What is the safety and efficacy of different factor VII dosing strategies for post-op cardiac surgery bleeding?

Comment by InpharmD Researcher

Scattered studies compare or evaluate very low dose to high dose administration of recombinant activated factor VII (rFVIIa) in the setting of cardiac surgery. Recent data supports the efficacy of very low doses (<20 mcg/kg), which have been found to achieve hemostasis without increased risk of complications. Overall, the data are mixed, without a clear or optimal dosing strategy. Many studies have utilized single bolus doses of 90 mcg/kg or less, and some experts recommend doses of 40 to 100 mcg/kg for uncontrolled post-cardiac surgery bleeding, with consideration of a second dose if there is no response.

factor vii dosing s/p cardiac surgery; factor vii dosing post-cardiac surgery

Background

The 2024 EACTS/EACTAIC guidelines on patient blood management in adult cardiac surgery describe recombinant activated factor VII (rFVIIa) as a last-resort treatment for uncontrollable bleeding after conventional surgical exploration, blood products, and antifibrinolytic agents have failed. The guidelines report that recent findings suggest very low doses (<20 mcg/kg) can achieve hemostasis without increasing thromboembolic events in patients with refractory bleeding; however, they emphasize extreme caution and the need for further research comparing the safety and effectiveness of these doses with higher-dose rescue treatment. Safety concerns include serious adverse events, particularly stroke, reported in studies evaluating prophylactic administration. Accordingly, prophylactic rFVIIa is not recommended to prevent bleeding complications (class III, level B), whereas off-label use may be considered for refractory, nonsurgical bleeding (class IIb, level B). [1]

The 2024 EACTS/EACTAIC guidelines on patient blood management in adult cardiac surgery describe recombinant activated factor VII (rFVIIa) as a last-resort treatment for uncontrollable bleeding after conventional surgical exploration, blood products, and antifibrinolytic agents have failed. The guidelines report that recent findings suggest very low doses (<20 mcg/kg) can achieve hemostasis without increasing thromboembolic events in patients with refractory bleeding; however, they emphasize extreme caution and the need for further research comparing the safety and effectiveness of these doses with higher-dose rescue treatment. Safety concerns include serious adverse events, particularly stroke, reported in studies evaluating prophylactic administration. Accordingly, prophylactic rFVIIa is not recommended to prevent bleeding complications (class III, level B), whereas off-label use may be considered for refractory, nonsurgical bleeding (class IIb, level B). [2]

A 2009 systematic review suggests that recombinant activated factor VII (rFVIIa) may help reduce surgical blood loss and the need for blood product transfusions in cardiac surgery. However, the true risks of using rFVIIa in this setting remain unclear, particularly when it is administered alongside other potent pro-hemostatic agents. While an optimal dose of rFVIIa has not been definitively established, many studies have employed single bolus doses of 90 mcg/kg or less. Some experts have recommended doses of 40 to 100 mcg/kg for uncontrolled post-cardiac surgery bleeding, with consideration of a second dose if there is no response after 30 to 60 minutes. While rFVIIa appears to reduce bleeding, blood product use, and re-operation rates, the relatively small and uncontrolled nature of most studies makes it difficult to definitively determine whether adverse thrombotic events are directly related to rFVIIa use or the critical condition of the patients receiving it. The authors state that the off-label use of rFVIIa is likely to continue, and clinicians should be aware of both the potential risks and benefits when using this potent thrombin-generating agent. The authors' institutional practice is to use rFVIIa at a dose of 90 mcg/kg in the operating room to ensure there is no correctable surgical source of bleeding before closing the chest. Notably, the authors do not address any potential maximum dose caps for initial or repeat administrations. [3], [4]

A 2011 systematic review assessed the comparative effectiveness of rFVIIa for off-label in-hospital use, finding limited evidence to support its use. The review of 2 randomized controlled trials (RCTs) and 4 observational studies involving 251 adult cardiac surgery patients found mixed results for the use of rFVIIa. While there was no significant effect on mortality compared to usual care, the use of rFVIIa was associated with an increased risk of thromboembolism. The studies also suggested a possible reduction in red blood cell transfusion requirements with rFVIIa, but this trend was only seen in the higher-quality studies. Results regarding intensive care unit length of stay were inconsistent across the studies. Overall, the evidence suggests that the benefits and harms of rFVIIa use in cardiac surgery are relatively balanced, but its use does increase the risk of potentially serious thromboembolic events. [5]

According to a 2023 article, rFVIIa has historically been used off-label to manage intractable bleeding after cardiac surgery, with early studies reporting the use of high-dose regimens (up to 206 mcg/kg) as "salvage therapy". However, subsequent randomized controlled trials and retrospective analyses have demonstrated that more modest, prophylactic dosing strategies (typically 40-90 mcg/kg) can reduce blood product transfusions and chest tube drainage without significantly increasing thromboembolic complications. More recently, there has been a trend towards using even lower doses of rFVIIa (less than 20 mcg/kg), which appear to achieve hemostasis without increasing adverse events. The authors suggest that a "gentle and early" approach of administering very low-dose rFVIIa (e.g. after 0-1 other hemostatic agents) may be the most beneficial strategy, avoiding the potential risks associated with higher dosing or delayed administration. They caution that even low-dose rFVIIa use should still be carefully considered in high-risk patients, such as those on mechanical circulatory support. Overall, the authors conclude that rFVIIa can be a useful adjunct for cardiac surgical bleeding, with lower dosing regimens (<20 mcg/kg) appearing to offer the most favorable risk-benefit profile based on current evidence. [6]

A 2007 review advised against the prophylactic or routine use of rFVIIa in cardiac surgery, as current evidence does not demonstrate that the benefits outweigh the potential risks compared to standard hemostatic therapies. However, the panel made a weak recommendation (grade 2C) for using rFVIIa (one to two doses of 35-70 μg/kg) as rescue therapy for blood loss that is refractory to standard hemostatic therapies, despite the lack of randomized controlled trial data for this indication. The panel emphasized the need for caution, especially in patients at high risk of thromboembolic complications, and recommended that the decision to use rFVIIa involve consultation with the patient's next of kin whenever possible (un-graded recommendation). The consensus panel concluded that the risks and benefits of rFVIIa in cardiac surgery are unclear, but current evidence suggests its benefits may outweigh risks for rescue therapy in selected patients. The panel recommended methodologically rigorous studies to further clarify the risk-benefit profile of rFVIIa in cardiac surgery patients. [7]

Background References: [1] Casselman FPA, Lance MD, Ahmed A, et al. 2024 EACTS/EACTAIC Guidelines on patient blood management in adult cardiac surgery in collaboration with EBCP. Eur J Cardiothorac Surg. 2025;67(5):ezae352. doi:10.1093/ejcts/ezae352
[2] Casselman FPA, Lance MD, Ahmed A, et al. 2024 EACTS/EACTAIC Guidelines on patient blood management in adult cardiac surgery in collaboration with EBCP. Eur J Cardiothorac Surg. 2025;67(5):ezae352. doi:10.1093/ejcts/ezae352
[3] Warren O, Mandal K, Hadjianastassiou V, et al. Recombinant activated factor VII in cardiac surgery: a systematic review. Ann Thorac Surg. 2007;83(2):707-714. doi:10.1016/j.athoracsur.2006.10.033
[4] Richardson A, Herbertson M, Gill R. The role of recombinant activated factor VII in cardiac surgery. HSR Proc Intensive Care Cardiovasc Anesth. 2009;1(3):9-12.
[5] Yank V, Tuohy CV, Logan AC, et al. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011;154(8):529-540. doi:10.7326/0003-4819-154-8-201104190-00004
[6] Flynn BC, Steiner ME, Mazzeffi M. Off-label Use of Recombinant Activated Factor VII for Cardiac Surgical Bleeding. Anesthesiology. 2023;139(2):197-210. doi:10.1097/ALN.0000000000004569
[7] Karkouti K, Beattie WS, Crowther MA, et al. The role of recombinant factor VIIa in on-pump cardiac surgery: proceedings of the Canadian Consensus Conference. Can J Anaesth. 2007;54(7):573-582. doi:10.1007/BF03022322
Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the safety and efficacy of different factor VII dosing strategies for post-op cardiac surgery bleeding?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-7 for your response.

 

Recombinant Factor VIIa Treatment of Severe Bleeding in Cardiac Surgery Patients: A Retrospective Analysis of Dosing, Efficacy, and Safety Outcomes

Design

Retrospective chart review

N= 93

Objective

 To describe rFVIIa dosing and clinical outcomes in cardiovascular surgery patients with refractory bleeding

Study Groups

 All study patients (N= 93)

Inclusion Criteria

 Cardiovascular surgery patients older than 18 years who received rFVIIa during the specified study period.

Exclusion Criteria

 Patients with known or acquired coagulopathy or incomplete records to assess study endpoints.

Methods

A retrospective analysis was conducted to examine rFVIIa administration based on clinical judgment. The mean dose of rFVIIa was 56.2 ± 26.5 micrograms per kilogram of body weight. The use of blood products before and after the administration of rFVIIa was recorded as part of this analysis.

The administration of rFVIIa and its dosing were determined by the treating surgical, anesthesia and intensive care teams based on an individualized risk/benefit analysis following insufficient response to conventional blood product therapy. Blood product administration both before and after rFVIIa use was similarly at the discretion of these providers. During the study period, there were no formal guidelines governing the use of rFVIIa, leaving treatment decisions to clinical judgment.

Duration

 Study period from January 1, 2004, to September 30, 2005

Outcome Measures

 Reduction in blood product consumption 6 hours before and after rFVIIa administration.

Baseline Characteristics

  

Study patients (N= 93)

    
Age, years

60.6

    
Male

72%

    

Comorbidities

Hypertension

Coronary artery disease (CAD)

Congestive heart failure

Hyperlipidemia

Previous DVT or PE

Diabetes

CVA/TIA

COPD

Chronic renal failure

End-stage renal disease

 

62.4%

48.4%

31.2%

26.9%

2.2%

25.8%

9.7%

12.9%

6.5%

1.1%

    

Antiplatelet and anticoagulation

Aspirin

Warfarin

Clopidogrel

Enoxaparin

Unfractionated heparin

 

31.2%

20.4%

9.7%

6.5%

4.3%

    

Results

Endpoint

Before rFVIIa administration

After rFVIIa administration

p-Value

Packed red blood cells, U

7.6 ± 6.8

3.5 ± 4.7

< 0.0001

Fresh-frozen plasma, U

6.9 ± 7.3

1.7 ± 3.39

< 0.001

Platelets, U

6.04 ± 12

1.07 ± 1.9

0.001

Cryoprecipitate, U

16.1 ± 19.9

8.1 ± 24.6

0.012

Adverse Events

 No thromboembolic events were confirmed; 10.8% developed new chronic dialysis requirement; 2.2% incidence of hemorrhagic stroke. Additionally, all-cause inpatient mortality in this sample was 22.6%.

Study Author Conclusions

 rFVIIa effectively reduces blood product use in cardiovascular surgery patients having massive blood loss. Although the optimal dose of rFVIIa for use in cardiovascular surgery remains undetermined, these data provide evidence that dosing regimens using <90 μg/kg are effective in this population and may provide guidance for centers establishing standardized protocols for rFVIIa use in cardiovascular surgery patients.

InpharmD Researcher Critique

 Limitations include retrospective design, lack of standardized treatment protocols, and potential confounding factors such as aprotinin use.



Table 1 References:
[8] Masud F, Bostan F, Chi E, et al. Recombinant factor VIIa treatment of severe bleeding in cardiac surgery patients: a retrospective analysis of dosing, efficacy, and safety outcomes. J Cardiothorac Vasc Anesth. 2009;23(1):28-33. doi:10.1053/j.jvca.2008.08.003

 

Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery
Design

Randomized, double-blind, placebo-controlled, phase II, dose-escalation study

N= 172
Objective To investigate the safety and possible benefits of rFVIIa in patients bleeding after cardiac surgery
Study Groups

Placebo (n= 68)

40 mcg/kg rFVIIa (n= 35)

80 mcg/kg rFVIIa (n= 69)
Inclusion Criteria Patients who had undergone cardiac surgery requiring cardiopulmonary bypass (CPB), admitted to a postoperative care environment (e.g., ICU) for at least 30 minutes, and reached a prespecified bleeding rate.
Exclusion Criteria Not explicitly detailed in the provided text.
Methods

Initially, patients were to be allocated sequentially to 3 cohorts of escalating rFVIIa doses (40, 80, and 160 mcg/kg rFVIIa). Cohort 1 was allocated (1:1) to 40 mcg/kg rFVIIa or placebo, while Cohort 2 was allocated (2:1) to 80 mcg/kg rFVIIa or placebo. Safety and efficacy data were evaluated at the end of cohort 1, then after every 10 patients randomized in cohort 2a, and every month in cohort 2b. After completion of the original cohort 2 (cohort 2a), the protocol was amended by including an additional cohort (cohort 2b) randomized (2:1) to 80 mcg/kg rFVIIa or placebo for sufficient data collection. The study was terminated before starting cohort 3 (160 mcg/kg rFVIIa vs. placebo) based on committee advice citing cardiac literature supporting rFVIIa doses around 60 mcg/kg.

After randomization, freeze-dried powdered (4.8 mg) rFVIIa or placebo was reconstituted with 8.5 mL sterile water and administered as a bolus injection. The transfusion protocol was applied from randomization to day 5 but was suspended during reoperations. 
Duration

Trial duration: August 2004 to November 2007

Follow-up: 30 days post-administration
Outcome Measures

Primary: Incidence of critical serious adverse events (cSAEs) from trial drug administration to day 30

Secondary: Rates of reoperation within 30 days after rebleeding, drainage volumes from cardiothoracic cavity, transfusion of allogeneic blood and blood products
Baseline Characteristics Characteristic and Treatment Placebo (n= 68) 40 mcg/kg (n= 35) 80 mcg/kg (n= 69)
Age, years Mean: 62±16, Median: 67, Range: 28–84 Mean: 68±12, Median: 71, Range: 30–83 Mean: 63±16, Median: 65, Range: 22–84
Male sex 55 (81%) 24 (69%) 49 (71%)
Body surface area ≥1.9 m² 25 (37%) 17 (49%) 24 (35%)
Body mass index, kg/m² 25.1±4.5 26.9±3.9 25.5±4.4
Mean baseline creatinine ≥130 µmol/L 3 (4%) 3 (9%) 7 (10%)
Antifibrinolytic treatment 36 (53%) 23 (66%) 30 (43%)
No prior cardiac surgery 57 (84%) 31 (89%) 55 (80%)

Surgery classification

Elective

Urgent/emergent

 

56 (82%)

12 (18%)

 

24 (69%)

11 (31%)

 

60 (87%)

9 (13%)

CPB time, min

 122±47 122±52 115±47
Cross-clamp time, min 89±39 85±35 84±38
Time from ICU admission to dosing, min 166±75 165±77 176±80
Volume chest drains (ICU admission to dosing), mL 597±403 616±264 657±448

Predose allogeneic transfusion volumes, mL

RBC

FFP

Platelets

 

353±533

223±381

89±199

 

641±819

405±633

125±222

 

450±653

230±440

160±355
Results cSAEs Placebo (n= 68) 40 mcg/kg (n= 35) 80 mcg/kg (n= 69) rFVIIa Combined
Death 4 (6%) 4 (11%) 6 (9%) -
Cerebral infarction 0 2 (6%) 2 (3%) -
Myocardial infarction 1 (2%) 0 0 -
Other thrombotic events 0 1 (3%) 2 (3%) -
Patients with cSAEs 5 (7%) 5 (14%) 8 (12%) 13 (12%)
p-Value - 0.25 0.43 0.40
Odds ratio (95% CI) - 2.16 (0.58–8.12) 1.61 (0.50–5.25 1.67 (0.50–5.47)

Abbreviations: CI= confidence interval

After randomization, significantly fewer patients in the rFVIIa group underwent a reoperation as a result of bleeding (p= 0.03) or required allogeneic transfusions (p= 0.01).
Adverse Events See Results
Study Author Conclusions On the basis of this preliminary evidence, rFVIIa may be beneficial for treating bleeding after cardiac surgery, but caution should be applied and further clinical trials are required because there is an increase in the number of critical serious adverse events, including stroke, in those patients randomized to receive rFVIIa.
Critique

The major limitations of this study are its small sample size, which increases the potential for Type II error, and the imbalance in baseline characteristics (e.g., older patients, longer CPB duration, more transfusions). Additionally, the prolonged study duration (4 years) and the method of counting all placebo patients as one cohort while having multiple rFVIIa cohorts could introduce bias and skew the data.

 

Table 2 References:
[9] Gill R, Herbertson M, Vuylsteke A, et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009;120(1):21-27. doi:10.1161/CIRCULATIONAHA.108.834275

A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study
Design

Prospective observational study

N= 281
Objective

To analyze the safety and efficacy of very-low-dose recombinant activated factor VII (vdl-rFVIIa) at a very low dose in cardiosurgical patients with refractory bleeding
Study Groups

Patients receiving vld-rFVIIa (n= 167)

Control group without rFVIIa (n= 114)
Inclusion Criteria

Cardiosurgical patients at risk of bleeding, fulfilling criteria for enhanced risk of bleeding such as aortic surgery, heart transplantation, VAD implantation, Ross procedure, endocarditis, or specific coagulation findings
Exclusion Criteria

Not explicitly stated
Methods

Tranexamic acid (10 mg/kg bolus, followed by 8 mg/kg/h continuous infusion) was the only prophylactic hemostatic medication administered (to patients in both groups). Additional hemostatic medications were allowed depending on patient criteria: desmopressin, platelet concentrates, fibrinogen concentrate, prothrombin complex concentrate, factor XIII concentrate, and fresh-frozen plasma.

During surgery, if bleeding was still occurring despite other treatments, then the patient received a single shot of very low-dose recombinant activated factor VII 20 mg/kg or less (1 mg for patients weighing <100 kg; 2 mg if >100 kg).
Duration August 2013 to December 2014
Outcome Measures

Primary: Occurrence of in-hospital thromboembolic complications, stroke, early stroke, AMI, DVT, PE, or death within the first 30 postoperative days

Secondary: Hemostatic effect of vld-rFVIIa, achievement of hemostasis, amounts of other hemotherapeutics, postoperative transfusion volumes
Baseline Characteristics   vld-rFVIIa (n= 167)

no rFVIIa (n= 114)

 p-value
Age, years (IQR) 71 (60-77) 68 (58-75) .271
Female 56 (33.5%) 30 (26.3%) .236
BMI, kg/m2 (IQR) 25.9 (23.0-30.0) 26.1 (24.2-28.5) .595
LVEF<30% 13 (7.8%) 26 (22.8%) .001
Arterial hypertension 108 (64.7%) 67 (58.8%) .320
Creatinine, mg/dL (IQR) 1.0 (0.9-1.4) 1.0 (0.9-1.2) .812

Anticoagulant use

Aspirin

DAPT

DOAC

Vitamin K antagonist

Heparin

 

73 (43.7%)

22 (13.2%)

6 (3.6%)

28 (16.8%)

29 (17.4%)

 

64 (56.1%)

17 (14.9%)

4 (3.5%)

16 (14.0%)

22 (19.3%)

 

.052

.727

1.000

.617

.753
Results  

vld-rFVIIa (n= 167)

 no rFVIIa (n= 114) p-value
30-d mortality 7 (4.2%) 8 (7.0%) .418

In-hospital thromboembolism

Stroke

Early stroke

Acute myocardial infarction

Deep vein thrombosis

Pulmonary embolism

11 (6.6%)

10 (6.0%)

3 (1.9%)

0

0

1 (0.6%)

11 (9.6%)

6 (5.3%)

3 (2.7%)

3 (2.6%)

1 (0.9%)

1 (0.9%)

.372

1.000

.691

.066

.406

1.000
Duration of hospital stay, days (IQR) 16 (12-26) 15 (11-27) .701
Reexploration for hemorrhage ≤24 h postoperatively 6 (3.6%) 3 (2.6%) .743
Delayed sternal closure 2 (1.2%) 0 .516
Adverse Events

No increase in rates of mortality, thromboembolic complications, renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving it
Study Author Conclusions

When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events.
Critique

The study provides valuable insights into the safety and efficacy of very low-dose recombinant activated factor VII in managing refractory bleeding after cardiac surgery. However, the single-center setting and observational design may limit the generalizability of the findings. The study's strength lies in its prospective approach and large sample size, but the lack of a randomized control group is a limitation.

 

Table 3 References:
[10] Hoffmann T, Assmann A, Dierksen A, et al. A role for very low-dose recombinant activated factor VII in refractory bleeding after cardiac surgery: Lessons from an observational study. J Thorac Cardiovasc Surg. 2018;156(4):1564-1573.e8. doi:10.1016/j.jtcvs.2018.03.167

Comparison of Low‑ And High‑Dose Recombinant Activated Factor VII for Postcardiac Surgical Bleeding
Design

Retrospective observational study

N= 254
Objective

To compare safety and efficacy of high and low doses of recombinant activated factor VIIa (rFVIIa) in severe postcardiac surgical bleeding
Study Groups

Low dose (40-50 mcg/kg; n= 98)

High dose (90-120 mcg/kg; n= 156)
Inclusion Criteria

All adult patients who received rFVIIa for postoperative bleeding in the Intensive Care Unit (ICU) between January 2004 and December 2014
Exclusion Criteria

Patients <18 years old, pregnant females, history of primary coagulation defect, history of peripheral vascular disease, received rFVIIa in the operating room, surgery for congenital heart diseases, requiring mechanical circulatory support
Methods

Medical records were reviewed for 254 patients grouped by rFVIIa dose. For persistent chest tube output ≥3 mL/kg/h, rFVIIa was considered after excluding surgical bleeding, administering blood products, correcting coagulation and physiologic abnormalities, and giving desmopressin and tranexamic acid. ICU and surgical teams selected the dose based on treatment options, risks, and hemodynamic status; repeat doses used the initial concentration. Clinical and operative data were collected, and risk was assessed using EuroSCORE II. Suspected thromboembolic events were confirmed with imaging and laboratory testing. Outcomes were compared using Mann–Whitney U, Fisher exact, and log-rank tests.
Duration

January 2004 to December 2014
Outcome Measures

Primary: Reduction in chest tube bleeding, transfusion requirement

Secondary: Incidence of thromboembolic adverse events, all-cause mortality at 30 days and at discharge, incidence of surgical re-exploration, days on mechanical ventilation, length of stay in ICU and hospital
Baseline Characteristics

 

 Group 1 (n= 98) Group 2 (n= 156)

Age, years

 59 (31-77) 61 (26-72)

Weight, kg

 85 (52-112) 81 (49-107)

Male

 63 (64.3%) 97 (62.2%)

Euro-score

 6.5 (4-17) 8 (4-19)

Diabetes

 30 (30.6%) 39 (25%)

Creatinine >1.4 mg/dl

 28 (28.5%) 52 (33.3%)

LVEF <40%

 22 (22.4%) 32 (20.5%)

Previous MI

 19 (19.3%) 26 (16.6%)

Previous CVA

 11 (11.2%) 8 (5.1%)

Pulmonary embolism

 2 (2%) 0 (0%)

Emergency surgery

 24 (24.4%) 25 (16%)

Redo surgery

 50 (51%) 69 (44.2%)

Preoperative anticoagulant

 38 (38.7%) 46 (29.5%)

Preoperative antiplatelet

 59 (60.2%) 85 (54.5%)

Single valve surgery

 23 (23%) 28 (17.9%)

Multiple valves surgery

 40 (40.8%) 47 (30.1%)

CABG

 23 (23.5%) 22 (14.1%)

CABG with valve(s)

 22 (22.4%) 20 (12.8%)

Aortic surgery

 4 (4.1%) 17 (10.9%)

Heart transplant

 2 (2%) 12 (7.7%)

CPB time, min

 121 (71-167) 133 (69-176)

Cross clamp time, min

 84 (53-119) 106 (62-153)

Circulatory arrest time, min

 17 (13-28) 23 (15-36)
Results

 

 Group 1 (n= 98) Group 2 (n= 156) p-value

Chest tube output 0-1 h, ml/kg/h

 4.7 (3.3-6.7) 5.3 (3.8-7.4) 0.1

Chest tube output 1-2 h, ml/kg/h

 4.3 (3.4-7.2) 4.8 (3.7-6.2) 0.3

Chest tube output 2-3 h, ml/kg/h

 3.4 (2.1-5.8) 3.7 (2.5-6.5) 0.9

Chest tube output 3-4 h, ml/kg/h

 1.2 (1.6-2.2) 1.4 (1.2-2.1) 0.5

Chest tube output 4-5 h, ml/kg/h

 0.9 (0.3-1.8) 1 (0.6-1.7) 0.8

Chest tube output 5-6 h, ml/kg/h

 0.7 (0.5-0.9) 0.5 (0.2-0.8) 0.7

FFP units

 4 (2-8) 3 (2-6) 0.9

Platelets units

 2 (2-8) 4 (2-6) 0.3

Cryoprecipitate units

 2 (2-4) 2 (0-4) 0.5

PRBCs units

 2 (0-3) 3 (1-5) 0.7
Adverse Events

A total of 15 patients (5.9%) had thromboembolic adverse events. Seven (7.1%) patients in Group 1 compared to 8 (5.1%) patients in Group 2, p= 0.58.
Study Author Conclusions

Low-dose rFVIIa showed equivalent efficacy and safety to high-dose rFVIIa. Further prospective randomized studies are needed to confirm these findings.
Critique

The direct dose comparison within a single institution using a standardized bleeding-management protocol supports relevance to postoperative rescue treatment, but retrospective, clinician-directed dose selection leaves substantial potential for confounding. The absence of statistically significant differences does not establish equivalence, particularly with only 15 thromboembolic events and symptom-triggered confirmatory testing; the findings also do not address doses below 40 mcg/kg.
Table 4 References:
[11] Habib AM. Comparison of low- and high-dose recombinant activated factor VII for postcardiac surgical bleeding. Indian J Crit Care Med. 2016;20(9):497-503. doi:10.4103/0972-5229.190365

 

Rescue Therapy With Factor VII for Refractory Cardiac Surgical Bleeding: A Propensity-Score-Matched Study
Design

Retrospective observational single-centre propensity score-matched study

N= 97
Objective

To compare effectiveness and safety of rescue therapy approach with recombinant Factor VII activated (rFVIIa) for refractory bleeding in cardiac surgery compared with a propensity-score-matched control group at a single academic institution
Study Groups

rFVIIa group (n= 81)

Control group (n= 81)
Inclusion Criteria Administration of rFVIIa in cardiac surgery with CPB intra- or postoperatively
Exclusion Criteria Patients who received rFVIIa based on a medical condition, for cardiac surgery without CBP, or non-cardiac surgery
Methods

Recombinant activated factor VII (rFVIIa) was administered as rescue therapy for refractory, non-surgical bleeding after cardiac surgery with cardiopulmonary bypass (CPB). Patients received general anaesthesia, anticoagulation with heparin, reversal with protamine, and tranexamic acid. Transfusion of blood products was guided by point of care tests. Effectiveness was assessed by bleeding control, reoperation for bleeding, and chest tube drainage. 
Duration January 1, 2009, to December 31, 2019
Outcome Measures

Primary: Effective bleeding control, reoperation for bleeding, chest tube drainage

Secondary: Mortality, stroke, renal failure, thrombo-embolic complications, blood transfusion requirements
Baseline Characteristics   Matched control (n = 81) Matched rFVIIa (n = 81) Standardized difference post-match
Age, y, median, IQR 63, 55.0-72.0 64.0, 50.0-73.0 0.061
Male sex 56 (69.1%) 56 (69.1%) 0.000
Cardiogenic shock 3 (3.7%) 4 (4.9%) 0.061
PVD 34 (42.0%) 29 (35.8%) 0.127
Cerebrovascular disease 16 (19.8%) 13 (16.0%) 0.097
CKD/Dialysis 10 (12.3%) 15 (18.5%) 0.171
Diabetes 14 (17.3%) 16 (19.6%) 0.064
PHT 6 (7.4%) 7 (8.6%) 0.045
COPD 15 (18.5%) 14 (17.3%) 0.032
Infectious endocarditis 3 (3.7%) 3 (3.7%) 0.000
CHF 23 (28.4%) 22 (27.2%) 0.028
ACE inhibitor/RAS 46 (56.8%) 42 (51.9%) 0.099
ASA/Clopidogrel 70 (86.4%) 64 (79.0%) 0.128
Heparin 19 (23.5%) 20 (24.7%) 0.029
Inotropes 6 (7.4%) 6 (7.4%) 0.000
Lowest core temperature, °C (IQR) 30.1 (25.0-32.2) 30.1 (24.9-32.1) 0.005
Clamp time, median (IQR) 127.0 (87.0-195.0) 133.0 (77.0-185.0) 0.011
CPB time, median (IQR) 237.0 (146.0-281.0) 222.0 (152.0-295.0) 0.079
CABG 16 (19.8%) 11 (13.6%) 0.166
Valve(s) 30 (37.0%) 30 (37.0%) 1.000a
Aortic root 13 (16.0%) 19 (23.5%) 0.1797
Aortic root dissection 8 (9.9%) 9 (11.1%) 0.7630
Transplant/LVAD 14 (17.3%) 12 (14.8%) 0.6171

For rFVIIa, mean initial dose was 42 µg/kg, and the median cumulative dose was 55.6 µg/kg (interquartile range, 37.4-80.0 µg/kg).

Among 97 recipients, 64 received one dose and 33 received multiple doses; the first dose was administered a median of 176 minutes after separation from CPB.
Results  

rFVIIa group

 Control group Odds ratio (95% CI); p-value
Mortality 25 (30.8%) 10 (12.3%) 3.17 (1.41-7.14); 0.0054
Thrombo-embolism 11.1% 1.23% 10.59 (1.64-117.5); 0.0196
Stroke 8.6% 4.9% 1.82 (0.51-6.48); 0.35
Renal failure 39.5% 33.3% 1.31 (0.69-2.48); 0.41
Blood products volume intraoperatively + 4.4x more Reference 0.0001
Blood products volume postoperatively + 1.97x more Reference 0.02
Adverse Events

Mortality and thrombo-embolism were higher in the rFVIIa group. Stroke and renal failure rates were not statistically different between groups
Study Author Conclusions

Rescue therapy with rFVIIa seems to effectively control bleeding. However, we observed an association with increased mortality, thromboembolism, and transfusion. We did not find rFVIIa association with risk of stroke or renal failure.
Critique

The study's retrospective design and single-centre nature may limit generalizability. The propensity score matching was thorough, but residual confounding may exist due to differences in baseline characteristics. The long inclusion period could introduce variability in practice standards over time.

 

Table 5 References:
[12] Neira VM, Neira CD, Matheson K, et al. Rescue Therapy With Factor VII for Refractory Cardiac Surgical Bleeding: A Propensity-Score-Matched Study. Interdiscip Cardiovasc Thorac Surg. 2025;40(8):ivaf185. doi:10.1093/icvts/ivaf185

Use of rFVIIa for critical bleeding in cardiac surgery: dose variation and patient outcomes
Design

Retrospective analysis using data from the Haemostasis Registry

N= 804
Objective

To investigate the use of different rFVIIa dosing practices on response to bleeding and patient outcomes in cardiac surgery patients
Study Groups

≤40 µg/kg (n= 42)

41-60 µg/kg (n= 107)

61-80 µg/kg (n= 104)

81-100 µg/kg (n= 368)

>100 µg/kg (n= 183)
Inclusion Criteria

Patients aged more than 15 years who received rFVIIa from September 2005 to November 2008 for the treatment of bleeding associated with cardiac surgery
Exclusion Criteria Not specified
Methods

Data were extracted from the Haemostasis Registry in Australia and New Zealand. Patients were divided into five dose categories based on the initial rFVIIa dose volume. Univariate analyses compared patients on key parameters. 
Duration September 2005 to November 2008
Outcome Measures

Primary: Response to bleeding, 28-day mortality

Secondary: Rate of thromboembolic adverse events (TAEs)
Baseline Characteristics  

≤40 µg/kg (n= 42)

 41-60 µg/kg (n= 107) 61-80 µg/kg (n= 104) 81-100 µg/kg (n= 368) >100 µg/kg (n= 183)
Age, years (IQR) 63 (48-74) 68 (58-75) 67 (59-78) 67 (54-74) 67 (54-75)
Weight, kg 81.4 ± 15.5 79.9 ± 15.3 77.6 ± 17.8 78.5 ± 15.8 69.2 ± 14.5
Female 12 (28.6%) 27 (25.2%) 26 (25.0%) 98 (26.6%) 59 (32.0%)
Aspirin 16 (38.1%) 42 (39.3%) 27 (26.0%) 140 (38.0%) 52 (28.4%)
INR (IQR) 1.5 (1.3-1.8) 1.4 (1.3-1.6) 1.5 (1.3-1.9) 1.6 (1.3-1.9) 1.5 (1.3-1.8)
Fibrinogen, g/L (IQR) 2.7 (1.8-3.8) 2.2 (1.7-3.1) 2.2 (1.7-2.8) 2.1 (1.7-2.6) 2.0 (1.7-2.7)
Total FVIIa dose, µg/kg (IQR) 32 (25–40) 56 (51–92)  75 (67–80) 94 (89-99) 111 (104–128) 
Received 2 or more FVIIa doses 10 (23.8%) 32 (29.9%) 22 (21.2%) 54 (14.7%) 23 (12.6%)
Results  

≤40 µg/kg (n= 42)

 41-60 µg/kg (n= 107) 61-80 µg/kg (n= 104) 81-100 µg/kg (n= 368) >100 µg/kg (n= 183) p-value

Recorded effect on bleeding

Responded to dose 1

35 (83%)

27 (77%)

94 (88%)

75 (80%)

90 (87%)

67 (74%)

335 (91%)

273 (81%)

161 (88%)

127 (79%)

0.664
28-Day mortality 7 (17%) 15 (14%) 17 (16%) 67 (18%) 36 (20%) 0.788
Adverse Events

Cerebrovascular accident (CVA) was the most frequently occurring adverse event (40 events across the dose categories). Total thromboembolic adverse event (TAE) rate was 7.2%
Study Author Conclusions

These findings raise the important question of whether lower doses of rFVIIa may be as effective as higher doses in the treatment of severe bleeding in cardiac surgery patients.
Critique

The study's retrospective design and reliance on registry data without a control group limit the ability to establish causality. The variation in baseline characteristics between dose groups may affect the interpretation of results.

 

Table 6 References:
[13] Willis C, Bird R, Mullany D, Cameron P, Phillips L. Use of rFVIIa for critical bleeding in cardiac surgery: dose variation and patient outcomes. Vox Sang. 2010;98(4):531-537. doi:10.1111/j.1423-0410.2009.01276.x

Treatment of Refractory Bleeding after Cardiac Operations with Low-Dose Recombinant Activated Factor VII (Novosevenw): A Propensity Score Analysis
Design

Propensity score analysis

N= 40
Objective

To evaluate the effectiveness of low-dose recombinant activated factor VII (rFVIIa) in reducing blood loss and transfusion requirements in patients with refractory bleeding after cardiac surgery
Study Groups

Low-dose rFVIIa (n= 40)

Matched controls without rFVIIa (n= 40)
Inclusion Criteria

Patients with refractory bleeding after cardiac surgery, defined as bleeding compromising hemodynamics or exceeding specific thresholds postoperatively
Exclusion Criteria

No formal exclusion criteria were applied
Methods

Patients received a low dose of rFVIIa (median: 18 mg/kg, interquartile range: 9—16 mg/kg) as a slow intravenous bolus. The dose was repeated if bleeding persisted. Propensity score-based greedy matched controls were used for comparison. Data were collected and analyzed for blood loss, transfusion requirements, and coagulation variables.
Duration

September 2005 to June 2007
Outcome Measures

Primary: Blood loss reduction, transfusion requirements

Secondary: Changes in coagulation laboratory findings, clinical outcomes (ICU length of stay, mechanical ventilation time)
Baseline Characteristics

 

 Low-dose rFVIIa (n= 40) Matched controls without rFVIIa (n= 40)

Age, years

 70.1 ± 9.2 75.8 ± 9.8

Male

 21 (52.5%) 95 (41.6%)

BSA

 1.7 ± 0.1 1.7 ± 0.2

NYHA class 

 3 [3—4] 3[3—4]

Atrial fibrillation

 5 (12.5%) 44 (16.0%)

Congestive heart failure

 2 (5.0%) 3 (1.3%)

Endocarditis

 5 (12.5%) 11 (4.8%)

LVEF ≤ 35%

 5 (12.5%) 21 (9.2%)

EuroScore Additive

 8.3 [5—10] 10.4 [9—14]

EuroScore Logistic

 15 [11—19] 18 [15—20]

Hypertension

 8 (20.0%) 57 (25.0%)

Diabetes

 7 (17.5%) 51 (22.3%)

Chronic obstructive pulmonary disease

 6 (15.0%) 44 (19.2%)

Renal insufficiency

 3 (7.5%) 2 (0.8%)

Creatinine, mg/dl

 1.2 [1.1—1.4] 1.1 [1.0—1.2]

Cerebral vascular disease

 2 (5.0%) 10 (4.3%)

Peripheral vascular disease

 1 (2.5%) 11 (4.8%)

Baseline coagulation findings

PT

INR

aPTT

FBG

PLT

 

86 [75—94]

1.2 [0.9—1.4]

46 [41—54]

375 [322—397]

171 [140—191]

 

109 [80—125]

1.0 [0.6—1.3]

25 [22—36]

410 [335—411]

182 [150—196]

Baseline Hb

 12 [10—13] 13 [12—14]

Antiplatelet therapy

 7 (17.5%) 45 (19.7%)

Anticoagulant therapy

 5 (12.5%) 21 (9.2%)

Urgency/emergency

 7 (17.5%) 41 (18.0%)

Redo surgery

 4 (10.0%) 15 (6.5%)

Surgical procedures

CABG

Aortic valve surgery

MV surgery

CABG + valve surgery

Multiple valve

Ascending aorta replacement

Aortic arch replacement

Complex surgery

 

17 (42.5%)

4 (10.0%)

4 (10.0%)

4 (10.0%)

2 (5.0%)

5 (12.5%)

4 (10.0%)

15 (37.5%)

 

114 (50.0%)

11 (4.8%)

13 (5.8%)

30 (13.1%)

19 (8.3%)

23 (10.1%)

18 (7.9%)

110 (48.2%)

CPB time

 140 [80—188] 175 [120—210]

CCL time

 80 [60—120] 91 [80—151]

DHCA

 6 (15.0%) 28 (12.2%)

DHCA time

 40 [18—38] 34 [16—77]

ACP

 5 (12.5%) 33 (14.4%)

ACP time

 20 [11—41] 18 [15—34]

Nadir Hct on CPB

 22 [18—24] 20 [16—20]

Tranexamic acid

 40 (100) 228 (100)

Aprotinin

 9 (22.5%) 51 (22.3%)

Bleeding

 1685 [1590—1770] 1290 [970—1510]
Results

Among 40 patients receiving low-dose rFVIIa and 40 propensity score–matched controls, median 24-hour blood loss was 1,610 mL (interquartile range [IQR] 1,285–1,800) versus 3,171 mL (IQR 2,725–3,760), respectively (p< 0.001).

Median 24-hour transfusion requirements were lower with rFVIIa for red blood cells (6.5 vs 17 units), fresh frozen plasma (7 vs 12 units), and platelets (1 vs 9.5 units; all p< 0.001).

A single dose reduced postoperative bleeding in 92.5% of treated patients; further surgical re-exploration was required in 3 treated patients (7.5%) with persistent bleeding after a second dose versus 35 controls (87.5%; p< 0.001), with a surgical bleeding source identified in all 3 treated patients.

Median ICU length of stay (151 vs 443 hours) and mechanical ventilation duration (13 vs 73 hours) were shorter with rFVIIa (both p< 0.001).

Overall complication rates (20.0% vs 17.5%) and mortality (5.0% vs 7.5%) did not differ significantly (both p> 0.9).

Two rFVIIa-treated patients (5.0%) experienced postoperative stroke, with predisposing factors identified in both; no thromboembolic complication was detected in the remaining treated patients.
Adverse Events

No thromboembolic-related event was detected in the study cohort.
Study Author Conclusions

In our experience low-dose rFVIIa was associated with reduced blood loss, improvement of coagulation variables and decreased need for transfusions. Our findings need to be confirmed by further larger studies.
Critique

Standardized treatment protocols and propensity matching strengthen the comparison, but retrospective treatment selection, concomitant PCC, and internal reporting inconsistencies limit interpretation of efficacy and safety. This study compared one fixed low-dose strategy with no rFVIIa, so it cannot establish comparative efficacy or safety across doses; the small treated cohort and clinically triggered thromboembolic investigations also limit assessment of uncommon thrombotic events.
Table 7 References:
[14] Gelsomino S, Lorusso R, Romagnoli S, et al. Treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven): a propensity score analysis. Eur J Cardiothorac Surg. 2008;33(1):64-71. doi:10.1016/j.ejcts.2007.10.004