Peripherally inserted central catheter (PICC) lines, a distinct type of central venous access device (CVAD), have become an essential component of intravenous therapy. Insertion of PICC lines is less invasive, poses fewer risks, and has a lower likelihood of complications than insertion of traditional central venous catheters (CVCs).¹ Despite the advances that have been made in vascular access technology, all intravenous lines continue to be associated with a risk of thrombosis and occlusion.² Replacing dysfunctional CVADs, including PICC lines, is expensive and uncomfortable for patients.³ As such, prevention or resolution of thrombotic occlusions and avoidance of line replacement are of critical importance with regard to these devices.

Alteplase, also known as tissue plasminogen activator (tPA), is a fibrinolytic agent indicated for the restoration of thrombotically occluded CVADs as assessed by the ability to successfully withdraw blood from the line.⁴ Alteplase’s mechanism of action involves prolonged contact with occlusions via line dwell. It is commercially available as a single dose vial of lyophilized powder for reconstitution to a concentration of 2 mg/2 mL, or it can be aliquotted from a larger vial into unit dose syringes that can be frozen for up to 45 days and thawed immediately prior to use.⁵ The adult dose is 2 mg/2 mL, whereas the package insert states that patients weighing 30 kg or less should receive a dose of 110% of the occluded line’s intraluminal volume (at the same concentration as the adult dose).

The safety and efficacy of the approved 2 mg/2 mL dose of alteplase in CVCs has been well studied,⁶ and there are some data regarding its use in PICC lines specifically.¹ Additionally, some studies have been done on the efficacy of the intraluminal volume dose used for patients weighing 30 kg or less.^7,8 Considering the fact that alteplase exerts its mechanism of action via prolonged line dwell, it stands to reason that administering any volume of drug sufficient to completely fill the occluded line should be noninferior to the standard approved dose. To this point, there have been very few studies investigating this idea of “intraluminal volume” alteplase dosing, and the limited data available come almost exclusively from studies involving hemodialysis catheters.^9,10 The intraluminal volume of most commercially available PICC lines is less than 0.8 mL.^11-13 As a result, approximately half of each standard alteplase dose is wasted as it enters the patient’s systemic circulation, at significant cost to institutions.⁸ 

Although there are some data regarding the efficacy of standard (2 mg/2 mL) dose alteplase for the clearance of occluded PICC lines, very little research has been done regarding the efficacy of an intraluminal volume 1 mg/1 mL dose. The purpose of this study is to determine the efficacy and cost-effectiveness of a maximum of 2 doses of 1 mg/1 mL intraluminal volume alteplase as compared to a maximum of 2 doses of standard 2 mg/2 mL dose alteplase for the restoration of patency of occluded PICC lines at our long-term acute care hospital (LTACH; HealthEa-st Bethesda Hospital, St. Paul, MN). It was hypothesized that dosing alteplase intraluminally at 1 mg/1 mL as opposed to the standard 2 mg/2 mL dose would provide equal efficacy in restoring PICC line patency at a decreased cost.

METHODS

Study Design

This study was approved by the HealthEast institutional review board. It was an open-label, nonrandomized quasi-experimental trial that took place over a 3-month period from December 2013 to March 2014. Patients were distributed in a 2:1 ratio into the 2 treatment groups. The first group of patients had a standing order of standard 2 mg/2 mL alteplase entered into their medication profile for any potential PICC line occlusions, whereas the second group of patients had a standing order of the intraluminal volume dose 1 mg/1 mL alteplase entered into their profile for any potential occlusions. 

For enrollment, a daily report identified all patients in the facility with a standing order for alteplase, and any patients ordered 2 mg/2 mL were invited to participate in the study. Those who consented to enrollment were placed into the intraluminal volume 1 mg/1 mL dose group and those who declined were placed into the standard 2 mg/2 mL dose group. This method of nonrandom group assignment was necessary to meet power due to a fewer than anticipated number of patients consenting to enrollment in the study. It was determined that to achieve 80% power, a total of 270 occlusion events (180 2 mg/2 mL and 90 1 mg/1 mL) would need to be observed/recorded.

Patients were eligible for enrollment if they were 18 years of age or older and had an identifiable, documented PICC line with a standing order of alteplase for occlusion clearance. Patients were excluded from the study if they had a documented allergy to alteplase, refused to consent to the study (excluded from 1 mg/1 mL group), or were previously enrolled in study, discharged, and readmitted to hospital.

Once patients were enrolled, a second daily report identified patients who had received any dose of alteplase in the previous 24 hours and a review of the occlusion event was performed via chart review. Data were collected by the primary researcher via paper event reporting forms and aggregated on an electronic Excel spreadsheet for analysis. All data were obtained via the HealthEast electronic health record. Demographic information collected included medical record number (MRN), age, gender, weight, and type of PICC line (single, double, or triple lumen). Occlusion event-specific information collected included date/time occlusion first reported, type of occlusion (partial vs total), number of lumens occluded, time first dose of alteplase administered, time second dose of alteplase administered (if applicable), time occlusion  resolution reported (if applicable), total doses of alteplase administered, and time (in days) to reocclusion from date of previous occlusion (if applicable).

Statistical Analysis

After collection, all data were entered into a database (Microsoft Excel, 2010; Microsoft Corporation) for analysis, and the validity of the data was ensured through review. All statistical analyses were performed using the Excel Statistical Software Program. A 2-tailed z test for 2 proportions was used to evaluate the data available for the proportion of PICC line occlusions cleared after administration of both 1 and 2 doses of alteplase, as well as the proportion of patients reoccluding at least once. A 2-tailed z test for 2 means was used to evaluate the data available for mean time to reocclusion as well as the mean number of occlusions per patient. The 2-tailed z test for 2 means was also used to evaluate the demographic age and weight data of the patients in the 2 treatment groups. The a priori level of significance for all statistical tests was .05.

RESULTS

Demographics and Efficacy Outcomes

During the 3-month trial period, data were available for a total of 270 occlusions in 168 patients. Of these, 90 occlusions occurred in a total of 54 patients in the intraluminal volume dose alteplase group and 180 occurred in a total of 114 patients in the standard dose alteplase group. Efficacy information was based upon the number of occlusions and not per patient. There was no significant difference between the groups in age (P = .75) or weight (P = .86). Demographic information of treated patients can be seen in Table 1. 

A summary of the primary efficacy outcome is presented in Figure 1. For this study, the following definitions applied: patency was defined as the ability to flush 5 mL of saline and withdraw 3 mL of blood from the PICC line. A partial occlusion was a line able to flush but not draw, and a total occlusion was a line unable to flush or draw.

The proportion of patients in the standard 2 mg/2 mL dose group achieving clearance of their occlusion and restoration of line patency after 1 and 2 doses of alteplase was 87.2% and 94.4%, respectively. In the intraluminal volume 1 mg/1 mL dose group, 85.6% of patients achieved successful clearance of their occlusion after 1 dose of alteplase; a
second dose increased the success rate to 93.3%. Results of a z test analysis of these outcomes indicated no statistical difference between the treatment groups after either 1 (P = .71) or 2 (P = .72) doses.

Table 2 summarizes patient occlusion characteristics as well as the remaining secondary study outcomes. The majority of occlusions (54.4%) occurring in the intraluminal volume 1 mg/1 mL dose group were partial occlusions. For the standard dose 2 mg/2 mL group, the majority of occlusion occurring were also partial (63.9%). The proportion of patients reoccluding at least once was 36.8% in the standard 2 mg/2 mL dose group and 33.3% in the intraluminal volume 1 mg/1 mL dose group once. The mean number of reocclusions per patient was 2.0 in the intraluminal volume dose group and 1.6 in the standard dose group. The mean time to reocclusion in the standard and intraluminal volume groups was 6.7 and 5.3 days, respectively. Results of a 2-tailed z test for 2 proportions as well as a 2-tailed z test for 2 means showed no significant difference between groups in the proportion of patients reoccluding at least once (P = .66), the mean number of reocclusions per patient (P = .23), or the mean time to reocclusion (P = .11).

Cost Minimization Analysis

Since this study found no statistical difference in efficacy between the 1 mg/1 mL and 2 mg/2 mL alteplase doses, a cost minimization analysis was performed. The average wholesale price (AWP) of an alteplase (Activase) 50 mg vial is $2,970.49 (AmeriSource Bergen Inc., 2014). The 50 mg vial yields 24 2 mg/2 mL aliquots of alteplase or 49 1 mg/1 mL aliquots. The lower than expected yields are due to residual drug remaining in the vial. Using the AWP of the alteplase 50 mg vial, an economic evaluation was performed. The calculated cost per dose was found to be $123.77 for an aliquot of 2 mg/2 mL alteplase and $60.62 for a 1 mg/1 mL aliquot. Preparation supplies and labor costs were not included in the analysis as they were deemed likely to make only a negligible difference in the final costs per dose.

DISCUSSION

PICC lines are commonly placed in patients for medication administration, blood sampling, and nutritional support. These devices, although important in therapeutic management of chronically and critically ill patients, remain associated with a variety of complications, including occlusions. PICC occlusion may result in a variety of problems, including interruption of the delivery of intravenous therapies, increased risk of catheter-related infection, and extended hospital stay, all of which result in higher health care costs.

Treating PICC line occlusions is less expensive and faster than surgically removing and replacing these devices. It also reduces the risk of adverse events to the patient. The standard intervention at HealthEast Bethesda Hospital to restore PICC line patency had been the instillation of up to 2 aliquotted standard 2 mg/2mL doses of alteplase.

This study comparing the efficacy of a standard 2 mg/2 mL dose of alteplase to an intraluminal volume 1 mg/1 mL dose found that 1 dose of intraluminal volume alteplase successfully cleared 85.6% of PICC line occlusions. Administration of a second dose increased the success rate to 93.3%. Results of a z test proportion analysis demonstrated that there was no statistical difference in efficacy outcomes between the intraluminal volume and standard dose alteplase groups (see Figure 1). 

The proportion of patients reoccluding at least once was slightly higher in the standard 2 mg/2 mL dose group (36.8% vs 33.3%), whereas the mean number of reocclusions per patient was similar between groups: 2.0 in the intraluminal volume 1 mg/1 mL dose group versus 1.6 in the standard 2 mg/2 mL dose group. The mean time to reocclusion was slightly shorter for patients receiving intraluminal volume as opposed to standard dose alteplase (5.3 vs 6.7 days respectively). Results of a 2-tailed z test for 2 means showed no significant difference between groups in the mean number of reocclusions per patient or the mean time to reocclusion. Results of a 2-tailed z test for 2 proportions showed no difference between groups in the proportion of patients reoccluding at least once.

The potential economic impact of selecting intraluminal volume dose alteplase as our primary agent for PICC line clearance was also evaluated, and it was determined the average cost per dose of 1 mg/1 mL alteplase was $60.62 and the average cost per dose of the standard 2 mg/2 mL dose was $123.77. In fiscal year (FY) 2013, our facility spent $196,052.16 on alteplase (Activase) 50 mg vials. A conservative estimate of a 50% reduction in the number of vials ordered annually extrapolates to a potential annual cost savings of close to $100,000 for the facility. 

One limitation of our cost calculation was that we did not analyze the number of alteplase doses in either group that ended up being wasted due to expiration. Anecdotally, the pharmacy technicians at our institution reported that during the study period they did not notice a higher number of doses expiring and being wasted in one group as opposed to the other. Another cost-related concern was that patients receiving the intraluminal volume alteplase may end up requiring 2 doses as opposed to 1 more frequently or reoccluding more often, leading to an increase in the total number of doses dispensed. At the conclusion of the study, this was not found to be the case and the mean number of occlusions per patient was actually higher in the 2 mg/2 mL group (2.36 vs 1.68), although this result was not statistically significant. Approximately 93% of our LTACH facility’s use of alteplase was for PICC line occlusions, a number that may be higher than would be expected at a short-term acute care hospital. As such, it should be noted that the number of doses dispensed in a given time period as well as those wasted due to expiration could differ in other institutions or other studies; the doses and costs reported and analyzed were results of this study alone and may vary.

There are several limitations to this study that impact the validity of the efficacy results. Although the number of recorded occlusion events was adequate to meet power, the circumstances surrounding the necessity of nonrandomized distribution of patients into numerically unbalanced groups are less than ideal. Time from line placement to occlusion was not evaluated, and the etiology of occlusions in lines placed within the previous 48 hours is often nonthrombotic.¹ Additionally, collection of data via chart review can be problematic, as there may be inconsistencies in the accuracy of documentation between different patient care units and nurses. All of the registered nurses at HealthEast Bethesda Hospital have been trained regarding the appropriate procedure for administration of alteplase, and instructions describing the correct timing of alteplase doses for catheter occlusions are printed standard on the label of every alteplase syringe. That being said, the results presented in this study do not account for any potential variance among patients in the timing of initial and subsequent doses of alteplase. Further investigation via a larger prospective randomized study would be helpful to confirm the efficacy results obtained from this study.

Despite these limitations, the use of intraluminal volume dose alteplase appears to be at least as efficacious as standard dose alteplase. The major advantages of intraluminal volume dose alteplase use include a reduction for patients in unnecessary systemic alteplase exposure as well as a lower cost per dose, which correlates with a significant annual institutional cost savings. At our institution, a new policy utilizing 1 mg/1 mL alteplase for all PICC line occlusions was eventually approved by our Pharmacy & Therapeutics Committees and implemented at our facility. A follow-up cost analysis is scheduled for FY 2014 to validate the impact of this change.

ACKNOWLEDGMENTS

Amy Fehrer, MPH; Lisa Lendway, PhD

REFERENCES

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^*PGY-1 Pharmacy Resident, *Director of Pharmacy, Residency Program Director, Department of Pharmacy, HealthEast Bethesda Hospital, St. Paul, Minnesota. Corresponding author: Stephen P. Sapienza, PharmD, Department of Pharmacy, HealthEast Bethesda Hospital, 559 North Capitol Boulevard, St. Paul, MN 55101; phone: 651-232-2335; e-mail: spsapienza@healtheast.org