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Three Part Question

In [patients with intractable post-operative bleeding], does [Recombinant Activated Factor VII] reduce [post-operative bleeding without causing significant complications]?

Clinical Scenario

You are with a 72-year-old patient who is 15 h post emergency Type A dissection repair and CABGx1. It was a difficult operation with a long bypass time. Post-operatively he has been bleeding profusely. He has been reopened but no bleeding points have been found, and he has returned to the CICU packed and with the chest open. He has received 12 units of fresh frozen plasma and 2 pools of platelets and cryoprecipitate, but has still bled 400 ml per hour for the last 3 h. You discuss the patient with the haematologist and he tells you that they now have recombinant activated Factor VII available for use, and asks whether you would like to use it. He has no experience with this post-cardiac surgery and neither have you and you are a little anxious about the patency of the graft that you had to place, but you elect to give it and then search for reports of its use.

Search Strategy

Medline 1966–April 2006 using the OVID interface.
[Factor VII$.mp or exp factor VIIa/OR novoseven.mp OR eptacog alpha.mp] AND [cardiac surgery.mp OR cardiopulmonary bypass.mp OR Heart transplant.mp OR exp Cardiac surgical procedures/OR exp Coronary artery bypass/OR exp heart transplantation/] AND [exp blood loss, surgical/OR postoperative haemorrhage.mp OR bleeding.mp OR transfusion.mp OR Coagulopathy.mp]

Search Outcome

A total of 129 papers were identified using the reported search from which 13 represented the best evidence to answer the question. Of note case reports and paediatric cases were excluded.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bishop et al. 2006 Australia	12 pts with intractable bleeding post cardiac surgery 7 Bentalls/AVR 1 Thoracoabdominal repair 1 Triple valve replacement 3 other valve replacements Dose of factor VII 100 µg/kg after platelets FFP and cyroprecipitate	Retrospective case series (level 4)	Blood product usage pre-factor VIIa	FFP 18.7 units (10–40), Platelets 22 (10–40), Cryoprecipitate 20 (8–32), Red Cells 8 (0–18)	Very small study but with impressive results No accurate chest drainage figures pre and post Factor VII
			Blood product usage post-factor VIIa	FFP 0.15 units (0–2), Platelets 0, Cryoprecipitate 0, Red Cells 0.08 (0–1)
			Chest drainage	Mean 743 ml (245–1550) in 1st 24 h post sternotomy closure
			Complications	None, all patients survived
Levi et al. 2005 Holland	Systematic review of all published and un-published clinical studies using MEDLINE 1966-2004 and 'all other possible sources' 28 clinical trials, 124 case series, 176 case reports 1,854 patients included in all papers	Systematic review (level 1a)	Efficacy in haemophiliacs	156 articles over 90% at a dose of 90 µg/kg. Only 60% efficacy at 35 µg/kg If not effective after 2–3 h 16.5 µg/kg/h effective.	They report that there has been an RCT just completed with 400 µg/kg in 301 patients with severe blunt trauma, and there was significantly less RBC use and a trend to less organ dysfunction and 5% less mortality
			Factor VIIa during surgery	84 patients in case reports and 36 patients in the RCT 50% less blood loss when used prophylactically at a dose of 50 µg/kg
			Life threatening bleeding	33 articles in 37 patients reporting cessation or reduction in bleeding in 60% of patients
			Complications	1-2% incidence of severe thrombotic complications. 1.4% estimated risk of thromboembolism
Diprose et al. 2005 UK	20 patients undergoing complex cardiac surgery randomized to Factor VIIa or placebo after CPB and reversal of heparin Received 90 µg/kg. All patients received aprotinin Strict TEG based transfusion protocol used	Pilot PRCT (level 2b)	Transfusion rate of all blood products	Factor VIIa group 13 units in total. Placebo group 105 units P=0.011	Small study sponsored by NovoNordis A patient was excluded after unblinding 2 h post surgery. He received 72 units of blood, and 2 more doses of FVIIa
			Drain loss	Factor VIIa group 330 ml (185–765). Placebo group 630 ml (300–965) P=0.079
			Complications	None in either group
			Rescue treatment for cardiac surgery outside of the study	17 patients received Factor VIIa blood loss pre-VIIa. 933 ml/h post-VIIa 34 ml/h. Significant reductions of all blood products
von Heymann et al. 2005 USA	Retrospective cohort study with historic matched pair controls of patients receiving Factor VIIa after cardiac surgery 24 patients received Factor VIIa 24 matched controls identified with 1000 ml blood loss in 14 h, and type of operation 60–80 µg/kg, repeated at 4-8 h if no response	Case control study (level 3b)	Blood loss	Factor VIIa group Pre-VIIa mean 1800 ml, Post-VIIa mean 1300 ml P=0.032 18 of 24 patients reduced blood loss to <100 ml/h Control group 1st period mean 1600 ml 2nd period mean 600 ml P=0.02 17 of 24 patients reduced blood loss to <100 ml/h	Small study and thus the retrospective control arm is of questionable value
			Complications	No thrombotic complications related to Factor VIIa
Hyllner et al. 2005 Sweden	Retrospective review of 24 patients post cardiac surgery who received Factor VIIa for life-threatening bleeding Median bolus dose 60 µg/kg All patients received 2 g of tranexamic acid on induction and post bypass, and aprotinin is also given to high risk patients. For patients refractory to conventional haemostasis, they received platelets and 2 g of fibrinogen with Factor VIIa	Cohort study (level 3b)	Transfusion	No data given	15 patients re-explored, 6 found a surgical bleeding site
			Blood loss (only 6 patients had this recorded)	Pre-Factor VIIa 424±250 ml Post-Factor VIIa 230±259 ml
			Complications	No complications due to Factor VII seen. No patients died due to exsanguination
Karkouti et al. 2005 Canada	51 patients post cardiac surgery were compared to matched historical controls Definition of intractable blood loss was 2000 ml or 4 units of blood, surgical bleeding had been excluded, 5 units of platelets and 4 units of FFP, and full heparin reversal. 2.4 mg to 4.8 mg of Factor VIIa given (35 to 70 µg/kg)	Case-control study (level 2b)	Transfusion	Hour before VIIa RBC 8 units. All products 31 (22-43) Hour after VIIa RBC 2 units. All products 2 (0-8) p<0.001	8/51 patients did eventually have a surgical site identified
			Blood loss	Mean 100 ml less (70-285 ml) in the hour after Factor VII
			Complications	4 patients had a stroke. Three had clear predisposing factors for this (1 aortic atheroma, 2 prolonged cerebral hypoperfusion)
Vanek et al. 2004 Czech Republic	Retrospective analysis of 7 patients post cardiac surgery who suffered intractable bleeding. Most patients had also received platelets, FFP, prothromplex, and antithrombin III 90 µg/kg Factor VIIa given	Case series (level 4)	Transfusion	Not reported
			Blood loss	4 h pre-factor VIIa 630 ml (465-765 ml). 4 h post-factor VIIa 120 ml (105-165 ml). P<0.05
			Complications	No thrombotic complications
Aggarwal et al. 2004 USA	Retrospective analysis of 24 patients post cardiac surgery (and 16 other patients not described here) who received Factor VIIa for intractable bleeding 15CABG 5 aortic surgical procedures, 3 valve procedures and 1 VSD 90 µg/kg bolus of Factor VIIa	Cohort study (level 4)	Transfusion	Pre-Factor VIIa RBCs 17 units (5–39) Plts 18 units (6–37) FFP 18 units (6–33) Post-Factor VIIa RBCs 6 units (0–28) Plts 10 units (0–19) FFP 9 units (0–28)
			Blood loss	Not documented
			Survival	12 survived more than 4 h post-factor VIIa administration. 6 patients survived to discharge
			Complications	1 of 23 patients had a subclavian DVT in a vein with a central line
Halkos et al. 2005 USA	Retrospective review of 9 patients who underwent cardiac surgery and required Factor VIIa for intractable haemorrhage 2 aortic surgery, 4 CABG, 3 valve procedures 60–120 µg/kg of Factor VIIa as an intravenous bolus over 15 min	Case series (level 4)	Transfusion	Pre-Factor VIIa RBCs 9 units Plts 22 units FFP 7 units Cryoprecipitate 19 units Post-Factor VIIa RBCs 6 units (0–28) Plts 10 units (0–19) FFP 9 units (0–28)	Author sponsored by NovoNordisk
			Blood loss	Pre-factor VII. Mean blood loss 640 ml/h. Post-factor VII mean blood loss 100 ml/h
			Complications	None
Roberts et al. 2004 USA	Review of safety profile of Factor VIIa	Review (level 2a)	Half life	2.5 h	Report states that the FDA only approves use of Factor VIIa to patients with haemophilia A and B
			Usage up to Nov 2002	400,000 documented uses of Factor VIIa known (at dose of 90 µg/kg)
			Report from Haemophilia research society 1,939 cases	1% serious adverse events. 8% non serious adverse events
			Also 556 cases of 'mega dose' FVIIa Median dose 360 µg/kg	No safety problems
			Reported adverse events in Haemophiliacs 1996–2002	1 CVAs 2 cerebrovascular thrombosis 7 acute MI; 2 DIC, 6 DVT and 1 PE
DiDomenico et al. 2005 USA	Case report and summary of 20 case reports from the literature of Factor VIIa use after cardiac surgery and intractable bleeding Mean dose 57 µg/kg. 6 patients received a mean 3.4 doses of Factor VIIa.	Case report and review (level 4)	2 case reports	Case 1. Blood loss dropped from 1 1/h to under 100ml/h. Had 50 L of blood loss in total and 140 units of blood products prior to Factor VIIa. Second patients had more gradual improvement
			Review of 20 patients in literature treated with Factor VIIa for intractable blood loss.	Mean 1.4 doses Mean dose 101 µg/kg 14/20 patients had rapid blood loss reduction
			Complications	2 possible thrombotic complications (1 fatal) in literature. Patient who died developed massive cardiac and ECMO circuit thrombosis. Other patient had mediastinal thrombosis and a third had a suspected coronary thrombosis
Al Douri et al. 2000 UK	Report of 5 patients who received Factor VII for intractable blood loss including one child 30 µg/kg Factor VIIa used initially	Case series (level 4)	Pre Factor VII blood loss	2,700 ml to 8,000 ml
			Blood loss 4 h after administration	262 ml/h (220–334 ml/h)
			Complications	No thrombotic complications, one patient died from RV failure

Comment(s)

Roberts et al. in 2004 published a review of the current use of Factor VIIa across all specialties. Over 400,000 uses have been recorded, mostly in haemophiliacs, and its risk of serious adverse events was estimated as under 1%. The risk of non-serious treatment related adverse events was estimated as 8–13%. The usual dose was 90 µg/kg, but larger doses of 320 µg/kg have also been recorded without major adverse effects. Levi et al. in 2005 performed a systematic review of the efficacy and safety of recombinant Factor VIIa. They identified 28 clinical trials and 300 other case reports and series including 1854 patients. In haemophiliacs over 90% efficacy has been well demonstrated at a dose of 90 µg/kg in 156 articles. If after 2–3 h bleeding continues, then an infusion of 16.5 µg/kg may also be started. In a further 37 patients with severe bleeding they reported a 60% efficacy in bleeding reduction and reported that an RCT of 301 patients with severe blunt trauma that is soon to report will show significant reduction in RBC use, a 5% reduction in mortality (NS) and a trend to less organ dysfunction. They pooled the adverse event rates in non-haemophiliac and estimated the risk of thromboembolism to be 1.4%. Thus, Factor VIIa has been well tested and its safety established in haemophiliacs and non-cardiac surgical patients. In the Cardiothoracic Literature, Diprose et al. have performed the only randomised controlled trial in high-risk patients pre-cardiac surgery. They intended to recruit 32 patients for each arm, but unfortunately were unable to secure full funding for this. They eventually had 10 patients in their Factor VIIa arm and 10 placebo patients. The mean drain loss was halved (630 ml down to 330 ml) and blood product usage was 13 units in the Factor VIIa arm compared to 105 in the placebo arm. In a second paper by the authors they reported dramatic reductions in blood loss in 17 patients when Factor VIIa was used as rescue treatment in patients with very high blood loss post cardiac surgery. Karkouti reported 51 patients with intractable bleeding post cardiac surgery, who received between 35 and 70 µg/kg of Factor VIIa after at least 2000 ml blood loss, platelets and FFP. They reported a significant reduction in blood loss, and a substantial reduction in the use of blood products. Four people had a stroke, but one had loose atheroma in the aortic arch and two had a significant period of cerebral hypoperfusion. Aggarwal et al. reported the results of 24 patients post cardiac surgery who received 90 µg/kg of Factor VIIa for intractable bleeding. There was a significantly lower requirement for blood and blood products after administration. Only 6 patients survived to discharge and one patient suffered a subclavian DVT in a vein with a central line. Von Heymann et al. reported 24 patients who had Factor VIIa for intractable bleeding post cardiac surgery. They also identified a retrospective cohort for comparison. No thrombotic complications were seen and 18 of 24 patients reduced their blood loss to <100 ml/h. Interestingly in the control group where routine treatment had been given, 17 reduced their blood loss by a similar amount. Hyllner reported 24 cases of Factor VIIa use in post-cardiac patients with intractable bleeding. They reported that there was a significant reduction in blood loss, and no patients exsanguinated. There were also no thrombotic complications. In the remaining studies, Bishop reported 12 patients, Vanek reported 7 patients, Halkos reported 9 patients, Al Douri 4 cases and DiDomenico 2 cases of the use of Factor VIIa for intractable bleeding post cardiac surgery. DiDomenico et al. in their review reported a case of ECMO circuit and cardiac thrombosis, which resulted in death and a possible mediastinal thrombosis, but no other complications were documented in the other studies.

Clinical Bottom Line

Factor VIIa has proven efficacy and safety in over 400,000 uses worldwide outside the cardiothoracic surgical arena, mostly in haemophiliacs. Results from this experience show a 1% risk of serious thrombotic complications. In the cardiothoracic literature there have been more than 160 reports of its use for intractable bleeding and the serious complication rate is again around 1–2%. In addition, it has been found to be highly efficacious in 80–90% of cases with a single dose of 60–90 µg/kg which can be repeated after 2–4 h. Thus, for patients with intractable bleeding post cardiac surgery refractory to conventional haemostatic interventions, Factor VIIa is recommended and its complication rates are low.

References

1. Bishop CV, Renwick WEP, Hogan C, Haeusler M, Tuckfield A, Tatoulis J. Recombinant Activated Factor VII: treating postoperative hemorrhage in cardiac surgery. Ann Thorac Surg 2006; 81:875–879.
2. Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Critical Care Medicine 2005; 33:883–890.
3. Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomised double-blind placebo-controlled pilot study. Br J Anaesth 2005; 95:596–602.
4. Herbertson M. Recombinant activated factor VII in cardiac surgery. Blood Coagulation & Fibrinolysis 2004; 15:Suppl 1, S31–S32.
5. von Heymann C, Redlich U, Jain U, Kastrup M, Schroeder T, Sander M, Grosse J, Ziemer S, Koscielny J, Konertz WF, Wernecke KD, Spies C. Recombinant activated factor VII for refractory bleeding after cardiac surgery – a retrospective analysis of safety and efficacy. Crit Care Med 2005; 33:2241–2246.
6. Hyllner M, Houltz E, Jeppsson A. Recombinant activated factor VII in the management of life-threatening bleeding in cardiac surgery. Eur J Cardio-Thorac Surg 2005; 28:254–258.
7. Karkouti K, Beattie WS, Wijeysundera DN, Yau TM, McCluskey SA, Ghannam M, Sutton D, van Rensberg A, Karski J. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005; 45:26–34.
8. Vanek T, Straka Z, Hrabak J, Jares M, Brucek PJ, Votava J. Use of recombinant activated factor VII in cardiac surgery for an effective treatment of severe intractable bleeding. Jpn Heart J 2004; 45:855–860.
9. Aggarwal A, Malkovska V, Catlett JP, Alcorn K. Recombinant activated factor VII (RFVIIa) as salvage treatment for intractable hemorrhage. Thrombos J 2004; 2:9.
10. Halkos ME, Levy JH, Chen E, Reddy VS, Lattouf OM, Guyton RA, Song HK. Early experience with activated recombinant factor VII for intractable hemorrhage after cardiovascular surgery. Ann Thorac Surg 2005; 79:1303–1306.
11. Roberts HR, Monroe DM III, Hoffman M. Safety profile of recombinant factor VIIa. Seminars in Hematology 2005; 41:11, 101–108.
12. DiDomenico RJ, Massad MG, Kpodonu J, Navarro RA, Geha AS. Use of recombinant activated factor VII for bleeding following operations requiring cardiopulmonary bypass. Chest 2005; 127:1828–1835.
13. Al Douri M, Shafi T, Al Khudairi D, Al Bokhari E, Black L, Akinwale N, Osman MM, Al Homaidhi A, Al Fagih M, Borum AR. 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 Coag Fibrinolysis 2000; 11:Suppl 1, S121–127.