Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: Results of an open-label Phase I and a randomized, standard-of-care-controlled Phase I/II study

BMC Nephrology

James C Hart³  Sara Horn²  Jonathan Batiller³  Jessica Shen³  Bababhai Patel³  Ofer Nativ¹ 

[1] Bnai Zion Medical Center, Haifa, Israel;Omrix Biopharmaceuticals Ltd, Kiryat Ono, Israel;Ethicon, Inc, A Johnson and Johnson Company, P. O. Box #151, Somerville, NJ 08876-0151, USA

关键词: Thrombin;    Polyglactin 910;    Oxidized-regenerated cellulose;    Nephron-sparing surgery;    Hemostasis;    Fibrinogen;    Fibrin pad;   

Others  :  1083064
DOI  :  10.1186/1471-2369-13-147

 received in 2012-06-18, accepted in 2012-10-30,  发布年份 2012

【 摘 要 】

Background

Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages.

Methods

We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level.

Results

Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled.

Conclusions

The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage.

Trial registration

Phase I/II trial, NCT00598130

【 授权许可】

   
2012 Nativ et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H: Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000, 75:1236-1242.
• [2]Becker F, Siemer S, Humke U, Hack M, Ziegler M, Stockle M: Elective nephron sparing surgery should become standard treatment for small unilateral renal cell carcinoma: Long-term survival data of 216 patients. Eur Urol 2006, 49:308-313.
• [3]Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004, 351:1296-1305.
• [4]Weight CJ, Larson BT, Fergany AF, Gao T, Lane BR, Campbell SC, Kaouk JH, Klein EA, Novick AC: Nephrectomy induced chronic renal insufficiency is associated with increased risk of cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010, 183:1317-1323.
• [5]Cozar JM, Tallada M: Open partial nephrectomy in renal cancer: a feasible gold standard technique in all hospitals. Adv Urol 2008, 10:1155-1164.
• [6]Richter F, Schnorr D, Deger S, Trk I, Roigas J, Wille A, Loening SA: Improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (FloSeal). Urology 2003, 61:73-77.
• [7]Breda A, Stepanian SV, Lam JS, Liao JC, Gill IS, Colombo JR, Guazzoni G, Stifelman MD, Perry KT, Celia A, et al.: Use of haemostatic agents and glues during laparoscopic partial nephrectomy: a multi-institutional survey from the United States and Europe of 1347 cases. Eur Urol 2007, 52:798-803.
• [8]Cornum RL, Morey AF, Harris R, Gresham V, Daniels R, Knight RW, Beall D, Pusateri A, Holcomb J, Macphee M: Does the absorbable fibrin adhesive bandage facilitate partial nephrectomy? J Urol 2000, 164:864-867.
• [9]Abou-Elela A, Morsy A, Badawy H, Fathy M: Use of oxidized cellulose hemostats (surgicel) to support parenchymal closure and achieve hemostasis following partial nephrectomy. Surg Technol Int 2009, 18:75-79.
• [10]Porpiglia F, Renard J, Billia M, Morra I, Terrone C, Scarpa RM: Biological glues and collagen fleece for hemostasis during laparoscopic partial nephrectomy: technique and results of prospective study. J Endourol 2007, 21:423-428.
• [11]Mankad PS, Codispoti M: The role of fibrin sealants in hemostasis. Am J Surg 2001, 182(2 Suppl):21S-28S.
• [12]Jackson MR, Gillespie DL, Longenecker EG, Goff JM, Fiala LA, O’Donnell SD, Gomperts ED, Navalta LA, Hestlow T, Alving BM: Hemostatic efficacy of fibrin sealant (human) on expanded poly-tetrafluoroethylene carotid patch angioplasty: a randomized clinical trial. J Vasc Surg 1999, 30:461-466.
• [13]Hutchinson RW, Broughton D, Barbolt TA, Poandl T, Muench T, Rockar R, Johnson M, Hart J: Hemostatic effectiveness of fibrin pad after partial nephrectomy in Swine. J Surg Res 2011, 167:e291-e298.
• [14]Siemer S, Lahme S, Altziebler S, Machtens S, Strohmaier W, Wechsel HW, Goebell P, Schmeller N, Oberneder R, Stolzenburg JU, et al.: Efficacy and safety of TachoSil as haemostatic treatment versus standard suturing in kidney tumour resection: a randomised prospective study. Eur Urol 2007, 52:1156-1163.
• [15]Chalmers RT, Darling Iii RC, Wingard JT, Chetter I, Cutler B, Kern JA, Hart JC: Randomized clinical trial of tranexamic acid-free fibrin sealant during vascular surgical procedures. Br J Surg 2010, 97:1784-1789.
• [16]Finley DS, Lee DI, Eichel L, Uribe CA, McDougall EM, Clayman RV: Fibrin glue-oxidized cellulose sandwich for laparoscopic wedge resection of small renal lesions. J Urol 2005, 173:1477-1481.
• [17]McKiernan J, Simmons R, Katz J, Russo P: Natural history of chronic renal insufficiency after partial and radical nephrectomy. Urology 2002, 59:816-820.
• [18]Lee KC, Park SK, Lee KS: Neurosurgical application of fibrin adhesive. Yonsei Med J 1991, 32:53-57.
• [19]Thompson RH, Lane BR, Lohse CM, Leibovich BC, Fergany A, Frank I, Gill IS, Blute ML, Campbell SC: Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol 2010, 58:340-345.
• [20]Lang G, Csekeo A, Stamatis G, Lampl L, Hagman L, Marta GM, Mueller MR, Klepetko W: Efficacy and safety of topical application of human fibrinogen/thrombin-coated collagen patch (TachoComb) for treatment of air leakage after standard lobectomy. Eur J Cardiothorac Surg 2004, 25:160-166.
• [21]Frilling A, Stavrou GA, Mischinger HJ, de Hemptinne B, Rokkjaer M, Klempnauer J, Thorne A, Gloor B, Beckebaum S, Ghaffar MF, et al.: Effectiveness of a new carrier-bound fibrin sealant versus argon beamer as haemostatic agent during liver resection: a randomised prospective trial. Langenbecks Arch Surg 2005, 390:114-120.
• [22]Apel-Sarid L, Cochrane DD, Steinbok P, Byrne AT, Dunham C: Microfibrillar collagen hemostat-induced necrotizing granulomatous inflammation developing after craniotomy: a pediatric case series. J Neurosurg Pediatr 2010, 6:385-392.
• [23]Baumann LS, Kerdel F: The treatment of bovine collagen allergy with cyclosporin. Dermatol Surg 1999, 25:247-249.
• [24]de la Torre RA, Bachman SL, Wheeler AA, Bartow KN, Scott JS: Hemostasis and hemostatic agents in minimally invasive surgery. Surgery 2007, 142(4 Suppl):S39-S45.
• [25]Erdogan D, van Gulik TM: Evolution of fibrinogen-coated collagen patch for use as a topical hemostatic agent. J Biomed Mater Res B Appl Biomater 2008, 85:272-278.
• [26]Mosesson MW: Fibrinogen and fibrin polymerization: appraisal of the binding events that accompany fibrin generation and fibrin clot assembly. Blood Coagul Fibrinolysis 1997, 8:257-267.
• [27]Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M: High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010, 110:350-353.
• [28]Scheule AM, Beierlein W, Wendel HP, Eckstein FS, Heinemann MK, Ziemer G: Fibrin sealant, aprotinin, and immune response in children undergoing operations for congenital heart disease. J Thorac Cardiovasc Surg 1998, 115:883-889.
• [29]Dalpiaz O, Neururer R, Bartsch G, Peschel R: Haemostatic sealants in nephron-sparing surgery: what surgeons need to know. BJU Int 2008, 102:1502-1508.
• [30]Hollaus P, Pridun N: The use of Tachocomb in thoracic surgery. J Cardiovasc Surg (Torino) 1994, 35(6 Suppl 1):169-170.