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PURPOSE: Central venous access devices (CVADs) are a mainstay of current medical therapy but often become occluded by
thrombus. Tissue plasminogen activator (alteplase), at a dose of 2 mg per 2 mL, has been shown to be effective in restoring
flow to catheters proven by radiographic contrast injection to be occluded by thrombus. The purpose of this double-blind
placebo-controlled multicenter trial was to determine the efficacy of alteplase in occluded catheters without earlier contrast
injections or radiographic examinations.
MATERIALS AND METHODS: Patients were eligible for inclusion if blood could not be withdrawn from their catheter after
a period of normal function of at least 48 hours. Single or multiple catheters, peripherally inserted central catheters, catheters
with valves, and implanted ports were eligible; catheters used for hemodialysis were not included. Patients were randomly
assigned to one of two groups. In one group, patients received a first dose of 2 mg alteplase followed, if needed, by a second
dose of 2 mg alteplase and a third dose of placebo. The other group received placebo first followed by one 2-mg dose of
alteplase and then a second, if needed. Each dose was allowed to dwell for 2 hours and ability to withdraw blood from the
catheter was reassessed. The endpoint was restoration of the ability to withdraw and infuse through the catheter. One
hundred forty-nine patients were randomized: 74 received placebo first, 75 received alteplase first.
RESULTS: After the first 2-hour treatment, function was restored to 74% in the alteplase arm and 17% in the placebo arm
(P < .0001 compared to placebo). After one or two treatments, function was restored in 90% of patients. There were no serious
study-drug±related adverse events, no intracranial hemorrhage, no major hemorrhage, and no embolic events.
CONCLUSION: Infusion of alteplase appeared to be safe and effective in restoring flow to occluded catheters without need
for pretreatment radiographic evaluation.
Index terms: Central venous access · Thrombolysis · Tissue-type plasminogen activator · Urokinase
CENTRAL venous access devices and are used for infusion of chemo- other treatments requiring central ve-nous
(CVADs) have become increasingly therapy, blood products, pain medica- access. Unfortunately, these cath-eters
integral to modern medical therapy, tion, nutritional support, pressors, and become occluded as a result of thrombosis
at a rate that has been es-timated at 25%
per year (1). Catheter thrombosis is
quickly followed by
From the Division of Radiology (D.P.), Tri-City Medical final revision received April 10; accepted April 13. clinical thrombosis (catheter-related
Center, Oceanside; Departments of Medi-cine and Supported by Genentech, Inc., South San Francisco, CA. venous thrombosis or obstruction) in a
Oncology/Hematology (D.I.), Alta Bates Hospital, Address correspondence to E.R.M., Genentech, Inc., 1
Oakland, California; Division of Oncology and DNA Way, M/S 59, South San Francisco, CA 94080; E-
large number of patients (2).
Hematology (W.D.H.), Nebraska Medical Cen-ter, mail: tmc@gene.com Treatment of occluded CVADs had
Omaha, Nebraska; and Cardiovascular Clinical Unit 1 These authors have disclosed the existence of a been performed with use of urokinase
(P.A.H., X.L., E.R.M.), Genentech, Inc., South San potential conflict of interest.
Francisco, California. The COOL Investigators are listed
(3,4). Since the withdrawal of uroki-nase
at the end of this article. Received Decem-ber 19, 2000; from the market, other treatment options
revision requested January 16, 2001; © SCVIR, 2001 have become necessary. Re-
951
August 2001 JVIR
952 · Alteplase for Catheter Clearance
combinant tissue plasminogen activa-tor Withdrawal dysfunction was defined as domization); 74 in the placebo-first group
(alteplase) has previously been shown to the inability to withdraw 3 mL of blood. and 75 in the alteplase-first group. One
be very effective in restoring flow to Patients were excluded if it was not subject was treated (with alteplase first)
dysfunctional catheters that were proven possible to infuse fluids at the vol-ume but not formally ran-domized and was
by radiographic contrast injection to be necessary to infuse study drug into the therefore not in-cluded in the intent-to-
occluded by thrombus CVAD, if the CVAD had been inserted treat analysis but is included in the ªas-
(5). However, almost 40% of dysfunc- less than 48 hours before ran-domization, treatedº analysis. There were 10 patients
tional catheters are not occluded by or if the occlusion had been discovered ran-domized but not treated (four in pla-
thrombus (6); rather, they are ob-structed more than 24 hours before randomization. cebo first and six with alteplase first). The
by mechanical problems such as Also excluded were patients younger than catheter types randomized in the trial
migration and malposition of the 2 years of age, who weighed less than 10 included 19 single-lumen cathe-ters, 72
intravascular segment or kinking of the
kg, who had catheters with any evidence double-lumen catheters, 12 tri-ple-lumen
subcutaneous segment of the catheter.
Because clinical presentation is not of mechanical or nonthrombotic occlu- catheters, and 46 ports. A total of 26 sites
specific for the cause of obstruc-tion, sion, or who had received any fibrino- enrolled patients in the trial (17 enrolled
radiographic contrast material in-jection is lytic agent within 24 hours of 1± 4 patients, six en-rolled 5±10, one
believed necessary to deter-mine the randomization. Subjects who, in the enrolled 13, one en-rolled 23, and one
cause of obstruction and the type of opinion of the investigator, were at high enrolled 25). Enroll-ment occurred from
therapy necessary (thrombo-lytic or risk for bleeding events or em-bolic November 1999 through May 2000 with
mechanical repositioning) (6). complications, or had a known condition the last patient undergoing follow-up in
Unfortunately, contrast injection stud-ies for which bleeding consti-tutes a June 2000. Baseline and demographic
are often not readily available in clinical significant hazard, were also excluded at data are displayed in Table 1.
practice. Consequently, throm-bolytic the discretion of the indi-vidual
therapy is often administered empirically investigators.
to dysfunctional catheters. Consequently, Baseline studies consisted of a med- Study Procedure
we evaluated the abil-ity of alteplase to ical history, physical examination, and
restore both infusion and withdrawal CVAD history, including the date of Subjects were randomly assigned by
function in dysfunc-tional catheters CVAD insertion and the date the CVAD an interactive voice randomization service
without earlier radio-graphic contrast to one of two groups. Each group had one
was last known to function (withdrawal
material injection. opportunity to be treated with placebo and
and infusion function). An assessment of
CVAD function was performed and two oppor-tunities to be treated with study
MATERIALS AND METHODS recorded at baseline. In subjects with drug (Table 2). In one arm, the first study
multiple-lumen cath-eters, only one lumen drug vial contained placebo and the
Trial Design second and third vials contained ac-tive
of the catheter (chosen at the discretion of
This trial was a multicenter, dou-ble- the inves-tigator at the site) was used alteplase. In the other arm, the first and
blind, placebo-controlled compari-son of through-out the study for assessments of second study drug vials con-tained active
the rates of restoration of cath-eter function. Withdrawal function was de- alteplase and the third contained placebo.
function after treatment for 2 hours with termined by the following method: An
either alteplase (2 mg in 2 mL) or placebo empty 10-mL syringe was attached to the After the first vial of study drug was
(patients weighing be-tween 10 and 30 kg catheter, forming an airtight seal. The instilled and allowed to dwell for 120
were given a dose equal to 110% of the syringe plunger was pulled back to the 5- minutes, function was reassessed to
internal catheter volume). The secondary mL mark to attempt to with-draw blood. determine if both withdrawal and infusion
goal of the study was to determine the rate The CVAD was consid-ered to have function were present. If function was
of catheter function restoration after one withdrawal function if at least 3 mL of successfully restored, the patient exited
or two treatments with alteplase. Safety fluid (blood and any previously infused the study. Patients who did not have
endpoints of the study included the rates fluids) filled the syringe. Infusion successful restoration of function were
of study-drug±related intra-cranial function was deter-mined by the then treated by instilla-tion of the second
hemorrhages, major hemor-rhage, following method: A 10-mL syringe with vial of study drug that was again allowed
embolic events, and all drug-related 5 mL normal sa-line solution was attached to dwell for 120 minutes. Function was
serious adverse events. to the cath-eter to gently infuse the saline again as-sessed at the end of the second
solution. The CVAD was considered to 120-minute period. Patients who did not
have infusion function if the entire have successful restoration of function
Patient Population contents of the syringe could be in-fused after the second treatment were then
without significant resistance. treated by instillation of the third vial of
Patients were eligible if they were
clinically stable and had a dysfunc-tional study drug that was again allowed to
indwelling long-term CVAD (peripherally dwell for 120 minutes. Function was
Baseline Characteristics
inserted central cathe-ters, catheters with finally assessed at the end of the third
valves, and im-planted ports were A total of 150 subjects were en-rolled 120-minute period.
allowed; catheters used for hemodialysis in the study (149 were random-ized; one All adverse events that met ªgood
were not). was treated without ran- clinical practiceº criteria for ªseriousº
Volume 12 Number 8 Ponec et al · 953
plasminogen in the clot, systemic treatment was well tolerated and no central venous catheters. J Clin Oncol
thrombolysis can be avoided. Addition- adverse safety events were reported. 1985; 3:710 ±717.
ally, because alteplase is not easily Therefore, alteplase appears to be safe and 2. Tolar B, Gould JR. The timing and
washed off clots, unlike non±fibrin- effective for restoration of flow to sequence of multiple device-related
dysfunctional CVADs. complications in patients with long term
binding thrombolytic drugs, it is likely
indwelling Groshong catheters. Cancer
able to maintain a local effect and thereby 1996; 78:1308 ±1313.
require a lower (safer) total dose for Acknowledgment: the participants in the
COOL Efficacy Trial were: Jeffrey W. An-drey, 3. Hurtubise MR, Bottino JC, Lawson M,
successful restoration of catheter function. MD, Scripps Clinic, La Jolla, CA; John F. McCredie KB. Restoring patency of
Angle, MD, Department of Radiology, occluded central venous catheters. Arch
The current study did not include cath- Surg 1980; 115:212±213.
University of Virginia Health System, Char-
eters that were used for hemodialysis. lottesville, VA; Joseph M. Carrucciu, MD, J.T. 4. Haire WD, Lieberman RP, Lund GB, Ed-
However, catheters of similar type (tun- Mather Memorial Hospital, Port Jefferson, NY; ney J, Wieczorek BM. Obstructed cen-tral
neled 14-F apheresis catheters) were in- Carlos M. de Castro III, MD, Duke Uni-versity venous cathetersÐrestoring function with a
cluded in the trial and showed efficacy Medical Center, Morris Cancer Clinic, 12-hour infusion of low-dose urokinase.
rates similar to those seen in the overall Durham, North Carolina; George A. Fisher, Jr, Cancer 1990; 66:2279 ±2285.
study. Although numerous reports sug- MD, PhD, Departments of Medicine and 5. Haire WD, Atkinson JB, Stephens LC,
gest that alteplase may be safe and effec- Oncology, Stanford University Hospital, Palo Kotulak GD. Urokinase versus recom-
Alto, California; Paul S. Gaynon, MD, binant tissue plasminogen activator in
tive for restoration of function to catheters thrombosed central venous catheters: a
used in hemodialysis (11±14), no direct Children's Hospital Los Angeles, Los Ange-les,
California; Maria de Lourdes A.R. Gomes, double-blinded, randomized trial. Thromb
measure was made in the current study. Haemost 1994; 72:543±547.
MD, Department of Radiology, Uni-versity of
The safety of alteplase in the current Minnesota Academic Health Cen-ter, 6. Stephens LC, Haire WD, Kotulak GD. Are
study was encouraging. Although the Minneapolis, Minnesota; William D. Haire, clinical signs accurate indicators of the
doses of alteplase used in the current MD, University of Nebraska Medical Center, cause of central venous catheter oc-
study are between only 2%± 4% (2± 4 Omaha, Nebraska; Bruce P. Himel-stein, MD, clusions? J Parenteral Enteral Nutr 1995;
mg) of the usual dose for the treatment of Children's Hospital of Philadel-phia, 19:75±79.
acute myocardial infarction, case studies Philadelphia, Pennsylvania; David H. Irwin, 7. Atkinson JB, Bagnall HA, Gomperts E.
are unclear as to whether there is a dose of MD, Alta Bates Comprehensive Can-cer Investigational use of tissue plasmino-gen
Center, Berkeley, California; Jan Jansen, MD, activator (t-PA) for occluded central venous
alteplase below which there are no safety
PhD, Indiana Blood and Marrow Trans- catheters. JPEN 1990; 14:310 ±311.
issues. Because of the lim-ited number of
plantation, Indianapolis, Indiana; Sophie M. 8. Choi M, Masicotte MP, Marzinotto V,
subjects in the current study, only limited Chan AKC, Andrew M. Use of tissue
Lanzkron, Texas Transplant Institute at
safety conclusions can be drawn. More Southwest Texas Methodist Hospital, San plasminogen activator to clear blocked
detailed safety con-clusions await the Antonio, Texas; Jane L. Liesveld, MD, Uni- central venous lines in pediatric pa-tients:
results of the ongoing COOL 2 safety versity of Rochester Medical Center, Roches- a prospective cohort study [abstract].
trial. ter, New York; Steven P. Lipman, MD, Blood 1999; 94(suppl 1)25a.
The current study has several Englewood Hospital and Medical Center, 9. Davis SN, Vermeulen L, Banton J,
limitations. Because angiograms were not Englewood, New Jersey; John Lister, MD, Schwartz BS, Williams EC. Activity and
performed, no conclusions can be reached Division of Hematology/Oncology, Western dosage of alteplase dilution for clearing
as to the efficacy of restora-tion of flow Pennsylvania Hospital, Western Pennsylva-nia occlusions of venous-access devices. Am J
based on the cause of cath-eter Cancer Institute, Pittsburgh, Pennsylva-nia; Health Syst Pharm 2000; 57:1039 ±1045.
malfunction. Additionally, cathe-ters that Paul F. Mansfield, MD, The University of
Texas M.D. Anderson Cancer Center, Hous- 10. Isaac BF. Efficacy of cryopreserved
had been occluded for less than 48 hours ton, Texas; Geno J. Merli, MD, Thomas Jef- alteplase for declotting thrombosed central
were not studied in the current study ferson University Hospital, Philadelphia, catheters. Ann Pharmacother 2000;
because they are more likely to be Pennsylvania; Gerald P. Miletello, MD, He- 34:533±534.
occluded as a result of mechanical matology/Oncology Clinic, Baton Rouge, 11. Hannah A, Buttimore AL. Thromboly-sis
problems. Finally, the safety of any Louisiana; Hyman B. Muss, MD, Medical of blocked hemodialysis catheter us-ing
thrombolytic therapy cannot be Center Hospital of Vermont, Burlington, recombinant tissue-type plasmino-gen
established with the limited number of Vermont; Ellis J. Neufeld, MD, PhD, Chil- activator. Nephron 1991; 59:517±518.
patients treated in the cur-rent study; dren's Hospital, Boston, Massachusetts; Mi- 12. Paulsen D, Riesoether A, Aasen M, Fau-
therefore, an additional study establishing chael L. Nieder, MD, Rainbow Babies and chald P. Use of tissue plasminogen ac-
the safety of 1,000 patients treated with 2 Children's Hospital, Cleveland, Ohio; Timo-thy tivator for reopening of clotted dialysis
mg alteplase was conducted in parallel J. O'Rourke, MD, Grand Rapids Clinical catheters. Nephron 1993; 64:468 ± 470.
Oncology Program, Grand Rapids, Michi-gan; 13. Schenk P, Rosenkranz AR, Wolfl G, Horl
with this study and will be reported
Donald J. Ponec, MD, Tri-City Medical Center W, Traindl O. Recombinant tis-sue
elsewhere. Radiology Department, Oceanside, California; plasminogen activator is a useful
In summary, this study has shown a Dennis A. Priebat, MD, Washing-ton Hospital alternative to heparin in priming Quin-ton
profound benefit of alteplase (at a dose of Center, Washington, DC; Kanti R. Rai, MBBS, Permcath. Am J Kidney Dis 2000; 35:130
2 mg in 2 mL) compared to placebo for North Shore±Long Island Jew-ish Medical ±136.
the restoration of flow to dysfunctional Center, New Hyde Park, New York. 14. Daeihagn P, Jordan J, Chen J, Rocco M.
CVADs. This effect was seen in a Efficacy of tissue plasminogen activa-tor
clinically selected population of patients References administration on patency of hemo-
and did not require angio-graphic 1. Lokich JJ, Both A, Benotti P. Compli- dialysis access catheters. Am J Kidney Dis
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