RSS-Feed abonnieren
DOI: 10.1160/TH08-02-0110
Intermittent intravenous urokinase for critical limb ischemia in diabetic foot ulceration
Finanicial support: The present study was initiated and financed by the medac Gesellschaft für klinische Spezialpräparate, Wedel, Germany.Publikationsverlauf
Received
25. Februar 2008
Accepted after major revision
03. Juni 2008
Publikationsdatum:
22. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200803/lookinside/thumbnails/10-1160-th08-02-0110-1.jpg)
Summary
Patients with diabetic foot ulceration and critical limb ischemia have a high risk of major amputation, especially if limbs can not be revascularized. Urokinase is effective in improving microcirculation in critical limb ischemia and might improve outcomes. There are no data on the efficacy and safety of urokinase treatment (survival free of major amputation, ulcer healing and the rate of minor and major bleeding). Therefore, we aimed to investigate the effect of urokinase treatment in a phase II clinical trial. We performed an open, prospective, non-controlled, multi-center phase II cohort study in 77 type-2 diabetic patients with critical limb ischemia and diabetic foot ulceration. Patients had no surgical or endovascular treatment option based on interdisciplinary consensus. Urokinase (1 Mio IU if plasma fibrinogen ≥2.5 g/l, 0.5 Mio IU if fibrinogen < 2.5 g/l) was administered for 21 days as an intravenous infusion over 30 minutes. Each patient was followed up for 12 months. Treatment for a median of 21 days resulted in 33% of patients being alive, having no major amputation and completely healed ulcers after 12 months. Total survival rate was 84.6%,amputation-free survival 69.2% and rate of major amputation 21.1%.Eighty-two percent of patients experienced at least once a complete ulcer healing within the course of study. Three serious adverse events were urokinase-related. Urokinase treatment in diabetic patients with critical limb ischemia appears to be effective, feasible and safe. Although this calls for a larger, randomized and controlled trial, the results are highly relevant for clinical practice to prevent these patients from receiving major amputation due to diabetic foot syndrome.
Clinical Trial Registration No.: NCT00537498
-
References
- 1 Armstrong DG, Lavery LA. Diabetic foot ulcers: prevention, diagnosis and classification. Am Fam Physician 1998; 57: 1325-1332 1337–1338.
- 2 Alexander K. Diabetic angiopathies. Dt Ärzteblatt 1993; 90: 2376-2381.
- 3 Consensus Development Conference on Diabetic Foot Wound Care: 7–8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care 1999; 22: 1354-1360.
- 4 Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003; 361: 1545-1551.
- 5 Hicken GJ, Lossing AG, Rubin B. et al. Intra-arterial infusion of urokinase for acute, critical ischemia in the lower limb. Can J Surg 1995; 38: 486-491.
- 6 Leschke M, Schoebel FC, Strauer BE. Low-dose intermittent urokinase therapy in chronic symptomatic end-stage arterial disease--clinical relevance for patients with coronary artery disease or peripheral arterial occlusive disease. Clin Hemorheol Microcirc 1997; 17: 59-66.
- 7 Weck M, Laage C, Schab T. et al. Low-dose-urokinase therapy in acute angioneuropathic diabetic foot syndrome (DFS). Diab Stoffw 2001; 10: 13-21.
- 8 Weaver FA, Comerota AJ, Youngblood M. et al. Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity. J Vasc Surg 1996; 24: 513-523.
- 9 Böhme H. Die konservative Therapie der chronischen peripheren arteriellen Verschlusskrankheit. Chirurgische Gastroenterologie 1992; 08: 76-80.
- 10 Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998; 21: 855-859.
- 11 Labs KH, Dormandy JA, Jaeger KA. et al. Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group. Circulation 1999; 100: e75-81.
- 12 Hoffmann U, Schulte KL, Heidrich H. et al. Complete ulcer healing as primary endpoint in studies on critical limb ischemia? A critical reappraisal. Eur J Vasc Endovasc Surg 2007; 33: 311-318.
- 13 Nikol S, Baumgartner I, Van Belle E. et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008; 16: 972-978.
- 14 Wolfe JH, Wyatt MG. Critical and subcritical ischaemia. Eur J Vasc Endovasc Surg 1997; 13: 578-582.
- 15 Fratezi AC, Albers M, De Luccia ND. et al. Outcome and quality of life of patients with severe chronic limb ischaemia: a cohort study on the influence of diabetes. Eur J Vasc Endovasc Surg 1995; 10: 459-465.
- 16 Holstein PE, Sorensen S. Limb salvage experience in a multidisciplinary diabetic foot unit. Diabetes Care 1999; 22 (Suppl. 02) B97-103.
- 17 Faglia E, Favales F, Morabito A. New ulceration, new major amputation, and survival rates in diabetic subjects hospitalized for foot ulceration from 1990 to 1993: a 6.5-year follow-up. Diabetes Care 2001; 24: 78-83.
- 18 Volaco A, Chantelau E, Richter B. et al. Outcome of critical foot ischaemia in longstanding diabetic patients: a retrospective cohort study in a specialised tertiary care centre. Vasa 2004; 33: 36-41.
- 19 Adam DJ, Beard JD, Cleveland T. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005; 366: 1925-1934.
- 20 Stiegler H, Diehm C, Grom E. et al. Placebo controlled, double-blind study of the effectiveness of i.v. prostaglandin E1 in diabetic patients with stage IV arterial occlusive disease. Vasa Suppl 1992; 35: 164-166.
- 21 Brock FE, Abri O, Baitsch G. et al. Iloprost in the treatment of ischemic tissue lesions in diabetics. Results of a placebo-controlled multicenter study with a stable prostacyclin derivative. Schweiz Med Wochenschr 1990; 120: 1477-1482.
- 22 Norgren L, Alwmark A, Angqvist KA. et al. A stable prostacyclin analogue (iloprost) in the treatment of ischaemic ulcers of the lower limb. A Scandinavian-Polish placebo controlled, randomised multicenter study. Eur J Vasc Surg 1990; 04: 463-467.
- 23 Kalani M, Apelqvist J, Blomback M. et al. Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled study. Diabetes Care 2003; 26: 2575-2580.
- 24 Koenig W, Resch KL, Hombach V. et al. Fibrinogen and cardiovascular risk. Dt. Ärzteblatt 1994; 91: B1799-B1803.
- 25 Ehrly M. Influence of urokinase on hemorheological and microcirculatory parameters. Int J Microcirc 1986; 05: 245.
- 26 Krawzak HW, Jakel F, Strosche H. et al. Intra-arterial infusion therapy of progressive diabetic foot gangrene with prostaglandin E1 amd cefotaxime. Vasa 1989; 18: 312-315.
- 27 Stiegler H, Diehm C, Grom E. et al. Placebo controlled, double-blind study of the effectiveness of i.v. prostaglandin E1 in diabetic patients with stage IV arterial occlusive disease. Vasa Suppl 1992; 35: 164-166.