Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery

Summary

Bolus infusion (BI) recombinant factor VIIa (rFVIIa) administration is safe and effective in the surgical management of haemophilia patients with inhibitors but has not been compared directly with continuous infusion (CI). We conducted an open-label, randomized, multicenter trial comparing the efficacy and safety of rFVIIa administered by BI or CI for the surgical management of haemophilia A or B patients with inhibitors to FVIII or FIX. Safety was compared with that of a control group of noninhibitor patients receiving FVIII or FIX concentrates for major surgery. All inhibitor subjects received an initial bolus dose of 90 μg/kg rFVIIa and were then randomly assigned to BI (n=12) or CI (n=12). The BI group received 90 μg/kg rFVIIa every two hours (h) during surgery through day 5, then every four hours for days 6–10. The CI group received 50 μg/kg/h rFVIIa through day 5, then 25 mg/kg/h for days 6–10. The control group (n=12) received FVIII or FIX per institutional protocols. Twenty-two major surgeries included orthopedic procedures on the knee (n=13), hip (n=3), and abdominal/pelvis procedures (n=4). One patient with an autoimmune FVIII inhibitor randomized to the BI arm was excluded from efficacy analysis. Haemostatic efficacy of rFVIIa in each group was comparable: effective in 8/11 and 9/12 subjects in the BI and CI arms, respectively, and ineffective in three subjects in each arm. Serious adverse events were related to continued or increased bleeding. In conclusion, haemostatic efficacy and safety of BI and CI of rFVIIa are comparable for the surgical management of haemophilia subjects with inhibitors.

Keywords

Bolus - continuous - inhibitors - rFVIIa - surgery

• References

• 1 Schwaab R, Brackmann HH, Meyer C. et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74: 1402-1406.
• 2 Rodriguez-Merchan EC, Rocino A. Literature review of surgery management in inhibitor patients. Haemophilia 2004; 10 (Suppl. 02) 22-29.
• 3 Hedner U, Glazer S, Pingel K. et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet 1988; 2: 1193.
• 4 Lusher JM. Recombinant factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors. Haemostasis 1996; 26 (Suppl. 01) 124-130.
• 5 Rice KM, Savidge GF. NovoSeven (recombinant factor VIIa) in centeral nervous systems bleeds. Haemostasis 1996; 26 (Suppl. 01) 131-134.
• 6 Bech RM. Recombinant factor VIIa in joint and muscle bleeding episodes. Haemostasis 1996; 26 (Suppl. 01) 135-138.
• 7 Ingerslev J, Freidman D, Gastineau D. et al. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis 1996; 26 (Suppl. 01) 118-123.
• 8 Lusher J, Ingerslev J, Roberts H. et al. Clinical experience with recombinant factor VIIa. Blood Coagul Fibrinolysis 1998; 9: 119-128.
• 9 Tagariello G, Bisson R, Radossi P. et al. Concurrent total hip and knee replacements in a patient with haemophilia with inhibitors using recombinant factor VIIa by continuous infusion. Haemophilia 2003; 9: 738-740.
• 10 Smith OP. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high-responding inhibitors. Pathophysiol Haemost Thromb 2002; 32 (Suppl. 01) 22-25.
• 11 Hedner U. Dosing and monitoring NovoSeven treatment. Haemostasis 1996; 26 (Suppl. 01) 102-108.
• 12 Kavakli K, Makris M, Zulfikar B. et al. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95: 600-605.
• 13 Lindley CM, Sawyer WT, Macik BG. et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 1994; 55: 638-648.
• 14 Shapiro AD, Gilchrist GS, Hoots WK. et al. Prospective, randomised trial of two doses of rFVIIa (Novo- Seven) in haemophilia patients with inhibitors undergoing surgery. Thromb Haemost 1998; 80: 773-778.
• 15 Chowdary P, Dasani H, Jones JA. et al. Recombinant factor IX (BeneFix) by adjusted continuous infusion: a study of stability, sterility and clinical experience. Haemophilia 2001; 7: 140-145.
• 16 Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery. Br J Haematol 2000; 110: 715-720.
• 17 Batorova A, Martinowitz U. Continuous infusion of coagulation factors. Haemophilia 2002; 8: 170-177.
• 18 Hoots WK, Leissinger C, Stabler S. et al. Continuous intravenous infusion of a plasma-derived factor IX concentrate (Mononine) in haemophilia B. Haemophilia 2003; 9: 164-172.
• 19 McMillan CW, Webster WP, Roberts HR. et al. Continuous intravenous infusion of factor VIII in classic haemophilia. Br J Haematol 1970; 18: 659-667.
• 20 Schulman S. Safety, efficacy and lessons from continuous infusion with rFVIIa. rFVIIa-CI Group. Haemophilia 1998; 4: 564-567.
• 21 Schulman S. Continuous infusion of recombinant factor VIIa in haemophilic patients with inhibitors: safety, monitoring, and cost effectiveness. Semin Thromb Haemost 2000; 26: 421-424.
• 22 Mauser-Bunschoten EP, de Goede-Bolder A, Wielenga JJ. et al. Continuous infusion of recombinant factor VIIa in patients with haemophilia and inhibitors. Experience in The Netherlands and Belgium. Neth J Med 1998; 53: 249-255.
• 23 Santagostino E, Morfini M, Rocino A. et al. Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb Haemost 2001; 86: 954-958.
• 24 Smith MP, Ludlam CA, Collins PW. et al. Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: plasma factor VII activity of 10 IU/ml is associated with an increased incidence of bleeding. Thromb Haemost 2001; 86: 949-953.
• 25 World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc 2000; 284: 3043-3045.
• 26 Siemens H-JG, Brueckner S, Hagelberg S. et al. Course of molecular haemostatic markers during and after different surgical procedures. J Clin Anesth 1999; 11: 622-629.
• 27 Divanon F, Hecquard C, Borel-Derlon A. Experience with use of recombinant activated factor VII. J Clin Pharm Ther 2002; 27: 133-138.
• 28 Roberts HR. Clinical experience with activated factor VII: focus on safety aspects. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S115-118.
• 29 Carr Jr. ME, Loughran TP, Cardea JA. et al. Successful use of recombinant factor VIIa for haemostasis during total knee replacement in a severe haemophiliac with high-titer factor VIII inhibitor. Int J Haematol 2002; 75: 95-99.
• 30 Faradji A, Bonnomet F, Lecocq J. et al. Knee joint arthroplasty in a patient with haemophilia A and high inhibitor titre using recombinant factor VIIa (Novo- Seven): a new case report and review of the literature. Haemophilia 2001; 7: 321-326.
• 31 Scharrer I. Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. Haemophilia 1999; 5: 253-259.
• 32 Saba HI, Morelli GA, Azam RR. et al. Efficacy of NovoSeven during surgery on a haemophiliac with previous history of inhibitors. Haemophilia 2003; 9: 131-136.
• 33 Hedner U. Mechanism of action, development and clinical experience of recombinant FVIIa. J Biotechnol 2006; 124: 747-757.
• 34 Monroe DM, Hoffman M, Oliver JA. et al. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542-547.
• 35 Gerotziafas GT, Chakroun T, Depasse F. et al. The role of platelets and recombinant factor VIIa on thrombin generation, platelet activation and clot formation. Thromb Haemost 2004; 91: 977-985.
• 36 Blomback B, Carlsson K, Hessel B. et al. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity. Biochim Biophys Acta 1989; 997: 96-110.
• 37 Carr Jr. ME, Alving BM. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots. Blood Coagul Fibrinolysis 1995; 6: 567-573.
• 38 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chaem 1995; 270: 14477-14484.
• 39 Schulman S, Bech Jensen M, Varon D. et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 1996; 75: 432-436.
• 40 Schulman S, Martinowitz U. Design and assessment of clinical trials on continuous infusion. Blood Coagul Fibrinolysis 1996; 7 (Suppl. 01) S7-9.
• 41 Schulman S, d’Oiron R, Martinowitz U. et al. Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S97-101.
• 42 Ludlam CA, Smith MP, Morfini M. et al. A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation. Br J Haematol 2003; 120: 808-813.
• 43 Livnat T, Zivelin A, Martinowitz U. et al. Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI. J Thromb Haemost 2006; 4: 192-200.
• 44 van ’t Veer C, Golden NJ, Mann KG. Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of haemophilia A by factor VIIa. Blood 2000; 95: 1330-1335.
• 45 Hedner U. Treatment of patients with factor VIII and factor IX inhibitors with special focus on the use of recombinant factor VIIa. Thromb Haemost 1999; 82: 531-539.
• 46 Blomback B, Carlsson K, Fatah K. et al. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994; 75: 521-538.
• 47 Hoffman M, Harger A, Lenkowski A. et al. Cutaneous wound healing is impaired in haemophilia B. Blood 2006; 108: 3053-3060.
• 48 Aledort LM. Haemophilia replacement products, clinical trials: inhibitors and pharmacokinetics-can they be done?. J Thromb Haemost 2004; 2: 1855-1856.
• 49 Martinowitz U, Schulman S. Review of pumps for continuous infusion of coagulation factor concentrates: what are the options?. Blood Coagul Fibrinolysis 1996; 7 (Suppl. 01) S27-33.