The Efficacy of Reteplase in the Treatment of Thrombosed Hemodialysis Venous Catheters

The Efficacy of Reteplase in the Treatment of Thrombosed Hemodialysis Venous Catheters

Debra Castner

Tunneled cuffed venous catheters are the method of choice for temporary venous access in hemodialysis patients (National Kidney Foundation, 1997). However, maintaining patency by preventing and/or lysing thromboses in catheters remains a challenge (Northsea, 1996). The National Kidney Foundation (NKF)/DOQI (Dialysis Outcomes Quality Initiative) Guidelines for Vascular Access recommended the use of urokinase to resolve catheter thromboses before other, more invasive and costly techniques are employed (National Kidney Foundation [NKF], 1997). In 1999, use of urokinase declined due to quality assurance issues (Food and Drug Administration [FDA], 2000, July 13). Although the NKF Guidelines limit the use of venous catheters to less than 10% of the patient population, dialysis centers continue to need an alternative, safe, and cost-effective thrombolytic for the prevention and treatment of venous catheter thrombosis (NKF, 1997).

Thrombolytic agents catalyze the conversion of plasminogen to plasmin, which in turn dissolves the thrombus by degrading the fibrin matrix that binds the platelets and red blood cells (Semba et al., 2000). These agents are used in the treatment of acute myocardial infarction, acute ischemic stroke, pulmonary embolism, catheter clearance, and acute ischemic limbs (Gusto III Investigators, 1997; Haire, Atkinson, Stephens, & Kotulak, 1994; National Institute of Neurological Disorders and Stroke, 1995; Ouriel, Veith, & Sasahara, 1998; Tebbe et al., 1999).

Both reteplase and alteplase (t-PA) are tissue-plasminogen activators. Reteplase is a deletion mutein of t-PA and does not contain the kringle I, finger, and epidermal growth factor domains found on wild type t-PA and alteplase (Martin et al., 1993). Removal of these domains gives reteplase a longer plasma half-life and a lower affinity for fibrin-bound plasminogen compared with alteplase and enhances its ability to penetrate the clot (Fischer & Kohnert, 1997). The plasma half-life of reteplase is 13 to 16 minutes, comparable to the plasma half-life of urokinase of 20 minutes or less (Abbott Laboratories, 1999; Centocor, Inc., 2000). In contrast, alteplase has a plasma half-life of less than 6 minutes (Genentech, Inc., 1999). The relation of the plasma half lives of these products to their biological half lives has not been well studied in vivo. However, the clinical trials comparing the usage of alteplase vs reteplase for treatment of myocardial infarction, while supporting the faster lysis of clot with reteplase, did not show any differences in clinical outcomes such as mortality, intracranial hemorrhage, major bleeding, or allergic reactions (Bode et al., 1996; Centocor, Inc., 2000; Smalling et al., 1995). Because of its longer plasma half-life compared to alteplase, reteplase is administered as a double-bolus dose to treat patients with myocardial infarction (GUSTO III Investigators, 1997). This dosing strategy also has been used to treat pulmonary embolism (Tebbe et al., 1999).

Reteplase is reconstituted only in sterile water for injection, USP (without preservatives) to achieve a final concentration of 1 U/1 ml and remains biologically active for at least 8 hours (Centocor, Inc., 2000). Aliquots of reteplase can be frozen at -8 C at this concentration (1 U/1 ml) for up to 26 weeks without a loss of activity (Centocor, Inc, 2000). Since reteplase does not contain bacteriostatic agents, it should be reconstituted immediately before use if freezing is not available.

Reteplase was chosen as an alternative to urokinase due to its successful use in thrombolysis of arteriovenous grafts performed by the interventional radiologist to whom the dialysis center referred (Gibbens, DePalma, Albanese, Castner, & Troilo, 2000). Advantages offered by reteplase include: (a) perceived shorter dwell time (30 minutes versus 60 minutes to 120 minutes recommended when using alteplase); (b) evidence of better clot penetration compared to alteplase; and (c) a similar half-life to urokinase (Abbott Laboratories, 1999; Fischer & Kohnert, 1997).

Dialysis patients at both of our outpatient dialysis centers often had venous catheters as a “bridge” access or as their sole access. Because of this high percentage of dialysis catheters adequate function was important. A replacement for urokinase was desired by the nursing and medical staff to avoid delays in providing dialysis treatment when catheters malfunctioned.

Literature Review

Numerous research groups have studied the use of thrombolytic therapy in dialysis venous catheter clearance. Positive outcomes defined as improved flow, increased arterial pressure, and the prevention of occlusions have been demonstrated over the past 5 years with high-dose intradialytic urokinase, a combination of urokinase installation and frequent heparin flushes, and intrathrombotic heparin admixed with urokinase (Harrell, Kozlowski, Katz, & Hanks, 1996; Ray, Shenoy, McCarthy, Broderick, & Kaufman, 1999; Twardowski, 1998). As quality assurance issues with urokinase continued, the FDA suggested considering alteplase, streptokinase, anistreplase, or reteplase as alternative thrombolytics, although there were few studies to support their use for catheter clearance (FDA, 2000, July 13). None of these agents, with the exception of streptokinase (Streptase[R], AstraZeneca), is currently approved for catheter clearance.

Haire et al. (1994) compared the efficacy of urokinase with alteplase in clearing thrombosed central venous catheters used in an oncology population. After administration of a 2-mg dose of alteplase, patients showed a significant improvement in patency compared with urokinase as demonstrated by the ability to withdraw blood or infuse solution into the catheter without resistance. Similarly, Valji, Bookstein, and Roberts (1995) showed success with alteplase in clotted dialysis grafts using the pulse-spray pharmaco-mechanical technique. Based on these and other studies, the Advisory Panel on Catheter-Directed Thrombolytic Therapy, organized by the Society for Cardiovascular and Interventional Radiology, recommended a 2 mg (1 mg/1 ml) dose of alteplase for the clearance of each lumen of an occluded central venous catheter with a dwell time of up to 2 hours (Semba et al., 2000).

The use of reteplase in catheter clearance has not been previously studied. Aside from alteplase, the only other currently available thrombolytic agent studied in catheter clearance is streptokinase and there are continued concerns of allergic reactions and antistreptokinase antibody formation with the use of this agent (Astra Zeneca LP, 1998; Buchalter et al., 1992; Chesser & Mauro, 1994; Elliot et al., 1993; Lee, 1995; Singh & Hart, 1994). Reteplase has demonstrated a superior reperfusion profile and comparable clinical efficacy when compared to alteplase in both acute myocardial infarction and pulmonary embolism (Bode et al., 1996; Gusto III Investigators, 1997; Smalling et al., 1995; Tebbe et al., 1999). Investigation into the use of reteplase for catheter clearance as a thrombolytic is warranted based on its pharmacological profile and the benefit of having alternative drug choices when faced with potential future shortages or drug recalls.

Methods

The use of reteplase was reviewed and approved by the center’s medical and clinical director prior to use. The nursing staff was educated on how to reconstitute, freeze, administer reteplase, and record results via unit inservice programs and written communication. Informed, signed patient consent was obtained prior to the first dose. Patients who opted not to receive reteplase were referred to the vascular surgery or the interventional radiology departments. During the study period, reteplase was the only thrombolytic used.

Patients who received hemodialysis at one of two for-profit, outpatient, satellite hemodialysis centers and had signs of catheter failure, were at risk for catheter failure, and who gave written consent were selected for inclusion in the study. Signs of catheter failure included no or low arterial or venous flow from the catheter and high venous or arterial pressures, defined as venous resistance [is greater than] 350 mmHg, arterial resistance -250 mmHg, or arterial blood flow rate (BFR) [is less than] 250 cc/min.

Dialysis venous catheters used at both facilities were soft, polyurethane, double-lumen, and cuffed (Tesio[R] or Hemo-Cath[R], Medical Components, Inc., Harleysville, PA or Permcath[R], Kendall/Sherwood Services AG, Mansfield, MA). Catheter placement was exclusively in the internal jugular vein, except for one patient (transhepatic approach). Between the two dialysis centers, the total percentage of patients with indwelling catheters was 28%; 37.7% in the first center (n=70) and 18.3% in the second (n=188). Since patients were often transferred from one unit to the next, as space became available, the data sets were combined.

Dosing for reteplase was based on a ratio of clinical dosing of reteplase to alteplase used for the treatment of acute myocardial infarction, 1:5 (alteplase, 100 mg; reteplase, 20 U) (Centocor, Inc., 2000; Genetech, Inc., 1999). The selected dose for reteplase was 0.4 U/lumen, based on the dose of 2 mg/lumen of alteplase used at the time of this study. Information on stability, freezing, thawing, and activity comparisons was provided by Centocor, Inc., upon request. The doses were reviewed and approved by the medical director of the dialysis center.

Procedure

Vials of reteplase (10 U) were reconstituted by the nursing staff under aseptic conditions using sterile water for injection without preservatives, USP. The solution (0.4 U/0.4 ml) was withdrawn into a 3 cc syringe, labeled, dated, and then frozen in 0.4 U/0.4 ml aliquots at -8 C. The aliquots were kept frozen for up to 30 days. Required doses were removed minutes prior to use to allow for thawing and further dilution with 0.9% normal saline solution, USP. The aliquots were further diluted to provide volumes of solution that would fill the catheter lumen (ranging from 1.3-1.6 ml). Studies have been conducted examining the stability of diluting 10 U of reteplase in volumes up to 1000 ml of 0.9% normal saline solution, USP (Centocor). These studies indicate that the 0.01 U/ml reteplase solution is both physically and biochemically stable when stored at room temperature for up to 24 hours. Heparin in the catheter was withdrawn prior to instillation of reteplase. If staff could not aspirate the heparin from the catheter, an attempt to gently instill reteplase was made. Interactions between heparin and thrombolytic drags have been suggested in much higher doses. Since patients would be sent to radiology for a catheter change if the instillation was not successful, it was felt to be a minimal risk to add the dose of reteplase to the heparin dose used (5000 U/lumen). No drug was refrozen after being initially thawed. Based on the procedure recommended for urokinase, reteplase was instilled by intravenous push into the dialysis catheter. The catheter was clamped, and the medication dwelled for 20 to 30 minutes and then was aspirated by syringe and discarded (Abbott Laboratories, 1999; Northsea, 1996). Reteplase was not used if resistance was encountered during instillation of the medication. After the reteplase solution was aspirated, the catheter was checked for evidence of flow. If flow was not restored, the procedure was repeated once. After the second instillation, if flow still was not present, other treatment options were considered. Options included a thrombolytic infusion at the dialysis center, high dose thrombolysis in the radiology suite, catheter stripping, or most commonly, catheter replacement.

In patients with a history of prior catheter failure, reteplase was instilled prophylactically after the last dialysis treatment of the week. Patients were discharged from the center and the drug was removed prior to the next dialysis treatment (1 to 2 days later).

Efficacy results were prospectively documented for each dose on a worksheet (see Figure 1). Patient charts and associated worksheets were reviewed by the author and analyzed for specific outcomes. Efficacy results were reported to the dialysis unit medical director on a bimonthly basis. Successful outcome was defined as the ability of reteplase to restore patency of the dialysis catheter and allow the patient to complete the hemodialysis treatment. Successful outcomes included a blood flow rate of 250 cc/min or greater, reduction in arterial or venous pressure to allow completion of treatment, or patency of a catheter lumen in a no flow condition. Unsuccessful outcomes were no improvement in blood flow or pressure readings, or if the patient was sent to a radiologist or surgeon for evaluation of catheter failure due to nonthrombotic causes. Worksheets that were incomplete were not reviewed.

Figure 1

Reteplase (Retavase[R]) Catheter Clearance Worksheet

DATE

INDICATIONS FOR USE (Check all that apply)

High venous resistance > 350 mmHg

High arterial resistance > -250 mmHg

BFR < 250 cc/min

No flow–arterial

Catheter conditioning

TYPE OF CATHETER (check 1)

Tunneled and cuffed internal jugular catheter

Transhepatic catheter

OUTCOMES

Flow restored to 150 cc/min

Flow restored to 250 cc/min or greater

Flow restored on return to unit next treatment

Venous or arterial resistance reduced

No improvement; unable to complete treatment

Other:

SIGNATURE

Study Results

From September 1999 through March 2000, 62 patients received reteplase for a total of 199 installations. Forty-three patients received reteplase after demonstrating reduced arterial flow; and 9 patients received reteplase after demonstrating high arterial pressure (60.8% combined). Reteplase was administered in 10 patients with high venous resistance (9.5% combined) and in 13 patients with no flow (10.6%). It is important to note that patients may have had one or a combination of the dysfunctions noted above.

The 13 patients with no flow often required an overnight dwell of reteplase to keep the catheter patent. Of these 13 patients, 5 had no further problems after one dose, and 8 required follow-up dosing 2 to 7 days after the first dose (see Figure 2).

Figure 2

Reasons for the Selection of Reteplase

No flow High venous All

resistance veneous

together

Reduce flow 10.6% 60.8%

of high

arterial

pressure

High venous 1.5% 8.0%

resistance

with

decreased

arterial

flow

Catheter 9.5% 20.6%

cond.

prophylaxis

Note: Table made from a bar graph.

Repeat doses were required in 26 patients because of recurrent or new problems, with 24 patients requiring the use of the drag for more than one problem. These patients presented with different problems or with multiple concurrent problems, such as high venous/low arterial pressure. Because of recurrent occlusive problems, we started using reteplase prophylactically.

Eighteen patients received reteplase doses for catheter conditioning. Catheter conditioning was a technique by which reteplase was used prophylactically in patients after episodes of no flow, low arterial flow, or in patients considered high risk, i.e., patients in whom arteriovenous (AV) access could not be successfully placed or in whom multiple accesses failed. In these patients, reteplase (0.4 U/0.4 ml expanded to the fill volume of the catheter with 0.9% normal saline solution, USP) was instilled at the end of the dialysis session on the last day of the treatment schedule. This provided the longest gap in patient treatment to dwell the reteplase. Of these 18 patients, 5 patients had no further thrombotic episodes, and the remaining 13 experienced a reduction in incidents of approximately 80%.

Success was based on the ability of reteplase to restore patency and allow the patient to complete the hemodialysis treatment. The overall combined success rate in patients receiving reteplase doses was 91.4% (182/199). In patients with no flow through their catheters, the success rate was 90.5% (19/21); the success rate in patients with reduced arterial flow or high arterial pressure was 88.4% (107/121); and the success rate in patients with high venous resistance was 78.9% (15/19). The combined overall success when excluding patients who received catheter conditioning was 85.9% (171/199)(see Figure 3). The majority of the patients, 58%, required only one dose. No adverse reactions were noted or reported by the patients or staff during the study period.

Figure 3

Catheter Clearance Rates with Reteplase

19/21 107/121 15/19 171/199 182/199

No flow 90.5

Reduce flow 88.4

or high

arterial pressure

High venous 78.9

resistance

(combined)

Without 85.9

catheter

conditioning

All uses 91.4

(combined)

Note: Table made from a bar graph.

Practice Implications

Since dialysis centers are increasingly being moved from hospital complexes to satellite health centers, it has become crucial to find easy, reliable, incenter remedies for venous catheter dysfunction. Thrombolysis is a relatively inexpensive, simple procedure for catheter clearance compared with stripping or replacement and reinsertion (Gray et al., 2000; Merport, Egglin & Dubel, 2000). The 0.4 U dose of reteplase costs approximately $44, comparable to alteplase 2 mg and urokinase 5000 IU costs (1999 Drug Topics[R] Red Book, 1999). Nursing intervention and administration costs are minimal compared to the costs of a catheter replacement, which can exceed $1,000, including the hospital, medical, and nursing care required (Northsea, 1996). Thus, the ability to salvage an occluded catheter and continue treatment eliminates a hospital stay and reduces the need for more expensive catheter stripping or replacement of venous catheters. Most importantly, using thrombolytics to clear catheters or to prevent occlusions of the catheters maintains future venous sites rather than using an alternative site to place a catheter.

The procedure used to instill reteplase is familiar to staff who have similar experience with instilling urokinase or alteplase into venous catheters. It can therefore be incorporated into standard protocols with minimal education. Interestingly, catheter conditioning emerged late in the study as a common use of reteplase as the staff gained experience and moved toward attempts to prevent, rather than merely to treat, catheter malfunction. Our results with prophylactic reteplase, combined with the results of other studies using prophylactic thrombolytic administrations, suggest that the preventative use of reteplase can maintain catheter patency without waiting for a thrombus to affect catheter performance (Northsea, 1996; Ray et al., 1999).

Limitations and Recommendations

The limitations of this study include the absence of a direct comparison of thrombolytic agents or a placebo control. As in any clinical study, worksheets that were excluded or patients who declined to enter the study could possibly have changed the outcomes. There was no validity testing of the worksheets used in the study. Results of the study cannot be generalized to other populations outside of the adult hemodialysis population due to the size of the catheter diameters used and need for high flow rates as compared to other populations that use venous catheters.

Within these limitations, future studies should use a test-retest method or random assignment to various drugs in the same class and/or a placebo arm. Worksheets should be tested for interrater reliability and revised accordingly.

Research Implications

This is the first report on the use of reteplase for dialysis catheter clearance. Our results warrant further investigation to determine the most cost-effective, safe, and efficacious dose of reteplase. Studies using reteplase for high-dose intradialytic thrombolysis or as a prophylactic agent should be considered to potentially improve catheter performance while minimizing cost and adverse outcomes (Ray et al., 1999; Twardowski, 1998). Finally, reteplase can be studied in comparison to other thrombolytics to determine the most effective method for catheter clearance and patency management.

Summary

Reteplase is a thrombolytic agent that can clear thrombus in indwelling dialysis venous catheters. It is cost effective when compared to other agents in its class. It has practical advantages, such as a shorter dwell time, that can benefit the busy schedule of a dialysis outpatient center. Our results show that reteplase can be used effectively as an alternative to urokinase in maintaining venous catheter patency until an arteriovenous access can be used for dialysis. Additional randomized, prospective studies are warranted.

Acknowledgement: The author wishes to acknowledge John DePalma, DO, and Douglas Gibbens, MD, for their support and assistance during the course of the study.

Note: Submitted October 2000; accepted June 2001.

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Debra Castner, MSN, RN, APN-C, CNN, is an Acute Care Certified, Advanced Practice Nurse, Ocean Renal Associates, PA, Toms River, NJ, a private nephrology practice covering hemodialysis and peritoneal dialysis outpatients. She has over 20 years of experience in the nephrology field.

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