Randomized, double-blind, placebo-controlled, interventional phase IV investigation to assess the efficacy and safety of r-hirudin gel (1120I.U) in patients with hematomas

Hani El-Mowafi, Ahmed El Araby, Yasser Kandil, Ahmed Zaghloul, Hani El-Mowafi, Ahmed El Araby, Yasser Kandil, Ahmed Zaghloul

Abstract

Background: Hirudin is the most potent direct thrombin inhibitor, and recombinant forms are routinely used in anticoagulation therapy. Recombinant hirudin gels are commercially available for the treatment of hematomas and associated symptoms.

Objectives: To assess the efficacy and safety of a topically administered recombinant hirudin gel in patients with hematomas.

Patients/methods: This double-blind, placebo-controlled, phase IV investigation recruited patients presenting with at least one hematoma. Subjects were randomly assigned (1:1) recombinant hirudin gel (1120 IU/100 g) or a placebo, administered 2-3 times daily for 16 days. Changes in hematoma size, flare, and the proportion of patients achieving complete resolution of hematomas and associated edemas were investigated.

Results: By study end, a greater proportion of subjects in the treatment group achieved a complete resolution of hematomas versus placebo (98.0% vs 71.9%; P < .001) and edemas (99% vs 50%; P < .001). Patients in the recombinant hirudin group exhibited a marginally larger, yet significant, reduction in mean hematoma size versus placebo (99.9% vs 96.6%; P < .001) and flare (93.6% vs 78.6%; P < .001). Median time to hematoma resolution for the recombinant hirudin and placebo administered cohorts was 8 and 16 days, respectively (P < .001). No adverse events were reported for the recombinant hirudin cohort.

Conclusions: Topical recombinant hirudin is an effective, safe, and well tolerated intervention for the symptomatic treatment of hematomas. This trial was registered at http://www.clinicaltrials.gov as NCT01960569.

Keywords: administration; antithrombin; hematoma; hirudins; topical; trauma.

Figures

Figure 1
Figure 1
Flowchart of patient enrollment: 99 of the 200 enrolled participants were assigned to the treatment group (Arm 1)
Figure 2
Figure 2
The effect of topical r‐hirudin on hematomas: (A) mean hematoma size. (B) hematoma color. (C) proportion of patients without complete resolution of hematoma. Arrows show the percent decrease relative to baseline. *P < .05; **P < .001; NS, P > .05
Figure 3
Figure 3
The effect of topical r‐hirudin on hematoma‐associated symptoms: (A) Mean visual assessment scale score. (B) The proportion of patients without complete resolution of edema. Arrows show the percent decrease relative to baseline. **P < .001

References

    1. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost. 2008;99:819–29.
    1. Markwardt F. Hirudin as alternative anticoagulant–a historical review. Semin Thromb Hemost. 2002;28:405–14.
    1. Markwardt F. Hirudin as an inhibitor of thrombin. Methods Enzymol. 1970;19:924–32.
    1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral coagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141:e24S–43S.
    1. Capper C. The language of forensic medicine. The meaning of some terms employed. Med Sci Law. 2001;41:256–9.
    1. Vecchio C, Frisinghelli A. Topically applied heparins for the treatment of vascular disorders. Clin Drug Investig. 2008;28:603–14.
    1. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot‐bound thrombin is protected from inhibition by heparin‐antithrombin III but is susceptible to inactivation by antithrombin III‐independent inhibitors. J Clin Invest. 1990;86:385–91.
    1. Serruys PW, Herrman JP, Simon R, et al. Comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Eng J Med. 1995;333:757–63.
    1. Stamenova PK, Marchetti T, Simeonov I. Efficacy and safety of topical hirudin (Hirudex®): a double‐blind, placebo‐controlled study. Eur Rev Med Pharmacol Sci. 2001;5:37–42.
    1. Pirkle H. Hemostasis and animal venoms (hematology). New York: CRC Press; 1988.
    1. Fu K, Izquierdo R, Walenga JM, Fareed J. Comparative study on the use of anticoagulants heparin and recombinant hirudin in a rabbit traumatic anastomosis model. Thromb Res. 1995;78:421–8.
    1. Belcaro G, Cesarone MR, Dugall M, et al. Topical formulation of heparin is effective in reducing the symptoms of superficial venous thrombosis: a monocenter, observer‐blind, placebo‐controlled randomized study. Panminerva Med. 2011;53:3–11.
    1. Katzenschlager R, Hirschl M, Minar E, Ugurluoglu A. Liposomal heparin‐spraygel in comparison with subcutaneous low molecular weight heparin in patients with superficial venous thrombosis. A randomized, controlled, open multicentre study. Austrian. J Cardiology. 2003;10:375–8.
    1. Górski G, Szopiński P, Michalak J, et al. Liposomal heparin spray: a new formula in adjunctive treatment of superficial venous thrombosis. Angiology. 2005;56:9–17.
    1. Bichler J, Fritz H. Hirudin, a new therapeutic tool? Ann Hematol. 1991;63:67–76.
    1. Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Invasive Cardiol. 2000;12:27F–32F.
    1. Agnelli G, Renga C, Weitz JI, Nenci GG, Hirsh J. Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin. Blood. 1992;80:960–5.
    1. Stringer KA. Hirudins: antithrombin anticoagulants. Ann Pharmacother. 1992;26:1535–40.
    1. Zhang L, Huang B, Ding T. Curative effects of physical methods combined with hirudin cream on arteriovenous fistula. Journal of Kunming Medical University. 2014;35:156–67.
    1. Minar E, Zazgornik J. Local hirudin application–an aid in preventing occlusion of an arteriovenous fistula in dialysis patients? Klin Wochenschr. 1985;63:190–1.
    1. Eichler P, Friesen HJ, Lubenow N, et al. Antihirudin antibodies in patients with heparin‐induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood. 2000;96:2373–8.
    1. Spinner S, Stӧffler G, Fink E. Quantitative enzyme‐linked immunosorbent assay (ELISA) for hirudin. J Immunol Methods. 1986;87:79–83.
    1. Verstraete M, Hoet B, Tornai I, Stockmans P, Arnout J. Hirudin, a specific thrombin inhibitor: pharmacokinetics and hemostatic effects in man. Circulation. 1989;80:421.
    1. Byrd HS, Barton FE, Orenstein HH, et al. Safety and efficacy in an accredited outpatient plastic surgery facility: a review of 5316 consecutive cases. Plast Reconstr Surg. 2003;112:636–41.
    1. Venakatachalapathy TS, Mohan Kumar S, Saliba MJ. A comparative study of burns treated with topical heparin and without heparin. Ann Burns Fire Disasters. 2007;20:189.
    1. Agbenorku P, Fugar S, Akpaloo J, Hoyte‐Williams PE, Alhassan Z, Agyei F. Management of severe burn injuries with topical heparin: the first evidence‐based study in Ghana. Int J Burns Trauma. 2013;3:30.
    1. Mason RG, Shermer RW, Rodman NF. Reactions of blood with nonbiologic surfaces. Ultrastructural and clotting studies with normal and coagulation factor deficient bloods. Am J Pathol. 1972;69:271–88.
    1. Litzendorf ME, Satiani B. Superficial venous thrombosis: disease progression and evolving treatment approaches. Vasc Health Risk Manag. 2011;7:569.
    1. Cesarone MR, Belcaro G, Agus G, et al. Management of superficial vein thrombosis and thrombophlebitis: status and expert opinion document. Angiology. 2007;58:7S–14S.

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