MC-AT indicates 4F antithrombotic midline catheter; MC-AT-AM, 4.5F antithrombotic and antimicrobial midline catheter.
eAppendix. List of Vesicants/Irritants
eResults. Supplemental Results
eTable. Midline Catheter-Associated Causes of Removal
eDiscussion. Supplemental Discussion
Data Sharing Statement
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Bahl A, Diloreto E, Jankowski D, Hijazi M, Chen N. Comparison of 2 Midline Catheter Devices With Differing Antithrombogenic Mechanisms for Catheter-Related Thrombosis: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(10):e2127836. doi:10.1001/jamanetworkopen.2021.27836
Is there a difference in midline catheter-related thrombosis (deep vein thrombosis or superficial vein thrombophlebitis) using devices with 2 distinct antithrombogenic mechanisms?
In this randomized clinical trial of 191 adults randomized to receive an antithrombotic catheter or an antithrombotic, antimicrobial catheter, no difference was found in catheter-related thrombosis between the 2 trial devices (7.5% and 11.3%).
The catheter-related thrombosis rate was high in both catheters with no advantage of either antithrombogenic mechanism.
Data regarding upper extremity midline catheter (MC)–related thrombosis (CRT) are sparse, with some evidence indicating that MCs have a high rate of CRT.
To compare 2 MCs with differing antithrombogenic mechanisms for this outcome.
Design, Setting, and Participants
In this parallel, 2-arm randomized clinical trial, 496 adult patients hospitalized at a tertiary care suburban academic medical center who received an MC were assessed for eligibility between January 1, 2019, and October 31, 2020, and 212 were randomized.
Inpatients were randomized to receive a 4F antithrombotic MC (MC-AT) or a 4.5F antithrombotic and antimicrobial MC (MC-AT-AM).
Main Outcomes and Measures
The primary outcome was symptomatic midline CRT inclusive of deep vein thrombosis or superficial venous thrombophlebitis within 30 days after insertion. Secondary outcomes included catheter-associated bloodstream infection and catheter failure.
A total of 191 patients (mean [SD] age, 60.2 [16.7] years; 114 [59.7%] female) were included in the final analysis: 94 patients in the MC-AT group and 97 in the MC-AT-AM group. Symptomatic midline CRT occurred in 7 patients (7.5%) in the MC-AT group and 11 (11.3%) in the MC-AT-AM group (P = .46). Deep vein thrombosis occurred in 5 patients (5.3%) in the MC-AT group and 5 patients (5.2%) in the MC-AT-AM group (P > .99). Pulmonary embolism occurred in 1 patient in the MC-AT group. No catheter-associated bloodstream infection occurred in either group. Premature catheter failure occurred in 22 patients (23.4%) in the MC-AT group and 20 (20.6%) in the MC-AT-AM group (P = .64). In Cox proportional hazards regression analysis, no statistically significant difference was found between groups for the risk of catheter failure (hazard ratio, 1.27; 95% CI, 0.67-2.43; P = .46).
Conclusions and Relevance
No difference was found in thrombosis in MCs with 2 distinct antithrombogenic mechanisms; however, the risk of CRT in both groups was high. Practitioners should strongly consider the safety risks associated with MCs when determining the appropriate vascular access device.
ClinicalTrials.gov Identifier: NCT03725293
Midline catheters (MCs) have rapidly infiltrated the marketplace since 2015, with nearly 850 000 units sold in the US in 2019.1 Guidelines highlight MCs as the ideal choice for intermediate duration of therapy and the best choice for many patients with difficult vascular access (DVA).2,3 These recommendations are largely based on expert opinion focussing on the functionality of MCs rather than the risks of these devices.2,4-6 Despite the rapid expansion of MCs across the globe, few randomized clinical trials and limited high-quality prospective investigations exist that explore complication risks, including catheter-associated bloodstream infection (CABSI) and catheter-related thromboembolism (CRT).6-8
Symptomatic CRT is one of the most serious complications of catheter insertion. Thrombosis interrupts and delays venous therapy, increases cost of care, and can lead to significant adverse patient outcomes, such as bloodstream infection, pulmonary embolism, and postthrombotic syndrome.9-11 The current data on this complication remain extremely limited, equivocal, and highly variable, with rates of symptomatic CRT ranging from 0% to 12%.6,8,12,13
In 2019, a large retrospective analysis13 of 1094 MCs found that 12% were associated with symptomatic CRT. All catheters in this cohort were manufactured with the addition of a polymer to the base polyurethane that was found to reduce thrombosis in vitro.3,14-16 Despite this enhancement, these MCs demonstrated a CRT risk that was substantially higher than even that of central venous access devices (CVADs).3,15,16 Given the high risk in 1 protected catheter, we aimed to evaluate whether the thrombosis risk can be mitigated by using an alternative MC with a distinct antithrombotic mechanism: a chlorhexidine gluconate coating that reduces fibrin sheath development in in vivo ovine models.17
We performed a single-site, parallel, 2-arm randomized clinical trial to assess for symptomatic CRT inclusive of deep vein thrombosis (DVT) or superficial venous thrombophlebitis (SVT), comparing 2 single-lumen midline catheters: 4F antithrombotic MC (MC-AT) (BioFlo 4F, AngioDynamics) and 4.5F antithrombotic and antimicrobial MC (MC-AT-AM) (Arrowg+ard Blue Advance 4.5F, Teleflex Inc). Both catheters are US Food and Drug Administration–approved midline devices. The study was conducted in the US at a large, academic, suburban tertiary care center with 1100 hospital beds. Written informed consent was obtained from all enrolled patients or a legally authorized representative. The trial protocol (Supplement 1) was approved by the Beaumont Health Institutional Review Board. All data were deidentified. This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
On weekdays between January 1, 2019, and October 31, 2020, trained research associates (D.J. and M.H.) recruited consecutive inpatients who met the inclusion criteria. Inpatients 18 years and older who required MC placement by the bedside vascular access team were eligible participants. Indications for midline placement at our facility include DVA, intermediate-duration antibiotics (7-28 days), or both. Patients were excluded if multiple lumens were required; a catheter with an alternative diameter was used; they had been previously enrolled in the study; they withdrew voluntarily; or they were receiving oral, intravenous, or subcutaneous treatment dose anticoagulation (prophylaxis with anticoagulant was permissible).
Advanced practice providers (physician assistants and nurse practitioners) within the bedside vascular access team were eligible to place catheters for this investigation. These 15 practitioners are credentialed in placing ultrasound-guided peripheral intravenous catheters, MCs, and peripherally inserted central catheters. All practitioners had more than 1 year of experience with these procedures before study enrollment. All proceduralists had experience using MC-AT because it was the standard of care midline device for the institution. None of the practitioners had previous experience with MC-AT-AM. The clinical team from Teleflex provided an educational and training pathway (didactic and insertion of 1 to 3 proctored MCs) for practitioners to develop competency on MC-AT-AM placements before study enrollment.
An independent data coordinator within the division of informatics and biostatistics applied the PLAN procedure in SAS software, version 9.4 (SAS Institute Inc) for a randomization list of 2 treatment assignment allocations at a 1:1 ratio using sealed opaque envelopes. Research assistants (D.J. and M.H.) opened each sealed randomization envelope only when eligibility was confirmed and consent obtained. The research staff, clinical treatment team, and study participants were not blinded to the intervention because the devices are visibly different. However, the outcome is objective, and radiologists and epidemiologists were masked when determining thrombosis and infection.
The proceduralist (E.D.) performed the insertion with ultrasound guidance. The inserter captured digital images with measurements of vessel depth and diameter. After cannulation and securement, the inserter (E.D.) confirmed functionality with blood sampling (10 mL) and flushing without resistance. Both trial devices were inserted using a modified Seldinger technique and received the same care and maintenance during hospitalization.
The research team documented practitioner details, vascular access device (VAD) details (type, insertion time, indication [DVA or antibiotics], orientation, attempts, need for a rescue inserter, and vein details [vein name, depth, and diameter]). Electronic medical record data included age, sex, body mass index (BMI), vital signs, and relevant medical history. Specific medical history of interest included the following: venous thromboembolism; cancer (within the past 6 months); hypercoagulable condition (pregnancy or up to 8 weeks postpartum, estrogen supplementation, or inflammatory diseases); major surgery or major trauma within past 4 weeks; travel of more than 6 hours within the past 4 weeks; and immobilization for more than 72 hours.
Research staff performed follow-up assessments on all catheters within 24 hours of insertion and then daily while the patient was hospitalized. At each follow-up interval, the researcher evaluated functionality. If research staff identified a failed MC during the follow-up assessment, the date and time of failure were considered the assessment time. If the catheter failed or was removed before follow-up assessment, research staff extracted failure details from the medical record. Researchers noted reinsertion data for all (reinsertion of the midline or escalation to a peripherally inserted central catheter, central venous catheter, or ultrasound-guided peripheral intravenous catheter). If the patient was discharged before the time of the follow-up assessment, the VAD was presumed to be functional until time of discharge unless otherwise noted in the electronic medical record.
If the patient was discharged with an MC for continued therapy, the research team followed up with the patient or caregiver via telephone within 48 to 72 hours of discharge to assess for functionality and complications. Once therapy was completed and the catheter was removed, the research staff followed up with the patient and caregiver on a weekly basis via telephone to inquire about the access site. Research staff specifically inquired about insertion site pain and redness and whether radiographic testing for CRT had been performed. Researchers queried the medical record for up to 30 days after catheter insertion for testing and results pertaining to CRT and CABSI. The medication administration record was queried for medications given through the midline catheters including administration of vesicants (eAppendix in Supplement 2).
The primary outcome of this study was the incidence of symptomatic midline CRT, inclusive of DVT or SVT. The secondary outcomes included catheter failure and CABSI.
Midline CRT was defined as the presence of DVT or SVT in the same arm as the catheter up to 30 days after MC insertion diagnosed on evaluation with compression venous duplex ultrasonography, the first-line imaging modality for evaluation of CRT.18 The clinical treatment team ordered all ultrasonograms based on symptoms (ie, pain or swelling), and imaging results were interpreted by blinded board-certified radiologists.
Catheter failure was defined as unresolvable malfunction or complication that resulted in catheter removal before completion of therapy. Daily MC site and catheter evaluations performed by the research staff were used to identify functionality and premature catheter failure. A catheter was functional if clinical staff were able to withdraw 3 to 5 mL of blood and/or if the VAD flushed without resistance using 5 mL of normal saline. Research staff abstracted the cause of failure from the medical record, although this was not a prespecified aim.
CABSI was identified based on the National Healthcare Safety Network’s definition of noncentral CABSI.19
Previous data demonstrated a 12% rate of symptomatic CRT when using the product MC-AT.13 Other existing literature on midline CRT reported substantially lower rates (0%-4.5%).20,21 Therefore, we assumed a 12% rate of CRT for the MC-AT group and a clinically significant reduction of approximately 10% in the alternative group (MC-AT-AM). We thought that a 10% reduction was a realistic assumption considering existing data and that the alternative antithrombogenic MC had demonstrated reduction of thrombosis in vivo.17 Power analysis was calculated based on a 1-sided Fisher exact 2-proportions test with a type I error α = .05. A sample size of 212 patients (106 per group) conferred 80% power to detect an absolute difference of 9% to 10% in the reduction of thrombosis rate for the alternative group (MC-AT-AM); however, there was a smaller power range from 19% to 62% for detecting the smaller absolute difference of 4% to 8% in the reduction between groups. Alternatively, for 80% power, a sample size of 1476 (738 per group) may have been required to detect the absolute difference of 4% or larger in reduction between groups.
The analysis of patients undergoing treatment included all patients who were eligible and randomly assigned to receive MC-AT-AM or MC-AT with complete follow-up. Categorical data given as numbers (percentages) and continuous data as means (SDs) for each study group were compared by using a t test and χ2 test (or equivalent Fisher exact test), respectively.
For the primary outcome, we calculated and compared the difference of rates of symptomatic midline CRT between study MCs using the Fisher exact test. Comparisons of incidences per 1000 catheter-days between groups were also analyzed by univariable Poisson regression, in which the incidence was used as the numerator and the number of catheter-days for patients was used as the denominator to form an incidence rate ratio. Exact Poisson 95% CIs were reported. Univariable Cox proportional hazards regression was further used to assess the relative risk of MC-AT-AM vs MC-AT for the symptomatic midline CRT. The Firth bias correction was used for rare events in study sample, and the corresponding 95% profile likelihood-based CIs of the hazard ratio (HR) were reported.
For the secondary outcomes, the premature catheter failure was compared between groups using time to event methods. We fitted a multivariable Cox proportional hazards regression model to assess the HR for catheter failure, adjusted for variables associated with the catheter failure at P < .20 on bivariate regression and specified by practitioners based on clinical rationale, including heart rate, temperature, blood oxygen saturation, immobilization, location of catheters, distance from antecubital fossa, infusates, and catheter-vein ratio. No violation of proportional hazards assumption based on the Schoenfeld residuals occurred. All tests with a 2-sided P < .05 were considered to indicate statistical significance. All statistical analyses were performed with SAS, version 9.4.
A total of 212 patients were enrolled and randomized with 21 excluded, leaving 191 patients in the final analysis (mean [SD] age, 60.2 [16.7] years; 114 [59.7%] female), with 94 patients in the MC-AT group and 97 in the MC-AT-AM group (Figure). The median hospital length of stay was 8 days (range, 5-14 days) in the MC-AT-AM group and 11 days (range, 7-20) in the MC-AT group (P = .33). A total of 45 patients (46.4%) in the MC-AT-AM group and 52 (55.3%) in the MC-AT group were discharged home with an MC (P = .22). Patient characteristics and MC-related insertion variables were similar in both groups except for BMI, systolic blood pressure, and catheter-vein ratio. A total of 116 catheters (60.7%) were placed for antibiotics administration, with 62 (32.5%) placed for DVA (Table 1).
Venous duplex sonography was conducted on 25 study participants (11 in the MC-AT group and 14 in the MC-AT-AM group), with 18 (72.0%) demonstrating CRT. Symptomatic CRT (DVT or SVT) occurred in 7 patients (7.5%) in the MC-AT group and 11 (11.3%) in the MC-AT-AM group a difference that was not statistically significant (P = .46) (incidences of 6.6 vs 12.5 per 1000 catheter-days, P = .24); the risk of symptomatic midline CRT was not statistically significantly higher for in MC-AT-AM group (HR, 1.41; 95% CI, 0.56-3.75; P = .49). Deep vein thrombosis occurred in 5 patients (5.3%) in the MC-AT group and 5 patients (5.2%) in the MC-AT-AM group (P > .99) (incidences of 4.7 vs 5.7 per 1000 catheter-days, P > .99), and the risk of DVT was not statistically significantly higher for the MC-AT-AM goup (HR, 1.31; 95% CI, 0.39-4.49; P = .67) (Table 2). Proximal DVT (axillary) occurred in 60% of 10 DVT cases. Time to DVT diagnosis ranged from 2 to 23 days after catheter removal (Table 3). Nineteen patients experienced leaking and/or pain, common symptoms of thrombosis, and 10 patients (4 in the MC-AT group and 6 in the MC-AT-AM group) with these symptoms did not undergo ultrasonography. Pulmonary embolism occurred in 1 patient in the MC-AT group. No cases of CABSI occurred in either group.
Premature catheter failure occurred in 22 patients (23.4%) in the MC-AT group and 20 (20.6%) in the MC-AT-AM group. In multivariable Cox proportional hazards regression analysis, accounting for indwelling time, no statistically significant difference was found between groups in the risk of catheter failure (HR, 1.27; 95% CI, 0.67-2.43; P = .46). The causes of MC failure are given in the eResults and eTable in Supplement 2.
This randomized clinical trial found no statistically significant difference in the incidence of CRT between study catheters despite a difference in the antithrombogenic mechanism. Both study catheters demonstrated reduction of thrombosis in vitro or in vivo, but those results did not translate to patients in this clinical trial.17,22,23 To our knowledge, no outcomes data are available in humans on antithrombogenic catheter technologies in peripheral catheters. Because these antithrombogenic properties have been more widely applied in CVADs, some evidence from CVADs exists. Notably, a systematic review and meta-analysis of CVAD material and design found that there was no difference in CRT between standard CVADs and devices coated or impregnated with antithrombogenic materials or devices with designs aimed at reducing thrombosis.24 Although this investigation did not evaluate peripheral devices, the conclusions are consistent with our trial findings in MCs, possibly reflecting similar materials and designs.
Our trial incidence of midline CRT was higher than in most of the existing, largely retrospective, published evidence.7,20,21 Regardless of the antithrombogenic catheter enhancements, the CRT rates approximated the higher extremes of CVADs rather than lower rates reported in other peripheral catheter types.25 Notably, in 60% of DVTs, thrombosis was proximal and involved the axillary vein, and in several cases, thrombosis was extensive and involved multiple vessels, even extending to central vasculature. Only 1 other prospective evaluation8 has been published in which symptomatic thrombosis is the primary outcome. Lisova et al8 published a prospective, observational study of 439 MCs and found a thrombosis rate of 4.5% or 3.3 per 1000 catheter-days. It was unclear from the publication whether all symptomatic patients underwent ultrasonography. These results are similar to our DVT incidence of 5% and higher than in several other published retrospective studies.7,20,21 A key limitation of most of the current literature on this topic is the lack of accounting regarding whether all symptomatic upper limbs were assessed using ultrasonography. We believe the discrepancy in incidence of thrombosis is attributable to a lack of testing rather than a true reflection of the disease. At our institution, the primary treatment team is responsible for initiating the ultrasonography order if the patient is symptomatic, not the vascular access team. Because health care professional practices are variable, even in this scenario, some symptomatic arms were likely not assessed with ultrasonography. We observed this finding in our trials because 10 of 19 patients who had leaking or pain as a reason for catheter removal were never assessed further with ultrasonography (eDiscussion in Supplement 2). Thus, this study potentially underestimates the true incidence of symptomatic CRT.
Our study has some limitations. This study was conducted at a single site; the patient population, hospital resources, protocols, policies, and staffing were unique to the site, and results may not translate to all settings. Although there are numerous US Food and Drug Administration–approved MCs on the market, this study considered only 2 catheters. Because there are variabilities in catheters, it is possible that the results do not apply to all MCs. Both catheters in this trial had antithrombogenic properties, and CRT in uncoated MCs was not assessed. Because uncoated MCs are commonly used, it is possible that the thrombosis potential may be even higher in those catheters. This issue was a major patient safety consideration when choosing the catheters for comparison in this trial. Finally, the ad hoc sample size estimation was limited given the sparse existing literature on the topic. Some key assumptions that influenced this calculation about suspected improvements in outcomes using an antithrombogenic and antimicrobial catheter did not come to fruition. The limited existing data at the time were also considered, which generally reported lower rates of thrombosis ranging from 0% to 4.5%, validating the sample size estimation. It is possible that there may be a difference between the investigational MCs that was undetected because of the sample size limitation. In addition, the sample size was not powered for the outcome of CABSI. During the study design process, we recognized that this end point would require a substantially larger sample size and likely a multicenter approach to adequately assess. Although no cases were associated with bloodstream infection in our cohort, this outcome was likely inadequately assessed.
This randomized clinical trial found that both MCs had high rates of symptomatic CRT. Furthermore, the study found no difference in thrombosis in the 2 MCs despite enhancement with distinct antithrombotic mechanisms. These results suggest that practitioners should strongly consider the safety risks associated with MCs when determining an appropriate VAD.
Accepted for Publication: July 22, 2021.
Published: October 6, 2021. doi:10.1001/jamanetworkopen.2021.27836
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2021 Bahl A et al. JAMA Network Open.
Corresponding Author: Amit Bahl, MD, MPH, Department of Emergency Medicine, Beaumont Hospital, Royal Oak, 3601 13 Mile Rd, Royal Oak, MI 48073 (firstname.lastname@example.org).
Author Contributions: Dr Bahl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Bahl, Diloreto.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Bahl, Diloreto, Hijazi, Chen.
Critical revision of the manuscript for important intellectual content: Bahl, Diloreto, Jankowski, Chen.
Statistical analysis: Hijazi, Chen.
Obtained funding: Bahl.
Administrative, technical, or material support: Bahl, Diloreto, Jankowski.
Supervision: Bahl, Diloreto, Hijazi.
Conflict of Interest Disclosures: Dr Bahl reported receiving grants from Teleflex during the conduct of the study and personal fees from the Teleflex Key Opinion Leader program outside the submitted work. Ms Diloreto reported receiving grants from Teleflex and BD during the conduct of the study outside the submitted work. No other disclosures were reported.
Funding/Support: The research was funded via an educational grant for research from Teleflex.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.