What are available recommendations for the safety and efficacy of using alteplase (cathflo) with an extended dwell time (leaving to dwell 48 hours between dialysis sessions) instead of the standard recommended treatment duration of up to 120 minutes?

Comment by InpharmD Researcher

Per the Cathflo® Activase® package insert, a dwell time of at least 30 minutes is recommended for restoration of catheter patency (ability to draw blood) in central venous access devices, with a repeated dose instilled if the catheter remains completely obstructed. A comprehensive search revealed one study that compared a 1-hour dwell time versus a 48-72-hour dwell time and found no significant difference in the likelihood of catheter patency at 2 weeks (see Table 1). Ultimately, the lack of clinical data directly comparing a 48-hour dwell time versus a 120-minute dwell time precludes inferences of relative efficacy & safety. Additional published literature comparing other alternative dwell times have evaluated dwell times ranging overall from 0.5 hours to 4 hours (see summaries below).

Background

A 2013 review pertaining to the efficacy of alteplase in restoring patency of occluded venous and dialysis catheters in pediatric patients identified 10 studies, 8 specific to the central venous catheter (CVC) and 2 specific to dialysis catheter occlusion. Alteplase doses of 0.5 to 2 mg were instilled into the lumen of a CVC with dwell times ranging from 30 to >240 minutes, with the potential for repeat dosing. One referenced 2001 retrospective case-control study compared alteplase (at concentrations of 2 mg/2 mL; range of 0.2 to 1.4 mL; suggested dwell time of 1-2 hours) versus urokinase (at concentrations of 5,000 IU/mL) in the restoration of occluded catheters. The results found a significant restoration of CVC function in favor of alteplase use, with 93.2% efficacy versus 54.5% in the urokinase group ( odds ratio [OR] 11.39; 95% confidence interval [CI] 3.2 to 40; p<0.001). The mean alteplase dwell time was 206 ± 295 minutes, while the mean urokinase dwell time was 207 ± 255 minutes. In general, the overall efficacy of alteplase ranges from 50% to 90%, with greater efficacy with larger doses and longer dwell times for treating thrombus-related venous catheter occlusion in pediatric patients. Data on use in occluded dialysis catheters, however, remain limited. [1], [2]

Another 2012 review on thrombolytic therapy for CVC occlusion revealed, based on 10 studies specific to alteplase use, that alteplase clears 52% of obstructed catheters within 30 minutes with 86% overall clearance (given 2 doses, when necessary). Dosages of alteplase ranged from 0.22 mg to 2 mg for children, while doses of alteplase mainly consisted of 2 mg for adults, with a dwelling time of 30 to 120 minutes (dose repeated if no resolution; maximum 2 doses). One referenced prospective consecutive cohort study published in 2001 instilled alteplase in children based on weight (0.5 mg ≤ 10 kg; 1-2 mg > 10 kg), using a dwell time of either 1 to 4 hours or overnight. A total of 34 courses were administered in 25 children, of which 29 courses (85%) completely restored central venous line patency. Due to the study having been conducted in the United Kingdom, the small sample size, and the dated nature of the study, results may not be generalizable to the current U.S. patient population. [3], [4]

Pertaining to occlusion and thrombosis associated with long-term indwelling CVC, a 2009 review suggests a low dose of alteplase may be infused over 6 to 8 hours in case of an incomplete restoration of catheter patency. However, the authors did not provide specific references for the suggested duration of infusion time. [5]

Relevant Prescribing Information

CATHFLO ACTIVASE (alteplase):

DOSAGE AND ADMINISTRATION
Cathflo Activase (Alteplase) is for instillation into the dysfunctional catheter at a concentration of 1 mg/mL.
Patients weighing ≥30 kg: 2 mg in 2 mL
Patients weighing <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL
If catheter function is not restored at 120 minutes after 1 dose of Cathflo Activase, a second dose may be instilled. There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2‑mg doses). [6]

Instillation of Solution into the Catheter
1. Inspect the product prior to administration for foreign matter and discoloration.
2. Withdraw 2 mL (2 mg) of solution from the reconstituted vial.
3. Instill the appropriate dose of Cathflo Activase (see DOSAGE AND ADMINISTRATION) into the occluded catheter.
4. After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 5.
5. After 120 minutes of dwell time, assess catheter function by attempting to aspirate blood and catheter contents. If the catheter is functional, go to Step 7. If the catheter is not functional, go to Step 6.
6. If catheter function is not restored after one dose of Cathflo Activase, a second dose of equal amount may be instilled. Repeat the procedure beginning with Step 1 under Preparation of Solution.
7. If catheter function has been restored, aspirate 4–5 mL of blood in patients ≥10 kg or 3 mL in patients <10 kg to remove Cathflo Activase and residual clot, and gently irrigate the catheter with 0.9% Sodium Chloride Injection, USP. [6]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What are available recommendations for the safety and efficacy of using alteplase (cathflo) with an extended dwell time (leaving to dwell 48 hours between dialysis sessions) vs. the standard recommended treatment duration of up to 120 minutes?

Level of evidence

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Please see Tables 1-2 for your response.

Short and Long Alteplase Dwells in Dysfunctional Hemodialysis Catheters
Design	Prospective, single-center, randomized, non-blinded study N= 60
Objective	To determine if alteplase (TPA) dwell time affects short- or long-term catheter patency rates
Study Groups	1 hr dwell (n= 26) Until next hemodialysis (HD) (48-72 hr) dwell (n= 34)
Inclusion Criteria	Aged >18 years and dialysis via a temporary or cuffed HD catheter with an episode of catheter dysfunction (CD)
Exclusion Criteria	Hemodynamically unstable and in urgent need of dialysis therapy, had a K+ of ≥ 6mmol/L, had a clot documented on a recent catheter dye study, had received TPA within the past two weeks
Methods	Eligible patients in Canada were randomized to receive either short (1 h) or long (48-72 h) TPA dwell. After identifying CD, the HD nursing staff received instructions to adhere to a standard unit protocol. This protocol included patient repositioning and catheter flushing with saline to restore blood flow. In case these measures proved ineffective, the attending physician was alerted. Subsequently, a preprinted TPA study form was dispatched to the pharmacy for block randomization of patients. The dialysis run sheet was examined to gather the average blood pump speeds (BPS) recorded prior to TPA instillation and the average BPS following the administration of TPA. To assess the ongoing functionality of catheters following the administration of the study TPA, patient dialysis records were examined at two-week intervals and subsequently on a monthly basis.
Duration	Study: October 2001 to May 2002 (8 months) Follow-up: Until June 15, 2002
Outcome Measures	Primary: catheter patency (BPS of > 250 mL/min) at the subsequent HD run and catheter patency at 2 weeks Secondary: the time from study entry to the next catheter intervention (including subsequent TPA installation)
Baseline Characteristics		1-hr dwell (n= 26)	Until next HD (48-72 hr) dwell (n= 34)
	Age, years	67	67
	Male	69%	60%
	Comorbidities Diabetes mellitus status Peripheral vascular disease Coronary artery disease	42% 23% 50%	38% 21% 35%
	Catheters Previous catheters Two or more previous catheters Temporary catheter Current catheter duration, days	58% 15% 15% 99	56% 26% 21% 45
	TPA TPA used in past Two or more TPA used in past	54% 35%	41% 29%
	Laboratory values Hemoglobin, g/L Erythropoietin weekly dose, U/kg International normalized ratio >1.5	106 144 15%	111 159 9%
	Medications Aspirin Warfarin	35% 31%	18% 29%
Results	Endpoint	1-hr dwell (n= 26)	Until next HD (48-72 hr) dwell (n= 34)	p-value
	BPS, mL/min Before TPA After TPA Change from before to after >250 mL/min next HD run >250 mL/min at 2 weeks	183 ± 47.6 301 ± 57.4 118 ± 73.9 20 (76.9%) 11 (42.3%)	200 ± 48.1 302 ± 57.8 102 ± 71.2 27 (79.4%) 18 (52.9%)	0.179 0.942 0.403 0.817 0.414
	CD-free status, days*	14 (4–83)	18 (4–77)	0.621
	*Median (25th and 75th percentiles) Abbreviations: HD = hemodialysis; TPA = alteplase; CD = catheter dysfunction
	There is no difference in catheter survival between the short or long dwell groups (with a median of 14 days for the short dwell and 18 days for the long dwell, p= 0.621).
Adverse Events	Not disclosed
Study Author Conclusions	This study demonstrates that although patency for the next HD run can be achieved with either short or long TPA dwell, neither is reliable in terms of long-term patency. Strategies that employ TPA for CD are temporary and allow a 2-week window during which more definitive therapies for HD access should be sought.
InpharmD Researcher Critique	The study has limitations, including the assumption of thrombus-related CD without radiologic confirmation, potentially leading to TPA failures in cases not involving thrombus formation. Additionally, the sample size fell short of recommendations, with recruitment stopped at 60 patients due to logistical constraints, highlighting a need for caution in generalizing findings. Future studies may benefit from a multicenter approach to enhance sample size and broaden the study's applicability.

References:

Macrae JM, Loh G, Djurdjev O, et al. Short and long alteplase dwells in dysfunctional hemodialysis catheters. Hemodial Int. 2005;9(2):189-195. doi:10.1111/j.1492-7535.2005.01131.x

Efficacy of Low-dose Alteplase for Treatment of Hemodialysis Catheter Occlusions
Design	Prospective, single-center, open-label trial N= 50
Objective	To assess the efficacy of low-dose alteplase in restoring hemodialysis (HD) catheter patency; determine the duration of catheter line patency following alteplase instillation; and evaluate the financial implications of this new protocol
Study Groups	Study group (N= 50)
Inclusion Criteria	Patients requiring alteplase to clear an occluded permanent, tunneled central venous catheter (CVC)
Exclusion Criteria	Receiving alteplase routinely for prophylaxis; receiving HD via a temporary, non-tunneled catheter
Methods	As instructed per protocol, upon identification from nursing staff at a Canadian institution, dysfunctional catheters were forcefully flushed with 10 mL of normal saline at least twice in an attempt to restore patency of the occluded lumen. If unsuccessful, an order was placed for alteplase 1 mg/lumen to dwell in each completely occluded catheter for 60 minutes. The dwelling period was extended to 48-72 hours between HD sessions for patients with partially occluded catheters. Each catheter lumen was first filled with 1 mg/mL of alteplase, and then with enough normal saline (NS) to cover the lumen capacity of the catheter plus an additional 0.2 mL. Up to May 2004, alteplase was provided in pre-filled frozen syringes containing 1 mg/mL, which were made from alteplase 50 mg vials by a central pharmacy. The pre-filled syringes were no longer used in June 2004 when the HD unit began receiving alteplase 2 mg/2 mL vials. An alteplase therapy regimen included one or two doses administered consecutively. Patients were to be sent to interventional radiology for a linogram if more than two treatment courses were needed in the first two weeks of therapy. Patients were monitored for four months to record any radiological or surgical line interventions, and for two months to record the requirement for further alteplase therapy sessions.
Duration	From 2003 to 2004
Outcome Measures	Primary: Successful restoration of catheter patency following alteplase administration Secondary: Duration of line patency
Baseline Characteristics		Study group (N= 50)
	Age, years	65 ± 16.0
	Male	28%
	Weight, kg	65 ± 26.8
	Hemoglobin, g/L	119 ± 19.1
	Blood flow rate prior to alteplase, mL/min	270 ± 60.9
	Median duration of dialysis, (range)	13 (0.1-130)
	Median time to first alteplase dose, days (range)	40 (0-2,072)
	Vascular access site Intrajugular right/left Subclavian right/left Translumbar	72%/18% 6%/2% 2%
	Catheter lumen volumes ≥2 mL 1.5-1.9 mL <1.5 mL	78% 20% 2%
	Disease co-morbidities Coronary artery disease Diabetes Peripheral vascular disease	42% 54% 2%
	Anticoagulant/Antiplatelet therapy Antiplatelet (aspirin ± clopidogrel) Warfarin None	50% 12% 38%
Results	Endpoint	Study group (N= 50)
	Success rate of alteplase 1st alteplase dose 2nd alteplase dose (note: 2 patients who failed alteplase did not receive a second dose)	72% 83%
	Success rate per catheter volume ≥ 2 mL, 1st dose/2nd dose 1.5-1.9 mL, 1st dose/2nd dose 1.3 mL (n=1), 1st dose	77%/82% 60%/70% 100%
	Subsequent alteplase dose within 2 months after the 1st alteplase dose No further alteplase administered Median time to next course, days (range) Median no. courses required (range)	38% 14 (2-58) 2 (1-7)
	Further line interventions within 4 months after the 1st alteplase dose None Linogram Line stripping New line insertion	62% 22% 14% 16%
	Radiological interventions were ordered in 38% of patients, resulting in 8 line replacements and 7 line strippings.
Adverse Events	N/A
Study Author Conclusions	Low-dose alteplase 1 mg/lumen successfully treated occlusion of permanent hemodialysis catheters, with a resulting cost reduction.
InpharmD Researcher Critique	The absence of a prospective comparison group is one of the study's limitations. The nephrologists had complete discretion over who was chosen as a patient; no stringent criteria were in place. Thrombosis may not have been the only reason for catheter malfunction and other factors unknown may have influenced the results. Lastly, the limited trial population for low-dosage alteplase includes only those with long-term, tunneled catheters, which may reduce generalizability.

References:

Haymond J, Shalansky K, Jastrzebski J. Efficacy of low-dose alteplase for treatment of hemodialysis catheter occlusions. J Vasc Access. 2005;6(2):76-82. doi:10.1177/112972980500600206