summary effects were calculated by means of fixed- or random-effects models according to the heterogeneity and inconsistency detected using the Cochran Q test and I2, respectively.54,55 Publication bias was assessed by visual inspection of funnel plots and by computing the Egger test.56 In the case of a significant (P < .05) Egger test for publication bias, adequate corrections were applied according to the trim and fill method.57

The number of null or negative studies needed to void the findings from the meta-analysis was computed according to the Klein formula.58 Statistical significance was set at the 2-tailed P < .05 level (α) for hypothesis testing and at P < .10 (β) for heterogeneity testing. I2 values of approximately 25%, 50%, and 75% were considered to represent low, moderate, and severe statistical inconsistency, respectively.56 Unadjusted P values are reported throughout the text, tables, and figures. Computations were performed using a software program (Comprehensive Meta Analysis Version 2.2; Biostat, Engelwood, New Jersey). This study was performed in compliance with the Quality of Reporting of Meta-analyses guidelines.59

RESULTS

Database searches and other sources yielded a total of 288 studies (Figure 1). On the basis of title and abstract, 172 studies were excluded (nonhuman studies, human studies on patients with congenital hemostasis and coagulation defects, and biochemical studies without outcome measurements). Another 49 studies were classified as case reports and case series and were excluded. The remaining 67 articles were retrieved in complete form and were assessed according to the selection criteria. Of these articles, 53 were review articles, and, after cross-checking the references for possible missing articles, they were excluded from the meta-analysis. Careful revision of the remaining 14 articles led to the exclusion of 7 studies: 1 study40 was a preliminary report of a subsequently completed RCT, 2 studies21,42 focused on minor surgical procedures in patients with acquired coagulopathy, and 4 studies3739,42 were uncontrolled clinical trials. The final group of selected studies comprised 7 RCTs4349 dealing with major surgical procedures in patients without congenital hemostasis and coagulation defects.

STUDY CHARACTERISTICS

The 7 selected RCTs randomized 772 patients: 265 were placebo controlled and 507 underwent rFVIIa treatment at different doses (Table 2). To investigate the role of the dose, the analysis was repeated for the subgroups of patients receiving a low dose (<50 μg/kg) or a high dose (≥50 μg/kg). Four studies were performed in hepatic surgery (transplantation or resection in cirrhotic and noncirrhotic patients), 1 in cardiac surgery (patients at high risk for bleeding), 1 in abdominal prostatic surgery, and 1 in orthopedic trauma surgery of the pelvis. The timing and total dose of rFVIIa varied across the studies. Three studies report a single bolus administration, and 4 applied a repeated bolus protocol. The reported dose range is 20 μg/kg (single bolus) to 360 μg/kg (6 repeated boluses of 60 μg/kg).

QUANTITATIVE RESULTS: rFVIIa EFFICACY

The analysis of the primary outcome variable for assessing rFVIIa efficacy (number of patients receiving homologous PRBCs) was conducted in 5 of 7 trials, with 8 dose-related subgroups and a total of 468 patients (298 treated and 170 placebo controlled). The study by Shao et al46 was excluded from this analysis owing to lack of a transfusion protocol and, therefore, a possible bias in the efficacy end point determination, and the study by Planinsic et al45 was excluded owing to absence of the number of patients transfused within the outcome variables. Patients receiving rFVIIa treatment (regardless of dose) had a reduced risk of homologous PRBC transfusion (166/298 [55.7%] vs 115/170 [67.6%] in the control arm; fixed-effects OR, 0.52; 95% CI, 0.31-0.86; P = .01 for effect) (Figure 2).

A subgroup analysis was applied by separating the group where the rFVIIa dose was always 50 μg/kg or higher (high dose) from the group receiving less than 50 μg/kg (low dose) (Figure 2). The high-dose group included the RCTs by Diprose and coworkers,49 Raobaikady et al,47 Lodge et al,43 and the 80 μg/kg subgroup of the second RCTs from Lodge and coworkers,44 for a total of 369 patients (211 treated and 158 placebo controlled). The low-dose group included 162 patients (87 treated [63 from the low-dose (20 μg/kg) subgroup of Lodge et al44 and 24 from the RCT by Friederich et al48 (subgroups taking 20 and 40 μg/kg)] and 75 placebo controlled).

Patients receiving high-dose rFVIIa treatment had a reduced risk of homologous PRBC transfusion (137/211 [64.9%] vs 108/158 [68.4%] in the control arm; fixed-effects OR, 0.43; 95% CI, 0.23-0.78; P = .006 for effect). Patients receiving low-dose rFVIIa treatment had no significantly different risk of homologous PRBC transfusion (29/87 [33.3%] vs 30/75 [40.0%] in the control arm; fixed-effects OR, 0.89; 95% CI, 0.46-1.71; P = .71 for effect).

QUANTITATIVE RESULTS: SAFETY

All the selected studies were used for the safety meta-analysis. The safety issue was addressed by computing the ORs (95% CIs) for thromboembolic events and mortality. There were 36 thromboembolic complications in 507 patients (7.1%) in the rFVIIa-treated group vs 14 in 265 patients (5.3%) in the placebo-controlled group (OR, 1.32; 95% CI, 0.69-2.52; P = .40 for effect, in a fixed-effects model) (Figure 3). Mortality was 2.8% (14 of 507) in the rFVIIa-treated group and 2.3% (6 of 265) in the placebo-controlled group, indicating no effect of rFVIIa treatment on the mortality rate (OR, 0.99; 95% CI, 0.37-2.68; P = .99 for effect, in a fixed-effects model) (Figure 4).

ADDITIONAL ANALYSES

Additional analyses addressed the existence of heterogeneity, the inconsistency of data, and publication bias and provided possible corrective tools.

Efficacy of Treatment (Regardless of Dose)

Heterogeneity was assessed using the Cochran Q test (Q = 10.2; P = .04) and I2 (60%, suggestive of moderate to severe inconsistency). According to current practice,60 being in the presence of heterogeneity, random-effects variables have been computed: the random-effects OR was 0.29 (95% CI, 0.10-0.80; P = .02 for effect). Publication bias was assessed using funnel plot inspection and the Egger test: both at visual inspection by computing the Egger regression intercept test(α = −2.8; 95% CI, −4.4 to 1.1; P = .01 for bias), the efficacy analysis revealed a significant publication bias. The number of negative or null studies required to make not significant the results of the meta-analysis for the efficacy of rFVIIa treatment was established at 14. By applying the trim and fill technique, 2 studies were trimmed and a new model was estimated. After this correction, the OR (random effects) for homologous PRBC transfusions became 0.61 (95% CI, 0.38-0.98), with a still significant P value for effect.

Efficacy of Treatment (High-Dose Subgroup)

In this subgroup, the Cochran Q value was 3.6 (I2 = 18%; P = .3 for heterogeneity), not significant for heterogeneity or inconsistency of data. Therefore, no random-effects model was applied. Visual inspection of the funnel plot and the Egger regression intercept test (α = −2.14; 95% CI, −3.5 to −0.7; P = .02 for bias) revealed a significant publication bias. The number of negative or null studies required to make not significant the results of the meta-analysis for the efficacy of high-dose rFVIIa treatment was established at 8. By applying the trim and fill technique, 2 studies were trimmed, and a new model was estimated. After this correction, the OR for homologous PRBC transfusions became 0.53 (95% CI, 0.30-0.94), with a still significant P value for effect.

Safety of Treatment

Thromboembolic event analysis had a Q value of 0.99 (I2 = 0%; P = .99 for heterogeneity), indicating no heterogeneity or inconsistency of data. Visual inspection of the funnel plot and the Egger intercept test (α = −0.37; 95% CI, −1.07 to 0.34; P = .24 for bias) did not demonstrate a significant publication bias. Mortality analysis had a Q value of 1.7 (I2 = 0%; P = .94 for heterogeneity), indicating no heterogeneity or inconsistency of data. Visual inspection of the funnel plot and the Egger intercept test (α = 0.07; 95% CI, −1.15 to 1.30; P = .24 for bias) did not demonstrate a significant publication bias.

OTHER OUTCOME MEASUREMENTS NOT INCLUDED IN THE META-ANALYSIS

Other outcome measurements were present in the 7 selected RCTs; however, they were not included in the meta-analysis owing to (1) nonhomogeneous ways of presenting the information for continuous variables (eg, mean[SD] of the mean or median and range); (2) nonhomogeneous method for outcome variable measurement (eg, operative bleeding or postoperative bleeding), and (3) outcome variable measured in no more than 2 studies (eg, perioperative hematocrit variation).

COMMENT

The main results of the present meta-analysis can be summarized as follows. First, there is a significant effect of rFVIIa treatment in terms of reduction in the number of patients being exposed to allogeneic PRBC transfusions, regardless of the dose applied. There is significant heterogeneity of the data and significant publication bias; however, after adjustment for both of these confounding effects, the treatment effect remained significant.

Second, in the subgroup of patients receiving at least 50 μg/kg of rFVIIa, there is a significant effect of the treatment in reducing the number of patients being exposed to allogeneic PRBC transfusions. In this subgroup, data are homogeneous and consistent; there is a residual reduced, albeit still significant, publication bias, but after correction, the treatment remained significantly associated with a decrease in allogeneic PRBC transfusion exposure. In the subgroup receiving a low dose of rFVIIa, there is apparently no effect on the transfusion rate. However, this subgroup has a low sample size and a wide CI for the effect; therefore, the issue of dose-related effects of rFVIIa deserves further studies correlating doses and effects.

Third, treatment with rFVIIa is not associated with increased rates of thromboembolic events or mortality; safety data are homogeneous, consistent, and not burdened by any publication bias. However, mortality rates were low in the studies included in this analysis, and the resulting wide CI does not allow a clear statement.

The main reasons for the heterogeneity of the efficacy data are the existence of different dose regimens and the co-existence of trials with an overall very high transfusion rate (eg, liver transplantation, 94%) and with a less pronounced transfusion rate (eg, retropubic prostatectomy, 30%). Moreover, these factors interplayed together, because low doses were more frequent in the studies where the transfusion rate was lower. Another heterogeneity factor in this study is the presence of different surgical procedures, which can raise the problem of pooling the data. For this reason, and the existence of a publication bias, the significant effect of rFVIIa treatment regardless of dose should be considered with considerable caution. Conversely, the information about the positive effect of high-dose rFVIIa treatment is more sound, not biased by heterogeneity, and convincing even after accounting for the moderately significant publication bias. In fact, the “high dose” (≥50 μg/kg) is closer to the therapeutic single dose suggested for the treatment of patients with hemophilia or factor XI deficiency.61,62

Other outcome measurements related to bleeding and transfusion needs are unavailable for the meta-analysis owing to the heterogeneous measurements in the selected RCTs. However, it is worthwhile to consider that 2 of 7 studies demonstrated a significant reduction in the volume of PRBCs transfused: 1 study48 demonstrated a significant reduction in blood loss and the other44 a significantly better preservation of the hematocrit value. No RCT demonstrated any difference in terms of intensive care unit or hospital stay.

Many case reports or case series presenting a positive experience with the use of rFVIIa in different surgical settings have been published. The most represented surgical scenario is adult and pediatric cardiac surgery.7,15,18,19,22,23,27,32,34,35 In this setting, there are some retrospective trials with historical controls: Karkouti and coworkers37 demonstrated a beneficial effect of rFVIIa in terms of blood loss and blood product use in patients with intractable bleeding after cardiac surgery; von Heymann and coworkers39 reported similar results in the period immediately after treatment, but in a 24-hour period the only difference was reduced platelet concentrate use. The only RCT is that by Diprose et al,49 where in a limited number of patients preemptive treatment with rFVIIa exerted a beneficial effect in terms of the nontransfused patient rate. Another well-represented surgical setting is liver resection and transplantation in cirrhotic and noncirrhotic patients: for liver transplantation, 1 case series25 and 2 nonrandomized, uncontrolled studies36,38 exist, the last 2 reporting a reduction in transfusion needs in rFVIIa-treated patients. Two large multicenter RCTs43,45 have been published, with different results: in both the articles there is no impact of rFVIIa treatment in terms of blood loss or total amount of blood products transfused; conversely, 1 study43 reports a significantly lower rate of patients needing allogeneic blood products, whereas the other does not address this end point. Liver resection accounts for the other 2 multicenter RCTs,44,46 with neither demonstrating a beneficial effect of rFVIIa treatment. Finally, liver biopsy in cirrhotic patients has been addressed by a case series21 and an uncontrolled, randomized, dose-ranging study.42 Both the articles report a positive experience.

Many case reports dealing with gynecologic and obstetric surgery have been published,35,10,13,17 all reporting successful experiences in patients with intractable, often life-threatening, perioperative bleeding. Three successful case reports6,9,16 where intractable bleeding was stopped after rFVIIa treatment are reported in kidney transplantation. In orthopedic surgery, there is 1 case report28 and 1 RCT, where treatment with rFVIIa failed to reduce blood loss or transfusion requirements47 in patients operated on for traumatic pelvis fracture.

In abdominal surgery there is an important RCT48 in patients undergoing retropubic prostatectomy: patients treated with rFVIIa had significant reductions in blood loss, the number of PRBC units transfused, and the transfusion rate. Other successful case reports and series where rFVIIa was used for treating severe perioperative bleeding have been described in vascular surgery,12,14,29,33 general surgery,20,24,30 neurosurgery,8,26,31 and pediatric surgery.23

There is an important methodological difference between the RCTs and the case reports, case series, and even uncontrolled trials. All the RCTs have an experimental design based on prophylactic use of rFVIIa in surgical patients at high risk for bleeding and allogeneic transfusions; conversely, all the other studies report the results of rFVIIa as a “salvage” treatment in patients being already polytransfused due to severe bleeding after different surgical procedures. In this last setting, the results seem promising, but there is no RCT published yet, even as a large multicenter trial at different rFVII doses is currently ongoing in cardiac surgery.

From this meta-analysis, the prophylactic use of rFVIIa]= is effective in reducing the rate of patients receiving allogeneic PRBCs; after adjustment for heterogeneity and publication bias, the best significant OR found in this analysis was 0.43 for patients receiving a dose of at least 50 μg/kg. This introduces the important issue of the financial impact of prophylactic treatment with rFVIIa. For a single-dose regimen of 90 μg/kg, the cost of treatment may be considered in the range of €5000 (about US $7000) per patient (with significant country-to-country variations). Considering that no RCT could demonstrate any significant benefit in terms of intensive care unit or hospital stay, or any difference in mortality rates, this huge financial burden should be compared only, from a cost-benefit point of view, with the cost of blood products saved. If we accept a risk reduction of 50%, and consider a mean cost for 1 U of PRBCs of €250, (US $350) the cost-benefit ratio is favorable only if each transfused patient is expected to receive 40 PRBC units.

Safety issues have been repeatedly raised in the literature. The main concern is that use of a procoagulant drug, with strong thrombin-generation properties, may induce thromboembolic complications, especially in patients with a high risk profile for these kinds of complications. Of course, it is difficult to attribute a thromboembolic event to a drug with a reasonable level of certainty because many other factors could be considered responsible. However, there are case reports50,51 in which the researchers attribute thromboembolic events to the use of rFVIIa in nonhemophilic patients. Some case series showed a high rate of thromboembolic events in patients treated with rFVIIa,30,49,63 and in a recent RCT52 where patients with intracerebral hemorrhage were randomized to receive rFVIIa or placebo, a significantly higher rate of thromboembolic complications was found in the rFVIIa group. However, 2 retrospective studies37,39 did not demonstrate different rates of thromboembolic complications in patients undergoing cardiac surgery, and all 7 RCTs considered in this meta-analysis did not find any difference in thromboembolic complication rates. Review articles64,65 and a recent expert recommendations article66 confirm that the present knowledge does not enable the assertion that in surgical patients the use of rFVIIa is associated with an increased thromboembolic risk, even if in selected high-risk patients this possibility cannot be excluded. In particular, patients with procoagulant diseases (eg, cancer or infections) or with a history of thromboembolic events and patients receiving concomitant procoagulant drugs (eg, aprotinin or tranexamic acid) were not studied as a subgroup in the present analysis.

In conclusion, the huge amount of heterogeneous information about the off-label use of rFVIIa has raised increasing interest in the past 2 years. Review articles exploring the role of this drug in selected settings6772 or in the general population6466 provided a comprehensive analysis of the published articles and left the possibility open that rFVIIa may have a role in the surgical setting. Most of these articles conclude that the prophylactic use is still debated or not recommended66 and that the therapeutic use is still based on uncontrolled trials and experiences.

We believe that this meta-analysis may offer quantitative information on the size effects of rFVIIa in the surgical setting: its results confirm that prophylactic use is significantly but marginally effective and probably burdened by a high cost-benefit ratio. Additional quantitative information confirms that presently there is no evidence of increased thromboembolic risk in surgical patients. There is evidence of different effects at different doses, which introduces the need for more dose-oriented trials. Large RCTs on rFVIIa as therapeutic rather than prophylactic treatment are required to finally define its role in the surgical environment. To approach this crucial point, a possible RCT should include patients at high risk for bleeding submitted to surgical procedures, randomizing them to receive placebo or rFVIIa (≥60 μg/kg) once bleeding is evident (eg, after cardiopulmonary bypass in cardiac procedures) and before starting massive blood product transfusions. End points should not only be the rate of patients being transfused but even the number of units transfused. With the hypothesis of a transfusion rate of 60% in patients receiving placebo and a reduction to 30% in treated patients (OR, 0.5), the total number of patients to be enrolled is 80 (40 in each group).

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Article Information

Correspondence: Marco Ranucci, MD, Department of Cardiovascular Anaesthesia, IRCCS Policlinico S. Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy (cardioanestesia@virgilio.it).

Accepted for Publication: January 23, 2007.

Author Contributions: Dr Ranucci had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Ranucci. Acquisition of data: Ranucci, Isgrò, Soro, Conti, and De Toffol. Analysis and interpretation of data: Ranucci and De Toffol. Drafting of the manuscript: Isgrò, Soro, Conti, and De Toffol. Critical revision of the manuscript for important intellectual content: Ranucci. Statistical analysis: Ranucci and Soro.

Financial Disclosure: None reported.

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