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Published online before print April 26, 2006, 10.1148/radiol.2393050620
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(Radiology 2006;239:892-900.)
© RSNA, 2006

Vascular and Interventional Radiology

Peripheral Arteries: Treatment with Antibodies of Platelet Receptors and Reteplase for Thrombolysis—APART Trial1

Gunnar Tepe, MD, Claudius Hopfenzitz, MD, Klaus Dietz, PhD, Jakub Wiskirchen, MD, Stephan Heller, MD, Kenneth Ouriel, MD, Gerhard Ziemer, MD, Claus D. Claussen, MD and Stephan H. Duda, MD

1 From the Department of Diagnostic Radiology (G.T., C.H., J.W., S.H, C.D.C., S.H.D.), Department of Thoracic, Cardiac, and Vascular Surgery (G.Z.), and Department of Medical Biometry (K.D.), University of Tübingen, Eberhard-Karls-University, Hoppe-Seyler-Strasse 3, D-72076 Tübingen, Germany; and Department of Vascular Surgery, the Cleveland Clinic Foundation, Cleveland, Ohio (K.O.). From the 2003 RSNA Annual Meeting. Received April 14, 2005; revision requested June 14; revision received June 26; accepted August 1; final version accepted September 1. Address correspondence to G.T. (e-mail: gunnar.tepe{at}med.uni-tuebingen.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively compare the safety and efficacy of combination therapy with the glycoprotein IIb/IIIa antagonist abciximab plus the third-generation thrombolytic agent reteplase versus those of therapy with the standard thrombolytic agent urokinase plus abciximab.

Materials and Methods: The study was approved by the local ethics committee, and patient informed consent was obtained. Patients with peripheral arterial occlusions less than 60 days old (n = 120) were enrolled in the study: 50 patients (32 men, 18 women; mean age, 67 years; range, 23–88 years) received reteplase plus abciximab and 70 patients (36 men, 34 women; mean age, 68 years; range, 28–88 years) received urokinase plus abciximab. Study end points were the rate of major complications at 30 days, therapeutic success, and survival without open surgery or major amputation at follow-up. Fisher exact test was used to compare treatment groups with respect to dichotomous variables, and the event-free-survival probabilities were calculated with the Kaplan-Meier method. For the comparison of the lengths of occlusions among the groups, a two-sample t test was used.

Results: Therapeutic success (P = .7) did not differ between the groups, whereas the time required for thrombolysis was lower in the urokinase-plus-abciximab group (P = .001). Patients who received reteplase plus abciximab tended to develop more minor complications (mainly bleeding events) (P < .001). During long-term follow-up (2–4 years), no group differences were observed. The reocclusion rate was 48% (22 of 46) in the reteplase-plus-abciximab group and 45% (29 of 64) in the urokinase-plus-abciximab group. Only two of 120 major amputations were counted in the follow-up period.

Conclusion: The proposed regimen resulted in only a limited number of major complications, and the low amputation rate in both groups may be attributed to abciximab.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
The Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis (PROMPT) study (1), for which patients were randomly assigned to receive thrombolytic therapy with or without the glycoprotein IIb/IIIa receptor inhibitor, showed faster thrombolysis and slightly higher bleeding complications in the combination therapy group. For the PROMPT study, only a limited number of patients were enrolled, and urokinase, a first-generation thrombolytic agent, was used (2). The remaining question was whether—in combination with a glycoprotein IIb/IIIa antagonist—a newer thrombolytic agent would be as safe as urokinase and even more effective. To our knowledge, no data exist to date about results from a prospective comparison of last-generation thrombolytic drugs with older agents. In addition, publications about the use of glycoprotein IIb/IIIa antagonists in peripheral arterial disease are limited. Thus, the purpose of our study was to prospectively compare the safety and efficacy of combination therapy with the glycoprotein IIb/IIIa antagonist abciximab plus the third-generation thrombolytic agent reteplase versus those of therapy with the standard thrombolytic agent urokinase plus abciximab.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Abciximab (ReoPro; Centocor, Leiden, the Netherlands, and Eli Lilly, Bad Homburg, Germany) was provided by the manufacturers. The authors had control of the data and the information submitted for publication.

Protocol
Between June 2001 and March 2003, 70 patients (36 men, 34 women; mean age, 68 years; range, 28–88 years) with peripheral arterial occlusions aged 60 days or less, an age estimated on the basis of the sudden onset of symptoms in either native iliac or femoropopliteal arteries or bypass grafts, were enrolled in the study. The patients were prospectively randomized to one of two treatment groups: reteplase plus abciximab or urokinase (Medac, Hamburg, Germany) plus abciximab. The Antibodies of Platelet Receptors and Reteplase for Thrombolysis (APART) study was organized as a prospective blinded trial in the same fashion as the PROMPT trial (1) to create a common database for further analysis. Inclusion and exclusion criteria, comedications, and follow-up investigations were kept identical (as noted later). In addition, administration of the study drug in the urokinase-plus-abciximab group was the same as that in the PROMPT protocol. Because data from 50 patients who had already received urokinase plus abciximab were already available from the PROMPT trial (32 men, 18 women; mean age, 67 years; range, 23–88 years), randomization in the APART trial was performed in a 5:2 ratio in favor of the group that received reteplase (Rapilysin; Roche Products, Welwyn Garden City, Hertfordshire, England) plus abciximab: From the 70 patients who were enrolled, 50 received reteplase plus abciximab and 20 received urokinase plus abciximab. A single-center approach was chosen to ensure patient homogeneity and uniform procedural conduct. This single-blinded prospective study was approved by the local ethics committee and was performed in accordance with good clinical practice rules. All subjects gave written informed consent.

Patients were eligible for inclusion if they were between 18 and 90 years of age. Patients were excluded if they met any of the following criteria: acute limb-threatening ischemia that required immediate action and restoration of flow within less than 1 hour; recent major trauma including resuscitation, surgery, or gastrointestinal or genitourinary bleeding in the past 60 days; history of bleeding diathesis or a platelet count of less than 100 000/mm3 (100 x 109/L); recent stroke; or malignancy with known metastasis in the brain.

Treatment
Urokinase or reteplase was administered as a pulsed-spray lytic agent according to a modified protocol for local thrombolysis of occlusions of the lower extremity as initially suggested by Kandarpa et al (3) and according to our own experience (1,4). The occlusion was passed with a guidewire, and then a multiside-slit catheter (Angiodynamics, Queensbury, NY) that was adjusted to the thrombus length was placed into the thrombus. After the bolus administration, a pulsed-spray infusion was started (0.2–0.4 mL of bolus every 15 seconds) with a 5-F catheter and infusion pump (AngioDynamics, Glens Falls, NY). The dosage of the bolus per 10 cm of thrombus length was 25 000 IU urokinase or 0.5 U reteplase, respectively. Administration of urokinase was continued as a pulsed-spray infusion of 4000 IU/min for the first two hours and as that of 2000 IU/min until completion of lysis. Reteplase was administered at a pulsed-spray infusion rate of 1 U/h during the first 2 hours and reduced to that of 0.5 U/h thereafter. If no degree of recanalization was observed after 4 hours, the infusion was stopped and percutaneous angioplasty was performed.

At the start of reteplase or urokinase infusion, abciximab was administered 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/kg per minute). After 4 hours, we continued with balloon angioplasty or thrombaspiration because we thought that the origin of occlusion would be older (plaque or embolus) and therefore would not respond to fibrinolysis. An activated partial thromboplastin time of less than 50 seconds prior to thrombolytic intervention mandated that 70 IU/kg of heparin (Liquemin; Roche, Basel, Switzerland) be administered. During intervention, an activated partial thromboplastin time of shorter than 55 seconds prompted us to administer a heparin bolus of 50 IU/kg, followed by continuous intravenous infusion of 7 IU/kg per hour. If the patient was not already receiving aspirin, a loading dose of 300 mg was administered, starting 1–6 hours before the procedure; the patient received continued therapy orally for 6 months at a dose of 100 mg/d. If aspirin had been administered in the past 3 days before the procedure, only 100 mg/d of aspirin was administered orally before the intervention.

Evaluation of Therapeutic Success
For evaluation of therapeutic success, angiography was performed every 30 minutes (1st hour) and every 60 minutes (subsequent hours) during thrombolysis. When a residual stenosis (>80%) due to an underlying atherosclerotic lesion remained, adjunctive angioplasty, stent application (if necessary), and thrombaspiration with a 5- or 6-F catheter (Envoy; Cordis, Miami, Fla), if thrombus was present, were performed. Administration of heparin was not discontinued prior to sheath removal. The femoral artery puncture was closed with percutaneous placement of one or two nonabsorbable 3-0 sutures (Perclose; Abbott Vascular, Redwood City, Calif). The intervention was monitored for the amount of thrombolytic agent, time for thrombolysis, therapeutic success, additional procedures, and rate of complications. All interventions were performed by three experienced interventionalists (G.T., J.W., and S.H.D., with 10, 8, and 14 years of experience, respectively).

Patient Follow-up
All patients were followed up at least twice. The first follow-up was performed with Doppler ultrasonography (US) after a mean of 6 months ± 2 (standard deviation). The second follow-up was performed with US, magnetic resonance (MR) imaging, computed tomography (CT), or digital subtraction angiography (DSA). If reocclusion occurred or amputation was performed, the location of occlusion, the time of event-free survival, and the type of treatment of the event (conservative, interventional, or surgical) were recorded.

Image Interpretation
Two experienced readers (G.T., J.W.) who were unaware of the subjects' group assignments analyzed the DSA images as they related to the study end points and performed a final reading in consensus. All follow-up images were obtained in two projections. For the quantification of thrombolytic success, a scale was established as follows: good (≥90% desobliteration with antegrade flow), intermediate (51%–89%), poor (≤50%), and refractory to thrombolytic treatment.

Study End Points
The primary safety end point was defined as the combined rate of major complications at 30 days (death, major bleeding [decrease of hemoglobin level of <50 g/L], repair of vascular injury or fasciotomy, transfusion of blood components or whole blood, groin infection requiring antibiotics, or prolonged hospitalization). Secondary end points included the efficacy of the regimen measured by the technical success rate (desobliteration successful or not), the required time for thrombolysis, and the combined point of amputation-free survival and survival without bypass surgery at follow-up. Events that did not require additional medical care (eg, groin hematoma) were classified as minor complications.

Statistical Analysis
The treatment groups were compared with respect to dichotomous variables by using the Fisher exact test (Tables 1–4), and the event-free survival probabilities were calculated with the Kaplan-Meier method. For the comparison of the lengths of occlusions among the groups, we used a two-sample t test after logarithmic transformation because the Bartlett test for the comparison of the variances showed a significant difference for the untransformed data. The age, duration of symptoms, and time for thrombolysis were compared with the two-sample t test. All statistical tests were two sided, and all calculations were performed with a computer statistical software package (JMP, version 5.1; SAS institute, Cary, NC; also available at www.jmp.com). A P value of less than .05 was considered statistically significant.


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  		Table 1. Baseline and Occlusion Characteristics in Urokinase-plus-Abciximab Groups Randomized in APART and PROMPT Studies

 

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  		Table 2. Baseline and Occlusion Characteristics in Reteplase-plus-Abciximab and Urokinase-plus-Abciximab Groups Randomized in APART and PROMPT Studies

 

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  		Table 3. Data about Intervention

 

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  		Table 4. Major and Minor Complications

 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patient Characteristics
Comparative analysis of data from the 20 patients who received urokinase plus abciximab in the APART study and of data from 50 patients treated with the same regimen in the PROMPT study revealed no significant differences (Tables 1, 2). In view of the findings showing that the differences in the baseline characteristics of the patients enrolled in the PROMPT trial and in those enrolled in the APART trial were not significant (Table 1), the comparison of 50 patients who were assigned to the reteplase-plus-abciximab group and 70 patients (20 from the APART study and 50 from the PROMPT study) who received urokinase plus abciximab is justified. Independently of the groups, the male patients were 5.7 years younger than the female patients (male age [n = 68], 63.1 years ± 1.6; female age [n = 52], 68.8 years ± 1.9; P = .023, t test).

Intervention
Dose of study drug and thrombolytic efficacy.—The results in the urokinase-plus-abciximab group from the APART study (n = 20) and those in that from the PROMPT study (n = 50) were combined and compared with the results in the reteplase-plus-abciximab group (n = 50).

In the reteplase-plus-abciximab group, the mean treatment time was 200 minutes (range, 60–660 minutes), compared with 120 minutes (range, 60–360 minutes) in the urokinase-plus-abciximab group (P = .001). Between the groups, the number of patients in whom recanalization failed was not significantly different. Approximately two-thirds of the angiographic outcome was rated good (≥90% thrombolysis), with no differences between the groups (P = .7) (Table 3). As an example, Figure 1 shows pre- and posttreatment DSA images in a patient in the reteplase-plus-abciximab group.


Figure 1
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  		Figure 1a: Frontal intraarterial DSA images in 54-year-old woman show occlusion of the superficial femoral artery (a) before and (b) after treatment with reteplase plus abciximab for 50 minutes, with restoration of antegrade flow.

 

Figure 1
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  		Figure 1b: Frontal intraarterial DSA images in 54-year-old woman show occlusion of the superficial femoral artery (a) before and (b) after treatment with reteplase plus abciximab for 50 minutes, with restoration of antegrade flow.

 
Complications (primary end point).—There were no procedure-related deaths or intracranial hemorrhages in any of the patients. The risk of major complications (Table 4) was higher in the reteplase-plus-abciximab group (10%) than it was in the urokinase-plus-abciximab group (6%), but the difference did not attain statistical significance (P = .49). All patients apart from one who had a major complication received a blood transfusion. The differences between the two groups became greater when we focused on minor complications. A total of 48% of patients in the reteplase-plus-abciximab group had minor complications, mainly attributable to bleeding at the puncture site, whereas only 17% in the urokinase-plus-abciximab group had minor complications (P < .001).

Follow-up
Because the additional 50 patients in the urokinase-plus-abciximab group were randomized in the previous PROMPT study, the mean follow-up time in this group was longer (1127 days ± 443) than it was in the reteplase-plus-abciximab group (750 days ± 208). During long-term follow-up, four patients in the reteplase-plus-abciximab group died. The patency of the target vessel was investigated with Doppler US in 36 patients, with DSA in three patients, and with CT angiography and MR angiography in one patient each. One patient was lost to follow-up after the first visit. In the urokinase-plus-abciximab group, nine patients died during long-term follow-up. Investigations were performed with Doppler US (n = 21), DSA (n = 14), CT angiography (n = 1), and MR angiography (n = 10). Thirteen patients were lost to follow-up or refused to participate in the follow-up beyond the first visit. In both groups, patients in whom the primary treatment (thrombolysis) failed were not assessed for target vessel patency at follow-up.

The amputation rate (Fig 2) was low (4%) in both groups. During long-term follow-up, the reocclusion rate was 48% (22 of 46) in the reteplase-plus-abciximab group and 45% (29 of 64) in the urokinase-plus-abciximab group (P = .94). In both groups, 69% of the reocclusions were treated with revascularization, and 31% received conservative treatment only (Table 5). During follow-up, no differences in regard to results between the treatment groups were observed.


Figure 2
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  		Figure 2a: Graphs show Kaplan-Meier estimates based on reteplase-plus-abciximab (solid line) or urokinase-plus-abciximab (dotted line) treatment in (a) patients free from amputation in whom amputation rate was low in both treatment groups and amputation occurred only within the first 5 weeks after intervention; (b) patients free from surgical intervention (including amputation) in whom no major differences were observed between groups, with most surgical interventions becoming necessary within the 1st year after index treatment; (c) patients with open vessels in whom patency rate was not influenced by the initial treatment and reocclusion rate was approximately 50% after 2 years; and (d) patients who were alive in whom survival time was not influenced by treatment.

 

Figure 2
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  		Figure 2b: Graphs show Kaplan-Meier estimates based on reteplase-plus-abciximab (solid line) or urokinase-plus-abciximab (dotted line) treatment in (a) patients free from amputation in whom amputation rate was low in both treatment groups and amputation occurred only within the first 5 weeks after intervention; (b) patients free from surgical intervention (including amputation) in whom no major differences were observed between groups, with most surgical interventions becoming necessary within the 1st year after index treatment; (c) patients with open vessels in whom patency rate was not influenced by the initial treatment and reocclusion rate was approximately 50% after 2 years; and (d) patients who were alive in whom survival time was not influenced by treatment.

 

Figure 2
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  		Figure 2c: Graphs show Kaplan-Meier estimates based on reteplase-plus-abciximab (solid line) or urokinase-plus-abciximab (dotted line) treatment in (a) patients free from amputation in whom amputation rate was low in both treatment groups and amputation occurred only within the first 5 weeks after intervention; (b) patients free from surgical intervention (including amputation) in whom no major differences were observed between groups, with most surgical interventions becoming necessary within the 1st year after index treatment; (c) patients with open vessels in whom patency rate was not influenced by the initial treatment and reocclusion rate was approximately 50% after 2 years; and (d) patients who were alive in whom survival time was not influenced by treatment.

 

Figure 2
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  		Figure 2d: Graphs show Kaplan-Meier estimates based on reteplase-plus-abciximab (solid line) or urokinase-plus-abciximab (dotted line) treatment in (a) patients free from amputation in whom amputation rate was low in both treatment groups and amputation occurred only within the first 5 weeks after intervention; (b) patients free from surgical intervention (including amputation) in whom no major differences were observed between groups, with most surgical interventions becoming necessary within the 1st year after index treatment; (c) patients with open vessels in whom patency rate was not influenced by the initial treatment and reocclusion rate was approximately 50% after 2 years; and (d) patients who were alive in whom survival time was not influenced by treatment.

 

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  		Table 5. Second Follow-up

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Background
Currently available alternative thrombolytic agents include streptokinase, anistreptase, reteplase, alteplase (recombinant tissue-type plasminogen activator), and tenecteplase (5,6). Although streptokinase is the only thrombolytic agent with approval of the U.S. Food and Drug Administration for the treatment of acute peripheral arterial occlusion, it is not often considered, because of its low efficacy and poor safety profile (7–9). Reteplase is a mutant of tissue plasminogen activator that is derived with recombinant methods and consists of 355 of the 527 amino acids that form alteplase (10,11). Important consequences of these structural changes include 70%–80% reduced fibrin binding, reduced binding to endothelial cells, and reduced clearance by the liver, and all of these consequences result in an approximately 5.4-fold longer half-life.

Few data have been published about the adjunctive use of glycoprotein IIb/IIIa platelet receptor inhibitors in patients with acute peripheral arterial disease (1,2,4,12–15). The use of glycoprotein IIb/IIIa receptor inhibitors in patients with acute peripheral arterial occlusive disease is aimed to inhibit rethrombosis during thrombolysis. Clot-bound thrombin is exposed as thrombolysis progresses, and this process results in the activation of platelets via the glycoprotein IIb/IIIa receptor and the initiation of the coagulation cascade; both of these actions incite new thrombus formation at the same site.

Thrombolytic Success
The success rate between the groups did not differ and was similar to rates in other published trials. In the Prourokinase vs Urokinase for Recanalization of Peripheral Occlusions, Safety and Efficacy, or PURPOSE, trial (16), recanalization occurred within 8 hours in 72%–74.1% of patients in the recombinant prourokinase groups, whereas it occurred within that time in 69.6% of patients in the urokinase group. The potential advantage of reteplase as opposed to urokinase because of the reduced fibrin binding did not result in an increase in either success or speed—at least in this setting with pulsed-spray administration and with abciximab in both treatment arms. In fact, the speed was higher in the urokinase-plus-abciximab group, but because the clinical success rate did not differ between the groups, it seems unclear whether this finding is of importance in the clinical situation.

Bleeding
In the recently published results of the Reteplase Monotherapy and Reteplase/Abciximab Combination Therapy in Peripheral Arterial Occlusive Disease (RELAX) trial (14), major bleeding was reported at a rate of 15% in the reteplase monotherapy group. Interestingly, the bleeding events did not significantly increase when abciximab was added to the protocol. In the APART trial, the major bleeding complication rates for reteplase and urokinase, both in combination with abciximab, were lower than those reported in other trials; these rates were 12.5% (Therapy of Patients with Acute Stroke, or TOPAS, trial); 14.8%–23.1%, depending on the dose and the group classification (Prourokinase vs Urokinase for Recanalization of Peripheral Occlusions, Safety and Efficacy trial); and 15%–20%, 15% with reteplase monotherapy and 20% followed by the reteplase-plus-abciximab regimen (RELAX trial). This finding may have been caused by pulsed-spray administration and much shorter times for thrombolysis (6,15–18). Nevertheless, the incidence of complications of bleeding was higher in the reteplase-plus-abciximab group than it was in the urokinase-plus-abciximab group. The difference between the regimens was smaller for major bleeding complications (6% vs 10%) but reached the level of a significant difference when we focused on minor complications (17% vs 48%).

It is possible that the bleeding complications in patients in the APART trial would have been lower with the fibrinolytic drug only and no adjunctive abciximab administration. In the PROMPT trial, additional administration of abciximab to urokinase led to an increased incidence of bleeding even though the difference was not significant when compared with the administration of urokinase alone (control group). To date, there are only limited data available about the comparison of different fibrinolytic agents for the treatment of acute peripheral artery occlusion. Ouriel et al (6) compared urokinase and alteplase in a retrospective study in 653 consecutive patients. Bleeding complications occurred less often in patients treated with urokinase than they did with alteplase (insertion hematoma, 21.9% vs 43%; any bleeding necessitating transfusion, 12.4% vs 22.2%). The higher incidences of bleeding in the reteplase-plus-abciximab group could not be ascribed to a lower dose of heparin, differences in the patient population, or other demographic variables. Nevertheless, although a reduced dose of heparin was used, sheath removal with percutaneous blood vessel closure was performed prior to discontinuation of heparin.

It may be possible that—in both groups—the incidence of bleeding events would have been even lower when heparin was reduced further or when heparin was discontinued before sheath removal. In addition, it is possible that our findings were the result of a suboptimal ranging of the dose to a higher or lower level. The only dose-ranging trial with reteplase for peripheral arterial use was the RELAX trial. Reteplase at doses of more than 0.2 U/h were effective at dissolving the thrombus and restoring patency. There was no clear dose-response relationship for reteplase. To our knowledge, there is only one report to date of patients treated with reteplase in a pulsed-spray fashion and there has been no dose-finding trial (19).

Long-term Follow-up
To date, researchers in most of the studies about the investigation of fibrinolytic agents for the treatment of acute peripheral arterial occlusion have focused on procedural success, and the studies were limited to follow-up data until discharge or 30 days after the intervention (thrombolysis) (14,16). In the multicenter prospective (Therapy of Patients with Acute Stroke) trial, an amputation rate of 28.2% at 6 months and 31.1% at 1 year was reported in the urokinase arm (17). In the majority of the studies, only major amputations were counted and toe amputations were not even considered. With these circumstances, in the APART trial, only one major amputation in each group was observed. Interestingly, we found that amputations only occurred within 4 weeks after thrombolysis. Amputations may be a result of the acute ischemic problems and the incidence of distal embolization during thrombolysis. We hypothesized that distal embolizations may be reduced with the use of abciximab. In the RELAX trial, the addition of abciximab led to a reduction in the occurrence of clinically significant distal embolic events from 31% to 5%. Administration of pulsed-spray lytic agents is known to increase the incidence of thromboembolic events (19,20). One may speculate that, especially in those cases, blockade of the glycoprotein IIb/IIIa receptor may be advantageous.

There are only few data about the long-term follow-up of patients who underwent thrombolysis. In a retrospective analysis, Nehler et al (21) reported the outcome of 104 patients with catheter-directed thrombolysis for arterial bypass occlusion of the lower extremity. The mean follow-up period was 45 months. Secondary patency rates were 32% and 19% at 1 and 5 years, respectively. In the APART trial, the primary patency rate was 55.1% in the reteplase-plus-abciximab group and 49.1% in the urokinase-plus-abciximab group. Both patency rates and limb salvage rates were higher than those reported by Nehler et al. Reocclusion tended to occur more often in the superficial femoral artery or bypass grafts than in the iliac or popliteal arteries. Interestingly, most reocclusions were of a nonacute nature because of restenosis; as a result, only four patients were subsequently treated with thrombolysis a second time. The survival rate, however, was not improved by any of the treatment regimens. Figure 2d shows more deaths after 5 years in the urokinase-plus-abciximab group. This result was caused by the longer mean follow-up in the urokinase group.

Although the APART trial represents the only comparative prospective randomized blinded study with reteplase and urokinase treatment for acute peripheral arterial occlusion, it has to be pointed out that the comparison between these two fibrinolytic agents was not a head-to-head comparison because abciximab was given as an adjunct in both arms of the study. In addition, reteplase and urokinase were administered with a pulsed-spray technique. Because lysis with pulsed-spray agents is pharmacomechanical lysis, the influence of the pharmacologic differences among various agents may be variably augmented or inhibited by the use of pulsed-spray lytic agents (19). In view of these considerations, results pertaining to speed of thrombolysis and the number of minor complications indicate that the urokinase-plus-abciximab regimen may be preferred, for no major differences between the groups were observed in regard to all other end points, such as major complications, therapeutic success, and long-term outcome.

Limitations
Some study limitations have to be addressed. First, because data from prior dose-ranging trials were not available, we could not ensure that the doses employed in the pulsed-spray protocol were optimal. Second, benefits that included a reduced incidence of peripheral embolization during the intervention that resulted in a lower amputation rate could not be rigorously evaluated because of the lack of comparison of results with those in a group in which a glycoprotein IIb/IIIa receptor antagonist was not administered. Although the results of the APART trial provide a framework for clinicians who are considering treating patients who have acute peripheral vascular occlusion with combination therapy, the findings should be corroborated by those in larger trials before widespread clinical adoption of combination therapy.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
Centocor, Leiden, the Netherlands, and Eli Lilly, Bad Homburg, Germany, provided abciximab.


   FOOTNOTES
 

Abbreviations: APART = Antibodies of Platelet Receptors and Reteplase for Thrombolysis • DSA = digital subtraction angiography • PROMPT = Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis • RELAX = Reteplase Monotherapy and Reteplase/Abciximab Combination Therapy in Peripheral Arterial Occlusive Disease

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, G.T., K.D.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, G.T., C.H., J.W., K.O., G.Z., S.H.D.; clinical studies, G.T., J.W., S.H., K.O., G.Z., C.D.C., S.H.D.; statistical analysis, G.T., C.H., K.D., K.O., G.Z., S.H.D.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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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.
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