Does the literature support an association between the use of Cathflo (alteplase) and an increased risk of central line associated blood stream infections?

Comment by InpharmD Researcher

Available evidence suggests an association between catheter-directed alteplase use and central line-associated bloodstream infection (CLABSI), although it is unclear whether this reflects an effect of alteplase itself. In the prospective COOL trials (see Table 1), Cathflo Activase was administered intraluminally to 1,064 patients, with 4 cases of catheter-related sepsis and 1 case of fever reported within 3 days of treatment, although only the fever was considered related to alteplase. Retrospective studies similarly found higher odds of catheter-associated bloodstream infection among patients receiving alteplase for catheter dysfunction; however, the specific alteplase product utilized was not always reported. Ultimately, these findings may be confounded by underlying catheter dysfunction or thrombus and do not establish that Cathflo independently increases the risk of CLABSI.

alteplase tPA "cathflo" CLABSI central line associated blood stream infections

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Does the literature support an association between the use of Cathflo (alteplase) and an increased risk of central line associated blood stream infections?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

Treatment of Occluded Central Venous Catheters with Alteplase: Results in 1,064 Patients
Design

Pooled analysis of two pivotal prospective phase-III clinical trials (Cardiovascular thrombolytic to Open Occluded Lines [COOL] Trials)

N= 1,064
Objective

To evaluate the cumulative safety and efficacy of serial administration of a maximum of two intraluminal doses of alteplase (2 mg per vial) in restoring function in occluded CVADs in two phase-III studies
Study Groups

All patients (n= 1,064)
Inclusion Criteria

Patients 2 years of age or older with body weights >10 kg with dysfunctional nondialysis CVADs, including peripherally inserted central catheters, apheresis catheters, and ports
Exclusion Criteria

Inability to infuse fluid volume necessary to fill catheter lumen with alteplase, ability to withdraw blood after repositioning, devices inserted less than 48 hours before enrollment, mechanical or nonthrombotic occlusion, age
Methods

Alteplase (2 mg/2 mL; Cathflo Activase; Genentech) was instilled into the lumen of the central venous catheter and allowed to dwell for up to 120 minutes. If occlusion persisted, a second dose was administered. Efficacy was assessed by restored function after a maximum of two doses. Safety was monitored for intracranial hemorrhage within 5 days.
Duration November 1999 through December 2000
Outcome Measures

Primary: Restored function after a maximum of two doses

Secondary: Incidence of intracranial hemorrhage within 5 days
Baseline Characteristics  

All patients (n= 1,064)
Mean age, years 50.7
Female 599 (56.3%)
White race 834 (78.4%)
Mean weight, kg 74.7

CVAD type

Single

Double

Triple

Port

 

266 (25.0%)

423 (39.8%)

66 (6.2%)

309 (29.0%)
Results   All patients (n= 1,064)
Restored function after first dose (95% CI) 75.0% (72.3% to 77.6%)
Restored function after second dose (95% CI) 85.1% (82.8% to 87.2%)
Adverse Events Five patients developed catheter-related sepsis (n=4) or fever (n=1) within 15 minutes to 3 days after alteplase. All had positive catheter or blood cultures within 24 hours of symptom onset, but only one fever event was considered related to alteplase. Two patients withdrew because of sepsis. Three cases of upper-extremity venous thrombosis occurred 3-7 days after treatment, none considered alteplase-related. Twenty-five patients (2.3%) died within 30 days, with five deaths occurring within 5 days of treatment. No deaths were considered related to alteplase.
Study Author Conclusions A regimen of as many as two 2-mg doses of alteplase is safe and effective for restoring flow to occluded central venous access devices.
Critique The study's strengths include a large sample size and multicenter design, providing robust data on the safety and efficacy of alteplase. However, the exclusion of hemodialysis catheters and the lack of radiographic imaging to confirm catheter occlusion may limit the applicability of the findings to all CVAD types. Additionally, the study did not evaluate the efficacy of different alteplase doses, which could have provided more comprehensive insights into optimal dosing strategies.

 

Table 1 References:
[1] Semba CP, Deitcher SR, Li X, et al. Treatment of occluded central venous catheters with alteplase: results in 1,064 patients. J Vasc Interv Radiol. 2002;13(12):1199-1205. doi:10.1016/s1051-0443(07)61965-4

 

The Role of Tissue Plasminogen Activator Use and Systemic Hypercoagulability in Central Line Associated Blood Stream Infections (CLABSIs)
Design

Retrospective analysis

N= 3,723
Objective

To establish whether in situ thrombosis results in increased risk of infection and to evaluate the role of a systemic primary or secondary hypercoagulable state in modulating this relationship
Study Groups

TPA administered (n= 1463)

No TPA administered (n= 2260)
Inclusion Criteria All adult and pediatric patients with documentation of PICC line placement between January 1, 2008 and December 31, 2011
Exclusion Criteria Patients without valid medical record numbers or dates of PICC line insertion
Methods

Retrospective analysis of ICU and non-ICU adult patients with PICCs at Boston Medical Center. Alteplase (TPA) was instilled into the PICC when flow was sluggish or blocked, followed by positive-pressure clamping and a 2-hour dwell. The catheter was then unclamped, and aspiration was attempted using a pull/pause technique. PICC patency was otherwise maintained with 20 mL saline flushes. Of note, the specific alteplase product was not specified. Discharge billing codes identified patients with hypercoagulable conditions and comorbidities. Charlson comorbidity index was used to predict long-term mortality.
Duration January 1, 2008 to December 31, 2011
Outcome Measures

CLABSI rates in patients receiving TPA vs. those not receiving TPA
Baseline Characteristics  

TPA administered (n= 1463)

 No TPA administered (n= 2260)
Mean age, years 47.0 57.1
CLABSI rate 2.2% 0.62%
Charlson comorbidity index score >= 2 Higher in TPA group Lower in non-TPA group
Results  

TPA administered (n= 1463)

 No TPA administered (n= 2260) p-value
CLABSI rate 2.2% 0.62% <0.001
Adjusted odds of developing CLABSI 3.59 times greater Reference <0.001
Adverse Events

Not specifically reported
Study Author Conclusions

The relative risk for CLABSIs in patients receiving TPA for PICC maintenance was over three times that of patients who did not require TPA. Thrombus formation may identify patients that would benefit from close surveillance for development of BSI.
Critique

The retrospective design limits the ability to control for confounding and establish causality. The study also did not specify the exact alteplase product used, and the absence of microbiology results and detailed clinical information limits interpretation of the findings. Additionally, the results may not be generalizable to catheter types other than PICCs. Despite these limitations, the study provides evidence of an association between thrombus formation and CLABSI risk and identifies an area for further investigation.

 

Table 2 References:
[2] Thakarar K, Collins M, Kwong L, Sulis C, Korn C, Bhadelia N. The role of tissue plasminogen activator use and systemic hypercoagulability in central line-associated bloodstream infections. Am J Infect Control. 2014;42(4):417-420. doi:10.1016/j.ajic.2013.11.016

 

Alteplase Use for Malfunctioning Central Venous Catheters Correlates With Catheter-Associated Bloodstream Infections
Design

Retrospective chart review

N= 3,289
Objective

To determine the correlation between the use of alteplase for malfunctioning central venous catheters and the development of catheter-associated bloodstream infections (CBSI)
Study Groups

All patients with central catheters admitted to the PICU (n= 3,289)
Inclusion Criteria

All patients with central venous catheters admitted to the PICU from July 2008 to December 2010
Exclusion Criteria

None specified
Methods

Retrospective review of electronic medical records for patients with CBSIs, focusing on the use of alteplase in the 5 days preceding positive blood cultures. Data on the number of CVCs, alteplase treatments, and CBSIs were collected from pharmacy, quality, and infection control records. Pearson chi-squared analysis and odds ratio calculations were used to assess the association between alteplase use and CBSI development.

The study does not explicitly state the administration procedure and does not identify the exact alteplase product.
Duration

July 2008 to December 2010
Outcome Measures

Primary: Correlation between alteplase use and CBSI development
Baseline Characteristics  

All patients (n= 3,289)
CVCs requiring alteplase 12%
CBSIs identified 40
CBSIs with alteplase use 28%
Average age of CVC at infection (alteplase) 16.1 days
Average age of CVC at infection (no alteplase) 25.6 days
Results  

All CVCs (n= 3,289)

 p-value
CVCs requiring alteplase 12% -
CBSIs identified 40 -
CBSIs with alteplase use 28% -
Odds ratio for CBSI with alteplase 2.87 0.002
Adverse Events

N/A
Study Author Conclusions

There is a positive correlation between the use of alteplase for malfunctioning central venous catheters and the development of a CASBI, likely due to the presence of an intraluminal fibrin sheath or thrombus. Further studies are needed to explore thromboprophylaxis as a potential strategy to decrease CBSI incidence.
Critique

The study provides valuable insights into the correlation between alteplase use and CBSI development, highlighting a potential marker for thrombus presence. However, the retrospective design limits the ability to establish causation. Additionally, the study does not specify the alteplase product that was utilized. The assumption that alteplase use indicates thrombosis or fibrin sheath presence may not be universally applicable, and the lack of standardized alteplase indications could introduce variability. Further prospective studies are needed to confirm these findings and explore preventive strategies.

 

Table 3 References:
[3] Rowan CM, Miller KE, Beardsley AL, et al. Alteplase use for malfunctioning central venous catheters correlates with catheter-associated bloodstream infections. Pediatr Crit Care Med. 2013;14(3):306-309. doi:10.1097/PCC.0b013e318271f48a

 

Alteplase for the Treatment of Central Venous Catheter Occlusion in Children: Results of a Prospective, Open-label, Single-arm Study (The Cathflo Activase Pediatric Study)
Design

Prospective, multicenter, open-label, single-arm, phase IV study

N= 310
Objective

To evaluate the safety and efficacy of alteplase in the treatment of CVAD occlusions in a pediatric population
Study Groups

All patients (n= 310)
Inclusion Criteria

Patient age less than 17 years with an occluded CVAD (single-, double-, and triple-lumen catheter or implanted port)
Exclusion Criteria

Patients with hemodialysis catheters, known mechanical occlusion, or considered at high risk for bleeding or embolization
Methods

A maximum of two doses (<2 mg per dose) of alteplase were administered. Assessment of function was made 30 and 120 minutes after each dose. Safety was measured by the incidence of intracranial hemorrhage (ICH) and other serious adverse events
Duration April 2002 to May 2003
Outcome Measures Primary: Incidence of intracranial hemorrhage (ICH) Secondary: Rate of restoration of CVAD function, incidence of serious adverse events
Baseline Characteristics   Age <2 y (n= 55) Age ≥2 y (n= 255) Total (N= 310)
Mean age, years (range) 0.9 (0.04–2.0) 8.6 (2.0–18.3) 7.2 (0.04–18.3)
Male 32 (58.2%) 142 (55.7%) 174 (56.1%)

Race

White

Black

 

41 (74.5%)

7 (12.7%)

 

177 (69.4%)

28 (11.0%)

 

218 (70.3%)

35 (11.3%)
Mean weight, kg (range) 8.0 (2.2–15.2) 35.2 (9.7–107.0) 30.3 (2.2–107.0)

CVAD type

Single

Double

Triple

Port

 

15 (27.3%)

27 (49.1%)

4 (7.3%)

9 (16.4%)

 

30 (11.8%)

66 (25.9%)

8 (3.1%)

151 (59.2%)

 

45 (14.5%)

93 (30.0%)

12 (3.9%)

160 (51.6%)
Results  

No. of Patients

 First Instillation 30 min First Instillation 120 min Second Instillation 30 min Second Instillation 120 min

Overall

 310 166 (53.5%) 233 (75.2%) 249 (80.3%) 257 (82.9%)
Age <2 y 55 24 (43.6%) 38 (69.1%) 40 (72.7%) 44 (80.0%)
Age ≥2 y 255 142 (55.7%) 195 (76.5%) 209 (82.0%) 213 (83.5%)
Male 174 80 (46.0%) 124 (71.3%) 136 (78.2%) 141 (81.0%)
Female 136 86 (63.2%) 109 (80.1%) 113 (83.1%) 116 (85.3%)
Adverse Events

No patients experienced ICH. Nine serious adverse events were noted in eight patients (2.6% incidence), two of which were attributed to study drug administration (one case of sepsis and one case of a ruptured catheter lumen)
Study Author Conclusions

The administration of alteplase is safe and effective for the restoration of function to CVADs in pediatric patients.
Critique

The study provides valuable prospective data on the use of alteplase in children, addressing a gap in pediatric-specific research. However, the single-arm design without a control group limits the ability to compare outcomes directly with other treatments. Additionally, the study did not include patients with hemodialysis catheters, limiting the generalizability of the findings to this subgroup. The protocol deviations, such as incorrect dosing and incomplete treatment algorithms, may also impact the study's reliability.

 

Table 4 References:
[4] Blaney M, Shen V, Kerner JA, et al. Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study). J Vasc Interv Radiol. 2006;17(11 Pt 1):1745-1751. doi:10.1097/01.RVI.0000241542.71063.83