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© 2002 American Society for Clinical Oncology Safety and Efficacy of Alteplase for Restoring Function in Occluded Central Venous Catheters: Results of the Cardiovascular Thrombolytic to Open Occluded Lines TrialByFrom the Cleveland Clinic Foundation, Cleveland, OH; Hutchinson Clinic, Hutchinson, KS; Allegheny General Hospital, Pittsburgh, PA; Genentech, Inc, South San Francisco; and Stanford University, Stanford, CA. Address reprint requests to Charles P. Semba, MD, Division of Cardiopulmonary/Specialty Therapeutics, Genentech, Inc, 1 DNA Way, MS:59, San Francisco, CA 94080-4990; email: cpsemba{at}gene.com
PURPOSE: To evaluate the safety and efficacy of alteplase (TPA) for restoring function to occluded central venous catheters (CVCs). PATIENTS AND METHODS: The study design was a phase III, open-label, single-arm multicenter trial. Subjects with occluded, nondialysis CVCs were enrolled. All subjects received a 2-mg dose of TPA within the dysfunctional catheter lumen that was allowed to dwell for 30 to 120 minutes. Functionality was tested at 30 and 120 minutes. If the CVC remained obstructed at 120 minutes, a second 2-mg TPA dose was allowed to dwell for 30 to 120 minutes. The primary safety end point was the rate of intracranial hemorrhage (ICH) within 5 days of treatment, and serious adverse events were recorded up to 30 days. RESULTS: Nine hundred ninety-five patients received treatment (female, 562; male, 433; mean age, 50.7 years; range, 2 to 91 years). CVCs treated were as follows: single (26%), double (39%), or triple (6%) lumen catheters or ports (29%). The primary end point was 0% ICH within 5 days. There were no cases of death, major bleeding episodes, or embolic events attributable to treatment. Flow was successfully restored in 52% and 78% of CVCs at 30 and 120 minutes after one dose, and 84% and 87% at 30 and 120 minutes after a second dose, respectively. Restoration of flow was 86%, 93%, 90%, and 79%, for single, double, and triple lumen catheters and ports, respectively. Estimated 30-day catheter patency was 74%. CONCLUSION: A regimen of up to two 2-mg doses of TPA is safe and effective for the restoration of flow to occluded central venous catheters.
CENTRAL VENOUS catheters (CVCs) have become increasingly essential in the management of patients undergoing complex and intensive therapies, especially in the field of oncology. CVCs facilitate the consistent and timely infusion of antineoplastic agents, antimicrobial agents, blood products, and total parenteral nutrition as well the acquisition of blood samples for testing. Despite advances in device design and insertion techniques, the catheter lumens remain prone to occlusion. Catheter occlusion can result in treatment delay, surgical replacement, patient discomfort, and increased cost of care. Estimates suggest that 25% of CVCs become occluded, with thrombosis as the most common etiology.1-3 Before 1999, the only approved pharmacologic agent for the medical treatment of thrombosed venous catheters was urokinase (Abbokinase-OpenCath, 5000 U; Abbott Laboratories, Abbott Park, IL) derived from human neonatal kidney cells. In January 1999, the Food and Drug Administration (FDA) suspended the distribution of urokinase because of the theoretical concern for the transmission of infectious agents.4,5 Streptokinase has been used as a potential replacement; however, it is not FDA-approved for catheter clearance. In December 1999, the manufacturer of streptokinase (SK) (Streptase; AstraZeneca, Wayne, PA) issued warnings regarding the risk of life-threatening anaphylaxis when SK is used for treating occluded catheters.6 Currently there are no approved alternatives to urokinase available in the United States for treating occluded venous catheters. Alteplase (tissue plasminogen activator [TPA]) has been shown to be effective in the restoration of function to CVCs. In 1994, Haire et al1 performed a double-blind, prospective, randomized trial of urokinase versus TPA (Genentech, Inc, San Francisco, CA) in dysfunctional catheters radiographically proven to be occluded by thrombus. Catheters were treated with 2 mg of TPA or 10,000 U of urokinase that was allowed to dwell in the device for 2 hours. After up to two treatments, TPA restored function in more catheters than urokinase (89% v 59%; P = .013). No treatment-related serious adverse events were reported during the serial delivery of up to two doses of either drug. Limitations of the study included the requirement of an interventional radiologist to inject the catheter in question with contrast and radiographically confirm the presence of clot at the catheter tip. Furthermore, the rate of spontaneous clearance remained unknown because there was no comparison to placebo. In July 1999, two pivotal FDA label-enabling phase III trials were initiated to determine the efficacy and safety of using up to two sequential 2-mg doses of TPA as an alternative to urokinase for CVC function restoration. The studies were designed to confirm the experience reported by Haire et al1 but without the need for x-ray contrast-injections of the affected catheter. The Cardiovascular thrombolytic to Open Occluded Lines (COOL)-1 was a double-blind, placebo-controlled, prospective randomized trial to primarily evaluate the efficacy of TPA.7,8 The end point was restoration of flow after administration of study drug (placebo or TPA). Function was restored in 74% of catheters treated with one dose of TPA versus 17% treated with placebo (P < .0001). Cumulative efficacy after up to two 2-mg doses of TPA was 90%. Although no significant adverse events were reported in COOL-1, the total study population was only 150 patients. To better evaluate the safety of TPA treatments, a larger single-arm, open-label multicenter trial was designed. The purpose of this report is to present the safety and efficacy results of the phase III COOL-2 trial that used TPA to treat dysfunctional central venous access devices in nearly 1,000 patients and present the largest, to our knowledge, reported study of patients undergoing thrombolytic treatment of CVCs.
Objectives The primary objective of the study was to evaluate the safety of serial administration of up to two intraluminal doses of TPA (2 mg and 2 mL) in restoring function in occluded CVCs. The secondary objectives were (1) to estimate the success rates at 30 and 120 minutes after administration of up to two doses of TPA and (2) to estimate the 30-day primary patency rate of catheters successfully treated with TPA on the first 450 patients enrolled.
Study Design
Inclusion criteria. Subjects were eligible if they were hemodynamically stable and had a dysfunctional long-term CVC. All types of catheters were included except any catheter used for hemodialysis. Catheters with valves (eg, Groshong catheter; Bard Vascular Access, Salt Lake City, UT), peripherally inserted central catheters (PICCs), apheresis catheters, and chest/arm ports were allowed. Catheter dysfunction was defined as the inability to withdraw 3 mL of blood from the device. If multiple lumens were occluded, investigators were allowed to choose and treat only one lumen for the study. Exclusion criteria. Subjects who met one or more of the following were excluded from participation: inability to infuse fluid volume necessary to fill catheter lumen with TPA, ability to successfully withdraw blood after repositioning patient, devices inserted less than 48 hours before enrollment, any evidence of mechanical or nonthrombotic occlusion, age less than 2 years, body weight of less than 10 kg, previously enrolled onto study, administration of any fibrinolytic agent within 24 hours of enrollment, known right-to-left shunt, patent foramen ovale, or atrial/ventricular septal defect. Subjects who were considered by the investigator to be at a high risk for bleeding events, embolic complications (eg, recent deep vein thrombosis or pulmonary embolism), or had a known condition for which bleeding constituted a significant hazard were also excluded.
TPA is commercially manufactured in the United States in 50-mg and 100-mg vials. At each site, the 50-mg vial of lyophilized TPA powder (Activase; Genentech, Inc) was reconstituted with 50 mL of sterile water for injection (United States Pharmacopeia, Rockville, MD) to obtain a final concentration of 1 mg/mL. Using an aseptic technique, the pharmacist aliquotted 2-mL volumes of TPA into 10 mL sterile plastic syringes, which were kept frozen at -20°C until needed for the study. The preservation of bioactivity of reconstituted, frozen TPA is stable for at least 6 months and has been documented previously (data on file, Genentech, Inc, San Francisco, CA).9,10 During the study, the frozen syringes were gently thawed at room temperature and used immediately. The final concentration used was 1 mg/mL, and the intraluminal volume administered was 2 mL per dose, unless the patient had low body weight (< 30 kg). Subjects weighing All subjects received an intraluminal dose of TPA that was allowed to dwell in the catheter for 30 minutes (± 10 minutes). CVC function was assessed by first attempting to aspirate 3 mL of blood and, if successful, attempting infusion of 5 mL normal saline. For CVCs that remained dysfunctional after 30 minutes, the drug was allowed to remain in the device an additional 90 minutes, for a total of 120 minutes (± 10 minutes) after TPA administration. A second assessment of function was repeated. CVCs that remained dysfunctional after a single dose of TPA were treated with a second dose. Assessment of catheter function was again performed at 30 minutes (± 10 minutes) after administration of the second dose. If function was not restored, another assessment was made at 120 minutes (± 10 minutes). Subjects exited the treatment algorithm when catheter function was restored or after assessment of CVC function after the second dose’s 120-minute dwell time, whichever occurred first. For catheters successfully treated, the catheter was locked with heparin or saline solutions per routine care. The safety evaluation had two components. First, serious adverse events were elicited from all subjects by telephone or in person at 5 days (± 1 day) after completion of the treatment algorithm. Serious adverse events of specific interest included intracranial hemorrhage (ICH), major hemorrhages, and embolic events. The second component was the collection of spontaneous serious adverse events confirmed by the investigators during the 30-day posttreatment period.
Outcome Variables The primary efficacy outcome variable was the overall rate of CVC function after serial administration of up to two intraluminal doses of TPA. Restored function was defined as the ability to withdraw 3 mL of blood from the CVC and infuse 5 mL of normal saline. Secondary efficacy outcome variable was the rate of restored catheter function at the end of 30 and 120 minutes after the first and second TPA dose and primary patency rate of successfully treated devices at 30 days for the first 450 patients enrolled.
Statistical Analysis Efficacy. For the primary efficacy outcome measure, the proportion of subjects with restored CVC function and 95% CIs after up to two doses of TPA were determined. For the secondary efficacy outcome measure, the proportion and 95% CIs of subjects with restored CVC function at 30 and 120 minutes after up to two doses of TPA were determined. For the 450 patients who had 30-day assessments of catheter patency, time to reocclusion was calculated using Kaplan-Meier analysis.
A total of 1,000 subjects were registered onto the study; however, three subjects were enrolled twice because of reocclusion, and, therefore, the actual number of subjects enrolled was 997. All subjects were scheduled to receive TPA; however, two patients had spontaneous return of catheter function and were not administered the study drug. A total of 995 subjects were treated with TPA and constitute the study population. The baseline characteristics of the study population are summarized in Table 1. The majority of subjects were female (56.5%) and white (78.6%). The overall mean age was 50.7 years (range, 2 to 91 years), and mean weight was 73.7 kg (range, 11.1 to 220.0 kg). The most common CVC treated was a double lumen external catheter (39.4%). Among the 997 subjects enrolled, 85 (8.5%) did not complete the 30-day study period. Table 2 summarizes the reasons for study discontinuation.
Safety Outcomes A summary of adverse events is presented in Table 3. For the primary end point, there were no subjects who experienced an ICH during the study (95% CI, 0.0% to 0.4%). For the secondary end points, there were three cases of major hemorrhage (0.3%; 95% CI, 0.1% to 0.9%), and no subjects experienced an embolic event (95% CI, 0.0%, 0.4%) within 5 days after treatment. There was no correlation between adverse events and total TPA dose (2 mg v 4 mg), catheter-type, age, sex, or body weight. Of the major hemorrhages, two were experienced by oncology patients (one undergoing stem-cell transplant for Ewing’s sarcoma 2 days after treatment and one undergoing chemotherapy for metastatic seminoma and subsequent Mallory-Weiss tear 2 days after treatment) who experienced hematemesis. One additional patient with an active flare of ulcerative colitis had an episode of hematochezia 3 days after treatment. None of the major bleeding incidences were interpreted by the investigator as related to TPA treatment.
Two subjects withdrew from the study as a result of serious adverse events (sepsis). Subject A, who had multiple myeloma, experienced fever and hypotension fifteen minutes after the administration of TPA. Peripheral-blood cultures were subsequently positive for Acinetobacter baumanii and Acinetobacter haemolyticus. The patient was treated with intravenous antibiotics and recovered. Subject B, who had renal cell carcinoma, recurrent fevers, and suspected catheter infection, experienced dyspnea that required intensive care unit monitoring 7 hours after administration of TPA. Because the catheter was suspected as the source of infection, the device was removed. Catheter blood cultures were unobtainable because the catheter was occluded; however, a culture of the catheter tip was positive for Staphylococcus epidermidis. A ventilation-perfusion lung scan was normal. Three subjects (0.3%) experienced adverse events that were considered possibly related to TPA therapy, including subject A, described above. Subject C, who had a history of a septic knee joint, experienced an episode of fever 8 hours after successful treatment of an occluded PICC line, and subject D, who had carcinomatosis from small-cell cancer of the lung, developed a septic episode 7 hours after successful treatment of an occluded catheter.
A total of 24 patients (2.4%) died during the 30-day study period, all within the
Efficacy Outcomes
Twenty-seven patients did not have complete catheter assessments (both withdrawal and infusion) at the end of treatment and were excluded from the primary analysis. Thirteen (48.1%) of 27 patients were administered infusion function at baseline. After withdrawal function was re-established, infusion function was not reassessed. If these 13 subjects were included in the analysis and catheter function considered fully restored, the success rate would be 87.4% (857 of 981). The remaining 14 subjects did not have catheter assessments for the following reasons: the subject or physician decided that the subject could not wait for the assessment, the nurse involved was not aware of the study, or the PICC line was broken and, thus, no assessment could be made. If these 14 subjects were included in the analysis and it was assumed that the treatment failed, the overall success rate would be 85.9% (844 of 982). The cumulative efficacy at 30 and 120 minutes after the first and second dose of TPA was 52.1%, 76.5%, 83.6%, and 87.2%, respectively (Table 5). Efficacy by catheter type after up to two doses of TPA was 86.2%, 93.3%, 89.7%, and 79.0% for single, double, and triple lumen catheters and ports, respectively. The majority of devices were cuffed, tunneled catheters or ports (76%; 755 of 995). PICC lines have become increasingly popular as a less invasive, simpler alternative to tunneled devices and were eligible for the trial. Of the 240 PICC lines treated, the efficacy at 30 and 120 minutes after the first and second dose of TPA was 59.4%, 81.1%, 89.1%, and 92.9%, respectively.
CVC function was restored at the end of treatment for 844 of the 995 treated subjects; 385 of these subjects were from the subset of 450 who were to have an assessment of CVC function 30 days after treatment. Among the 385 subjects, data were available from 346 regarding catheter patency at 30 days (39 subjects were lost to follow-up at 30 days). Catheter reocclusion had occurred in 26.3% (91 subjects), for a 30-day patency rate of 73.7%. A Kaplan-Meier survival analysis was plotted using a worst-case assumption that the 39 subjects had occluded devices, for a 30-day patency rate of 65% (Fig 2).
Central venous catheters have greatly improved the ability to provide medical therapy for patients who require long-term parenteral therapy. Despite the advances in catheter technology and improvements in catheter care, device failure remains a commonplace conundrum, especially for the intravenous therapy team.11-14 Not only is CVC occlusion a significant source of frustration for the caregiver and patient that delays needed therapy, it exposes the patient to additional risks arising from surgical revision, removal, and/or device replacement. Urokinase had been the established standard of care in troubleshooting venous access devices when simple saline or heparin flushes were unsuccessful. Though TPA has been shown to be a superior alternative to urokinase,1 TPA had never been studied in large-scale pivotal trials. Although the COOL-1 study robustly established the efficacy of TPA therapy in catheter clearance, a larger phase III experience was required to assess the overall safety profile of using up to two 2-mg intraluminal doses of TPA. The COOL-2 trial was performed to principally assess the safety of the procedure and represents one of the largest thrombolytic trials for the management of CVC dysfunction. The primary safety objective was the rate of intracranial hemorrhage within 5 days of treatment. There were no ICHs, embolic events, or study drug-related major hemorrhages or deaths. All of the serious adverse events that were reported were judged by the investigator to be related to the underlying disease with the exception of one event (fever). Two events of sepsis were judged by the investigator to be not related to study drug but were upgraded to possibly related by the trial sponsor. Because of the potential for TPA to liberate infected thrombotic material into the bloodstream, caution is warranted in the attempt to treat devices with suspected intraluminal infections. Our results also support the safety findings of both COOL-1 and Haire et al,1 showing no treatment-related adverse bleeding events or evidence of systemic fibrinolysis. In Haire et al,1 the mean pretreatment and posttreatment fibrinogen levels for patients treated with TPA was 392 mg/100 mL, and 385 mg/100 mL, respectively (not significant). Though many oncology patients have thrombocytopenia and are at increased risk for bleeding, studies evaluating the safety of TPA treatment in severely thrombocytopenic and/or neutropenic populations will require further investigation. Overall, the COOL-2 safety results were consistent with previous published studies and demonstrate a high margin of safety with no evidence of systemic fibrinolytic complications. The primary efficacy outcome measure of the trial was the rate of restoration of CVC function after up to two boluses of 2 mg/2 mL TPA. On the basis of the estimate of efficacy in restoring function to thrombotically occluded catheters (89%, based on Haire et al1) and the prediction that 64% of catheters were thrombotically occluded, an efficacy rate of 57% after two treatments of TPA was expected.1 The overall rate of CVC restoration in the current trial was 87.2%. This value is consistent with the predicted estimate if it is assumed that the investigators were highly effective in excluding mechanically occluded catheters (kinked devices or occlusions caused by nonthrombotic material) solely on the basis of clinical, bedside assessment of the device. TPA efficacy was high, regardless of catheter type, patient age, sex, race, or body weight. Efficacy seems to be related to duration of catheter dysfunction to treatment time. Catheters known to be occluded and treated more than 14 days after occlusion detection had a cumulative success rate of 77.6% (95% CI, 63.4% to 88.2.%), compared with 90.6% for devices treated on day 0 (95% CI, 88.0% to 92.8%). The demographic and baseline characteristics of the subjects were consistent with those expected in a typical clinical setting where patients have significant underlying disease that necessitates implantation of a CVC. The distribution of catheter types was within the expected range. Alteplase is the recombinantly derived analog of human TPA secreted from normal vascular endothelium and has higher fibrin specificity than urokinase (UK) and a shorter plasma half-life (UK, 16 minutes; TPA, 5 minutes). Currently, TPA is approved for acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. The derivation of a 2-mg dose for catheter clearance was based on the analysis of Haire et al1. A single FDA-approved dose of urokinase for catheter clearance is 5,000 U. This is equal to 1.6% of the FDA-approved bolus dose of urokinase used for treating pulmonary embolism in a 70-kg patient (4,400 U/kg). The approved dose of TPA for pulmonary embolism is 100 mg; therefore, Haire et al1 empirically used 2-mg (rounded up to 2%) as the study dose for catheter clearance. Because TPA is reconstituted 1:1 with sterile water, the volume of a 2-mg dose is 2 mL. For the vast majority of normal, unobstructed CVCs, the intraluminal volume is usually between 1 to 2 mL. Therefore, a 2-mg configuration is feasible for most CVCs. With children in whom shorter devices were used, a dose equal to 110% of the catheter volume was used to minimize excess TPA delivery into the bloodstream. Alternative agents to urokinase include TPA, SK, reteplase (Retavase; Centocor, Malvern, PA), and tenecteplase (TNKase; Genentech). Because of the potential for serious anaphylaxis, especially with repeated exposure, SK has not been considered a primary alternative to urokinase for catheter clearance.6 Reteplase and tenecteplase are recombinantly derived variants of TPA and are approved for myocardial infarction; however, there are no peer-reviewed studies that describe their use for catheter clearance. Low-dose warfarin has been demonstrated to reduce the rate of catheter-related venous thrombosis.15,16 Assessment of catheter clearance using TPA in conjunction with known prophylactic warfarin was not evaluated in this study. Although the COOL-2 study population was predominantly composed of oncology patients, the percentage of patients on prophylactic warfarin was not recorded and warrants future investigation. Routine use of warfarin could potentially enhance 30-day catheter patency after TPA treatment. With the unavailability of urokinase, many hospitals have resorted to using frozen aliquots of TPA; however, most outpatient facilities, such as skilled nursing facilities, free-standing clinics, or home infusion services, have not had access to frozen small-dose syringes because of a lack of access to freezers and/or a dedicated pharmacist. The COOL-2 trial used reconstituted and frozen syringes of TPA, and these results do not change the current constraints in the outpatient settings. However, the COOL trials are part of a phase III, FDA, label-enabling study that, if approved, would allow the availability of a 2-mg, single-use, patient-specific vial of TPA for use in catheter clearance and would obviate the need for aliquotting and freezing. In conclusion, the results of the COOL-2 study have demonstrated that TPA, when administered at a dose of 2 mg/2 mL for up to two serial administrations and allowed to dwell up in the catheter for 30 to 120 minutes, is safe and effective for the restoration of catheter function in subjects with occluded central venous catheters.
APPENDIX
Supported by Genentech, Inc, San Francisco, CA.
1. Haire WD, Atkinson JB, Stephens LC, et al: Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: A double-blinded, randomized trial. Thromb Haemost 72: 543-547, 1994[Medline] 2. Rubin RN: Local instillation of small doses of streptokinase for treatment of thrombotic occlusions of long-term access catheters. J Clin Oncol 1: 572-573, 1983[Abstract] 3. Lokich JJ, Both A, Benotti P: Complications and management of implanted central venous catheters. J Clin Oncol 3: 710-717, 1985[Abstract] 4. Zoon KC: Important Drug Warning: Safety Information Regarding Use of Abbokinase (Urokinase). United States Food and Drug Administration Med Watch. Http://www.fda.gov/cber/ltr/abb012599.htm. Accessed January 1999 5. Hartnell GG, Gates J: The case of Abbokinase and the FDA: The events leading to the suspension of Abbokinase supplies in the United States. J Vasc Interv Radiol 11: 841-847, 2000[Medline] 6. Neil G: Important Safety Information. Letter: Dear Hospital Pharmacy and Physician. AstraZeneca, Inc, December 10, 1999. United States Food and Drug Administration Med Watch. Available at: Http://www.fda.gov/medwatch/safety/1999/strept.htm. Accessed December 1999 7. Haire WD, Ponec D, Irwin D, et al: Thrombolysis with tissue plasminogen activator in occluded central venous catheters: The COOL-1 efficacy trial results. Presented at the Thirteenth Annual International Symposium on Endovascular Therapy, Miami, FL, January 24, 2000 8. Ponec D, Irwin D, Haire WD, et al: Double-blind placebo-controlled trial of recombinant tissue plasminogen activator for restoration of function in occluded central venous access devices: The Cardiovascular Thrombolytic to Open Occluded Lines (COOL) Efficacy Trial. J Vasc Interv Radiol 12: 951-955, 2001[Medline] 9. Calis KA, Cullinane AM, Horner MK: Bioactivity of cryopreserved alteplase solutions. Am J Health Syst Pharm 56: 2056-2057, 1999 10. Wiernikowski JT, Crowther M, Clase CM, et al: Stability and sterility of recombinant tissue plasminogen activator at -30°C. Lancet 355: 2221-2222, 2000[CrossRef][Medline] 11. Cobos E, Dixon S, Keung YK: Prevention and management of central venous catheter thrombosis. Curr Opin Hematol 5: 355-359, 1998[Medline] 12. Bagnall-Reeb H: Diagnosis of central venous access device occlusion: Implications for nursing practice. J Intraven Nurs 21: S115-S121, 1998 (suppl)[Medline] 13. Tschirart JM, Rao MK: Mechanism and management of persistent withdrawal occlusion. Am Surg 54: 326-328, 1998 14. Hooke C: Recombinant tissue plasminogen activator for central venous access device occlusion. J Pediatr Oncol Nurs 17: 174-178, 2000 15. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: A randomized prospective trial. Ann Intern Med 112: 423-428, 1990 16. Boraks P, Seale J, Price J, et al: Prevention of central venous catheter–associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haematol 101: 483-486, 1998[CrossRef][Medline] Submitted May 8, 2001; accepted August 2, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30 kg received a 2-mL intraluminal dose of TPA; subjects weighing 
