Is recombinant activated factor VII useful for intractable bleeding after cardiac surgery?
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《交互式心脏血管和胸部手术》
a Department of Cardiothoracic Surgery, Freeman Hospital, Newcastle-upon-Tyne, UK
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether use of Recombinant Activated Factor VII could help haemostasis for intractable bleeding, and decrease blood or blood product requirements in patients undergoing cardiac surgery without excessive risk from thrombosis. Altogether 129 papers were identified using the reported search strategy of which 13 represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that 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.
Key Words: Evidence-based medicine; Factor VIIa; Haemostasis; Bleeding; Blood products; Thoracic surgery
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. 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.
3. Three-part question
In [patients with intractable post-operative bleeding], does [Recombinant Activated Factor VII] reduce [post-operative bleeding without causing significant complications]?
4. 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]
5. 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. The papers are summarised in Table 1 [2–14].
6. Results
Roberts et al. in 2004 [12] 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 [3] 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 [4]. 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 [5].
Karkouti [8] 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. [10] 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 [6]. 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 [7] 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 [2] reported 12 patients, Vanek [9] reported 7 patients, Halkos [11] reported 9 patients, Al Douri [14] 4 cases and DiDomenico [13] 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.
7. Conclusion
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
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003; 2:405–409.
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.
Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. [Review] [59 Refs]. Critical Care Medicine 2005; 33:883–890.
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.
Herbertson M. Recombinant activated factor VII in cardiac surgery. [Review] [4 Refs]. Blood Coagulation & Fibrinolysis 2004; 15:Suppl 1, S31–S32.
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.
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.
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.
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.
Aggarwal A, Malkovska V, Catlett JP, Alcorn K. Recombinant activated factor VII (RFVIIa) as salvage treatment for intractable hemorrhage. Thrombos J 2004; 2:9.
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.
Roberts HR, Monroe DM III, Hoffman M. Safety profile of recombinant factor VIIa. [Review] [48 Refs]. Seminars in Hematology 2005; 41:11, 101–108.
DiDomenico RJ, Massad MG, Kpodonu J, Navarro RA, Geha AS. Use of recombinant activated factor VII for bleeding following operations requiring cardiopulmonary bypass. [Review] [32 Refs]. Chest 2005; 127:1828–1835.
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.(Marios Tanosa and Joel Du)
b Department of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether use of Recombinant Activated Factor VII could help haemostasis for intractable bleeding, and decrease blood or blood product requirements in patients undergoing cardiac surgery without excessive risk from thrombosis. Altogether 129 papers were identified using the reported search strategy of which 13 represented the best evidence on the topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that 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.
Key Words: Evidence-based medicine; Factor VIIa; Haemostasis; Bleeding; Blood products; Thoracic surgery
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. 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.
3. Three-part question
In [patients with intractable post-operative bleeding], does [Recombinant Activated Factor VII] reduce [post-operative bleeding without causing significant complications]?
4. 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]
5. 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. The papers are summarised in Table 1 [2–14].
6. Results
Roberts et al. in 2004 [12] 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 [3] 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 [4]. 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 [5].
Karkouti [8] 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. [10] 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 [6]. 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 [7] 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 [2] reported 12 patients, Vanek [9] reported 7 patients, Halkos [11] reported 9 patients, Al Douri [14] 4 cases and DiDomenico [13] 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.
7. Conclusion
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
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003; 2:405–409.
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.
Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. [Review] [59 Refs]. Critical Care Medicine 2005; 33:883–890.
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.
Herbertson M. Recombinant activated factor VII in cardiac surgery. [Review] [4 Refs]. Blood Coagulation & Fibrinolysis 2004; 15:Suppl 1, S31–S32.
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.
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.
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.
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.
Aggarwal A, Malkovska V, Catlett JP, Alcorn K. Recombinant activated factor VII (RFVIIa) as salvage treatment for intractable hemorrhage. Thrombos J 2004; 2:9.
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.
Roberts HR, Monroe DM III, Hoffman M. Safety profile of recombinant factor VIIa. [Review] [48 Refs]. Seminars in Hematology 2005; 41:11, 101–108.
DiDomenico RJ, Massad MG, Kpodonu J, Navarro RA, Geha AS. Use of recombinant activated factor VII for bleeding following operations requiring cardiopulmonary bypass. [Review] [32 Refs]. Chest 2005; 127:1828–1835.
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.(Marios Tanosa and Joel Du)