Vascular access failure is a major cause of morbidity for patients on hemodialysis.1,2 Hospitalizations for vascular access complications also significantly increase the cost of treatment. Whether as temporary or permanent vascular access, tunneled cuffed catheters (TCCs) are being increasingly used for the provision of hemodialysis despite their high rates of complications, including infections, thrombosis, or inadequate dialysis. The most important factors limiting long-term survival of TCCs are poor blood flow and catheter-related infections, each of which can predispose to the other and lead to frequent catheter replacement.3 Hence, patients with a history of recurrent thromboses requiring catheter replacement are considered at high risk for future TCC malfunction. Estimated 1-year TCC patency ranges from 30% to 74%.4
Although there are only limited data regarding the efficacy of systemic anticoagulation to prevent TCC thrombosis and malfunction (the latter presumably representing incipient thrombosis), anticoagulants are commonly used for this indication. Several anticoagulation strategies have been suggested for TCC malfunction prophylaxis.4–11 Fixed minidose warfarin (1 mg daily) has been suggested in hemodialysis patients in view of favorable results reported in cancer patients.12,13 However, fixed minidose warfarin has been shown to be ineffective in reducing TCC thrombosis in long-term hemodialysis patients.4,7 Other investigators have proposed the use of warfarin after the first episode of TCC malfunction to prevent recurrent episodes.8,11 In a study by Webb et al.,11 systemic anticoagulation was used after restoration of catheter patency with urokinase. This study suggested that anticoagulation was effective in preventing recurrent thrombosis when the international normalized ratio (INR) was maintained between 2.0 and 2.5. Twardowski8 reported similar results that suggested that anticoagulation was effective when INR was maintained between 1.5 and 2.5. Other investigators have proposed a stepwise increase in warfarin doses.9,10 Patients are started on low-dose warfarin and the dose is increased until no further thromboses occur. Pierratos et al.10 reported the results from 10 patients on nocturnal hemodialysis. To prevent catheter malfunction, the required average warfarin dose was 2.1 ± 1.6 mg and the required average INR was 1.5 ± 0.9.10 Twardowski9 also reported the results of a stepwise anticoagulation protocol. Although the majority of patients included in the study required an average INR of 0.7–1.1 to prevent catheter malfunction, a significant proportion of patients required INR values ≥ 1.5 and some patients required INR > 2.0.9 Thus, most reports suggest that an INR target > 1.5 may be required for preventing TCC malfunction, especially in high-risk patients.
Based on the above, we designed and implemented an anticoagulation protocol aimed at preventing TCC malfunction using a fixed INR target of 1.5–2.0 in high-risk dialysis patients (such as patients with a history of thrombosis of a previous catheter requiring its replacement). The goal of this study was to evaluate whether this protocol was associated with improved catheter outcome.
Patients and Methods
Study Design and Population Setting
All prevalent patients who underwent hemodialysis using a TCC in our hemodialysis unit as of September 2002 were included in this cohort study. The medical record and dialysis charts of all participants were analyzed from TCC insertion to September 2002. Patients requiring anticoagulation for indications other than TCCs including prothrombotic conditions (i.e., prosthetic heart valve, atrial fibrillation, deep venous thrombosis) were excluded from the present study, because the main objective of this analysis was to evaluate the efficacy of an adjusted-dose anticoagulation protocol to prevent TCC malfunction in high-risk patients.
Catheter Type and Localization
During the period covered by this study, different types of catheters were inserted, including Vas-Cath (14.5 F) and Hickman (13.5 F) catheters (both from Bard Access Systems, Salt Lake City, Utah, USA) in the majority of cases. The preferred insertion site for the TCC was the right internal jugular vein, except in cases of venous thrombosis of the right jugular vein, or if a fistula awaiting maturation or a synthetic graft was located on the right arm. Heparin was instilled into both lumens of the TCC after each dialysis treatment by the dialysis staff.
During the course of this study, the following anticoagulation protocol was used for TCC malfunction prophylaxis in high-risk patients. In the absence of an existing contraindication to anticoagulation, warfarin was prescribed to patients: 1) with a history of thrombosis of a previous catheter requiring its replacement, or 2) whose current catheter exhibited malfunction (cf. below for definition of malfunction) within 2 weeks of insertion in the absence of mechanical problem. All patients with malfunction occurring within 2 weeks of insertion were evaluated by an interventional radiologist who verified proper catheter insertion using either fluoroscopy or chest x-ray. Patients with improper tip position, catheter kinking, or catheter thrombosis had their catheters repositioned or new TCCs inserted but were excluded from further study. Patients with TCCs who did not meet the above criteria (i.e., low-risk patients) were not prescribed warfarin.
Warfarin dose was adjusted aiming for an INR of 1.5–2.0. INR was measured for all patients no less than once a week. For some patients with very unstable INR values, INR was measured up to three times a week (i.e., at each dialysis session). The decision regarding the frequency of INR measurements was based solely on the fluctuations of INR values around the target INR range. Warfarin was prescribed after each INR measurement for all patients in the study by the physician on duty in the dialysis unit. Only one physician was responsible for prescribing warfarin to all patients in the study for a given period (usually 2 weeks), thus limiting variations in anticoagulation prescription between patients due to variations in physician practice.
The decision to initiate anticoagulation was based on the above criteria and was independent of aspirin use. Physicians prescribing warfarin were left with the decision of stopping aspirin, reducing the dose of aspirin, or continuing the same dose of aspirin. The decision was based on the perceived anticipated risk/benefit ratio for each patient.
The following demographics and dialysis-related data were collected on all participants: gender, age, race, presence of diabetes mellitus, cause of end-stage renal disease, and regular use of aspirin. We also recorded the following catheter-related data: date of insertion, localization, indication for insertion (temporary vs. permanent), and the number of previous TCCs, if any. The reason for removal of previous catheters was also recorded if applicable. Other data obtained during the course of this study included single pool Kt/V (a standard measure of dialysis adequacy) and mean blood flow rate (BFR) 15 days after TCC insertion. Blood flow rate was recorded from the dialysis machines. We did not use any specific method to measure BFR such as dilution methods or ultrasound-based methods. Data on major bleeding events were also recorded (cf. below). All patients were followed up from the time of TCC insertion to the occurrence of the first episode of malfunction or end of the study.
Adequate anticoagulation was defined according to the percentage of measured INR values in the target range during follow-up and according to the INR value at the time of malfunction. INR was measured at least once a week or more frequently if indicated. INR was measured using the Neoplastine CI Plus reagent on a STA analyzer (both from Diagnostica Stago, Asnieres, France). Measurement of INR was performed via the arterial sampling port on the hemodialysis bloodline according to the technique described by McLaren et al.14 This method provides INR levels that are comparable to peripheral vein levels measured before dialysis and avoids the discarding of blood containing residues of the heparin lock left in the catheter lumens at the end of the previous dialysis session.14 Anticoagulation was considered adequate if: 1) more than 80% of INR values during follow-up were within the INR target range (i.e., 1.5–2.0), and 2) the INR value measured at the time of TCC malfunction was not below the INR target range.
Definition of Malfunction
Tunneled cuffed catheter malfunction was defined as the occurrence of an episode of inadequate BFR during dialysis when this episode met all of the following criteria: the episode 1) occurred > 2 weeks after insertion; 2) occurred despite repositioning of the patient for two consecutive treatments; 3) was sufficient to necessitate inversion of dialysis lines and/or recombinant tissue-type plasminogen activator infusion (rtPA) infusion in order to perform or to complete the hemodialysis session at the prescribed BFR; and, 4) was not associated with mechanical problems that explained TCC malfunction. Dialysis nurses were instructed to switch lines or to recommend tissue-type plasminogen activator when BFR was significantly reduced compared to the prescribed blood flow (i.e., approximately 25–30% reduction compared to prescribed BFR) to perform or to complete the hemodialysis session at the prescribed BFR. These criteria were defined a priori by the investigators and differ from the National Kidney Foundation's Dialysis Outcomes Quality Initiative (DOQI) guidelines, which recommend that a BFR of < 300 ml/min be used to define TCC malfunction.15 The DOQI definition was not used in the present cohort since there were several older patients with small body weight who had KT/V > 1.4 with prescribed BFR lower than or equal to the criteria set for TCC malfunction in the DOQI guidelines (i.e., 300 ml/min).
Major bleeding events were recorded during the study period. Major bleeds included fatal and life-threatening events and those requiring hospitalization or requiring specific medical interventions to stop the bleeding. Fatal bleeds were defined as those leading directly or indirectly to patient's death. Life-threatening bleeds were defined as occurring intracranially or in other potentially lethal sites, being associated with cardiopulmonary arrest or hypotension, requiring major interventions such as surgery or angiography, or leading to transfusion of blood products (packed red blood cells or fresh frozen plasma). Major bleeding events were documented by reviewing dialysis charts and hospital charts for all patients. All major bleeding events were likely to be captured because all dialysis visits, emergency room visits, in-hospital admissions, and special procedures results (e.g., gastroscopy or surgical procedure) are included in the patient medical records. However, bleeding events not categorized as major were not recorded during the course of this study.
Demographic characteristics and dialysis and catheter-related data were compared between patients who received warfarin (i.e., high-risk patients) and patients who were not prescribed anticoagulation (i.e., low-risk patients). These baseline characteristics were also compared between patients who achieved adequate anticoagulation and those who did not. The significance of differences in means between the groups was assessed using Student's t-test or Wilcoxon rank-sum test, as appropriate. Comparisons between proportions were performed using the chi-square statistic or Fisher's exact test, as appropriate.
The occurrence of TCC malfunction was compared between the different groups of patients using the chi-square statistic or Fisher's exact test, as appropriate. A survival analysis was performed to evaluate malfunction-free TCC survival according to anticoagulation adequacy. Survival curves comparing time with TCC malfunction were calculated using the Kaplan-Meier method. The log-rank test was used to assess differences between groups. Time was calculated from catheter insertion to the index TCC malfunction. If a patient had more than one TCC malfunction episode, the first episode occurring > 2 weeks after insertion was analyzed as the index event. Data were censored if a patient remained free of TCC malfunction at the end of the study period. Cox proportional hazards regression analysis was performed to adjust the above analysis for aspirin use.
All p values are two-tailed, and values less than 0.05 are considered statistically significant. Analyses were performed using Statistica 6.0 (Statsoft, Tulsa, OK).
As of September 2002, 70 patients were dialyzed using a TCC at our institution. Five patients were excluded from the analysis because they required anticoagulation for indications other than TCC (i.e., prosthetic heart valve, atrial fibrillation, and deep venous thrombosis).
Anticoagulation was used in 35 patients (53.8%) who were considered at high risk for TCC malfunction. Of those, 23 (65.7%) were prescribed warfarin because they had a history of catheter thrombosis requiring catheter replacement. Twelve patients (34.3 %) were prescribed warfarin because the current TCC exhibited malfunction within 2 weeks of insertion in the absence of a mechanical problem. The remaining patients (n = 30) were considered at low risk for TCC malfunction and did not receive anticoagulation.
Among patients receiving warfarin (n = 35), 19 patients (54.3%) achieved adequate anticoagulation (i.e., > 80% of follow-up INR values within target range and INR value at the time of malfunction not below range). Anticoagulation was considered inadequate in 16 patients (45.7%) because of: 1) persistent failure to achieve target levels (i.e., < 80% of INR values within target range) in 3 patients (18.8%); 2) INR level below range (< 1.5) at the time of TCC malfunction in 7 patients (43.8%); or 3) both criteria in 6 patients (37.4%).
Demographic and dialysis-related characteristics of patients with and without anticoagulation are provided in Table 1. There were no statistically significant differences between the different groups of patients in terms of demographic characteristics and dialysis-related characteristics. Aspirin use was the most frequent (53.3%) in patients who were not prescribed anticoagulation (i.e., No-AC group or low-risk patients), whereas it was the least frequent (31.6%) in high-risk patients with adequate anticoagulation (i.e., AC-adequate group) However, this difference was not statistically significant (p = 0.3).
Catheter-related characteristics were similar in all groups (Table 2). During the period covered by this study, the vast majority of catheters inserted were Vascath Optiflow and Hickman catheters. The predominant insertion site was the right internal jugular vein. The left internal jugular vein was occasionally used, notably in cases of thrombosis of the right jugular vein, or if a fistula awaiting maturation or a synthetic graft was located on the right arm. The study catheter was the first ever implanted in 73% patients in the low-risk group, whereas this proportion was only 17% in the high-risk group. The indication for TCC was temporary use in 68.4–75.0% of patients while it was used as a permanent access in 25.0–31.6% (Table 2).
Mean follow-up time was 4.2 ± 6.4 months (mean ± SD). There was no significant difference in TCC occurrence between the low-risk group (i.e., patients without anticoagulation or No-AC group) and the high-risk group taken as a whole (i.e., all patients with anticoagulation or AC-overall group) (Table 3). However, there was a significant difference in TCC malfunction (p = 0.02) when comparing patients with adequate anticoagulation and those failing to achieve adequate anticoagulation (Table 3). In terms of TCC occurrence rate, adequate anticoagulation was associated with a greater than fivefold decrease in TCC occurrence when compared with inadequate anticoagulation. TCC occurrence rate was 0.75 events per patient-year in patients with adequate anticoagulation (AC-adequate group) versus 3.95 events per patient-year in those failing to achieve adequate anticoagulation (AC-inadequate group).
Mean time from insertion to malfunction was 92.4 ± 96.4 days (range 16–440), with 12 (40%) and 22 (55%) episodes occurring before 30 and 60 days, respectively. Using Kaplan-Meier survival analysis, we found a statistically significant difference in mean time to malfunction between patients with adequate anticoagulation and those failing to achieve adequate anticoagulation (Figure 1). Malfunction-free catheter survival at 9 months was 47.1% in those with adequate anticoagulation compared with only 8.1% in those failing to achieve adequate anticoagulation (p = 0.01). After adjustment for aspirin use with Cox proportional hazards regression analysis, this difference remained statistically significant (p = 0.02).
No episode of major bleeding occurred during the duration of the study. However, bleeding events not categorized as major were not recorded during the study.
Whether as a temporary or permanent access, TCCs are increasingly used for the provision of hemodialysis. The changing patterns of the hemodialysis population (older age, diabetics) and the relative logistic ease of TCC insertion by interventional radiologists certainly contribute to the increasing TCC utilization rate. Hence, an expanding proportion of end-stage renal disease patients now rely on TCC for vascular access for the provision of hemodialysis. However, a major drawback of these vascular accesses, besides catheter-related infections, is catheter malfunction and thrombosis.
In the present study, achieving adequate systemic anticoagulation with adjusted-dose warfarin aiming for an INR of 1.5–2.0 was associated with improved catheter outcome in patients at high risk of TCC malfunction. Occurrence of TCC malfunction and malfunction-free survival were significantly improved in patients achieving adequate anticoagulation when compared to patients failing to achieve adequate anticoagulation. These results confirm a posteriori the accuracy of many clinical observations that have led to the widespread use of anticoagulation for maintaining TCC patency. They also confirm previous reports that suggested that an INR target < 1.5 may be ineffective in preventing TCC malfunction in a significant proportion of hemodialysis patients.
In the present study, anticoagulation was prescribed to patients at high risk of malfunction (i.e., patients with a history of previous catheter thrombosis requiring catheter replacement and patients with TCC malfunction occurring < 2 weeks after catheter insertion in the absence of mechanical problems). The rationale of this approach is to achieve some benefit of anticoagulation without an excessive risk of bleeding by targeting patients at high risk. Whether anticoagulation should be initiated in all patients, however, remains unknown.
When all patients receiving anticoagulation were compared with patients not receiving anticoagulation on an intention-to-treat type analysis (i.e., AC-overall group vs. No-AC group), there was no significant difference in terms of catheter outcome between the groups. This result is not unexpected because the two groups of patients presented with very different risk profiles in terms of TCC malfunction risk. Patients receiving warfarin were at high risk of TCC malfunction, whereas those not receiving anticoagulation were lower-risk patients. However, it is interesting to note that occurrence of TCC malfunction in the high-risk group was not significantly higher than occurrence in the lower-risk group (65% vs. 56%), suggesting a favorable effect of anticoagulation.
Failing to achieve adequate anticoagulation was observed in a significant proportion of patients on warfarin (45.7%) and was associated with poor catheter outcome. We believe that failure to achieve adequate anticoagulation is based on biologic factors rather than on the care and persistence of the physicians, because the anticoagulation protocol was applied uniformly to all patients. Warfarin was prescribed after each INR measurement for all patients by the physician on duty in the dialysis unit. Only one physician was responsible for prescribing warfarin to all patients in the study for a given period (usually 2 weeks), thus limiting variations in anticoagulation prescription between patients due to variations in physician practice.
However, the reasons for failing to achieve adequate anticoagulation are unclear. There was no evidence of procoagulant conditions in any patient included in the study, although we did not specifically measured procoagulant markers. A possible explanation could be the presence of intercurrent medical conditions (such as acute infection) affecting coagulation control. However, our study was not designed to study this hypothesis.
For the purpose of our study, we defined TCC malfunction as the requirement for dialysis line inversion and/or rtPA infusion to perform or complete the hemodialysis session. This definition differed from the DOQI guidelines, which recommend that a BFR of < 300 ml/min be used to define TCC malfunction (based on expert opinion—evidence level V).15 The DOQI definition was not used in the present cohort because there were several older patients with small body weight who had KT/V > 1.4 with prescribed BFR lower than or equal to the criteria set for TCC malfunction in the DOQI guidelines (i.e., 300 ml/min). The DOQI definition that uses a single cutoff value (e.g., 300 ml/min) may not be appropriate for all patients. For instance, a 300-ml/min cutoff may be appropriate for patients with prescribed BFR of 350 or 400 ml/min. However, it is inappropriate for patients with prescribed BFR of 300 ml/min or lower. In the present study, a single predetermined cutoff BFR was impossible to use because several patients had a prescribed BFR of 300 ml/min or lower. Rather, dialysis nurses were instructed to switch lines or to recommend TPA when blood flow was significantly reduced compared to the prescribed BFR (i.e., approximately 25–30% reduction compared to prescribed flow rate) to perform or complete the hemodialysis session at the prescribed BFR.
Bleeding remains the most common side effect of long-term oral systemic anticoagulation therapy. Risk factor for major bleeding complications associated with anticoagulation are well known.16 They include older age, uncontrolled hypertension, and poor drug compliance, many of which are present in the dialysis population. Although the bleeding risk is associated with achieved INR, limited data are available regarding bleeding risk when the INR target is < 2. It is generally believed that low-intensity anticoagulation is associated with a lower risk of bleeding events, although the issue remains controversial. No major bleeding event was reported during the study period. However, the occurrence of minor bleeding events was not recorded. The common practice at our unit is to withhold anticoagulation for patients at higher risk of bleeding and to stop anticoagulation for patients who present with any significant bleeding episode. Awareness of potential drug interactions and careful monitoring is required to minimize the risk of bleeding.
The impact of improving catheter outcome with anticoagulation is difficult to evaluate in terms of quality of care and cost–effectiveness. The present study was not designed to evaluate these questions. However, it is reasonable to hypothesize that adequate anticoagulation may improve hemodialysis efficiency (e.g., avoidance of recirculation caused by inversion of lines) and/or reduce the costs of treatment (e.g., rtPA infusions, catheter stripping or replacement).
Our results apply primarily to patients with Vascath and Hickman catheters. It is possible that other types of catheters (e.g., split tip catheters) have different survival rates in response to systemic anticoagulation. However, our study was not designed to specifically address this question.
One limitation of the present study was its nonrandomized design. The efficacy of the present anticoagulation protocol will need to be evaluated with a randomized controlled trial. In addition, future studies will need to determine the optimal level of anticoagulation for TCC malfunction prophylaxis. Finally, studies will need to evaluate the impact of anticoagulation in terms of quality of care and cost of treatment.
In summary, our study supports the use of anticoagulation for the prevention of TCC malfunction in long-term hemodialysis patients at high risk of malfunction. Achieving adequate anticoagulation with target INR 1.5–2.0 may prevent TCC malfunction and improve catheter outcome.
Preliminary results of this work were presented at the 2003 meeting of the American Society of Nephrology and have been published in abstract form (J Am Soc Nephrol 14: 242, 2003). FM is a scholar of the Fonds de la recherche en santé du Québec. The authors thank Danielle Binette for providing computer graphics and secretarial expertise.
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