Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Authors


  • See Editorial on Page 872

Abstract

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Orthotopic liver transplantation (OLT) is associated with excessive blood loss that requires transfusions, resulting in increased postoperative mortality,1–4 longer stays in the intensive care unit,1 increased infection rates, and reduced graft survival.3–6 Clinical strategies to reduce blood loss include the use of blood products to correct preexisting coagulopathy (fresh frozen plasma, platelets, cryoprecipitate) or antifibrinolytic agents to correct fibrinolysis that may occur during the procedure.7, 8 The primary concerns with antifibrinolytic therapy are determining the appropriate dosage and addressing the potential risk of serious thromboembolic events.8–12

Activated recombinant factor VII (rFVIIa; NovoSeven®, Novo Nordisk A/S, Bagsvaerd, Denmark) is a hemostatic agent approved for use in many countries for hemophilia patients. It has demonstrated efficacy in trauma patients13 and in Child-Turcotte-Pugh class B and C patients with upper gastrointestinal bleeding.14 Additionally, it was found to be safe and effective in a small, single-center trial with patients undergoing liver resection15 or OLT.16 Finally, administration of rFVIIa also enhanced thrombin generation in a localized, time-dependent manner, and did not lead to systemic coagulation or fibrinolysis in this earlier OLT study population.17

Recombinant FVIIa works by enhancing localized thrombin generation at the site of vascular injury by binding to the surface of activated platelets.18–20 The ability of rFVIIa to initiate coagulation at the site of bleeding without inducing systemic coagulation increases its potential application in OLT. Based on the small-scale trial that reported rFVIIa as safe and effective in patients undergoing OLT16, 17 and the reported mechanism of action of rFVIIa, this large-scale trial was undertaken to evaluate the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT.

Abbreviations

OLT, orthotopic liver transplantation; rFVIIa, activated recombinant factor VII; RBC, red blood cell; AE, adverse event.

Materials and Methods

Study Design and OLT Procedure

This multicenter, randomized, double-blind, placebo-controlled, exploratory trial enrolled patients scheduled for OLT into 1 of 4 parallel study groups to receive a single dose of rFVIIa (20, 40, or 80 μg/kg) or placebo. Randomization was performed on the day of surgery, with patients grouped in blocks of 8 and equally allocated among the 4 trial-product study groups.

The study product was administered as a slow intravenous injection over 2 minutes, within 10 minutes of the first skin incision. No additional administrations of study product were allowed.

OLT was conducted in accordance with institutional standard procedures. Prophylactic administration of hemostatic agents was not permitted during OLT but could be administered during the procedure when clinically indicated. Transfusion of blood products during surgery was restricted to the following guidelines. Red blood cell (RBC) transfusions were allowed when hematocrit levels fell below 25%. Fresh frozen plasma transfusions were permitted when the international normalized ratio was >1.5 or activated partial thromboplastin time was >1.5 × control. Platelet concentrate administration was permitted when platelet counts fell below 30,000/mm2. Cryoprecipitate or fibrinogen concentrate administrations were permitted when fibrinogen levels were <1.0 g/L. Fresh frozen plasma, platelet concentrate, cryoprecipitate, and fibrinogen concentrate transfusions could also be administered as indicated by thromboelastogram tracings. The protocol was approved by the local ethics committee of each participating center, and each patient signed a written informed consent.

Patient Population

Patients ≥18 years of age with end-stage liver disease (Child-Turcotte-Pugh class B or C) scheduled to undergo OLT were eligible for enrollment in this study.21 Exclusion criteria included previous liver transplantation, multiorgan transplantation, living related-donor transplantation, renal insufficiency requiring dialysis, documented inherited coagulation disorders, and documented history or presence of portal vein thrombosis.

Donor Liver Data

Donor liver data collected included donor-recipient blood group match, donor age and sex, cold and warm ischemia time, and a qualitative evaluation of the donor liver (prior to and after reperfusion). Surgical techniques or complications that increased bleeding risk, and the use of an autologous blood salvage transfusion system were also recorded.

Efficacy and Safety Assessments

The primary endpoint was the total number of RBC units transfused during the perioperative period, defined as surgical time and the first 24-hour postoperative period.

The secondary endpoints were the volume of other products transfused or infused perioperatively, including fresh frozen plasma, platelet concentrate, cryoprecipitate, crystalloids, and colloids. Blood loss was recorded during OLT and during the initial 24-hour postoperative period. In addition, the number of patients who received treatment with systemic hemostatic drugs other than transfusions during the perioperative period was also recorded. The number of intensive care unit days, plasma factor VII clotting activity, and the prothrombin time profiles were also recorded.

A physical examination, assessment of vital signs, and 12-lead electrocardiogram were performed on the day of treatment prior to trial product administration and 3 days postoperatively. Doppler ultrasonography of hepatic vessels was performed at 24 hours, 3 days, and 7 days postoperatively to detect evidence of intravascular thrombosis. Additional Doppler ultrasonography studies were performed in the event of suspected hepatic thrombosis.

The frequency and type of all adverse events (AEs), including thromboembolic events and bleeding complications, were recorded.

Laboratory Analyses

Blood sampling was conducted prior to trial product administration, at completion of wound closure, and at 24 hours, 3 days, and 7 days postoperatively for analysis of the following values: activated partial thromboplastin time, platelet count, fibrinogen concentration, D-dimer, antithrombin III, concentration of plasmin-α2-antiplasmin complexes, prothrombin fragment F1+2 levels, coagulation factors II, V, and X, hemoglobin, hematocrit, white blood cell counts, bilirubin, serum albumin and creatinine, calcium, potassium, and sodium, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Blood sampling for analysis of plasma factor VII clotting activity and prothrombin time was performed prior to bolus dose, 15 minutes after product administration, and at regular 1-hour intervals until the completion of surgery. Additional analyses were performed at 24 hours, 3 days, and 7 days postoperatively.

Statistical Analysis

The primary efficacy endpoint was the total number of RBC units transfused during the OLT procedure and in the first 24-hour postoperative period. A mean transfusion requirement of 20 U RBC (SD = 16 U) was assumed. Based on 80% power to detect a significant difference (P = 0.05, 2-sided) of 60% reduction in RBC transfusion requirement, 20 patients were required for each study group. The primary efficacy analysis is between placebo and the rFVIIa 80-μg/kg and 40-μg/kg treatment arms combined. The analysis was performed using a nonparametric trend test (Jonckheere-Terpstra test).22 For the safety analysis, the total number of patients experiencing thromboembolic AEs was compared between study groups using an exact 2-sided Jonckheere-Terpstra test. Similar, separate analyses were performed for portal vein thrombosis and hepatic artery thrombosis. The coagulation-related parameters were compared between study groups using F tests.

Results

Patient Demographics

Nine investigative sites enrolled patients undergoing OLT between February and September 2000. Of 96 patients screened for enrollment, 9 failed to meet inclusion criteria, and 4 had cancelled OLT; thus, 83 patients received trial product. One patient received rFVIIa 40 μg/kg but subsequently did not undergo OLT because of the unsatisfactory quality of the donor liver, leaving 82 evaluable patients for efficacy endpoints and 83 evaluable patients for safety endpoints (Fig. 1). Patient demographics, including age, sex, and ethnic origin, were comparable between study groups (Table 1).

Figure 1.

Patient flow diagram. OLT, orthotopic liver transplantation; rFVIIa, activated recombinant factor VII. Asterisk (*) indicates 1 patient who was dosed but did not undergo OLT and was part of the safety analysis only.

Table 1. Demographics and Baseline Characteristics
 Placebo (n = 19)rFVIIa 20 μg/kg (n = 18)rFVIIa 40 μg/kg (n = 24)rFVIIa 80 μg/kg (n = 22)
  • rFVIIa, activated recombinant factor VII; SD, standard deviation; OLT, orthotopic liver transplantation; PT, prothrombin time; aPTT, activated partial thromboplastin time.

  • *

    PT values were not assessed for all patients, leading to a discrepancy between total PT n value and the PT n value for each study group.

Age, mean y (SD)49.9 (11.0)49.4 (13.4)49.7 (10.1)51.9 (8.8)
Sex, n (%)    
 Male14 (74)12 (67)15 (63)16 (73)
 Female5 (26)6 (33)9 (38)6 (27)
Primary OLT indication, n (%)    
 Hepatitis C cirrhosis9 (47)9 (50)11 (46)7 (32)
 Hepatitis B cirrhosis0 (0)0 (0)0 (0)2 (9)
 Alcoholic cirrhosis3 (16)3 (17)7 (29)10 (45)
 Primary biliary cirrhosis2 (11)1 (6)1 (4)1 (5)
 Other5 (26)5 (28)5 (21)2 (9)
Child-Turcotte-Pugh score, n (%)    
 B7 (37)8 (44)10 (42)12 (55)
 C12 (63)10 (56)14 (58)10 (45)
Baseline PT* mean, n (%)    
 <4 s prolongation10 (53)8 (44)12 (50)14 (64)
 4-6 s prolongation2 (11)2 (11)6 (25)5 (23)
 >6 s prolongation5 (26)5 (28)4 (17)3 (14)
Baseline aPTT, mean s (SD)52 (12)55 (16)58 (16)51 (10)
Baseline fibrinogen, mean g/L (SD)1.6 (0.6)1.8 (1.3)1.7 (0.9)1.7 (0.8)
Baseline platelet, mean count × 109/L (SD)81.2 (42.5)90.9 (66.5)76.1 (42.5)84.1 (53.9)

Donor Liver and Surgery Characteristics

No notable differences between study groups were found with respect to surgical variables, cold and warm ischemia times of the graft, operation duration, surgical method, or the use of an autologous transfusion system.

Efficacy

There were no statistically significant differences in RBC requirements or other types of transfusions between the placebo and rFVIIa study groups (Table 2). In addition, no significant differences were found between study groups in terms of blood loss, total crystalloid and colloid replacement volume, and the number of patients receiving systemic hemostatic drugs in the perioperative period. The mean number of intensive care unit days was comparable between study groups.

Table 2. Transfusion Requirements*
 Placebo (n = 19)rFVIIa 20 μg/kg (n = 18)rFVIIa 40 μg/kg (n = 23)rFVIIa 80 μg/kg (n = 22)
  • rFVIIa, activated recombinant factor VII; RBC, red blood cell; FFP, fresh frozen plasma; PC, platelet concentrate.

  • All values in median.

  • *

    No significant difference (P > .05) in transfusion requirements between study groups.

Total RBC, U (interquartile range)11.1 (7.0-17.0)10.0 (3.0-18.0)13.0 (7.0-24.0)10.0 (3.2-21.0)
Allogeneic RBC, U (interquartile range)8.0 (6.0-15.0)8.5 (3.0-18.0)13.0 (6.0-22.0)7.0 (2.0-17.0)
Autologous RBC, U (interquartile range)0.9 (0.0-4.3)0.0 (0.0-4.5)0.9 (0.0-3.5)0.0 (0.0-3.7)
Total FFP, U (interquartile range)11.0 (6.0-32.0)8.5 (0.0-41.0)15.5 (8.8-24.0)6.0 (2.0-23.0)
PC, U (interquartile range)4.0 (1.0-10.0)5.5 (0.0-11.0)9.0 (0.0-19.0)1.5 (0.0-8.0)

Safety

The incidences of any type of AEs or serious AEs in the rFVIIa study groups were not higher than the incidences reported in the placebo group. Additionally, there was no apparent pattern to the type of AEs or serious AEs related to trial product.

A total of 42 serious AEs were experienced by 29 patients (Table 3). Ten patients experienced 12 thromboembolic events during the course of the trial (Table 3). Seven deaths occurred during the study period. In the placebo group, 1 patient died from shock due to bleeding during the procedure 12 hours after drug administration. In the 20-μg/kg group, 1 patient died from multiorgan failure 18 days after drug administration. In the 40-μg/kg group, 2 patients died from sepsis 38 and 39 days after drug administration, respectively. In the 80-μg/kg group, 1 patient with a history of obstructive lung diseases, severe hypertension, right ventricular insufficiency, and hypersplenia syndrome died from cardiac failure 10 hours after drug administration. The most commonly reported mild AEs included fever, constipation, nausea, hyperglycemia, anemia, abnormal renal function, and pleural effusion.

Table 3. Serious Adverse Events
 Placebo (n = 19) n (%)rFVIIa 20 μg/kg (n = 18) n (%)rFVIIa 40 μg/kg (n = 24) n (%)rFVIIa 80 μg/kg (n = 22) (%)
  • rFVIIa, activated recombinant factor VII; AE, adverse event; PT, prothrombin time.

  • *

    For each serious AE that was associated with a death, the number of patients who died after that event is stated in the text.

Number of patients experiencing one or more serious AEs*6 (32)5 (28)10 (42)8 (36)
Thromboembolic events    
 Arterial thrombosis2 (11)2 (11)1 (4)2 (9)
Cardiovascular system    
 Cardiac failure001 (4)1 (5)
 Myocardial infarct01 (6)00
Nervous system    
 Convulsions001 (4)0
Gastrointestinal system    
 Hematemesis01 (6)00
 Intra-abdominal hemorrhage1 (5)03 (13)0
Liver and biliary system    
 Ascites0002 (9)
 Hepatic failure2 (11)002 (9)
 Bile duct carcinoma01 (6)00
Metabolic system    
 Acidosis1 (5)000
Clotting system    
 PT increased0001 (5)
 Hemorrhage not specified1 (5)1 (6)02 (9)
 Thrombophlebitis1 (5)1 (6)1 (4)0
Resistance mechanism    
 Sepsis001 (4)1 (5)
Respiratory system    
 Dyspnea002 (8)0
 Respiratory failure001 (4)0
Urinary system    
 Anuria0001 (5)
 Renal failure01 (6)1 (4)0
Others    
 Inflicted injury1 (5)000

Laboratory Results

Changes in laboratory coagulation parameters from baseline, including activated partial thromboplastin time, fibrinogen, platelet counts, D-dimer levels, antithrombin III levels, plasmin-α2-antiplasmin and F1+2 levels, did not differ significantly between study groups from baseline to end of study (data not shown). Prothrombin time correction was significantly higher in a dose-dependent manner up to 4 hours after bolus administration compared with placebo (Fig. 2). Based on pharmacokinetic analysis of the plasma factor VII clotting activity results, the plasma clearance was estimated at 61.7 mL/kg/hour during the preanhepatic and anhepatic phases when there was no blood circulation through the liver.

Figure 2.

Prothrombin time profiles. Data are values, and bars represent the standard deviation of the mean. The gray bar represents the normal prothrombin time values. PT, prothrombin time.

Discussion

There were no statistically significant differences in perioperative RBC requirements or other types of transfusions between placebo and rFVIIa study groups. The incidences of AEs (mild or serious) in the rFVIIa study groups were not higher than the incidences in the placebo group.

The inability to demonstrate a reduction in the total number of RBC transfusions might have been due to insufficient dosing. The trial product was administered 10 minutes prior to the first skin incision, and the mean duration of surgery was 7.3 (range 7.1-7.4) hours. Clearance was 61.7 ml/kg/h, which is high compared with clearance for hemophilia patients23 and noncirrhotic bleeding patients.15 The duration of prothrombin time normalization within the first 3 hours after drug administration was dose dependent, and the prothrombin time value returned to baseline 4 hours after drug administration for all rFVIIa doses.

The rate of thromboembolic events was similar between the study groups and is comparable with the overall rate of thromboembolic events between 1% and 10% in OLT recipients.24 The results of this trial support a previous finding of no increased risk of thromboembolic events with the use of rFVIIa during OLT.16

In summary, rFVIIa is safe in doses up to 80 μg/kg administered prior to surgical incision during OLT. However, a reduction in total RBC transfusion requirements could not be shown in this population. Despite the inability of this study to show efficacy for rFVIIa at the doses administered, further investigation is warranted using a multiple and/or higher dosing schedule as well as an assessment of pharmacoeconomics.

Ancillary