Results from Finalized Trials Outside the Current Indication

10.5.3.1.1 Patients with Liver Disease

The liver is the principal site of synthesis and clearance of coagulation factors, components of the fibrinolytic system, and anticoagulants. The most frequently encountered hemato-logical abnormalities in patients with liver disease include prolonged PT and hyperfibri-nolysis [78,79]. The progressive loss of liver parenchymal cells associated with cirrhosis results in a decreased synthesis of the vitamin K-dependent coagulation factors (FII, FVII [most pronounced], FIX, FX), fibrinogen, and proteins C and S. When bleeding occurs, all these changes may contribute to an impaired coagulation process and thus impaired thrombin generation, and the formation of a less stable fibrin plug that is more easily dissolved by fibrinolytic enzymes.

During major surgical procedures in patients with liver disease, such as orthotopic liver transplantation, bleeding can be an important problem, and excess blood loss is associated with increased morbidity, mortality, and length of stay in the intensive-care unit [80].

A randomized, double-blind, placebo-controlled dose exploratory trial has been carried out in cirrhotic patients undergoing orthotopic liver transplantation to evaluate the hemo-static efficacy of two dose regimens of rFVIIa. One hundred and eighty-three patients were randomized to receive an initial bolus of 60 or 120 |g/kg b.w. rFVIIa or placebo. The product was administered within 10 min prior to first skin cut and repeated every 2 h until 30 min prior to expected start of reperfusion of the transplanted liver. An additional single dose was administered at completion of surgery. Results of this trial (rFVIIa group vs. placebo) indicate that significantly more patients avoided transfusion in the rFVIIa group, significantly less transfusion was seen in patients with normal red blood cell (RBC) levels, and that a similar level of serious adverse events was found in the two groups.

Variceal bleeding is a medical emergency that has a 6-week mortality in the range of 5 to 50%, depending on the severity of the underlying liver disease, mainly because of the high rate of failure to control bleeding during the first days after the initial onset of bleeding [81]. The treatment modalities available for the patient with advanced cirrhosis and active variceal bleeding remains unsatisfactory in terms of a safe and fast correction of the coagulopathy, guarantee of bleeding control, prevention of early rebleeding, and preventing death.

A randomized, double-blind, placebo-controlled trial has been carried out in cirrhotic patients with upper gastrointestinal (UGI) bleeding to evaluate the efficacy of rFVIIa. Two hundred and forty-five patients were randomized to receive eight doses of 100 |g/kg rFVIIa or placebo in addition to pharmacological and endoscopic treatment. The first dose was administered within 6 h after admission (or within 6 h of the index bleeding if the patient was already hospitalized); further doses were administered at 2, 4, 6, 12, 18, 24, and 30 h after first trial product administration. Primary composite endpoints were failure to control UGI bleeding within 24 h postdosing, failure to prevent rebleeding between 24 h and day 5, and 5-d mortality. Significantly fewer patients with severe liver disease (Child-Pugh score B and C) failed on the composite endpoint (p = 0.03) and the 24-h-bleeding control endpoint (p = 0.01) relative to placebo. rFVIIa did not improve the efficacy of standard treatment in Child-Pugh score A patients. Incidences of adverse events including thromboembolic events were similar between the two groups.

10.5.3.1.2 Surgery

Hepatectomy and prostatectomy are surgical procedures for patients suffering from cancer, and despite refinement of surgical techniques, they are still associated with substantial perioperative blood loss [82,83]. Blood transfusion therapy constitutes a risk factor for cancer recurrence, increased intraoperative morbidity, transmission of infectious disease, alloimmunization, transfusion reactions, and hemolytic reactions [82,84].

In a trial of 185 patients undergoing hepatectomy for hepatic cancer or metastasis to the liver, patients were randomized to receive prophylactically either placebo, 20 or 80 |g/kg of rFVIIa. The proportion of patients requiring perioperative transfusion of RBCs was 30% lower in the 80 |g/kg dose group when compared with placebo, whereas no effect of treatment was evident in the 20 |g/kg dose group. The incidences of any types of adverse events or serious adverse events in the rFVIIa-treated patients were not higher than the incidences reported by patients in the placebo group.

A recent trial in patients undergoing radical retropubic prostatectomy [83] showed that prophylactic administration of a single dose of 20 or 40 |g/kg rFVIIa significantly decreased the number of patients in need of transfusion with RBCs, with a dose of 40 |g/kg rFVIIa completely obviating the need for RBC transfusion.

10.5.3.1.3 Intracerebral Hemorrhage (ICH)

Spontaneous ICH constitutes about 15% of all strokes, and has an incidence of about 26 per 100,000 per year. It is the deadliest form of stroke, with a 30 d mortality of 35 to 50%. Currently, no treatment exists for ICH. In either spontaneous (when related to high blood pressure) or traumatic ICH, a significant proportion of the patients exhibit hematoma growth in the hours following the insult [85,86]. Furthermore, a large proportion of the traumatically induced insults lead to systemic disturbances in hemostasis [87]. Since hematoma size has been described as the strongest predictor of outcome in such patients [88], this has been the basis for testing the ability of rFVIIa to halt hematoma expansion if administered immediately after the insult. To date, results from two dose-escalation trials [89,90] have been published demonstrating safety in 88 patients dosed in the range of 5 to 160 |g/kg. Based on these results, a large efficacy trial including 400 patients was initiated. The results were available in June 2004. Overall rFVIIa reduced the hemorrhage growth from a baseline CT scan within 3 hours of onset to 24 hours by more than 50%. Mortality at day 90 was 38% lower in patients receiving active drug compared with placebo, and the proportion of patients with a severe outcome at day 90 was 69% in placebo compared with 52% in the groups who received active drug. The incidence of thromboembolic SAEs increased from 2% in placebo to 7% in the active-drug groups. This increase is however included in the above outcome results indicating a vastly beneficial benefit-risk-ratio [91].

10.5.3.1.4 Trauma

Following severe trauma, a number of changes occur, resulting in impaired hemostasis. The loss of circulating blood volume caused by bleeding leads to a decrease in blood pressure. As blood pressure decreases below colloid osmotic pressure, interstitial fluid moves into the vascular space and dilutes the coagulation factors that remain in the circulation. Infusion of resuscitation fluids and blood components that do not contain sufficient amounts of coagulation factors leads to a further dilution [72].

Coagulopathy in trauma patients with severe bleeding is multifactorial and may be caused by depletion of platelets and coagulation factors through extravascular loss, intra-vascular consumption, and dilution by resuscitation fluids. Acidosis resulting from hypoxemia, anaerobic metabolism, accumulation of lactic acid as well as hypothermia, the result of poor perfusion and transfusions of stored refrigerated blood components, can further worsen coagulopathy [72]. Furthermore, in case of severe tissue damage, fibrino-lytic enzymes are released from damaged cells, leading to increased fibrinolysis and disruption of the formed fibrin clots. Conventional means of controlling bleeding are often successful, and include local pressure, ligation, or embolization of specific vessels, fibrin sealants, and transfusion of allogenic blood.

Recently, a randomized prospective placebo-controlled trial [92] evaluating rFVIIa in the treatment of critical bleeding in 283 severely injured penetrating or blunt trauma patients has been finalized. Once a transfusion trigger of >8 units of packed RBC was met, dosing of 200 |g/kg rFVIIa took place followed by a second dose of 100 |g/kg 1 h later, and a third dose of 100 |g/kg 2 h after that. The study showed significant reduction in the number of transfusions needed in the blunt trauma group treated with rFVIIa. No safety concerns were reported with an exactly equal distribution of thromboembolic events in the active and placebo arms, but a trend toward reduction in the incidence of acute respiratory distress syndrome and multiorgan failure was observed.

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