Comparison of Low Dose Recombinant Factor VIIa and 4-Factor Prothrombin Complex Concentrate for Treatment of Bleeding Related to Cardiac Surgery.

Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa (<30 mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18 hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P = .5359) or in the median amount of pRBC transfused (500 mL vs 640 mL, P = .0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P = .0015), develop AKI (12.8% vs 25.7%, P = .0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P = .0487] and greater in-hospital mortality (2.6% vs 10.9%, P = .033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted.

Very low-dose recombinant Factor VIIa administration for cardiac surgical bleeding reduces red blood cell transfusions and renal risk: a matched cohort study.

Outcomes following administration of very-low-dose recombinant activated factor VIIa (vld-rFVIIa) for cardiac surgical bleeding remain debatable. We sought to determine the association of vld-rFVIIa and adverse surgical outcomes. Retrospective, cohort matching of patients undergoing cardiac surgery who received vld-rFVIIa (median 13.02 µg/kg) for perioperative bleeding were matched to cardiac surgical patients who had bleeding and received standard of care for bleeding without Factor VIIa administration. Of the 362 matched patients (182 in each group), patients who received rFVIIa required significantly less red blood cell transfusions [median 3 units (range 0--60, IQR = 4 units) versus 4 units (range 2-34, IQR = 4 units); P = 0.0004], decreased length of hospital stay (median 8 versus 9 days; P = 0.0158) and decreased renal risk (P < 0.0001). Incidence of renal failure, postoperative infection, postoperative thrombosis, prolonged ventilation, total ICU hours and 30-day mortality were not different between the two groups. Vld-rFVIIa for cardiac surgical bleeding was associated with decreased red blood cell transfusion, renal risk and length of hospital stay without increased thromboembolism or mortality when compared to patients who had cardiac surgical bleeding and received standard of care without Factor VIIa.

Association of Serum IL-6 (Interleukin 6) With Functional Outcome After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. RESULTS: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P=0.002), with a stronger association seen in lobar (ß, 12.51 [95% CI, 6.47-18.55], P<0.001) versus nonlobar (ß 5.32 [95% CI, 3.36-7.28], P<0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (ß 1.22 [95% CI, 0.15-2.29], P=0.03). Treatment group was not associated with IL-6 levels or outcome. CONCLUSIONS: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Clot waveform analysis for perioperative hemostatic monitoring of arthroscopic synovectomy in a pediatric patient with hemophilia A and inhibitor receiving emicizumab prophylaxis.

Emicizumab reduces bleeding in patients with hemophilia A and inhibitors (PwHA-I). Coagulation potential during the perioperative period in emicizumab-treated PwHA-I undergoing surgery remains to be evaluated. We describe a 14-year-old boy with HA-I receiving emicizumab prophylaxis who experienced arthroscopic synovectomy. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 80 µg/kg) immediately before surgery, and treatment continued at the same dose every 3 h on day 1, every 4 h on day 2, and every 6 h on day 3. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potential throughout the perioperative period was retrospectively assessed with an easy-to-use clot waveform analysis (CWA). Measurements from CWA returned to within or near the normal range, suggesting successful hemostatic management. Coagulation potentials assessed by CWA showed a significant correspondence with those from a thrombin generation assay (TGA) that is already in use. CWA and TGA could both provide useful data for assessing coagulation potential in the perioperative hemostatic management of emicizumab-treated PwHA-I.

Use of rFVIIa in Preventing Recurrent Intra-articular Hemorrhages in a 15-Year-Old Patient With Glanzmann Thrombasthenia.

Glanzmann thrombasthenia is a rare congenital thrombocytopathy. The first-line treatment in severe life-threatening bleeding is a transfusion of platelet concentrate or recombinant factor VIIa in the case of platelet transfusion refractoriness. We present the case of a 16-year-old boy with Glanzmann thrombasthenia who was admitted to hospital with severe bleeding into the quadriceps femoris muscle. At the age of 15 years, he was hospitalized again because of chronic bleeding into the right ankle joint, resulting in joint destruction. Here we give a scheme of management and treatment of this patient. Hemostatic therapy followed by radiosynovectomy of the right ankle joint and introduction of secondary preventive treatment with recombinant factor VIIa proved to be efficacious and safe.

Identifying risk factors and optimizing standard of care for patients with acquired haemophilia A: Results from a Czech patient cohort.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare autoimmune disorder, characterized by bleeds of varying severity caused by autoantibodies against factor VIII (FVIII). AIM: Identify risk factors associated with AHA-related deaths/relapses and assess the effect of increased corticosteroid doses. METHODS: AHA patients treated across two specialist centres in the Czech Republic, generally receiving first-line haemostatic therapy with rFVIIa and immunosuppression with corticosteroids/cyclophosphamide, were included. We analysed the association between early death (within 8 weeks of diagnosis [considered disease-related]) and age, malignancy, FVIII levels and bleeding severity. Risk factors associated with reduced 2-year survival and relapse incidence, and the effect of increased corticosteroid doses on early death and remission were also assessed. RESULTS: The demographics of the described cohort (n = 66) were similar to other AHA registries. Early death occurred in 20% of cases. Unlike age and malignancy, FVIII levels <1% and severe bleeding were associated significantly with early death (P = .010 and P = .046, respectively). Patients with underlying malignancy or requiring continued haemostatic therapy exhibited significantly decreased 2-year survival compared with those without these risk factors (P = .007 and P = .006, respectively). Patients with an underlying autoimmune disease relapsed significantly more than those without (P = .015). Higher corticosteroid doses were associated with a significantly increased incidence of early deaths (P < .001), but also with early remission (P < .001). CONCLUSION: Based on this rather large patient cohort, we were able to evaluate the significance of several risk factors associated with treatment outcomes in AHA and the effect of initial treatment with corticosteroids on survival and time to remission.

Minimally invasive surgery for haemophilic pseudotumour of the limbs: 28 years of experience.

INTRODUCTION: Haemophilic pseudotumour (HP) is an encapsulated haematoma in patients with haemophilia (PWH) which has a tendency to progress and produce clinical symptoms related to its anatomical location. AIM: To show the experience of one surgeon who has been using mini-invasive technique to treat pseudotumours of limbs in PWH with and without inhibitors at one centre for 28 years. MATERIALS AND METHODS: Thirty-three patients with 39 HP were treated. All patients had haemophilia A. Twenty-four patients had no inhibitors (72.8%), and 9 had inhibitors (27.2%). The mean follow-up was 16 years (1-25). All patients had x-rays and MRIs. All of them received Buenos Aires protocol as conservative treatment for 6 weeks. MRIs were repeated after 6 weeks' treatment to assess response to treatment. Surgery was performed in patients who did not respond to conservative treatment. RESULTS: After Buenos Aires protocol, four pseudotumours did not shrink (10.24%), 33 (84.61%) shrank, and two (5.12%) healed. Thirty-seven pseudotumours had surgery, 35 pseudotumours (94.59%) healed with minimally invasive treatment, and two did not heal (5.41%). No infection was observed with this treatment. The mortality rate for the series was 0%. CONCLUSION: The minimally invasive treatment of pseudotumours was effective in 95% of the cases and resulted in no mortality in this series after 28 years.

Antithrombotic and hemostatic stewardship: evaluation of clinical outcomes and adverse events of recombinant factor VIIa (Novoseven®) utilization at a large academic medical center.

BACKGROUND: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. METHODS: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. RESULTS: A total of 63 patients [pediatric (n = 6), adult (n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. CONCLUSION: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

Prophylaxis therapy with bypassing agents in patients with haemophilia A and inhibitors undergoing surgery: A cost analysis in Spain.

OBJECTIVES: This study estimated the cost of prophylaxis with activated prothrombin complex concentrate (aPCC) and recombinant activated factor VIIa (rFVIIa) in surgical patients with haemophilia A and inhibitors in Spain. METHODS: A decision-analytic model was developed to estimate the cost to the Spanish National Health System of providing haemostatic coverage in this haemophilia population, with age distribution and average weight derived from the literature, and the annual number of surgeries (0.33 per patient) from local data. Drug costs were calculated from official ex-factory prices with a 7.5% mandatory deduction and recommended dosing regimens. RESULTS: The estimated average costs per patient were €10 100.73 (aPCC) and €14 265.89 (rFVIIa) for dental extraction, €24 043.88 (aPCC) and €62 301.08 (rFVIIa) for minor surgery and €126 595.81 (aPCC) and €347 731.09 (rFVIIa) for major surgery. Assuming an estimated 23 annual surgeries in this population (N = 69), distributed as 19% dental extraction, 50% minor surgery and 31% major surgery, the total annual cost of prophylaxis was €1 209 682.35 with aPCC and €3 221 929.28 with rFVIIa. CONCLUSIONS: aPCC costs were 62.5% lower than rFVIIa. Assuming potential clinical equivalence, aPCC is a potentially cost-saving option for surgical patients with haemophilia A and inhibitors.

A novel protocol for accurate and reliable postoperative bolus administration of recombinant factor VIIa using an automated mini-pump system.

INTRODUCTION: Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals. AIM: To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period. METHODS: It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire. RESULTS: Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump. CONCLUSION: This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa.

Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery.

BACKGROUND: Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products. OBJECTIVES: We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity. PATIENTS AND METHODS: Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 µg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration. RESULTS: All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic. CONCLUSION: A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.

Characteristics Associated With Mortality in 372 Patients Receiving Low-Dose Recombinant Factor VIIa (rFVIIa) for Cardiac Surgical Bleeding.

OBJECTIVE: Activated recombinant factor VII (rFVIIa) has been used to treat cardiac surgical bleeding in an off-label manner. This observational report analyzes the outcomes with use of a low dose and early administration of rFVIIa for cardiac surgical bleeding. DESIGN: A retrospective, observational study. SETTING: Single-center, tertiary care cardiothoracic surgical setting. PARTICIPANTS: A total of 6,862 patients underwent cardiac surgery from January 2012 to January 2018. Of those, 372 patients received rFVIIa perioperatively. INTERVENTIONS: An institutional policy directed low-dose, incremental aliquots of intravenous rFVIIa (0.5-1 mg). Characteristics and outcomes were compared among patients who survived (n = 328) and patients who died (n = 44). MEASUREMENTS AND MAIN RESULTS: The median dose of rFVIIa was low at 13.29 µg/kg. Higher doses were given to patients who died (15.79 µg/kg v 12.99 µg/kg; p = 0.0133). Patients who died received more blood and component transfusions (median 9 products in those who died v 6 products in survivors; p = 0.0022), although the median transfusion requirement for all patients was 6 units per patient. The rate of reoperation was not different in the 2 groups. Mortality was associated with emergent/urgent surgical procedures (p = 0.0282), type of surgical procedure with aortic procedures being highest risk (p = 0.0014), cardiogenic shock (p = 0.0028), postoperative renal failure (p = 0.0035), postoperative cardiac arrest (p = 0.0006), and ischemic stroke (p = 0.0084). CONCLUSION: Mortality after life-threatening cardiac surgical bleeding treated with rFVIIa was more common in aortic procedures and emergent and urgent surgeries. Lower doses of rFVIIa than previously reported may achieve bleeding cessation because overall blood component transfusions were low in this cohort.

A Propensity-Score Matched Analysis on Outcomes Using Recombinant Activated Factor VII in Pediatric Cardiac Surgery.

OBJECTIVE: To evaluate the effect of recombinant activated factor VII (rFVIIa) administration on outcomes in pediatric cardiac surgery patients with postoperative bleeding. DESIGN: A propensity score-matched retrospective study. SETTING: Single tertiary medical center. PARTICIPANTS: The study comprised 151 patients who received treatment with rFVIIa and were matched with control patients at a 1:2 ratio. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoints were thrombotic events, renal replacement therapy (RRT), and mortality. The secondary endpoints were length of intensive care unit stay and the reexploration rate. Patients in the rFVIIa group showed no significant differences in thrombotic events (odds ratio [OR] 1.03; 95% confidence interval [CI] 0.48-2.21; p = 0.948), mortality (OR 0.94; 95% CI 0.42-2.13; p = 0.891), and RRT (OR 1.38; 95% CI 0.73-2.58; p = 0.319). However, patients in the rFVIIa group experienced a prolonged length of intensive care unit stay (5.65 [3.00-12.28] d v 3.91 [1.83-6.77] d) and an increased reexploration rate (8.2% v 3.1%). High-dose rFVIIa was an independent risk factor of thrombotic events (OR 5.17; 95% CI 1.19-22.49; p = 0.029). CONCLUSION: This study found that rFVIIa is not associated with increased risks of postoperative thrombotic events, mortality, or RRT in pediatric patients undergoing cardiac surgery. Nevertheless, rFVIIa was associated with longer intensive care unit stay and increased reexploration rate. Furthermore, the risk for thrombotic events may increase with high-dose rFVIIa.

Factor VII deficiency: do all need replacement for cardiac surgery?

In cardiac surgery, supplementation with recombinant factor VIIa is the treatment of choice for patients with factor VII deficiency, but overzealous administration can be associated with thromboembolic side-effects. A 53-year-old man with factor VII activity 15.2%, international normalized ratio 2.9, and acute thrombotic critical coronary anatomy, underwent coronary artery bypass surgery and a thoracotomy with decortication 5 months later. He was managed successfully without recombinant factor VIIa supplementation. This case demonstrates that current bedside and laboratory tests such as thromboelastography, prothrombin time or international normalized ratio, and factor VII activity may not predict replacement therapy in these patients.

Efficacy and Safety of Recombinant Activated Factor VII Off-label Use in a Pediatric Hematology/Oncology Cohort.

BACKGROUND: Recombinant activated factor VII (rFVIIa) has been used off-label to treat or prevent severe bleeding in patients for whom conventional treatments are unsuccessful. However, studies in children remain limited. PROCEDURE: To examine the efficacy and safety of rFVIIa, we performed a retrospective analysis of rFVIIa off-label use in a pediatric hematology/oncology cohort at a single center from 2006 to 2014. RESULTS: Of 58 patients identified, 46 (79.3%) received rFVIIa to treat bleeding and 12 (20.7%) to prevent bleeding. Thirty-three (71.7%) patients had life-threatening bleeding. In the treatment group, 63.0% patients were responders (ie, bleeding decreased or stopped) and 37.0% were nonresponders (ie, bleeding did not change). Blood products usage was similar between responders and nonresponders. After rFVIIa administration, prothrombin time, partial thromboplastin time and lactate were significantly lower, but fibrinogen was significantly higher in responders than nonresponders. Venous thromboembolism developed in 5.2% (3/58) patients, but its relation to rFVIIa remains unclear. Responders had significantly lower mortality than nonresponders (17.2% vs. 82.4%, P<0.0001). CONCLUSIONS: rFVIIa controlled most bleeding events in this cohort, despite predominance of life-threatening bleeding, suggesting good efficacy. Venous thromboembolism rate was low. Further studies are warranted to identify predictors of favorable response to rFVIIa in similar patients.

Nebulised recombinant activated factor VII (rFVIIa) does not attenuate the haemorrhagic effects of blast lung injury.

INTRODUCTION: Primary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from a range of medical causes, but its efficacy in blast lung is unknown. The aim of this study was to investigate whether nebulised rFVIIa attenuates the haemorrhagic effects of blast lung injury in an animal model. METHODS: Terminally anaesthetised rabbits subjected to blast lung injury were randomised to receive either rFVIIa or placebo via a nebuliser. The primary outcome was the level of blood iron-transferrin complex, a marker of the extent of blast lung injury, analysed using low temperature electron paramagnetic resonance spectroscopy. RESULTS: Blast exposure led to a significant fall in iron-bound transferrin in both groups of animals (p<0.001), which remained depressed during the study. There were no significant differences in iron-transferrin between the rFVIIa and placebo treatment groups over the duration of the study (p=0.081), and there was no trend towards elevated iron-transferrin in the rFVIIa-treated group once drug treatment had started. There was suggestive evidence of systemic absorption of rFVIIa given via the inhaled route. CONCLUSION: A single dose of nebulised rFVIIa did not attenuate pulmonary haemorrhage in a rabbit model of blast lung injury. As there was some evidence of systemic absorption, the inhaled route does not avoid the concern about potential thromboembolic complications from administration of rFVIIa.

Development of acquired haemophilia A in a patient treated with alemtuzumab for multiple sclerosis.

This case illustrates a 36-year-old man who presented with a factor VIII (FVIII) inhibitor (acquired haemophilia A) with cutaneous bleeding and a significant thigh haematoma. No traditional risk factors for the development of a FVIII inhibitor were identified. However, previous treatment with alemtuzumab for multiple sclerosis was noted in the patient's history. Alemtuzumab is an anti-CD52 monoclonal antibody and is known to be associated with the development of a number of autoimmune conditions, with a delay in onset of these conditions as long as 5 years after the cessation of treatment. To our knowledge, there have only been three previously documented cases of a FVIII inhibitor in the setting of alemtuzumab therapy. This case adds further evidence to the current body of literature suggesting alemtuzumab as a causative agent for the development of an FVIII inhibitor.

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

OBJECTIVES: Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. METHODS: This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 µg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. RESULTS: There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), 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 recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. 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.