Comparison of Retavase and Urokinase for Management of Spontaneous Subclavian Vein Thrombosis
Article Outline
Thrombolysis is an essential first step in the surgical management of acute spontaneous axillo-subclavian vein thrombosis (Paget-Schroetter syndrome). During the past decade, Urokinase became the standard thrombolytic agent until temporarily withdrawn from the market. In its absence, recombinant tissue plasminogen activator (r-TPA) was introduced and attained widespread use. A direct comparison of the efficacy of these two agents in this setting has not been published. The goal of this study is to compare thrombolytic agents in the management of acute Paget-Schroetter syndrome. This study is based on a retrospective review of 30 consecutive patients (15 Urokinase, 15 r-TPA) who underwent thrombolysis and surgery for Paget-Schroetter syndrome. Our hypothesis is that thromblysis with Urokinase and r-TPA is equally safe and effective in management of acute axillo-subclavian vein thrombosis. Primary outcome measures include success of lysis, hemorrhagic complications, subclavian vein patency at completion of treatment, resolution of presenting symptoms, and restitution of normal arm function. There were no significant differences in the primary outcome measures: success of lysis, hemorrhagic complication, perioperative bleeding, and subclavian vein patency. Time to completion of lysis was slightly shorter with r-TPA (but this did not achieve statistical significance). One patient in each group suffered incomplete lysis of thrombus. One patient in the r-TPA group required transfusion due to surgical bleeding. No patient received transfusion due to thrombolysis-related bleeding. All patients experienced resolution of symptoms and return of arm function. Our findings support the hypothesis that Urokinase and r-TPA are similarly safe and successful for management of spontaneous axillo-subclavian vein thrombosis. Given these results, secondary factors such as cost, availability, and familiarity with the different agents will likely determine the agent of choice.
Introduction
Spontaneous thrombosis of the axillo-subclavian vein or Paget-Schroetter syndrome (PSS) remains an infrequent yet potentially debilitating condition. The natural history is that of repeated thrombotic events with subsequent development of venous insufficiency and disabling upper extremity venous congestion.1, 2, 3, 4
The advent of catheter directed thrombolytic therapy represents a significant advance in the management of these patients. Initial efforts with Streptokinase highlighted the limitations of this thrombolytic agent: variable dose response and occasional allergic reactions.5 Urokinase was found to be an ideal agent with predictable efficacy and reasonable safety.6
The withdrawal of Urokinase from clinical use resulted in a search for alternative agents. Retavase, a genetically engineered version of the tissue plasminogen activator molecule, benefits from improved clot penetration, a shorter half-life, and more rapid initiation of thrombolysis.7, 8 It has become our preferred thrombolytic agent for the management of PSS.
An evidence-based approach to medical care requires data comparing the safety and efficacy of competing therapies. The absence of data on the efficacy and safety of Retavase versus Urokinase for treating PSS prompted this review. The object of this review is to compare our experience using Retavase and Urokinase for management of this disorder.
Materials and Methods
Our study group was drawn from 15 consecutive patients presenting with PSS due to venous compression at the thoracic outlet who were managed with Retavase. These were compared to the prior 15 consecutive patients who presented with the same disease and were managed with Urokinase. This study encompasses patients seen between 1993 and 2002. Demographic data, risk factors, and thrombolytic parameters (dose, duration, efficacy, and complications) were collected, and clinical outcomes were analyzed.
Data associated with thrombolytic therapy was compiled (thrombolytic variables). These included the total dose of the agent used, the duration of infusions, the time to clot resolution, the efficacy of the thrombolysis, the presence of allergic reactions and hemorrhagic complications, the need for blood transfusions, and the incidence of renal insufficiency or acute renal failure.
Treatment Algorithm
The management of patients presenting with spontaneous PSS follows the protocols that have previously been described: identification of the thrombus with ultrasonography, confirmation of the venous occlusion with venography, dissolution of the thrombus with catheter-directed thrombolysis, anticoagulation with Coumadin, subsequent surgical decompression, follow-up venography 2 weeks after surgery, and postoperative angioplasty when indicated by the presence of a significant stenosis.
Thrombolysis
The protocols employed for thrombolysis with Urokinase and Retavase have been previously published.6, 9, 10 Urokinase was administered using catheter-directed intravenous infusion either directly into or immediately adjacent to the thrombus. Dosing of Urokinase ranged between 60,000 and 120,000 units/hr. Duration of infusion was limited to 72 hours maximum. Heparin was administered concurrently (through the sheath at doses ranging between 0-500 units/hr).
Retavase was administered intravenously with catheter-directed infusions in a manner similar to the Urokinase. The infusion dose of Retavase was 0.5 mg/hr for the first 1-2 hr, followed by doses of 0.25 mg/hr for periods up to 72 hr. There was no coadministration of Heparin with Retavase.
Patient Selection
Patients were considered for surgical decompression only after thrombolysis revealed a high-grade stenosis of the subclavian vein consistent with extrinsic compression in the junction of the first rib and clavicle.
Surgical Approach
Transaxillary complete or near complete first rib resection with partial scalenectomy was employed in all patients for decompression of the axillo-subclavian vein and the thoracic outlet. The anterior aspect of the rib resection is taken to the costo-chondral junction. The posterior aspect of the rib is taken within 1 cm of the articulation with the vertebrae. Meticulous attention is given to clearing all impingement on the vein.
Anticoagulation
Following thrombolysis, all patients were anticoagulated initially with Heparin and subsequently with Coumadin. Target international normalized ratio (INR) was in the range of 2.5 to 3.0. Patients were maintained on Coumadin until 3 days prior to their operation. Coumadin was resumed the day of surgery after an observation period of 8 hours for postoperative bleeding. Coumadin was then continued for 2 weeks until the postoperative venograms were obtained. In the event of a normal postoperative venogram, Coumadin was then discontinued. Abnormal postoperative venography (when an occlusion or a stenosis was observed) mandated Coumadin therapy for an additional 3 months.
Follow-up StudiesFollow-up venography was routinely performed on all patients 2 weeks following surgical decompression. At the time of this venogram, the operated side is studied for evidence of thrombosis, residual venous stenosis, or the persistence of venous collaterals. If the contra lateral side was not studied at the time of the initial presentation, it is evaluated now.
Interval ThrombosisOn several occasions, the initial postoperative venogram revealed a recurrent thrombosis of the subclavian vein. These events are designated interval thrombosis to indicate that the vein that had been initially cleared of thrombus had rethrombosed. In these instances thrombolytic therapy was instituted.
AngioplastyAngioplasty was employed for residual stenosis of hemodynamic significance. The presence of collateral veins, a subclavian vein stenosis greater than 50%, or unanticipated restriction of the flow of contrast through the subclavian vein were our indications for angioplasty. Further venographic studies are obtained based on the clinical indication, but are not routinely performed.
OutcomesA determination of the final vein status is based on the last imaging study performed. In virtually all instances, this is the follow-up venogram obtained at the 2-week postoperative point. The studies are classified as either normal, irregular, recanalized, or occluded. These determinations are made independently by the interventional radiologist who performs the study.
Final Clinical StatusPatients were considered asymptomatic if they reported no symptoms in the affected limb. In the event of complaints of pain, swelling, congestion, color changes, venous engorgement, or any other symptom related to the limb, they were considered symptomatic. If a patient was unable to resume his/her normal work and avocations, and was on disability for the injury suffered to the extremity, then he/she was considered disabled.
Resumption of employment and avocation is used as a barometer of the successful rehabilitation and resolution of the initial injury. The status of patients is classified as returned to work, retrained for another line of work, or disabled.
Statistical AnalysisStatistical analysis was performed where applicable using a computer-based statistical package (In-Stat, GraphPad Software Inc., San Diego, CA). For most categories, a two-tailed Student's t-test was employed. Statistical significance was assigned to values at the 0.05 level.
Results
Demographics and Risk Factors
Fifteen consecutive patients undergoing thrombolysis with Retavase were compared to the last 15 consecutive patients who were managed with Urokinase.
Demographically, the two groups were remarkably comparable with the same number of male patients, and the same average age (Table I). The symptomatic presentation was virtually identical with the exception of paresthesia noted in one Urokinase patient and four Retavase patients. Similarly, no significant differences were noted in the number of athletes, weight training, trauma, and smoking. Alothough routine screening for coagulation abnormalities was not performed in all patients, the data were recorded whenever available. The only abnormality recorded was in one Retavase patient who was noted to have a weakly positive titer to anticardiolipin antibodies.
Table I. Demographics
| Demographics | Urokinase | Retavase | p |
|---|---|---|---|
| Age (yrs) | 33 | 31 | ns |
| Males | 7/15 (47%) | 6/15 (40%) | ns |
| Presenting symptoms | |||
 Swelling | 15/15 | 15/15 | ns |
| Pain | 6/15 | 11/15 | ns |
| Paresthesias | 1/15 (8%) | 4/12 (16%) | ns |
| Risk factors | |||
| Wt. Trainers | 8/15 (53%) | 6/15 (41%) | ns |
| Manual labor | 1/15 (7%) | 1/15 (7%) | ns |
| Athlete | 5/15 (41%) | 8/15 (58%) | ns |
| Prior trauma | 2/15 (13%) | 0/15 (0%) | ns |
| Smoker | 1/15 (7%) | 0/15 (0%) | ns |
| OCP use | 1/15 (7%) | 1/15 (7%) | ns |
| Coagulation ABN | 0/15 (0%) | 1/15 (7%) | ns |
Initial Study
The initial diagnosis of axillo-subclavian thrombosis was established with ultrasonography in six of the 15 Urokinase patients and 11 of the 15 Retavase patients. The remaining patients underwent venography as their initial diagnostic study.
Thrombolytic Variables
Thrombolysis was instituted at the time of initial venography in all patients (Table II). The average time from symptoms to initiation of thrombolysis was 4 (+/− 5.1) days in the Urokinase group and 3 (+/− 5.1) days in the Retavase group. The duration of thrombolysis was 24 to 72 hours in the Urokinase group and 18 to 72 hours in the Retavase group. The average time to the resolution of the thrombus was 41 (+/− 20) hours in the Urokinase group and 30 (+/− 16) hours in the Retavase group. The total dose of Urokinase averaged 4.01 (+/− 2.6) million units. The total dose of Retavase averaged 8 (+/− 4.5) mg. There were no instances of allergic reaction, hemorrhage, renal failure, renal insufficiency, or need for transfusion.
Table II. Thrombolytic parameters
| Urokinasea | Retavaseb | p | |
|---|---|---|---|
| Sx to lysis | 3.5 d | 2.9 d | ns |
| Total dose | 4.07 m U | 8 mg | - |
| Duration of lytic therapy | 24-72 hr | 18-72 hr | ns |
| Mean time to clot lysis | 41 hr | 30 hr | ns |
| Allergic reactions | 0 | 0 | ns |
| Bleeding | 0 | 0 | ns |
| Transfusion | 0 | 0 | ns |
| Renal insufficiency | 0 | 0 | ns |
aUrokinase doses = million Units. |
bRetavase doses = milligrams. |
Results of Thrombolysis
The initial attempt at thrombolysis was successful in all but two patients (Table III). One of these (Urokinase patient) was identified, in retrospect, to probably have incurred an acute thrombosis in the face of a chronic occlusion. The second (Retavase patient) underwent thrombolysis within 2 days of his presenting symptoms but failed to clear all thrombus. An angiojet device was used as an adjunct to thrombolysis in this patient at the time of initial thrombolysis.
Table III. Thrombolytic efficacy
| Urokinase | Retavase | p | |
|---|---|---|---|
| Number Pts | 15 | 15 | - |
| No clot lysis | 1 (7%) | 1 (7%) | ns |
| Partial lysis | 0 | 0 | ns |
| Complete lysis | 14 (93%) | 14 (93%) | ns |
Surgical Results
The results of surgery were similar in both groups, including: the duration of the operations, the blood loss, the incidence of hematomas, and the need for transfusion. It should be noted that one patient in the Retavase group suffered a laceration of an internal mammary artery during the course of surgery. This patient developed a hematoma and required transfusion. One Urokinase patient developed a postop hematoma. Postoperative length of stay is same between the groups. The mean time from thrombolysis to surgical decompression was 47.0 + 57.3 days for all patients.
Postoperative studies
All patients underwent postoperative venograms approximately 2 weeks following surgery. These studies identified lesions, which required angioplasty in five of 15 Urokinase patients and six of 15 Retavase patients. In one instance, the lesion that required angioplasty was a venous web, identified by the persistence of venous collaterals and irregular flow of contrast in the vein.
Postoperative venography revealed interval thrombosis of the axillo-subclavian vein in one Urokinase patient and two Retavase patients. All underwent successful repeat thrombolysis. In one Retavase patient, the vein was noted to have an irregular contour following repeat thrombolysis and was considered a recanalized vein (Fig. 1). Contralateral venography was performed in 22 of the 30 patients. This identified only one instance of contralateral axillo-subclavian venous compression.
Fig. 1
The final status of the subclavian vein. Thirty patients underwent rib resection: 27 (90%) had patent, normal vein; 1 (3%) had patent, recanalized vein; and 2 (7%) had occluded vein at final assessment. Yellow: Urokinase; red: Retavase.
Outcomes
In the final analysis, only two Urokinase patients and one Retavase patient reported residual symptoms. In all but one, the symptoms were transient and did not prevent them from resuming work or sporting activities. The nondisabling symptoms included occasional congestion of the arm or color changes in the hand. The patient with disabling symptoms was one (discussed below) with a traumatic brachial plexus injury.
Resumption of premorbid employment was used and an index of the successful recovery from injury. All patients were able to resume their employment, but one remained disabled due to persistent neuropathic pain in his shoulder. This patient suffered traumatic injury to the neck and shoulder resulting in a brachial plexus injury along with a clavicular fracture approximately 1 year prior. He subsequently presented with a subclavian vein thrombosis. Despite successful thrombolysis and thoracic outlet decompression, he remained disabled due to posttraumatic neuralgia.
Of the 30 patients, 14 were involved in competitive athletics, weight training, or athletic enthusiasts. All of the competitive athletes were able to resume their athletic pursuits following surgery.
Discussion
In 1948, Hughes coined the name Paget-Schroetter syndrome to designate spontaneous thrombosis of the axillo-subclavian venous system.11 He noted that the most successful nonoperative treatment of the condition at that time consisted of arm rest and elevation along with use of anticoagulants. The unfortunate consequence of this treatment was persistent symptomatology and disability in 20% of patients, with only partial recovery in 20%, and pulmonary embolization in 1%.
In a study of 48 patients with effort thrombosis, Tilney et al2 noted that approximately 75% of patients had persistent and residual symptoms after a 6.6-year interval. The authors reported 17% of their patients suffered recurrent episodes of thrombosis. Additionally, late venography demonstrated subclavian vein occlusion in 90% of those studies.
Adams et al.2 reported pulmonary embolization in 10% of patients managed conservatively with arm rest and anticoagulation. Residual disability was noted in 70% of these patients. Such poor results justified surgical interventions including thrombectomy and decompression of the thoracic outlet with scalenectomy and claviculectomy. The authors proceeded to report their results with these techniques as improving the outcome of their patients. They further noted the importance of compression at the thoracic outlet as both an initiating and sustaining element in the pathophysiology of the syndrome. Surgical decompression allowed a significant improvement in the patient's outcome.
The advent of catheter-directed thrombolysis allowed for safe and reliable dissolution of the thrombus and subsequent improvement in the ability to diagnose the underlying etiology of the thrombosis and a rational approach to care. Spontaneous thrombosis due to extrinsic compression at the thoracic outlet could be reliably diagnosed and managed appropriately.6 Patients whose thrombotic event was not associated with thoracic outlet compression could be managed with anticoagulation and spared unnecessary surgical intervention.
The algorithmic approach, published by Machleder9 in 1993, represented a significant advance in this arena. In this report, catheter-directed thrombolysis is followed by a period of anticoagulation, surgical decompression where appropriate, and follow-up venography. This is the basis upon which we treat patients today. Subsequent reports by Urschel et al.,12 Azakie et al.,13 and Adelman et al.14 have endorsed the use of catheter-directed thrombolysis as precursor to surgical decompression. Reports by Kreienberg et al.15 and Feugier et al.16 attest to the long-term success of this approach. In a report detailing treatment of 35 patients seen over a period of 10 years, Lee et al.17 have reported satisfactory results by using thrombolytic therapy, with surgical decompression reserved for symptomatic recurrence.
The introduction of Urokinase offered a predictable, safe, and effective thrombolytic agent. Its application in the area of venous thrombosis at the thoracic outlet was remarkably successful, and it soon became the agent of choice for management of PSS. The withdrawal of Urokinase from the market in 1999 resulted in a search for a new agent to fill this role.18 The eventual choice was Retavase (recombinant tPA).
Retavase is a genetically engineered molecule based on the naturally occurring tPA.19 The second kringle and the protease region of the original molecule are retained in Retavase. The result of this genetic engineering is a lytic agent possessing improved clot penetration, a shorter half-life, and more rapid initiation of thrombolysis. Initial experience with tPA and Retavase indicated that despite similarities, the clinical behavior of this agent was considerably different from that of Urokinase. The most notable difference was the tendency to bleeding when coadministered with Heparin.
In the absence of a study comparing Retavase to Urokinase, we have assembled a retrospective comparison of our recent experience with these two agents. In this report, the results of thrombolysis with Retavase are comparable with those of Urokinase by every significant measure. There were no deaths, no hemorrhagic complications, and no significant differences in the perioperative or postoperative event rates in the two groups of patients. Admittedly, the retrospective nature of the study and the relatively small size of the cohorts limit the power of the study. Still both agents appear to be safe and effective in this application.
Conclusion
Paget-Schroetter syndrome is a disabling condition that affects predominantly young, active people. Thrombolyiss followed by surgical decompression of the thoracic outlet affords effective resolution of this problem. Our experience indicates that this approach is attended by low morbidity.
The current thrust of best medical care and evidence-based medicine is to provide treatment based on objective data. Previously, data comparing Retavase and Urokinase for management of PSS were nonexistent. This study provides such data and indicates that Retavase appears to be as safe and effective as Urokinase for thrombolysis of PSS associated with thoracic outlet compression.
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Presented at the 24th Annual Meeting of the Southern California Vascular Surgery Society, Temecula, California, May 5-7, 2006.
PII: S0890-5096(07)00077-5
doi:10.1016/j.avsg.2006.10.016
© 2007 Annals of Vascular Surgery Inc. Published by Elsevier Inc All rights reserved.