Treatment of Occluded Central Venous Catheters with Alteplase: Results in 1,064 Patients

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1 Clinical Studies Treatment of Occluded Central Venous Catheters with Alteplase: Results in 1,064 Patients Charles P. Semba, MD, 1 Steven R. Deitcher, MD, Xin Li, PhD, 1 Laura Resnansky, RN, 1 Tri Tu, BS, 1 Edward R. McCluskey, MD, PhD, 1 for the COOL Investigators PURPOSE: Thrombosis of central venous access devices (CVADs) is a relatively frequent complication. Alteplase (tissue plasminogen activator) has been used to salvage dysfunctional devices. The purpose of this study was to analyze the safety and efficacy of alteplase after administration of a maximum of two 2-mg/2-mL doses to thrombosed CVADs. MATERIALS AND METHODS: A combined analysis was performed of two pivotal prospective phase-iii clinical trials (Cardiovascular thrombolytic to Open Occluded Lines [COOL] Trials) involving 80 centers enrolling patients from November 1999 through December Patients 2 years of age or older (with body weights >10 kg) with dysfunctional nondialysis CVADs were eligible, including those with peripherally inserted central catheters, apheresis catheters, and ports. Alteplase (2 mg/2 ml) was instilled into the lumen of the central venous catheter and allowed to dwell for as long as 120 minutes. For patients with body weights of kg, 110% of the internal lumen volume of alteplase (2 mg/2 ml) was administered. If the device was still occluded after a maximum of 120 minutes, a second alteplase dose was given and allowed to dwell for as long as 120 minutes. The primary efficacy endpoint was designated as restored function after a maximum of two doses. The primary safety endpoint was intracranial hemorrhage (ICH) within 5 days. RESULTS: A total of 1,064 patients (465 men, 599 women; mean age, 50.7 y; range, 2 91 y) with dysfunctional catheters were treated. After alteplase administration, function was restored in 798 patients (75.0%; 95% CI: 72.3%, 77.6%) after one dose and 905 (85.1%; 95% CI: 82.8%, 87.2%) after two doses. Efficacy rates were similar among catheter types (single-, double-, and triple-lumen catheters, and ports). Serious adverse events monitored within 30 days of treatment included ICH (0.0%), embolic events (0.0%), gastrointestinal bleeding (0.3%), thrombosis (0.3%), and sepsis (0.4%). One event (fever) was attributed to the study drug. Efficacy was independent of age, sex, body weight, and catheter type. CONCLUSION: A regimen of as many as two 2-mg doses of alteplase is safe and effective for restoring flow to occluded central venous access devices. Index terms: Thrombolysis Tissue-type plasminogen activator J Vasc Interv Radiol 2002; 13: Abbreviations: CVAD central venous access device, COOL Cardiovascular thrombolytic to Open Occluded Lines (trials), FDA Food and Drug Administration, ICH intracranial hemorrhage, UK urokinase From the Department of Vascular Medicine, Genentech (C.P.S., X.L., L.R., T.T., E.R.M.), South San Francisco; Department of Vascular and Interventional Radiology (C.P.S.), Stanford University Medical Center, Stanford, California; and the Department of Cardiovascular Medicine, Cleveland Clinic Foundation (S.R.D.), Cleveland, Ohio. A list of the COOL Investigators is given at the end of this article. Received May 22, 2002; revision requested July 9; revision received July 23; accepted July 25. From the 2002 SCVIR Annual Meeting. Address correspondence to C.P.S., Department of Vascular Medicine, BioTherapeutic Unit, Genentech, Inc., 1 DNA Way MS:59, South San Francisco, CA ; cpsemba@gene.com 1 These authors have disclosed the existence of a potential conflict of interest. SIR, 2002 DURING the past 5 years, implantation and management of central venous access devices (CVADs) by interventional radiologists has increased dramatically (1,2). The increase can be attributable to the increase in the number of therapies that require vascular access, a growing elderly population in the United States, and changes in referral patterns. Despite the advances in vascular access technology, the lumens remain vulnerable to thrombosis and occlusion. Before 1999, the only approved thrombolytic agent for restoring function to thrombosed catheters was human-derived urokinase (UK; Abbokinase Open-Cath; Abbott Laboratories, Abbott Park, IL). With the removal of UK from the market by the Food and Drug Administration (FDA) in 1999 (3), alternative plasminogen activators have been studied. Streptokinase (Streptase; AstraZeneca, Wayne, PA) has not been considered a primary alternative because of the risk of life-threatening anaphylaxis (4). Recombinantly derived alteplase (tissue plasminogen activator; Cathflo Activase; Genentech, South San Francisco, CA) has been shown to be effective in restoring function to CVADs and may be a superior alternative to UK. A head-to-head, double-blind, prospective, randomized trial of UK (10,000 U) versus alteplase (2 mg) in dysfunctional catheters proven venographically to be thrombosed was performed by Haire et al (5). Catheters were treated with a 2-hour instillation of the study drug. After a maximum of two treatments, alteplase restored function in more catheters than UK (89% vs 1199

2 1200 Alteplase Treatment of Occluded Central Venous Catheters December 2002 JVIR 2-mg/2-mL alteplase dose in restoring function to occluded catheters in 150 patients with catheter occlusion for as long as 24 hours (Fig 1). Patients were equally randomized at a 1:1 ratio to receive either alteplase or placebo instilled into the lumen of the catheter, and each catheter was assessed after 120 minutes. If the catheters were dysfunctional, alteplase was administered until function was restored or each patient has received a maximum of two active doses of study drug. Trial 2 was an open-label, singlearm trial in 995 patients with catheter dysfunction and included patients with occlusions present for any duration of time (Fig 2). Patients treated were treated with as many as two 2-mg/2-mL doses of alteplase instilled into the catheter. Assessment for restoration of function was performed 30 minutes after each instillation. If function was not restored, catheter function was reassessed at 120 minutes. Inclusion criteria. Subjects were eligible if they were in hemodynamically stable condition and had a dys- Figure 1. Treatment algorithm for trial 1. 59%; P.013). No serious adverse events were reported with the use of either drug. However, significant issues remained, including a small sample size (N 50), single-center enrollment, lack of placebo control, and the requirement of an interventional radiologist to obtain a venogram to confirm the presence of catheter thrombus. In July 1999, two large, multicenter, phase-iii clinical trials (Cardiovascular thrombolytic to Open Occluded Lines [COOL] trials) were initiated to determine the efficacy and safety of the use of as many as two sequential 2-mg doses of alteplase as an alternative to UK for CVAD function restoration (6,7). The studies were designed to confirm earlier reports but without the need for venography. The purpose of this report is to present the cumulative summary of safety and efficacy from two phase-iii trials of alteplase to treat dysfunctional central venous access devices in more than 1,000 patients. MATERIALS AND METHODS Objectives The primary objective of the study was to evaluate the cumulative safety and efficacy of serial administration of a maximum of two intraluminal doses of alteplase (2 mg per vial; Cathflo Activase; Genentech) in restoring function in occluded CVADs in two phase-iii studies. Study Design Two phase-iii clinical trials conducted at 80 sites in the United States (see Appendix) from November 1999 to December 2000 were performed in patients with dysfunctional CVADs. A placebo-controlled, double-blind, randomized trial (trial 1) and a larger single-arm, open-label trial (trial 2) investigated the use of alteplase in patients who had an indwelling CVAD for administration of chemotherapy, apheresis, total parenteral nutrition, longterm antibiotic drug regimens, or other medications. If multiple lumens were occluded, investigators were allowed to choose and treat only one lumen for the study (the other lumens were treated at the discretion of the investigator after completion of the study treatment). The primary efficacy endpoint was restored function after a maximum of two doses. The primary safety endpoint was intracranial hemorrhage (ICH) within 5 days. Genentech sponsored both phase-iii clinical trials. The protocols were approved by the institutional review boards from each study site and patients gave their full consent before enrollment. Trial 1 tested the efficacy of a Figure 2. Treatment algorithm for trial 2.

3 Volume 13 Number 12 Semba et al 1201 functional long-term CVAD. 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, apheresis catheters, and chest/arm ports were allowed. Catheter dysfunction was defined as the inability to withdraw 3 ml of blood from the device. Exclusion criteria. Subjects in whom one or more of the following criteria was met were excluded from participation: inability to infuse fluid volume necessary to fill catheter lumen with alteplase, ability to successfully withdraw blood after repositioning patient, devices inserted less than 48 hours before enrollment, any evidence of mechanical or nonthrombotic occlusion, age younger than 2 years of age, body weight less than 10 kg, previous enrollment in study, receipt 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 high risk for bleeding events or 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. Treatment protocol. For both trials, the alteplase concentration 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 at least 30 kg received a 2-mL intraluminal dose of alteplase; subjects weighing between 10 and 30 kg received intraluminal doses equal to 110% of the internal volume of the catheter lumen (not exceeding 2 ml). For trial 1, all patients randomized to receive alteplase received an intraluminal dose that was allowed to dwell in the catheter for 120 minutes 10. CVAD function was assessed by first attempting to aspirate 3 ml of blood and, if successful, then attempting infusion of 5 ml normal saline solution. CVADs that remained dysfunctional after a single dose of alteplase were treated with a second dose. For trial 2, all subjects received an intraluminal dose of alteplase that was allowed to dwell in the catheter for 30 minutes 10. CVAD function was assessed by first attempting to aspirate 3 ml of blood and, if successful, then attempting infusion of 5 ml normal saline solution. For CVADs 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 after alteplase administration. A second assessment of function was repeated. CVADs that remained dysfunctional after a single dose of alteplase were treated with a second dose. Assessment of catheter function was again performed at 30 minutes 10 after administration of the second dose. If function was not restored, another assessment was made at 120 minutes 10. Subjects exited the treatment algorithm when catheter function was restored or after assessment of CVAD function after 120-minute dwell time of the second dose, whichever occurred first. In both trials, successfully treated catheters were locked with heparin or saline solutions per routine care. Outcome Variables The primary efficacy outcome variable was the rate of restored catheter function at the end of 120 minutes after the first and second alteplase doses. Restored function was defined as the ability to withdraw 3 ml of blood from the CVAD and infuse 5 ml of normal saline solution. The primary safety outcome variable was the incidence of ICH documented by computed tomography within 5 days of completion of the treatment algorithm. The secondary safety outcome variables were as follows: (i) incidence of major hemorrhage (defined as severe blood loss [ 5 ml/kg] or blood loss requiring transfusion or causing hypotension) within 5 days of treatment, (ii) embolic events (any serious embolic event including pulmonary, arterial [eg, stroke, peripheral, or major organ], or cholesterol plaque) within 5 days of treatment, and (iii) incidence of any serious adverse event within 30 days of treatment. Statistical Analysis The trial population consisted of 1,070 patients (75 patients from trial 1, who were randomized to receive alteplase first, and 995 patients from trial 2); 1,064 (99.4%) patients were treated with alteplase and represent our analysis population. In trial 1, six patients (0.6%) were randomized to the alteplase group but did not receive treatment as a result of return of spontaneous flow and were excluded from analysis. To assess the efficacy and safety of subjects treated with as many as two doses of alteplase, subjects who were randomized to receive placebo in trial 1 were excluded. Even though subjects randomized to received placebo could have received a maximum of two doses of alteplase as well, placebo effects could confound the results. For the primary efficacy outcome measure, the proportion of patients with restored CVAD function at 120 minutes after a maximum of two doses of alteplase was determined. Confidence intervals (95%) were calculated with binomial distribution with use of SAS/STAT software version 8.0 (SAS, Cary, NC). For the primary safety outcome measures, the proportion of patients with an ICH within 30 days was reported. For the secondary safety outcome measures, the proportion of patients with serious adverse events up to 30 days after treatment was reported. All analyses were performed on the as-treated population. RESULTS Demographics and Efficacy Outcomes The demographics of the study population are summarized in Table 1. The majority of subjects were female (n 599; 56.4%) and white (n 834; 78.4%). The overall mean age was 50.7 years (range, 2 91 y) and mean body weight was 74 kg (range, kg). The most common CVAD treated was a double-lumen external catheter (39.8%), followed by ports (29.0%), single-lumen catheters (25.0%) and triple-lumen catheters (6.2%). A cumulative summary of efficacy is presented in Table 2. The proportion of patients in whom successful treatment was achieved after a single dose was 75.0% (95% CI: 72.3%, 77.6%) and success was achieved in 85.1% after two doses (95% CI: 82.8%, 87.2%). Efficacy

4 1202 Alteplase Treatment of Occluded Central Venous Catheters December 2002 JVIR Table 1 Demographics and Characteristics of the Study Population Characteristic was independent of sex, age, body weight, and catheter type. Efficacy rates by catheter type after as many as two doses of alteplase were 83.5%, 92.4%, 87.9%, and 75.7% for single-, double-, and triple-lumen catheters, and ports, respectively. Safety Outcomes A summary of serious adverse events is presented in Table 3. For the primary safety endpoint, there were no patients who experienced an ICH during the study. For the secondary endpoints, there were five cases of sepsis/fever, three cases of major hemorrhage, and three cases of thrombosis within 30 days of treatment. No subjects experienced an embolic event. No serious adverse events were reported in trial 1. There was no correlation between adverse events and total alteplase dose (2 mg vs 4 mg), catheter type, age, sex, or body weight. Three major hemorrhages were reported. Two of the patients were being treated for advanced cancers and experienced hematemesis 2 days after alteplase treatment. A third patient with active ulcerative colitis experienced Trial 1 (n 69) Trial 2 (n 995) Total (n 1,064) Sex Female 37 (53.6) 562 (56.5) 599 (56.3) Male 32 (46.4) 433 (43.5) 465 (43.7) Race White 52 (75.4) 782 (78.6) 834 (78.4) Black 8 (11.6) 126 (12.7) 134 (12.6) Asian/Pacific Islander 5 (7.3) 7 (0.7) 12 (1.1) Hispanic 3 (4.4) 64 (6.4) 67 (6.3) American Indian/Alaskan Native 0 (0.0) 4 (0.4) 4 (0.4) Other 1 (1.5) 12 (1.2) 13 (1.2) Mean age (y) (2.9) 83 (8.3) 85 (8.0) (5.8) 34 (3.4) 38 (3.6) (75.4) 615 (61.8) 667 (62.7) (15.9) 263 (26.4) 274 (25.8) Mean weight (kg) (2.9) 60 (6.0) 62 (5.8) (97.1) 935 (94.0) 1002 (94.2) CVAD type Single 10 (14.5) 256 (25.7) 266 (25.0) Double 31 (44.9) 392 (39.4) 423 (39.8) Triple 6 (8.7) 60 (6.0) 66 (6.2) Port 22 (31.9) 287 (28.8) 309 (29.0) Note. Numbers in parentheses are percentages. hematochezia 3 days after treatment. None of the bleeding events were interpreted by the investigator to be related to alteplase treatment. Five patients had reported catheterrelated sepsis (n 4) or fever (n 1) events occurring from 15 minutes to 3 days after alteplase treatment. All five had positive catheter or blood culture results within 24 hours of symptom onset. Only one of the events (fever) was considered related to alteplase treatment. The patient was being treated with intravenous antibiotics for a septic knee joint and experienced fever 8 hours after successful alteplase therapy. Two patients withdrew from the study as a result of sepsis. A patient with multiple myeloma experienced fever and hypotension 15 minutes after administration of alteplase. Peripheral blood cultures were subsequently positive for Acinetobacter baumanii and Acinetobacter haemolyticus. After administration of intravenous antibiotics, the patient recovered uneventfully. Another patient with renal cell carcinoma and suspected catheter infection experienced dyspnea that required intensive care unit monitoring 7 hours after administration of alteplase. The catheter was empirically removed because of suspicion of catheter infection. Three cases of upper extremity venous thrombosis were reported 3 7 days after treatment. None of these events were attributed by the investigators to be related to alteplase treatment. A total of 25 patients (2.3%; one from trial 1) died during the 30-day study period, all within the 30-kg weight stratum. No subjects died on the day of treatment and five (0.5%) died within 5 days of treatment. None of the deaths were considered by the investigator to be related to alteplase. All subjects had advanced malignancies and/or multiorgan failure. DISCUSSION The use of CVADs is increasingly common as medical therapies become more complex. For the interventionalist, the CVAD is both a blessing and a curse: it allows dedicated, same-day vascular access service to be provided by the interventionalist for patients and their providers, but it pushes aside more appealing technologies such as vascular endografts as the interventionalist s case load becomes inundated with vascular access procedures including managing thrombosed devices. Before 1999, UK was the only thrombolytic drug approved to treat clotted devices in a noninvasive manner. With the FDA s withdrawal of human-derived UK, a large unmet need remained for development of a safe and efficacious alternative for treatment of catheter dysfunction. A combined analysis of two large phase-iii FDA trials involving alteplase for restoration of catheter function was performed. To our knowledge, this study represents the largest reported prospective thrombolytic data set for catheter clearance. The efficacy of the use of a maximum of two instilled 2-mg/2-mL doses of alteplase was 85% and is similar to Haire et al s observed rate of 89% (5). No direct comparison can be made with UK because it was FDAapproved during the 1970s without a pivotal phase-iii trial. Alteplase efficacy was similar across all subgroups, but it demonstrated lower efficacy in ports compared to external catheters. The trend toward reduced efficacy

5 Volume 13 Number 12 Semba et al 1203 Table 2 Cumulative Efficacy by Dose and Subgroup Trial 1 (n 69) Trial 2 (n 995) Total (n 1,064) Cumulative efficacy After first dose 51 (73.9/61.9, 83.8)* 747 (75.1/72.3, 77.7) 798 (75.0/72.3, 77.6) After second dose 61 (88.4/78.4, 94.9) 844 (84.8/82.4, 87.0) 905 (85.1/82.8, 87.2) Overall efficacy by subgroup Sex Female 32 (86.5/71.2, 95.5) 474 (84.3/81.1, 87.3) 506 (84.5/81.3, 87.3) Male 29 (90.6/75.0, 98.2) 370 (85.5/81.8, 88.6) 399 (85.8/82.3, 88.9) Age (y) (50.0/1.3, 98.7) 71 (85.5/76.1, 92.3) 72 (84.7/75.2, 91.6) (100/39.8, 100) 29 (85.3/68.9, 95.1) 33 (86.8/71.9, 95.6) (86.5/74.2, 94.4) 522 (84.9/81.8, 87.6) 567 (85.1/82.1, 87.6) (100/71.5, 100) 222 (84.4/79.5, 88.6) 233 (85.0/80.3, 89.0) Weight (kg) (50.0/1.3, 98.7) 51 (85.0/73.4, 92.9) 52 (83.9/72.3, 92.0) (89.6/79.7, 95.7) 793 (84.8/82.4, 87.1) 853 (85.1/82.8, 87.3) CVAD Type Single 8 (80.0/44.4, 97.5) 214 (83.6/78.5, 87.9) 222 (83.5/78.4, 87.7) Double 30 (96.8/83.3, 99.9) 360 (92.1/89.0, 94.6) 390 (92.4/89.5, 94.8) Triple 6 (100/54.1, 100) 52 (86.7/75.4, 94.1) 58 (87.9/77.5, 94.6) Port 17 (77.3/54.6, 92.2) 217 (75.6/70.2, 80.5) 234 (75.7/70.5, 80.4) Note. Numbers in parentheses are percentages and 95% CIs. may be related to higher priming volumes of ports in general. A 2-mL dose may be less effective because the total volume of the port reservoir and catheter lumen on average may exceed 2 ml, thereby decreasing the ability of the instilled dose to permeate the entire catheter lumen. A regimen of as many as two 2-mg doses of alteplase has demonstrated an acceptably good safety profile. The most serious adverse events reported after treatment were sepsis (0.4%), gastrointestinal bleeding (0.3%), and venous thrombosis (0.3%). Across both studies, only one serious adverse event (fever) was reported by the investigator to be attributable to treatment. There were no reported deaths, intracranial hemorrhage, embolic events, or adverse treatment-related bleeding events. In general, adverse bleeding events are the most common complication ascribed to thrombolytic therapy, particularly with direct systemic intravenous administration of high doses (eg, acute myocardial infarction, pulmonary embolism, acute ischemic stroke). The incidence of adverse bleeding events during catheter clearance was anticipated to be low because of the need for significantly lower doses, high fibrin specificity of alteplase, and lack of systemic exposure. Because alteplase is instilled into Table 3 Summary of Serious Adverse Events (SAEs) Reported within 30 Days of Alteplase Treatment Trial 1 (n 69) Trial 2 (n 995) Total (n 1,064) All causes of death ( 30 d) 1 (1.4) 24 (2.4) 25 (2.3) All drug-related SAEs Fever 0 (0.0) 1 (0.1) 1 (0.1) Major hemorrhage Intracranial 0 (0.0) 0 (0.0) 0 (0.0) Gastrointestinal 0 (0.0) 1 (0.1) 1 (0.1) Hematemesis 0 (0.0) 2 (0.2) 2 (0.2) Embolic events Pulmonary 0 (0.0) 0 (0.0) 0 (0.0) Arterial 0 (0.0) 0 (0.0) 0 (0.0) Thrombosis Deep vein thrombosis 0 (0.0) 2 (0.2) 2 (0.2) Catheter-related 0 (0.0) 1 (0.1) 1 (0.1) Septic events Fever 0 (0.0) 1 (0.1) 1 (0.1) Sepsis 0 (0.0) 4 (0.4) 4 (0.4) Allergic events 0 (0.0) 0 (0.0) 0 (0.0) Note. Numbers in parentheses are percentages. the catheter lumen and aspirated before catheter use, little if any alteplase is introduced into the circulation. Any alteplase introduced into the bloodstream is rapidly metabolized by the liver (plasma half-life, 5 minutes) (8). Because of the observation of septic episodes after alteplase treatment, caution should be exercised when treating catheters that are suspected to be infected. Instillation of alteplase could potentially release infected luminal contents into the circulation and trigger a systemic response. The selection of a 2-mg/2-mL dose was derived empirically through earlier work by Haire et al (5). The FDAapproved dose of UK for pulmonary

6 1204 Alteplase Treatment of Occluded Central Venous Catheters December 2002 JVIR embolism is 4,400 U/kg, which is equivalent to 308,000 U in a 70-kg patient. The approved dose of UK for catheter clearance is 5,000 U, which represents 1.6% of the approved dose for pulmonary embolism (rounded up to 2%). Haire et al (5) chose 2 mg because it is 2% of the approved alteplase dose for pulmonary embolism (100 mg). Fortuitously, the vast majority of catheters have priming volumes of 2 ml per lumen. Our study did not evaluate whether higher or lower doses of alteplase would have significantly altered the observed outcomes. The safety and efficacy of alteplase appear similar in children as in adults; however, the pediatric population was too small to allow us to draw any firm conclusions. Recently, Jacobs et al (9) reported the use of alteplase in managing occluded catheters in 228 children. The overall efficacy rate was 91% with no adverse events attributable to alteplase treatment. Currently, a Genentech-sponsored phase-iiib, multicenter, prospective, single-arm, openlabel FDA study is being conducted in the pediatric population (Cathflo Activase in Pediatrics Study [CAPS]). The study population will consist of approximately 300 pediatric patients, including 50 in the subgroup of patients younger than 2 years of age and/or smaller than 10 kg. Trials 1 and 2 excluded patients with hemodialysis catheters. The design of the dosing protocols were based on Haire et al s studies that used a nondialysis, predominately oncology population (5). Alteplase (2 mg/2 ml) has been used successfully for treating dysfunctional hemodialysis catheters. A meta-analysis of the published medical literature from 1996 to 2000 was performed by Clase et al (10). Studies of catheter instillation with 1 2 mg of alteplase per lumen reported short-term success in 83% 98% of uses. In Clase et al s review (10), randomized comparisons suggested that 1 mg alteplase was likely equivalent in thrombolytic potency to 36,000 U urokinase and concluded that 1 2mg alteplase (per lumen) is a suitable dose for hemodialysis catheters. A 2-mg/ 2-mL dose of alteplase has also been used as an alternative to standard heparin in priming ( locking ) hemodialysis catheters. Schenk et al (11) compared 2,000 U heparin to 2 mg alteplase as a priming agent over an 8-month period with use of a crossover design. Alteplase was superior to heparin in maintaining higher flow rates (P.0001), lower venous pressures (P.0001), and higher arterial pressures (P.0002), with fewer clotting episodes or need for thrombolytic interventions. No serious adverse events related to alteplase treatment were recorded. Therefore, based on the emerging evidence, it seems probable that alteplase will demonstrate good safety and efficacy profiles in prospective studies of dialysis devices. Although interventional radiologists commonly use real-time fluoroscopy to confirm tip placement of the catheter, in this study, no radiographic imaging was performed. The number of catheters with occlusions secondary to a malpositioned tip cannot be determined from these trials. Occluded catheters that had been implanted less than 48 hours before enrollment were excluded because, in our opinion, these devices have a higher likelihood of nonthrombotic etiologies (eg, malpositioning, kinking). Our goal was to perform a study that would duplicate decision-making and treatment in the outpatient setting, in which access to radiography or fluoroscopy is not readily available. In conclusion, a 2-mg/2-mL-per-lumen regimen of alteplase for restoring flow to a dysfunctional catheter is safe and efficacious based on the prospective, multicenter data in more than 1,000 patients. Acknowledgment: The COOL Investigators are as follows: Jeffrey W. Andrey, MD, Scripps Clinic, La Jolla, CA; John F. Angle, MD, University of Virginia, Charlottesville, VA; Joseph M. Carriciu, MD, J.T. Mather Memorial Hospital, Port Jefferson, NY; Carlos M. decastro, MD, Duke University, Durham, NC; Steven R. Deitcher, MD, Cleveland Clinic Foundation, Cleveland, OH; Solveig G. Ericson, MD, West Virginia University Hospital, Morgantown, WV; Marc S. Ernstoff, MD, Dartmouth Hitchcock Medical Center, Lebanon, NH; Mark R. Fesen, MD, Hutchinson Clinic, Hutchinson, KS; George A. Fisher, Jr, MD, PhD, Stanford University, Stanford, CA; Andrew. S. Freiberg, MD, Milton S. Hershey Medical Center, Hershey, PA; Paul S. Gaynon, MD, Children s Hospital, Los Angeles, CA; Renuka Gera, MD, Michigan State University, East Lansing, MI; Stuart L. Goldberg, MD, Northern New Jersey Cancer Center, Hackensack, NJ; Maria A. R. Gomes, MD, University of Minnesota Health Center, Minneapolis, MN; James B. Gosset, MD, Wisconsin Heart and Vascular Clinic, Milwaukee, WI; Jeffrey S. Groeger, MD, Memorial Sloan Kettering Cancer Center, New York, NY; Atul K. Gupta, MD, Roswell Park Cancer Institute, Buffalo, NY; William D. Haire, MD, University of Nebraska Medical Center, Omaha, NE; Paul B. Harrison, MD, Wesley Medical Center, Wichita, KS; Bruce P. Himelstein, MD, Children s Hospital, Philadelphia, PA; Paul J. Hesketh, MD, St. Elizabeth s Medical Center, Boston, MA; Douglas N. Homnick, MD, Michigan State University, East Lansing, MI; Jeffrey D. Hord, MD, Children s Hospital Medical Center, Akron, OH; Michael O. Huntington, MD, Eastern Idaho Regional Medical Center, Idaho Falls, ID; Jainulabdeen Ifthikharuddin, MD, University of Rochester, Rochester, NY; David H. Irwin, MD, Alta Bates Comprehensive Cancer Center, Berkeley, CA; James W. Jaffe, MD, Lehigh Valley Hospital, Allentown, PA; Mohammad Jahanzeb, MBBS, Comprehensive Cancer Research Group, Boca Raton, FL; Nalini Janakiraman, MD, Henry Ford Hospital, Detroit, MI; Jan Jansen, MD, PhD, Indiana Blood and Marrow Transplant, Indianapolis, IN; L. Wayne Keiser, MD, Redwood Regional Medical Group, Santa Rosa, CA; John A. Kerner, Jr, MD, Stanford University, Stanford, CA; Paul M. Kiproff, MD, Allegheny General Hospital, Pittsburgh, PA; Michael F. Knox, MD, St. Vincent s Infirmary Medical Center, Little Rock, AR; Sophie M. Lanzkron, MD, Southwest Texas Methodist Hospital, San Antonio, TX; Howard Levy, MBBS, University of New Mexico, Albuquerque, NM; Jane L. Liesveld, MD, University of Rochester, Rochester, NY; Steven P. Lipman, MD, Englewood Hospital, Englewood, NJ; John Lister, MD, Western Pennsylvania Hospital, Pittsburgh, PA; Paul F. Mansfield, MD, MD Anderson Cancer Center, Houston, TX; Fred S. Marcus, MD, Sequoia Hospital, Redwood City, CA; Geno J. Merli, MD, Thomas Jefferson University Hospital, Philadelphia, PA; Gerald P. Miletello, MD, Hematology/Oncology Clinic, Baton Rouge, LA; Joanne E. Mortimer, MD, Washington University Banard Cancer Center, St. Louis, MO; Kenneth D. Murphy, MD, SUNY Health Science Center, Syracuse, NY; Hyman B. Muss, MD, Fletcher Allen Health Care, Burlington, VT; Ellis J. Neufield, MD, PhD, Children s Hospital, Boston, MA; Michael L. Nieder, MD, Rainbow Babies and Children s Hospital, Cleveland, OH; John L. Nosher, MD, UMDNJ Robert Wood Johnson, New Brunswick, NJ; Timothy J. O Rourke, MD, Grand Rapids Clinical Oncology Program, Grand Rapids, MI; David S. Owens, MD, St. Joseph s Hospital, Atlanta, GA; Steven W. Papish, MD, Morristown Memorial Hospital, Morristown, NJ; Matthew A. Passalacqua, DO, Forum Health, Youngstown,

7 Volume 13 Number 12 Semba et al 1205 OH; Janak A. Patel, MBBS, University of Texas Galveston, Galveston, TX; Scott E. Patrick, MD, Lawrence Memorial Hospital, Lawrence, KS; Jay T. Peterson, MD. Oncology and Hematology Associates, Kansas City, MO; Alvaro A. Pineda, MD, Mayo Clinic, Rochester, MN; Luis A. Pineiro, MD, Baylor University Medical Center, Dallas, TX; Dennis A. Priebat, MD, Washington Hospital Center Cancer Institute, Washington, DC; Donald J. Ponec, MD, Tri-City Medical Center, Oceanside, CA; Kanti R. Rai, MD, North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; David A. Rinaldi, MD, Louisiana Oncology Associates, Lafayette, LA; William J. Romano, MD, William Beaumont Hospital, Royal Oak, MI; Hans-Christoph Rossbach, MD, All Children s Hospital, St. Petersburg, FL; Eric K. Rowinsky, MD, Cancer Therapy and Research Center, San Antonio, TX; Jeffrey R. Rubin, MD, Forum Health, Youngstown, OH; Patrick E. Sewell, Jr, MD, University of Mississippi, Jackson, MI; Violet Shen, MD, Children s Hospital, Orange, CA; Robert J. Schulman, MD, Baylor College of Medicine, Houston, TX; Daniel A. Siragusa, MD, Shands Jacksonville University Medical Center, Jacksonville, FL; David B. Sokol, MD, Medical Center at Princeton, Princeton, NJ; Peter N. Swischuk, MD, Shands Jacksonville University Medical Center, Jacksonville, FL; Mubin I. Syed, MD, Mercy Medical Center, Springfield, OH; Kenneth E. Symington, MD, Medical Imaging Center, Syracuse, NY; Cameron K. Tebbi, MD, Tampa Children s Hospital at St. Joseph s, Tampa, FL; Terry A. Vik, MD, James Whitcomb Riley Hospital for Children, Indianapolis, IN; David M. Waterhouse, MD, MPH, Oncology/Hematology Care, Inc., Cincinnati, OH; James K. Weick, MD, JFK Medical Center, Lake Worth, FL; Mark Weiss, MD, Hurley Medical Center, Flint, MI; Eric H. Westin, MD, West Virginia University Hospital, Morgantown, WV; Mark H. Wholey, MD, Pittsburgh Vascular Institute, Pittsburgh, PA; Gerald Zemel, MD, Miami Cardiac and Vascular Institute, Miami, FL. References 1. Reeves AR, Seshadri R, Trerotola SO. Recent trends in central venous catheter placement: a comparison of interventional radiology with other specialties. J Vasc Interv Radiol 2001; 12: Silberzweig JE, Sacks D, Khorsandi AS, Bakal CW. Reporting standards for central venous access. J Vasc Interv Radiol 2000; 11: US Food and Drug Administration Med Watch. Important drug warning: safety information regarding use of Abbokinase (Urokinase). Available at: htm. Accessed September US Food and Drug Administration Med Watch. Important safety information letter: dear hospital pharmacy and physician (AstraZeneca, Inc.), December 10, Available at: strept.htm. Accessed September Haire WD, Atkinson JB, Stephens LC, Kotulak GD. Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: a double-blinded, randomized trial. Thromb Haemost 1994; 72: Ponec D, Irwin D, Haire WD, Hill PA, Li X, McCluskey ER. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial. J Vasc Interv Radiol 2001; 12: Deitcher SR, Fesen MR, Kiproff PM, et al. Safety and efficacy of alteplase for restoring function in occluded central venous catheters. J Clin Oncol 2002; 20: Tanswell P, Tebbe U, Neuhaus KL, Glasle-Schwarz L, Wojick J, Seifried E. Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol 1992; 19: Jacobs BR, Haygood M, Hingl J. Recombinant tissue plasminogen activator in the treatment of central venous catheter occlusion in children. J Pediatr 2001; 139: Clase CM, Crowther MA, Ingram AJ, Cina CS. Thrombolysis for restoration of patency to hemodialysis central venous catheters: a systematic review. J Thromb Thrombolysis 2001; 11: Schenk P, Rosenkranz AR, Wolfl G, Horl WH, Traindl O. Recombinant tissue plasminogen activator is a useful alternative to heparin in priming Quinton Permcath. Am J Kidney Dis 2000; 35: