H E M A P H E R E S I S

Acid-citrate-dextrose Formula A versus heparin as primarycatheter lock solutions for therapeutic apheresis

Melanie Osby, Pat Barton, Chun Nok Lam, and Minh-Ha Tran

BACKGROUND: Unfractionated heparin (UFH) is acommonly used catheter lock solution, but may lead tovarious complications. Acid-citrate-dextrose Formula A(ACD-A), the standard anticoagulant used in therapeuticapheresis (TA), is an alternative. We compared the effi-cacy of these two anticoagulants as primary catheterlock solutions.STUDY DESIGN AND METHODS: The following out-comes were analyzed retrospectively for all TA proce-dures performed between July 2009 and March 2012:patent, partial occlusion, total occlusion, catheter-related blood stream infection, tissue plasminogen acti-vator use, and premature catheter removal.RESULTS: Our primary data set included 5964 totalcatheter days, 3020 procedures, and 427 TA courses.The UFH group comprised 3444 catheter days and1880 procedures; the ACD-A group, 2520 catheter daysand 1140 procedures. Overall catheter-related out-comes differed by not more than 5.3% for the primaryanalysis and when stratified by short-term (�10 days)duration or short dwell times (<3 days). When stratifiedby long-term duration (>10 days) and long dwell times(>3 days), differences increased to not more than 10.4and 22.4%, respectively.CONCLUSIONS: For short-term courses and shortdwell times, UFH and ACD-A appear equally effective;UFH appears superior to ACD-A in the setting of long-term courses and long dwell times. Major catheter-related complications were rare and occurred withsimilar frequency in both groups. For most indications,ACD-A appears to be a reasonable alternative toheparin; however, an adequately powered, randomizedtrial would be required to definitively address this issue.

The ability to achieve stable flow rates duringtherapeutic apheresis (TA) procedures oftenrequires effective access. Catheter occlusionsresult in reduced flow rates, high-pressure

alarms, may serve as a nidus for microbial colonization,and may require catheter replacement. Such occlusionstypically result from development of biofilms and fibrinthrombi, which in turn may predispose to local or sys-temic infection.1,2 In practice, therefore, clinicians rou-tinely instill, or “lock,” the lumens of indwelling catheterswith an anticoagulant to prevent development of intralu-minal occlusions. The duration of time this lock solutionresides, or “dwells,” within the catheter lumens betweenprocedures is referred to as the dwell time. Numerous locksolutions have been described in the literature.3,4

HemaCare Corp., a provider of mobile apheresis ser-vices to University of California Irvine Medical Centerand more than 70 other centers throughout SouthernCalifornia, routinely utilizes a variety of catheter locksolutions according to physician preference at eachcenter. Overall, unfractionated heparin (UFH) is the stan-dard lock solution utilized in most hospitals.2 The use ofUFH, however, can be problematic as systemic exposurecan result in prolongation of the activated partial

ABBREVIATIONS: CRBSI(s) = catheter-related blood stream

infection(s); TA = therapeutic apheresis; TPA = tissue

plasminogen activator; UFH = unfractionated heparin.

From the Department of Pathology and the Department of

Emergency Medicine, Keck School of Medicine of USC, Los

Angeles, California; HemaCare Corp., Van Nuys, California; and

the Department of Pathology and Laboratory Medicine,

University of California at Irvine, Irvine, California.

Address correspondence to: Melanie Osby, HemaCare

Corporation, 15350 Sherman Way, Van Nuys, CA 91406-4297;

e-mail: mosby@hemacare.com.

This study was performed without external support.

Received for publication January 8, 2013; revision received

May 7, 2013, and accepted May 10, 2013.

doi: 10.1111/trf.12310

TRANSFUSION 2014;54:735-743.

Volume 54, March 2014 TRANSFUSION 735

thromboplastin time, bleeding complications, and thepotential for heparin-induced thrombocytopenia andthrombosis.5,6 In addition, heparin shortages and recallsdue to contamination or other problems during manu-facturing occur, resulting in the need to use an alterna-tive lock solution.7,8

A number of studies have now been published com-paring the efficacy of alternative lock solutions toheparin in the dialysis setting. Citrate, in concentrationsvarying from 2.2% (as found in acid-citrate-dextroseFormula A [ACD-A],) to 4% to 46.7% (trisodium citrate)has generally demonstrated similar efficacy and lowercost compared to UFH (5000-10,000 U/mL) as a catheterlock solution.9-16 In addition, the American Society forDiagnostic and Interventional Nephrology supports 4%citrate as a primary lock solution for dialysis patients.17

To our knowledge this is the first large study com-paring ACD-A to heparin as a primary catheter lock solu-tion in the TA setting. ACD-A, the standard anticoagulantused for TA,18,19 is available as 500-, 750-, or 1000-mL pre-mixed bags, although most procedures can be completedwith less than 400 mL. Given that the required volumefor the catheter lock solution is low (<2 mL per lumen),the residual volume of ACD-A remaining at the end ofthe procedure is more than sufficient. Thus, it hasbecome standard practice at the University of California,Irvine, using sterile precautions and aseptic technique,to withdraw residual ACD-A from the bag to utilize asa catheter lock solution after completion of the TAprocedure.20

The other HemaCare contracted facilities relied pri-marily on the patient’s primary ordering physicianto oversee the apheresis procedures. In the absence ofcenter-specific preference for an alternative catheterlock solution, HemaCare Corp. utilized heparin as theprimary lock solution, while ACD-A was used as an alter-native lock solution in patients with a contraindication toheparin use (e.g., heparin-induced thrombocytopeniaand thrombosis). HemaCare routinely utilized the sameprocedure as University of California, Irvine, whenACD-A was requested as the primary or alternative locksolution. The decision to utilize tissue plasminogen acti-vator (TPA) was left to the discretion of clinicians at eachcenter; therefore, the use of TPA is not standardized andreflects clinical variability. The use of TPA, therefore, wasnot synonymous with a total occlusion event, and someclinicians may have a lower threshold than others whendeciding to instill TPA into a partially or totally occludedcatheter.

Both centers have experienced excellent outcomeswith inpatient and outpatient procedures using ACD-A asa primary lock solution. We therefore sought to combineour data to compare catheter-based outcomes wheneither UFH or ACD-A were used as the primary lock solu-tion for TA procedures.

MATERIALS AND METHODS

Permission was obtained from HemaCare Corp. and therespective institutional review boards at University ofSouthern California and the University of California,Irvine, to conduct a retrospective chart review to comparecatheter-based outcomes in TA courses.

A retrospective analysis of all TA procedures from July2009 to March 2012 was performed. Information pertain-ing to catheter lock solution and catheter performancewas taken from apheresis procedural documentationrecorded at each procedure. Catheter patency was notedusing descriptors such as “patent,” “sluggish,” “clotted,” or“occluded.” The use of recombinant human TPA wasrecorded. We included both systemic (defined as clinicalsymptoms of infection associated with concordant bacte-rial speciation between catheter tip and peripheral bloodcultures) or local (erythema with purulent discharge butno systemic infection) infections when enumeratingcatheter-related blood stream infections (CRBSIs). Allcatheters were either temporary (rigid) or tunneled, ind-welling hemodialysis type. The specific makes and modelsof the catheters were not recorded. For the primary dataset, therapeutic courses were excluded if fewer than threeprocedures were performed in a course, access other thana central venous catheter was used, or if more than onelock solution was used throughout the course of the pro-cedure. This latter circumstance was addressed in a sepa-rate analysis and defined as the “mixed group.”

The following catheter-related outcomes were gath-ered from procedure notes and analyzed: patent, partialocclusion, total occlusion, TPA use, CRBSI, and catheterremoved due to dysfunction. Partial occlusion wasdefined as one or both ports being sluggish, while totalocclusion was defined as the inability to draw from one orboth ports. The analysis was stratified for duration ofTA course: not more than 10 days versus more than10 days, representing short- and long-term apheresiscourses, respectively. Further analyses were performed onextended-duration courses (>30 days). Mean interapher-esis intervals were calculated as the total number of cath-eter days divided by the number of procedures. Thediagnostic indication for TA was also recorded.

Statistical analysisResults were entered into a computer spreadsheet (Excel,Microsoft Corp., Redmond, WA) database and analyzedfor descriptive statistics and proportional comparisons(STATA 12, StataCorp LP, College Station, TX). Fisher’sexact test was used to compare the proportion of patientoutcomes resulting in patent, partial occlusion, totalocclusion, CRBSI, and TPA use between the ACD-A andheparin groups. To be included in either group, theselected lock solution had to have been applied through-out the apheresis course. These comparisons were further

OSBY ET AL.

736 TRANSFUSION Volume 54, March 2014

examined by stratifying the duration of TA courses of morethan 10 catheter days and equal to or less than 10 catheterdays. All tests of significance were two sided, and differ-ences were considered significant with a p value of lessthan 0.05. In a separate analysis, a mixed group was sepa-rately analyzed due to the utilization of both lock solu-tions during major portions of each catheter course.

Data integrityData were complete for 287 of 295 (97.2%) heparin coursesand 120 of 132 (90.9%) ACD-A courses. In the heparingroup, 21 of 1880 (1.1%) data points were missing and 18of 1140 (1.6%) ACD-A data points were missing. Analysisproceeded with all 295 heparin courses and all 132 ACD-Acourses using the available data as an intention-to-treatanalysis. Data for the mixed group were complete.

RESULTS

Our primary data set included 427 total TA courses over5964 catheter days, comprising 3020 procedures. As a con-sequence of our inclusion criteria requiring a minimumof three consecutive procedures, those indications thattypically require only one or two procedures (such asleukocytapheresis or erythrocytapheresis) were effectivelyexcluded. Therefore, the majority of procedures weretherapeutic plasma exchanges.

In the heparin group, there were 295 TA courses over3444 catheter days, comprising 1880 procedures; afterexclusion of one catheter removed, the total became 294patients and 1843 procedures. In the ACD-A group, therewere 132 TA courses over 2520 catheter days, comprising1140 procedures; after exclusion of one catheter removed,the total became 131 patients and 1134 procedures. In themixed group, there were 31 TA courses over 823 catheterdays, comprising 543 procedures. No significant bleedingcomplications were reported.

For the primary data set, TA course characteristicsand primary diagnostic indications for TA are presented inTable 1 and Fig. 1. In general, the ACD-A group were pre-dominantly patients diagnosed with thrombotic thromb-

ocytopenic purpura (33.7% vs. 12.6%), and had greaternumbers of procedures per course (8.6 vs. 6.4) and cath-eter days per course (19.2 vs. 11.7). In comparing TAcourses with durations greater than 30 days, the ACD-Agroup had a greater mean, (median), and standard devia-tion (SD) duration than did the heparin group (127.7,[79.0], [130.3] vs. 67.1, [49.5], [45.8]).

Catheter-related outcomes are presented in Tables 2through 4). The major difference between groups involvedpartial occlusion events (see Fig. 2). Total occlusionevents, CRBSIs, and catheter dysfunction resulting incatheter removal were similar across all groups.

In the overall analysis, outcomes differed by 5.3% orless between UFH and ACD-A groups. Important modifi-ers of event likelihood included catheter duration of notmore than 10 days versus more than 10 days (�3.6% vs.�10.4%—see Table 2), and dwell time of fewer than 3 daysversus 3 days or more (�1.7% vs. �22%—see Table 3); dif-ferences favored the heparin group.

Dwell times of fewer than 3 days were most common,comprising 87% of all procedures. Mean dwell times (esti-mated as catheter days/number of procedures) for ACDand UFH groups were 2.2 and 1.8 days, respectively; dwelltimes of 3 days or more were associated with 80% of allTPA use.

Utilization of TPA was concentrated within a smallproportion of catheters. In the heparin group, all TPA useoccurred with three of 295 (1%) catheters; nine of 11 (82%)instances involved one catheter that was in place for 155days. In the ACD-A group, all TPA use occurred with eightof 132 (6.1%) catheters; 16 of 23 (70%) instances involvedtwo catheters, one in place for 114 days, and the other for458 days.

There were 31 catheter courses (comprising 543 pro-cedures and 823 catheter days—see Table 4) in which bothlock solutions were utilized. In this group, referred to asmixed group, the mean, (SD), (range), and median courseduration, in days, were 26.5, (29), (4-117), and 16, respec-tively. The mean dwell time and number of procedures percourse was 1.5 days and 17.5, respectively.

For the mixed group, outcomes strongly favoredACD-A, with differences up to 27.6%. Differences in the

TABLE 1. TA course characteristicsDescription UFH group ACD-A group

Total number of courses (procedures) (catheter days) 295 (1880) (3444) 132 (1140) (2520)Mean procedure number 6.4 8.6Mean catheter days 11.7 19.2Mean dwell time (days) 1.8 2.2Short-term courses, number (%) 225/295 (76.3%) 93/132 (70.5%)Long-term courses, number (%) 70/295 (23.7%) 39/132 (29.6%)Number of courses (%) with catheter days > 30 20/295 (6.8%) 12/132 (9.1%)Catheter days of extended courses, mean, median, (SD), (range) 67.1, 49.5, (45.8), (31-184) 127.7, 79.0, (130.3), (31-458)Procedure numbers of extended courses, mean, median, (SD), (range) 20.0, 15, (14.6), (4-49) 27.0, 26, (14.0), (11-55)Mean dwell time for extended courses (days) 3.4 4.7

ACD-A VS. UFH AS CATHETER LOCK IN TA

Volume 54, March 2014 TRANSFUSION 737

Fig. 1. Distribution of diagnoses: heparin (�) versus ACD-A (�). MG = myasthenia gravis; TTP = thrombotic thrombocytopenic

purpura; GBS =Guillain-Barre Syndrome; MS = multiple sclerosis; MM = multiple myeloma; RR = antibody-mediated renal trans-

plant rejection.

Fig. 2. Partial occlusions per catheter by catheter duration (�) ACD-A; (�) UFH.

OSBY ET AL.

738 TRANSFUSION Volume 54, March 2014

TAB

LE

2.R

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lts

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ys.

ACD-A VS. UFH AS CATHETER LOCK IN TA

Volume 54, March 2014 TRANSFUSION 739

TAB

LE

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05.

OSBY ET AL.

740 TRANSFUSION Volume 54, March 2014

patient disease state between the primary data set(heparin vs. ACD-A) and mixed groups may explain thisdifference. The proportion of TA courses for TTP increasedacross groups: heparin group, 12.6%; ACD-A group, 33.7%;mixed group, 61%; as did the number of procedure daysper course (6.4, 8.6, and 17.5, respectively) and catheterdays per course (11.7, 19.7, and 26.5, respectively). Meandwell time, however, was highest in the ACD-A group andlowest in the mixed group: ACD-A, 2.2 days; UFH, 1.8 days;and mixed group, 1.5 days.

DISCUSSION

We conducted a retrospective review of apheresis proce-dural documentation comparing catheter-related out-comes using UFH and ACD-A as primary catheter locksolutions. Overall efficacy is similar, with rates of partialocclusion, total occlusion, and TPA use differing by only5%. For all analyses, premature catheter removal andCRBSI were rare events that did not appear related toduration, dwell time, or catheter lock solution.

For short dwell times (�3 days) and course durations(�10 days) UFH and ACD-A appear equally effective,whereas UFH appears superior to ACD-A in the setting oflong dwell (>3 days) times and courses of longer duration(>10 days). Longer duration courses were generally char-acterized by longer dwell times. Of interest, ACD-Aappeared superior to UFH in the mixed group, which alsohad the shortest mean dwell time but also the highestmean procedure number and catheter duration, suggest-ing that dwell time may have a stronger impact on partialocclusion rates than overall course duration.

Partial occlusion may be an overly sensitive outcomemeasure since its occurrence does not appear to predict

more important catheter-related outcomes such as totalocclusion, CRBSI, or catheter removal. This may be due tothe subjective nature of this outcome measure. Catheteror patient positioning, which was not always reflected inthe documentation, may affect flow as well as thrombusformation.

In terms of dwell time, the usual schedule of daily TPEtreatments in the setting of thrombotic thrombocytopenicpurpura supports that enrichment for this diagnosis withina particular group would drive down mean dwell times. Theoverall dwell time in the ACD-A group, however, was stilllonger than the heparin group due to an offset introduced bythe greater number of extended courses. Mean dwell timewas lowest in the mixed group, where ACD-A appearedsuperior to UFH. For dwell times of not more than 3 days(comparable to mean dwell times in the dialysis population)our data are generally in agreement with the published lit-erature and support equivalent outcomes whether heparinor ACD-A is used as the primary lock solution.

Weaknesses of our study include its retrospectivedesign and the heterogeneity of patients between groups.Catheter patency evaluation was subject to interobservervariation and our data set contained missing data points,the number of which was small and unlikely to have madea major impact upon the results. The use of TPA was notstandardized and thus its use was not necessarily associ-ated with a total occlusion event. Specific details of eachcatheter (temporary vs. tunneled, brand, internal coating,etc.) were unavailable, but may have impacted perfor-mance. In addition, extended-duration procedures—which were associated with the larger differences inoutcome—are relatively uncommon but happened tocomprise nearly 7% of the UFH group and 10% of theACD-A group.

TABLE 4. Mixed lock solution group*

Outcomes Total

Mixed group

Difference Heparin ACD-A p value

Total number of procedures 543 308 (56.8%) 235 (43.2%)Patent

Number 419 27.5%† 201 218 <0.001†Percent 77.2% 65.3% 92.8%

Partially occludedNumber 122 27.6%† 106 16 <0.001†Percent 22.5% 34.4% 6.8%

Totally occludedNumber 1 0.4% 0 1 1.000Percent 0.2% 0.0% 0.4%

TPA useNumber 1 0.3% 0 1 1.000Percent 0.2% 0.0% 0.3%

CRBSINumber 0 0.0% 0 0 1.000Percent 0.0% 0.0% 0.0%

* No catheters in this group were removed prematurely.† p < 0.05.

ACD-A VS. UFH AS CATHETER LOCK IN TA

Volume 54, March 2014 TRANSFUSION 741

Case reports of a fatal cardiac arrest related to inad-vertent catheter lock injection led to voluntary recalls byCytosol Labs and MedComp21 after a MAUDE AdverseEvent Report involving a MedComp ASH Split hemodialy-sis catheter preinstilled with 46.7% trisodium citrate solu-tion (triCitrasol, Cytosol Laboratories, Braintree, MA).22

This concentration is no longer on the market. To ourknowledge, fatalities have not been reported with lowerconcentration citrate solutions.

Overall, this study demonstrated that ACD-A could beused safely and successfully as an alternative lock solutionfor a large number of apheresis procedures. UtilizingACD-A from the same bag already purchased for the pro-cedure imparts a cost advantage over heparin; however,a formal cost analysis was not a part of this study. Anadequately powered, randomized, prospective, double-blind study comparing UFH (of a specified concentration)to ACD-A would be required to definitively address issuesof superiority or equivalence.

ACKNOWLEDGMENT

We acknowledge the efforts of Anya Coultas for her assistance

with our project.

CONFLICT OF INTEREST

MO is the medical director and consultant for HemaCare Corp.,

which provides TA services to hospitals throughout Southern

California, including University of California Irvine Medical

Center. The decisions regarding treatment courses and antico-

agulant used as a lock solution were made solely by the primary

providers caring for the patients at the respective hospitals. PB is

the Director, Therapeutic Apheresis Services, for HemaCare

Corp., which provides TA services to hospitals throughout South-

ern California, including University of California Irvine Medical

Center. The decisions regarding treatment courses and antico-

agulant used as a lock solution were made solely by the primary

providers caring for the patients at the respective hospitals. CNL

and MHT have no conflict of interest.

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