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Vascular and Interventional Radiology |
1 From the Dept of Diagnostic Radiology (S.H.D., G.T., O.L., U.H., P.P., C.D.C.); Div of Thoracic, Cardiac, and Vascular Surgery (G.Z.); Dept of Medical Biometry (K.D.); and Dept of Internal Medicine III (C.M.E.), Univ of Tübingen, Eberhard-Karls-Univ, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany; Dept of Vascular Surgery, The Cleveland Clinic Foundation, Ohio (K.O.); and Eli Lilly and Company, Bad Homburg, Germany (P.M.). Received Feb 1, 2001; revision requested Mar 26; revision received Apr 25; accepted May 25. Supported by a grant from Centocor, Malvern, Pa, and Lilly Deutschland, Bad Homburg, Germany. Address correspondence to S.H.D. (e-mail: stephan.duda@med.uni-tuebingen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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6 weeks) arterial occlusion of the legs. MATERIALS AND METHODS: Seventy patients with lower extremity arterial occlusion of less than 6 weeks duration were randomly separated into two treatment groups: urokinase plus abciximab or urokinase plus placebo. Primary end points were the rate of major complications at 30 days after randomization and the rates of amputation-free survival and survival without open surgery or major amputation at follow-up of 90 days. Two readers unaware of the patients’ treatment group assignments analyzed digital subtraction angiograms as they related to the study end points, with a final consensus reading.
RESULTS: Thrombolysis relative to clot length was faster in the urokinase-plus-abciximab group (odds ratio, 0.52; 95% CI: 0.35, 0.76; P < .001). There were no procedure-related deaths or intracranial hemorrhages, but the rate of nonfatal major bleeding was higher with urokinase plus abciximab (four of 50 patients) than with urokinase alone (none of 20 patients; P = .32). At 90 days, amputation-free survival was 96% (48 of 50 patients) in the urokinase-plus-abciximab group compared with 80% (16 of 20 patients) in the urokinase alone group. The hazard ratio for the two Kaplan-Meier curves was 0.42 (95% CI: 0.16, 0.96; P = .04).
CONCLUSION: In patients with lower extremity arterial occlusion who were undergoing urokinase thrombolysis, adjunctive abciximab treatment resulted in faster thrombus dissolution and improved amputation-free survival, despite an increase in major bleeding.
Index terms: Arteries, stenosis or obstruction, 92.721 • Extremities, angiography, 92.1222 • Extremities, thrombosis, 92.721 • Thrombolysis, 92.1265, 92.1274 • Urokinase
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Although the unavailability of urokinase in the United States has encouraged practitioners to seek alternative lytic therapy options for patients with vascular occlusion (6), the use of urokinase, a long-standing thrombolytic agent of choice in this setting, was retained in the PROMPT trial. Abciximab was the first approved GpIIb/IIIa receptor inhibitor and is one of the most thoroughly studied agents in this class of drugs—both alone (3,7,8) and in combination with a fibrinolytic agent (1,9,10). The purpose of our prospective and randomized single-blinded study was to evaluate the combination of abciximab and urokinase for the treatment of recent (6 weeks) arterial occlusion of the legs.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Patients were eligible for inclusion in the study if they were between the ages of 18 and 90 years and had had peripheral arterial occlusion for 6 weeks or less in either the iliac or femoropopliteal vessels. At study enrollment, after informed consent was obtained and diagnostic angiographic findings confirmed the presence of arterial occlusion, eligible patients were randomly assigned to one of two treatment groups—urokinase plus abciximab or urokinase plus placebo—according to an independent computer-generated randomization list. Patients were excluded if they met any of the following criteria: acute limb-threatening ischemia requiring immediate action and restoration of flow within 1 hour; female patient with childbearing potential; recent major trauma, including resuscitation or active internal bleeding (eg, gastrointestinal or genitourinary); known severe hepatic or renal disorder (ie, Child-Pugh class B or C cirrhosis or serum creatinine level >221 µmol/L); history of bleeding diathesis or platelet count less than 10 x 109/L per; known autoimmune disorders; recent (within 2 weeks) thrombolysis; inclusion in another clinical trial; prior inclusion in the current trial; contraindication or known allergic reactions to abciximab; or contraindication to urokinase, heparin, or aspirin.
Study Design
A single-blinded trial to compare urokinase plus abciximab with urokinase plus placebo (ie, urokinase alone) was conducted between June 1998 and October 1999. A single-blinded design was chosen because the study vials were shipped from the United States, where study agent blinding for an investigator-initiated study conducted in Germany would have delayed the start of the study for several months because of regulatory reasons. A single-center approach was chosen to ensure patient homogeneity and uniform procedural conduct. The study medication allocation schedule was computer generated by the local Institute for Medical Informatics.
Seventy patients were randomly assigned to one of two treatment groups: urokinase plus abciximab or urokinase alone (Fig 1). Randomization was performed in a 5:2 ratio of urokinase plus abciximab to urokinase alone. A 5:2 ratio in favor of the urokinase-plus-abciximab group was chosen to optimize our assessment of the safety of the combination therapy.
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Protocol
In patients with Rutherford categories IIa and IIb of acute limb ischemia, treatment was begun immediately (11). In patients with Rutherford category I, treatment started the day after the initial angiogram was obtained. In the patients assigned to urokinase-plus-abciximab therapy, abciximab was administered at the start of urokinase infusion as an intravenous bolus injection of 0.25 mg per kilogram of body weight, followed by an intravenous maintenance infusion of 0.125 µg/kg per minute for 12 hours (maximum, 10 µg per minute) (2). In the urokinase alone group, the abciximab protocol was used to administer 0.9% saline solution intravenously.
In both treatment groups, a 5–30-cm–long multiside slit catheter (Angiodynamics, Queensbury, NY) was passed through the entire thrombus, and urokinase (Medac, Hamburg, Germany) was administered as an initial bolus of 25,000 IU per 10 cm of thrombus delivered with an automated pulsed-spray infusion pump (Angiodynamics) (12). Urokinase was then continued as an infusion of 4,000 IU per minute for the first 2 hours and 2,000 IU per minute for 2 more hours if necessary. If either the reduction of the thrombus mass or the antegrade flow was insufficient after 4 hours, urokinase was increased to 4,000 IU per minute for 2 additional hours. If no degree of recanalization was observed after 4 hours, urokinase was stopped and thromboaspiration or percutaneous transluminal angioplasty was performed.
Digital subtraction angiography was performed before the initiation of thrombolysis, every 30 minutes during the first 2 hours of treatment, and at 60-minute intervals thereafter. The angiograms were evaluated for location and length of the occlusions, angiographic patency, amount of residual thrombus, and potential underlying lesions. An arterial segment was considered patent when brisk antegrade flow from the residual mural thrombus was observed with a less than 30% diameter reduction. Residual stenoses from underlying lesions that remained after successful thrombolysis were treated with balloon angioplasty with or without concomitant stent placement (Palmaz or Palmaz-Corinthian; Cordis, Haan, Germany). Immediately after the procedure, the sheath was removed without discontinuing intravenous heparin administration, and the femoral artery puncture sites were closed with a 6- or 8-F percutaneous arterial closure device (Perclose, Redwood City, Calif). All interventional procedures were performed by either board-certified radiologists (S.H.D., U.H., P.P.) or fellows (including G.T.).
The platelet count; hematocrit, hemoglobin, and serum fibrinogen levels; activated partial thromboplastin time; and international normalized ratio were measured before therapy, at 2 and 4 hours after the start of therapy, and daily for 3 days following therapy. The ankle-brachial arterial pressure index (ABI) was measured by means of Doppler ultrasonography (US) at the same intervals that the laboratory evaluations were performed. After discharge from the hospital, patients were examined clinically and with ABI measurements at 1 month and then every 3 months thereafter. Patients in both treatment groups received heparin according to the low-dose, weight-adjusted regimen used in the EPILOG (Evaluation in PTCA to Improve Long-term Outcome with Abciximab GpIIb/IIIa Blockade) trial (2).
The activated partial thromboplastin time was monitored (CoaguChek; Boehringer Mannheim, Mannheim, Germany) to maintain a range of 1.5–2.5 times the local control value. An activated partial thromboplastin time of less than 50 seconds prior to thrombolytic intervention mandated the administration of 70 IU of heparin per kilogram of body weight. During intervention, an activated partial thromboplastin time of less than 55 seconds prompted a heparin bolus of 50 IU/kg followed by continuous intravenous infusion of 7 IU/kg per hour. Patients who were not already taking aspirin received 300 mg of aspirin orally 1–6 hours before thrombolytic therapy and continued taking 100 mg of aspirin daily for at least 6 months. Warfarin therapy was to be initiated in any patient who had an occlusion of embolic origin, required prosthetic graft placement in the infrapopliteal arteries, or was thought to have a hypercoagulable syndrome.
The vascular surgeon (G.Z.) together with either the operator (S.H.D., G.T. U.H., P.P.) or the clinical research physician (O.L.) performed clinical assessment for bleeding and other adverse events every hour on the day of intervention and once on the day after intervention. Clinical assessment at the end of follow-up was performed by the clinical research physician (O.L.). The follow-up period ranged from 3 to 14 months for both treatment groups (median, 7.0 months for urokinase-plus-abciximab arm and 5.6 months for urokinase alone arm). The clinical research physician (O.L.) performed duplex US in 65 of the 70 patients during follow-up to determine the presence or absence of reocclusion. The remaining five patients refused to undergo follow-up duplex US.
Study End Points
The primary safety end point was the rate of major complications at 30 days after randomization. Major complications were defined as procedure-related death, major bleeding—that is, any intracranial, retroperitoneal, or intraocular hemorrhage or any clinical bleeding event associated with a hemoglobin level decrease of greater than 50 g/L—transfusion of blood components or whole blood (even with a hemoglobin level decrease of <50 g/L), or prolonged hospitalization. The primary effectiveness end points of the study were amputation-free survival and survival without open surgery or major amputation at 90 days.
Secondary end points were angiographic patency and the time required for thrombolytic therapy to restore flow per centimeter of thrombus. Minor complications, which were defined as morbid events that did not meet the criteria for major complications, also were recorded.
Statistical Analyses
Explorative analysis of the following baseline patient characteristics was performed: age, sex, smoking history, concurrent medical illnesses (ie, diabetes mellitus, arterial hypertension, hypercholesterolemia, hepatic or renal insufficiency, coronary artery disease, thromboangiitis obliterans, cancer), prestudy antithrombotic or anticoagulant medication, and Rutherford stages of acute limb ischemia. The occlusion characteristics—namely, type and cause of occlusion, symptom duration, location of occlusions, number of runoff vessels, and ABI before and after treatment—also were described. Analytic statistical analysis of the following variables was performed: length of occlusions, rate of adverse events, clinical effectiveness (ie, survival without surgical revascularization or amputation), and angiographic findings (ie, patency of occluded vessels with thrombolysis alone and after subsequent percutaneous intervention and median duration of thrombolytic infusion relative to clot length).
We compared the two treatment groups by using Cox regression analysis and calculated the event-free survivals by using the Kaplan-Meier method. The cumulative incidence of complications during the first 30 days after treatment (including the initial hospitalization) was evaluated with the Fisher exact test. We performed statistical analysis of the lengths of occlusions and the time-related effectiveness of thrombolysis in both treatment groups by using the two-sample t test after logarithmic transformation. All statistical tests were two sided. All calculations were performed with a computer statistical software package (JMP, version 3.2; SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The median total dose of urokinase administered in the study population was 500,000 IU (range, 250,000–2,250,000 IU). The median duration of thrombolytic therapy was 120 minutes in both groups (range, 60–360 minutes in the urokinase-plus-abciximab group and 60–440 minutes in the urokinase alone group). The median duration of infusion, relative to clot length, was 7.8 minutes per centimeter of thrombus for the urokinase-plus-abciximab group versus 13.8 minutes per centimeter of thrombus for the urokinase alone group (geometric mean ratio, 0.52; 95% CI: 0.35, 0.76; P < .001).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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These clinical benefits were achieved despite an increased rate of major bleeding complications in the patients treated with urokinase plus abciximab (8%). There were no fatal hemorrhagic complications or episodes of intracranial bleeding. Moreover, the elevated frequency of major bleeding did not differ substantially from the previously reported major bleeding rates with the other conventional thrombolytic regimens used in the peripheral arteries: 6.0% in a population treated with an alteplase bolus (13), 7.0% (14) and 7.1% (15) in populations treated with alteplase administered with pulsed-spray techniques, 8% in a population treated with urokinase, 15% in a population treated with alteplase in a study to compare the two drugs (16), and up to 19% in a population treated with alteplase (17).
A recent analysis of findings in 483 patients who were treated with catheter-directed urokinase revealed an insertion site–related hematoma rate of 21.9% and a transfusion rate of 12.4% (18). The absence of major bleeding in the urokinase only arm of this study was likely related to the small sample size. Conversely, given the possibility that alteplase, when used for peripheral thrombolysis, may be associated with a higher rate of bleeding complications than urokinase, we must caution that the effect of abciximab with alteplase or reteplase is not yet known and may be different from that of abciximab with urokinase.
If the risk level seen in the PROMPT trial is replicated in future studies, acceptance of the use of abciximab plus urokinase in the periphery vessels probably will be limited, regardless of the potential clinical benefits. It is possible that the continued administration of heparin during sheath removal contributed to the elevated bleeding levels. Heparin administration was continued because of the increased thrombogenicity of peripheral artery lesions with low flow and a large endovascular area. Adjusting this heparin protocol may be important in improving bleeding complications in future clinical trials. In the interim, it is clear that GpIIb/IIIa receptor inhibitors should be used cautiously in patients receiving thrombolytic agents for peripheral arterial occlusion.
We chose to study the combination of abciximab plus urokinase because thrombolytic therapy alone, as compared with surgical management of peripheral arterial occlusion, has not consistently improved outcomes. The results of several trials support the use of thrombolytic therapy. Pilger (19) reported a 6-month event-free survival rate of 85% in patients with acute lower limb ischemia who were treated with thrombolysis, as compared with 63% in patients treated with surgery; the event-free survival at 1 year was 75% in the thrombolysis group versus 52% in the surgery group. Diffin and Kandarpa (20) combined two prospective studies with a large retrospective trial and achieved a 30-day limb salvage rate of 93.0% with thrombolysis, as compared with 85.5% with surgical revascularization; the rates were 89% versus 73%, respectively, after 6–12 months of follow-up. The mortality rate was 4% with thrombolytic treatment versus 15% with surgery at 30 days and 8% versus 29%, respectively, after 6–12 months.
Ouriel and co-workers (21) reported a significantly higher 12-month survival rate with thrombolysis than with surgery—84% versus 58%, respectively; this was attributed to a reduction in in-hospital cardiopulmonary complications with thrombolytic therapy. Nevertheless, thrombolysis neither improved the limb salvage rate in the Ouriel et al trial nor affected the outcomes in the randomized multicenter TOPAS (Thrombolysis or Peripheral Arterial Surgery) trial (22), in which the 6-month amputation-free survival was 71.8% in the urokinase group compared with 74.8% in the surgery group; the 1-year survival was 65% versus 69%, respectively. Results of the prospective STILE (Surgery versus Thrombolysis for Ischemia of the Lower Extremity) trial (23) showed a 1-year major amputation rate of 10% with thrombolysis compared with a 0% rate with surgical revascularization. However, the 6-month mortality rate was lower for the patients who underwent thrombolysis. Considered together, the results of these previous studies demonstrate that thrombolytic therapy needs to be more effective if it is to serve as a viable alternative to surgery.
The idea of using antiplatelet therapy to enhance thrombolysis originated from the recognition that the thrombolytic breakdown of the fibrin mesh in clots causes platelet activation and results in increased thrombin activity (24,25). It also has been recognized that after initially successful thrombolysis, thrombi consisting mainly of platelets can resist thrombolysis and promote reocclusion (26). Abciximab may be of particular use in this setting because it has a dethrombotic effect on platelet-rich thrombi. Theoretically, an antithrombotic strategy that involves the use of an antiplatelet agent in addition to a fibrinolytic agent would have a positive influence on the thrombolytic drug dosage needed, the duration of thrombolysis, and the reocclusion rate.
This antiplatelet agent plus fibrinolytic agent approach has been applied primarily in the setting of acute coronary syndromes and most recently in the setting of acute myocardial infarction (1,10). For example, data from the TIMI (Thrombolysis in Myocardial Infarction) 14 trial (1), in which various fibrinolytic-plus-antiplatelet regimens were compared in patients with acute myocardial infarction, showed that the most favorable results of thrombolysis were associated with the addition of abciximab to a reduced dose of either alteplase or reteplase. This improved effectiveness was achieved without an increased risk of major bleeding. Thus, thrombolytic agent dose reduction may be another important way to reduce bleeding risk while maintaining the clinical effectiveness of combination therapy for peripheral occlusion.
The PROMPT trial had limitations. The relatively small sample size of 70 patients and the randomization scheme of a 5:2 study group (urokinase-plus-abciximab)–to–control group (urokinase alone) ratio may have magnified the differences between the groups in favor of the study arm. The underlying conditions of the patients in the two groups may not have been evenly matched. For example, the proportions of men and of patients with a history of smoking were greater in the control group. A higher proportion of patients in the study group had Rutherford grade I ischemia, and the occlusion characteristics that can affect amenability to thrombolysis or angioplasty may not have been well matched. Also, the long-term follow-up period differed slightly between the two groups.
However, this pilot trial may be a starting point for further large-scale studies, and its limitations could guide future investigations. This trial may also provide a preliminary framework for clinicians who are treating or are considering treating patients who have peripheral vascular occlusion with a fibrinolytic agent and GpIIb/IIIa receptor inhibitor. The unavailability of urokinase in the United States has encouraged interventionists to seek alternative treatment modalities and thus paved the way for new approaches such as a fibrinolytic agent–GpIIb/IIIa receptor inhibitor combination. Studies of GpIIb/IIIa receptor inhibitors combined with the newer fibrinolytic agents, such as alteplase, reteplase, and tenecteplase, should provide further guidance for using this drug class.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, S.H.D.; study concepts and design, S.H.D.; literature research, O.L., G.T.; clinical studies, S.H.D., G.T., U.H.; data acquisition, O.L., P.M.; data analysis/interpretation, S.H.D., G.T.; statistical analysis, K.D., K.O.; manuscript preparation, S.H.D., O.L.; manuscript definition of intellectual content, C.D.C.; manuscript editing, K.O., C.M.E.; manuscript revision/review, P.P., G.Z.; manuscript final version approval, S.H.D., K.O.
S.H.D. is a consultant for Centocor.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  M. Sobel and R. Verhaeghe Antithrombotic Therapy for Peripheral Artery Occlusive Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 815S - 843S. [Abstract] [Full Text] [PDF]
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 G. Tepe, C. Hopfenzitz, K. Dietz, J. Wiskirchen, S. Heller, K. Ouriel, G. Ziemer, C. D. Claussen, and S. H. Duda Peripheral Arteries: Treatment with Antibodies of Platelet Receptors and Reteplase for Thrombolysis--APART Trial Radiology, June 1, 2006; 239(3): 892 - 900. [Abstract] [Full Text] [PDF]
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J. Dorffler-Melly, F. Mahler, D.-D. Do, J. Triller, and I. Baumgartner Adjunctive Abciximab Improves Patency and Functional Outcome in Endovascular Treatment of Femoropopliteal Occlusions: Initial Experience Radiology, December 1, 2005; 237(3): 1103 - 1109. [Abstract] [Full Text] [PDF]
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G. P. Clagett, M. Sobel, M. R. Jackson, G. Y. H. Lip, M. Tangelder, and R. Verhaeghe Antithrombotic Therapy in Peripheral Arterial Occlusive Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 609S - 626S. [Abstract] [Full Text] [PDF]
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 P. Drescher, J. McGuckin, W. S. Rilling, and M. R. Crain Catheter-Directed Thrombolytic Therapy in Peripheral Artery Occlusions: Combining Reteplase and Abciximab Am. J. Roentgenol., May 1, 2003; 180(5): 1385 - 1391. [Abstract] [Full Text] [PDF]
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 Additional articles abstracted in ACP Journal Club Evid. Based Med., July 1, 2002; 7(4): 99 - 99. [Full Text] [PDF]
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= time points where clinical events occurred, 
= time points where patients were censored. The respective numbers of patients at risk are above the x axis: The numbers on the top represent the urokinase-plus-abciximab group, and the numbers on the bottom represent the urokinase alone group.