This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Timoney, J. P. Articles by Saltz, L. B. Search for Related Content PubMed PubMed Citation Articles by Timoney, J. P. Articles by Saltz, L. B.

Safe and Cost Effective Use of Alteplase for the Clearance of Occluded Central Venous Access Devices

From the Departments of Medicine, Neurology, and Pediatrics, Divisions of Nursing and Pharmacy Services, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to John P. Timoney, PharmD, Division of Pharmacy Services, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: timoneyj{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine whether cryopreserved solutions of the thrombolytic agent alteplase could be used as a safe, effective, and economically reasonable alternative to urokinase in patients presenting with occluded central venous access devices (CVADs).

MATERIALS AND METHODS: Alteplase has been reported as an efficacious alternative to urokinase for treatment of occluded CVADs. However, the practicality of using alteplase as the thrombolytic of choice for this indication remained conjectural. To make this approach economically feasible, alteplase was diluted to 1 mg/mL and 2.5-mL aliquots were stored at -20°C until use. A need to confirm that the cryopreserving and thawing of the reconstituted solution did not compromise the safety and efficacy reported from prior trials was recognized. A quality assessment initiative was undertaken to concurrently monitor the safety and efficacy of this approach. Patients presenting with occluded CVADs received a sufficient volume of the thawed alteplase solution to fill the occluded catheter(s). Data, including efficacy, adverse reactions, dwell time, and catheter type, were collected over a 5-month period.

RESULTS: One hundred twenty-one patients accounting for 168 attempted clearances were assessable for safety and efficacy. One hundred thirty-six (81%) of the 168 catheter clearance attempts resulted in successful catheter clearance (95% confidence interval, 74% to 86%). No adverse events were reported.

CONCLUSION: Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVADs when stored at -20°C for 30 days. The ability to cryopreserve alteplase aliquots makes it an economically reasonable alternative to urokinase in the setting of CVAD occlusion.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
CENTRAL VENOUS access devices (CVADs) are used commonly in clinical practice and have become a cornerstone in the delivery of treatments to oncology patients. They provide chronic parenteral access, facilitating the treatment and monitoring of patients. Compared with repeated peripheral administrations, CVADs enable patients to receive chemotherapy more safely and with less discomfort. They also facilitate blood component therapy, blood sampling, continuous infusion therapy, multidrug therapy, total parenteral nutrition, and the ability to deliver these treatments in the home setting.^1,2 Consequences of inadequate venous access can include painful venipunctures, serious or even life-threatening pneumothorax or hemothorax from percutaneous central line insertion, or medication-induced extravasation resulting in necrosis and ulceration.³

CVADs require routine care (ie, saline or heparin flushes, dressing care, and so on) and routine assessment to reduce the incidence of complications. These complications may result in morbidity and/or removal of the device. Removal of the device can result in treatment delays, limit treatment options, and eliminate the facilitative component of the CVAD. Potential complications commonly encountered include occlusion, infection, and mechanical malfunction. Occlusion may be partial or complete and may be described, respectively, as difficulty or inability in instilling or withdrawing fluid from the catheter. Occlusions may be due to a variety of conditions, including fibrin sheath formation, thrombosis, malpositioning, or kinking of the catheter.^2,3

At Memorial Sloan-Kettering Cancer Center (MSKCC), a clinical pathway is used for assessment and treatment of patients who present with a suspected CVAD occlusion. Until February 1999, this clinical pathway used urokinase (Abbokinase; Abbott Laboratories, Abbott Park, IL) as the agent of choice for the treatment of a suspected CVAD occlusion. Urokinase is currently the only thrombolytic agent that has an indication approved by the United States Food and Drug Administration (FDA) for use in the treatment of occluded CVADs. However, FDA warnings in the first quarter of 1999 reported the potential for viral contamination of urokinase.⁴ These reports prompted the Pharmacy and Therapeutics (P&T) Committee of MSKCC to reconsider the use of urokinase and pursue feasible alternative agents for the clearance of occluded CVADs.

Alternative agents demonstrating effectiveness in their ability to clear occluded catheters include streptokinase (Streptase; Astra Pharmaceuticals, Westborough, MA) and recombinant alteplase (Activase; Genentech Inc, South San Francisco, CA). Streptokinase has demonstrated the ability to resolve occlusions without hemorrhagic side effects or coagulation changes when used in this capacity.⁵ The usefulness of streptokinase, however, does have its limitations, owing largely to the incidence of allergic reactions and the induction of antibody formation. Fever and shivering, occurring in 1% to 4% of patients, are the most commonly reported allergic reactions with intravenous use of streptokinase.^6-8 Anaphylactic reactions to streptokinase are rare but potentially life-threatening, occurring in 0.1% of patients treated with intravenous streptokinase.^6-8 Streptokinase can induce antibody formation, which may increase the potential for an allergic response. Streptokinase also has been reported to produce neutralizing antibodies that may persist for up to 12 weeks after an initial (1.5 million IU) dose that could preclude prolonged or follow-up administrations.⁹ These issues led to the determination that streptokinase was an unsuitable alternative for this indication.

Alteplase, a recombinant thrombolytic protein, has demonstrated a low incidence of allergic reactions (< 0.02%) and has no documented reports of sustained antibody formation after administration.¹⁰ After a review of the available information, the MSKCC P&T Committee concluded that use of alteplase for treatment of CVAD occlusions represented the safest alternative. The MSKCC treatment pathway was therefore modified to replace the use of urokinase with alteplase. To make this approach economically feasible, 2.5-mL aliquots of an alteplase 1 mg/mL solution were prepared and stored at -20°C until use. It was recognized, however, that there would need to be confirmation that cryopreserving and thawing a reconstituted solution did not compromise the safety and efficacy reported in prior trials. A quality assessment initiative was therefore undertaken by the P&T Committee in which the safety and efficacy of this approach was concurrently monitored over a 5-month period between February 1999 and July 1999. The results of this initiative are now reported.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The P&T Committee determined that sufficient data existed to conclude that alteplase was a safer alternative to urokinase and that it had demonstrated efficacy based on the limited data available. It was decided that 2.5-mL aliquots of the 1 mg/mL solution would be used. A volume of 2.5 mL per vial was selected to ensure that treating clinicians were able to obtain enough volume to fill the largest catheters available (2.2 mL) and to provide a sufficient overfill in the vial.

Alteplase was substituted for urokinase in the institutional treatment guidelines for clearance of occluded CVADs. Fifty milligram vials of alteplase, recombinant (Activase) were aseptically reconstituted with 50 mL of sterile water (United States Pharmacopeia). The 2.5-mL aliquots of the 1-mg/mL solution were aseptically placed in 5-mL sterile empty vials (American Pharmaceutical Partners Inc, Schaumburg, IL). The vials were labeled according to institutional policy and stored at -20°C until the time of administration. An expiration date of 30 days at -20°C was selected in the interest of infection control and based on negative reports of bacterial or fungal contamination from cryopreserved aliquots of alteplase from previous trials.⁹

This practice was concurrently monitored for safety and efficacy over a 5-month period. This project was not an investigational clinical trial but was rather a quality assessment initiative designed to assess the effects of a change in clinical practice, using alteplase for a clinical need for which there was not an FDA-approved agent available. The data reported here were collected in the context of a concurrent quality assessment initiative undertaken by the P&T Committee of MSKCC. The objective of this initiative was to monitor the safety and efficacy of what was deemed to be a necessary change in clinical practice. The decision to change clinical practice was made after a thorough evaluation of the catheter clearance literature and risk/benefit analysis given the available options. This was not regarded as an investigational clinical trial and was not conducted under institutional review board review.

An approved data collection form was initiated by the pharmacist, with each vial of alteplase dispensed and completed by the treating nurse. Data collection indicators included patient demographics, alteplase lot number, CVAD type, dwell time, outcome (successful or unsuccessful), adverse reactions (yes/no; if yes, please describe), and comments. The pharmacist completed the patient demographic information, the date, and alteplase lot number. The administering nurse recorded the catheter type, dwell time, occurrence of adverse reactions, and clinical comments and assessed the success or failure of the catheter clearance attempt. Attempts were defined as the instillation of one dose of alteplase into a catheter or catheter lumen(s) in multilumen devices. Success was defined as the ability to instill solution and withdraw blood from the device.

Occlusion is defined as either the inability to inject fluid or aspirate blood from a CVAD that has previously allowed both injection of fluid and aspiration of blood. The MSKCC procedure for restoring patency to an occluded CVAD is summarized. A trial of normal saline is used in an attempt to irrigate the catheter, gently, using a push-pull technique. If the attempt to instill normal saline and/or aspirate blood is unsuccessful, catheter clearance with alteplase is indicated. The nurse checks the patient medical record for the most recent chest x-ray report verifying catheter tip location. In addition, the nurse checks for patient allergies, contraindications to fibrinolytic therapy, and a valid prescriber order for alteplase. Lastly, the nurse determines whether any infusate has been infused that may cause a precipitate, indicating the need for alternate procedures, before the use of alteplase. When indicated, a sufficient volume of alteplase solution is instilled in the catheter and allowed to dwell for 30 minutes. This is followed by an attempt to aspirate the alteplase and residual clot. Aspiration attempts are repeated every 30 minutes. Once patency is restored, 4 to 5 mL of blood is aspirated to ensure removal of alteplase and the residual clot. The catheter is gently irrigated with normal saline to ensure the patency of the catheter.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The demographic information pertaining to the population of patients treated is listed in Table 1. A total of 168 attempted catheter clearances were performed in 121 patients. The patient population was fairly evenly balanced between male and female patients and between patients with solid and hematologic malignancies.

Ninety-three (77%) of the 121 patients received a single clearance attempt during the study period. There were 28 patients who had more than one clearance attempt during the study period, accounting for the difference between the number of patients and number of attempts. These 28 patients accounted for 75 (45%) of the 168 total clearance attempts. Thirty-one patients with multilumen devices had a clearance attempt of only one lumen.

Twenty-two of these 28 patients had transcutaneous multilumen devices and accounted for 58 attempts. Twenty-one of the 22 transcutaneous multilumen patients had subsequent attempts greater than 5 days from the prior attempt. One patient with a triple-lumen catheter had an attempted clearance of each lumen (three lumens) on 2 consecutive days. All three attempts on day 1 were unsuccessful and all three attempts on day 2 were successful, which was reported as three unsuccessful attempts and three successful attempts. Five of the 28 patients with more than one attempt had subcutaneous devices, accounting for 15 attempts. Each of these patients had subsequent attempts greater than 7 days from the prior attempt. One patient with a PICC line had two attempts that were separated by 28 days.

In retrospect, it was determined that there were eight patients treated with alteplase in this project who were previously treated for a catheter occlusion with urokinase before the institutional change in practice. There is no evidence to suggest that one agent was more effective or a more rapid clearing agent in this small subset of patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Atkinson et al¹¹ initially reported on their experience with using alteplase for the treatment of occluded central venous catheters for which treatment with urokinase failed. The investigators prospectively monitored 142 catheters for thrombotic events. Alteplase 2 mg/2 mL was used as a 4-hour instillation, repeated if needed, in central venous catheters failing a single 4-hour instillation of 10,000 units of urokinase. They reported 25 incidents of catheter occlusions occurring during the study period, and all patients were treated with urokinase as described above. Six (24%) of the 25 occlusions failed a clearance attempt with urokinase. Catheter patency was ultimately restored with alteplase in five (83%) of six urokinase failures, with two patients requiring more than one attempt.

Subsequently, Haire et al¹² reported that alteplase demonstrated better efficacy in clearing occluded CVADs when compared with urokinase in a small randomized trial of 50 patients. Seventy-eight catheters (76 patients) were screened for accrual over a 21-month period. Two patients were enrolled for different catheters at separate time periods. Of the 78 catheters, 50 (64%) were radiographically diagnosed with thrombosis. The remaining 28 catheters were excluded. The occluded catheters were randomized to either urokinase 10,000 units or 2 mg of alteplase. The treatments were allowed to dwell for a period of 2 hours. Repeat radiographic contrast injection was performed when catheter function was restored or after two doses of study drug were administered, whichever occurred first. Thirteen (59%) of the 22 catheters randomized to urokinase had full function restored, compared with 25 (89%) of 28 randomized to alteplase (P = .013). They concluded that alteplase restored catheter function more reliably and dissolved thrombi faster than urokinase. In the discussion of this randomized trial, the authors had difficulty developing an economic justification for recommending alteplase as the primary treatment of thrombotically occluded catheters, even though an efficacious advantage had been demonstrated. They offered that alteplase should be the treatment of choice in situations where rapid restoration of function is clinically determined to be a priority over financial cost.

The manufacturer of alteplase recommends that the agent be used within 8 hours of reconstitution.¹⁰ Adherence to the manufacturer’s recommendation to discard product after 8 hours, given the commercially available vial sizes, would result in significant wastage of the drug and would significantly increase the cost of treating this complication. In recognition of the potentially enormous economical impact of selecting alteplase as the agent of choice at MSKCC, the medical literature was researched for methods that had demonstrated extending the stability of alteplase. This review yielded limited reports documenting that alteplase was stable and demonstrated clinical activity after reconstitution, cryopreservation for a prolonged period of time, and thawing. Jaffe et al¹³ reported on the clinical efficacy of alteplase in ophthalmologic applications after it had been reconstituted, frozen at -70°C, and thawed. They reported that alteplase lost minimal activity and showed no bacterial or fungal contamination after cryopreservation and for up to 1 year. Furthermore, they verified that alteplase remained stable over this time using a solid-phase fibrin assay, as described.¹⁴ However, this ophthalmology report used a concentration of 0.25 mg/mL, a more dilute concentration than the 1 mg/mL used in the trials for catheter clearance.^11,12 These issues prompted us to concurrently monitor efficacy and safety of our newly implemented practice.

In response to the FDA warning regarding urokinase, it was decided that alteplase would be substituted for urokinase in our clinical pathway for the clearance of occluded CVADs. The dose was defined as a sufficient volume of the 1 mg/mL solution to fill the catheter. In most circumstances this would equate to a 2-mg dose. This definition was chosen as opposed to a 2-mg flat dose, as had been used in prior studies, recognizing that the fill volumes of catheters are quite variable depending on the type of catheter.

The potential economic impact of selecting alteplase as our primary agent for catheter clearance was evaluated, assuming that the extended stability would allow us to use the entire contents of the smallest available vial. The average wholesale price (AWP) of an Activase 50-mg vial is $1,375.¹⁵ It was determined that preparing aliquots of 2.5 mL of the 1-mg/mL solution would yield 20 doses of alteplase from one 50-mg vial. Using the AWP of the alteplase 50-mg vial, an economic evaluation of this aliquoting practice was performed. It was determined that the price for one dose of alteplase was $70.88 per 2.5-mg vial. In addition to the AWP of the alteplase 50-mg vial, this evaluation took into consideration the cost of all supplies used in the manufacturing (syringes, transfer devices, and sterile empty vials) and the cost of 2 hours of pharmacist time to prepare 40 aliquoted vials. This was determined to be less than the $103 AWP for a vial of Abbokinase Open-Cath 9,000 unit (1.8 mL).¹⁵ Before this dilemma, the urokinase 9,000-unit vial was the most commonly used product for catheter clearance at MSKCC.

Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVADs when stored at -20°C for 30 days. The ability to cryopreserve alteplase aliquots makes it an economically reasonable alternative to urokinase in the setting of CVAD occlusion and allows a means of implementing this practice in the institutional setting.

Several investigators have since confirmed the stability of reconstituted alteplase after cryopreservation.^16,17 The manufacturer of recombinant alteplase (Genentech) has performed limited studies on the effects of a single freeze-thaw cycle on the in vitro stability of reconstituted product. The tests included but were not limited to high-performance liquid chromatography and clot-lysis assays. The results indicate that reconstituted 1-mg/mL alteplase solutions were physically and chemically comparable to newly reconstituted product when stored at -20°C for 32 days (data on file, Genentech, Inc, South San Francisco, CA). Based on the results reported, we have continued to use cryopreserved alteplase as standard practice at MSKCC. This practice is a safe and cost-effective option at a large institution. We recognize that the methods and procedures we have outlined may not be of practical value to smaller institutions with lower volumes of usage under the current circumstances.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Herbst SL: Options for venous access in ambulatory care: Issues in selection and management. J Infus Chemother 6: 186-194, 1996[Medline]

2. Cobos E, Dixon S, Keung YK: Prevention and management of central venous catheter thrombosis. Curr Opin Hematol 5: 355-359, 1998[Medline]

3. Raaf JH: Results from use of 826 vascular access devices in cancer patients. Cancer 55: 1312-1321, 1985[CrossRef][Medline]

4. United States Food and Drug Administration: Important Drug Warning. Rockville, MD, United States Food and Drug Administration, January 25, 1999. Http://www.fda.gov/cber/ltr/abb012599.htm

5. 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]

6. Astra USA, Inc: Streptase (streptokinase) [product information brochure]. Westborough, MA, Astra USA, Inc, 1998

7. GISSI: Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1: 397-402, 1986[CrossRef][Medline]

8. ISIS-2 Collaborative Group: Randomized trial of streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction. Lancet 2: 349-360, 1988[Medline]

9. Hohage H, Schulte B, Mehrens T, et al: Serum antibody titers in a systemic lytic therapy with streptokinase. South Med J 91: 1019-1023, 1998[Medline]

10. Genentech Inc: Activase (alteplase, recombinant) [product information brochure]. South San Francisco, CA, Genentech, Inc, 1999

11. Atkinson JB, Bagnall HA, Bomperts E: Investigational use of tissue plasminogen activator (t-PA) for occluded central venous catheters. JPEN J Parenter Enteral Nutr 14: 310-311, 1990[Abstract]

12. Haire WD, Atkinson JB, Stephens LC, et al: Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: A double-blind randomized trial. Thromb Haemost 72: 549-547, 1994

13. Jaffe GJ, Green GD, Abrams GW: Stability of recombinant tissue plasminogen activator. Am J Ophthal 108: 90-91, 1989[Medline]

14. Jaffe GJ, Green GD, McKay BS: Intravitreal clearance of tissue plasminogen activator. Arch Ophthalmol 106: 969-972, 1988[Abstract]

15. Cardinale V (ed): Drug Topics Red Book. Montvale NJ, Medical Economics Co, April 2000

16. Calis KA, Cullinane AM, Horne MK: Bioactivity of cryopreserved alteplase solutions. Am J Health Syst Pharm 56: 2056-2057, 1999

17. Davis SN, Vermeulen L, Schwartz BS, et al: Activity and dosage of alteplase dilution for clearing occlusions of venous-access devices. Am J Health Syst Pharm 57: 1039-1045, 2000[Abstract/Free Full Text]

Submitted February 26, 2001; accepted December 11, 2001.

This article has been cited by other articles:

				E. A. Krzywda and D. A. Andris Twenty-five Years of Advances in Vascular Access: Bridging Research to Clinical Practice Nutr Clin Pract, December 1, 2005; 20(6): 597 - 606. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Timoney, J. P. Articles by Saltz, L. B. Search for Related Content PubMed PubMed Citation Articles by Timoney, J. P. Articles by Saltz, L. B.