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Journal of Clinical Oncology, Vol 24, No 9 (March 20), 2006: pp. 1404-1408 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.5600 Incidence, Risk Factors, and Outcomes of Catheter-Related Thrombosis in Adult Patients With Cancer
From the Departments of Medicine, Clinical Epidemiology & Biostatistics, and Radiology, McMaster University; and the Henderson Research Centre; and the Hamilton Health Sciences, Hamilton, Ontario, Canada Address reprint requests to Agnes Y.Y. Lee, MD, Hamilton Health Sciences Henderson Hospital, 711 Concession St, Hamilton, ON L8V 1C3 Canada; e-mail: alee{at}mcmaster.ca
PURPOSE: Thrombosis of long-term central venous catheters (CVC) is a serious complication that causes morbidity and interrupts the infusion of chemotherapy, intravenous medication, and blood products. We performed a prospective study to examine the incidence, risk factors, and long-term complications of symptomatic catheter-related thrombosis (CRT) in adults with cancer. PATIENTS AND METHODS: Consecutive patients with cancer, undergoing insertion of a CVC, were enrolled and prospectively followed while their catheter remained in place plus 4 subsequent weeks or a maximum of 52 weeks, whichever came first. Patients with symptomatic CRT were followed for an additional 52 weeks from the date of CRT diagnosis. The end points were symptomatic CRT, symptomatic pulmonary embolism (PE), postphlebitic syndrome, and catheter life span. RESULTS: Over 76,713 patient-days of follow-up, 19 of 444 patients (4.3%) had symptomatic CRT in 19 of 500 catheters (0.3 per 1,000 catheter-days). The median time to CRT was 30 days and the median catheter life span was 88 days. Significant baseline risk factors for CRT were: more than one insertion attempt (odds ratio [OR] = 5.5; 95% CI, 1.2 to 24.6; P = .03); ovarian cancer (OR = 4.8; 95% CI, 1.5 to 15.1; P = .01); and previous CVC insertion (OR = 3.8; 95% CI, 1.4 to 10.4; P = .01). Nine of the 19 CRT patients were treated with anticoagulants alone, eight patients were treated with anticoagulants and catheter removal, while two patients did not receive anticoagulation. None had recurrent CRT or symptomatic PE. Postphlebitic symptoms were infrequent. CONCLUSION: In adults with cancer, the incidence of symptomatic CRT is low and long-term complications are uncommon.
Hickman tunneled catheters, subcutaneously implanted ports, and peripherally inserted central catheters (PICCs) are long-term, indwelling devices used for facilitating access to the central venous system. These central venous catheters (CVCs) are commonly used for delivering chemotherapy, parenteral nutrition, blood products, and other intravenous therapy in patients with cancer. In addition, these catheters facilitate blood drawing and the administration of parenteral treatment at home for selected patients. Unfortunately, thrombosis of the catheterized vein is a potential complication.1,2 Although many cases are asymptomatic and are of uncertain clinical significance,3 catheter-related thrombosis (CRT) can cause serious morbidity, including pulmonary embolism (PE) and postphlebitic syndrome.4,5 Earlier studies have reported risks of symptomatic CRT as high as 28%, but more recent studies suggest a much lower incidence at 5% or less.2,3,6-12 The reasons for this discrepancy are not known but may include advances in catheter material and design, differences in patient populations, and methodologic limitations of some of the studies.2 In addition to the uncertainty about the incidence of CRT, there is also a lack of reliable data on the risk factors of CRT. Studies have suggested that catheter material, tip position, infection, previous catheterization, and other factors may influence the risk of CRT.2 Long-term sequelae of CRT, including recurrent CRT, PE, and postphlebitic syndrome, are also poorly documented. Most of the published data are from small studies with inadequate follow-up. Without accurate information on the clinical history of CRT, it is difficult to determine the need for thromboprophylaxis, identify patients who have a particularly high risk for CRT, and assess the benefits of therapy. To improve our knowledge about CRT and patient care, we designed a prospective cohort study to determine the incidence, risk factors, and long-term outcomes of symptomatic CRT in patients with cancer.
Patient Population Consecutive, adult patients with cancer, undergoing insertion of a long-term indwelling CVC into the upper limb venous vasculature, were eligible for this study. Patients were excluded if the expected duration of catheter placement was shorter than 2 weeks, if the catheter was intended for dialysis use, or follow-up was not possible. All patients attended the Juravinski Cancer Centre (Hamilton, Ontario, Canada) and received their catheters at the Hamilton Health Sciences Henderson Hospital (Hamilton, Ontario, Canada). Consenting patients were enrolled at the time of their CVC insertion, and baseline information on potential risk factors for CRT was recorded. All catheters were inserted using standard sterile techniques in the radiology department. A radiologist performed the venous access by ultrasound guidance and supervised the insertion procedure by a trained nurse. The PICCs were placed in the basilic vein mid way up the arm when possible. The cephalic and brachial veins were used only when the basilic vein was not suitable or previously thrombosed. The tunneled and port devices were installed almost exclusively in the internal jugular vein, always on the right side except when the vein was judged to be inadequate or absent. Catheter tip placement at the junction of the superior vena cava and right atrium was confirmed by fluoroscopy. Maintenance care for all catheters was provided by home-care nurses following standardized regional guidelines or by patients after they received adequate training. For all catheters, saline flushing was routinely used with the exception of implanted ports, which were flushed with heparin solution 100 U/mL. During the study, the following types of silicone catheters were inserted: PICCs (single or double lumen PASV clampless valved catheter, Boston Scientific, Natick, MA), implanted Ports (Vital Port, regular and petite, Cook Incorporated, Bloomington, IN), Hickman tunneled catheters (Leonard Dual Lumen CV Catheter, Bard Access Systems, Salt Lake City, UT), and pheresis tunneled catheters (Hickman Hemodialysis/Apheresis Central Venous Catheter, Bard Access Systems, Salt Lake City, UT). Anticoagulant prophylaxis and low-dose fibrinolytic flushes for occluded catheters were given according to the most responsible physicians’ discretion. The study was approved by the institutional review board and all participating patients provided written, informed consent.
Follow-Up Period All patients with confirmed symptomatic CRT were followed for an additional 52 weeks from the time of CRT diagnosis. They were contacted at 26 and 52 weeks from the date of their CRT diagnosis for long-term outcomes (eg, postphlebitic syndrome, PE) and were questioned using a standardized list of signs and symptoms. Patients with CRT were treated with anticoagulant therapy with or without removal of the catheter.
Study Outcomes Symptomatic PE. PE was diagnosed in patients with compatible symptoms if any one or more of the following were documented: a high probability ventilation-perfusion lung scan,14,15 intraluminal filling defect of a lobar artery or more proximal pulmonary arterial vasculature on spiral CT or MRI, or an abnormal ventilation-perfusion scan with a high clinical suspicion for PE and documented CRT. Recurrent CRT. Recurrent CRT was defined as objectively confirmed extension of a previously diagnosed CRT, using the same diagnostic imaging method for comparison. Postphlebitic syndrome. Postphlebitic syndrome was defined as the presence of chronic or recurrent swelling or heaviness of the involved arm, with or without discoloration, and not attributed to lymphedema or extrinsic venous obstruction. Catheter life span. The life span of a catheter was measured in catheter-days, starting from the time of insertion to the time of removal, or the time of the last follow-up or patient’s death, if the catheter was still in place.
Statistical Analysis Preselected baseline characteristics (Tables 1 and 2) were assessed as potential risk factors. Univariate analysis of symptomatic CRT by each potential risk factor was performed using logistic regression. A multivariable logistic main-effects regression model was used to simultaneously assess the relationship between the baseline factors and the probability of developing symptomatic CRT. Using a backward elimination modeling strategy, only factors that maintained a P value of less than .10 on the basis of the likelihood ratio test were retained in the final model. Odds ratios (ORs) and corresponding 95% CIs were calculated on the basis of the final model. All tests were two-sided. Because subsequent insertions in patients with multiple catheters are not independent cases, these analyses included only data from the first catheter insertion.
On the basis of published literature, we anticipated an incidence of symptomatic CRT of 15%. Consequently, the sample size was planned at 500 catheter insertions to obtain reasonably narrow confidence limits and to have 80% power to identify an OR of 2.5 or greater for a dichotomous risk factor present in at least 30% of insertions.
From March 2002 to July 2003, 735 CVCs were inserted in patients with cancer at the Hamilton Health Sciences Henderson Hospital. Ninety-five patients did not meet eligibility criteria and 140 patients did not provide informed consent. Accordingly, a total of 500 CVCs were inserted in 444 patients who consented to participate in the study. There were 246 women (55%) and 198 men (45%), with a mean age of 56 years (range, 18 to 91 years). Sixty-six percent of the patients had solid tumors, 64% of whom had metastatic disease, and 34% had hematologic malignancies. The baseline characteristics of the 444 patients and 500 insertions are outlined in Tables 1 and 2. Of the 444 patients, 38 patients had two catheters and eight patients had three or more catheters inserted during the recruitment period. At the time of catheter insertion, 47 patients were already receiving therapeutic doses of anticoagulant therapy for thrombotic indications (eg, atrial fibrillation) and all of them continued to receive anticoagulation after catheter insertion. During follow-up, 166 additional patients received anticoagulants (prophylactic or therapeutic doses) while 231 patients did not receive any anticoagulants. All patients completed follow-up. The total duration of follow-up was 76,713 patient-days and 59,931 catheter-days. A total of 134 patients died; nine patients had CRT, and none of the deaths were caused by fatal PE, according to their local physicians. The incidence of symptomatic CRT was 4.3% (19 of 444 patients; 95% CI, 2.6% to 6.6%) or 0.3 per 1,000 catheter-days (95% CI, 0.2 to 0.5 per 1,000 catheter-days). The median time to CRT was 30 days while the mean time was 53 days (range, six to 162 catheter-days). The median catheter life span was 88 catheter-days (range, two to 376 catheter-days) for all catheters, 89 catheter-days (range, two to 376 catheter-days) for the 481 catheters without CRT, and 57 catheter-days (range, six to 290 catheter-days) for catheters with CRT (log-rank P = .29 comparing catheters with and without CRT). Among catheters with CRT, the median catheter life span was 181 catheter-days (range, 31 to 290 catheter-days) for those treated with anticoagulant therapy alone and 24.5 catheter-days (range, six to 82 catheter-days) for those who also had the catheter removed (log-rank P = .0003). There was no statistically significant difference in the catheter life span between cases that did not have CRT and cases with CRT that were treated with anticoagulant therapy alone (log-rank P = .36). Multivariable logistic regression analysis identified three statistically significant baseline risk factors for CRT: two or more versus one insertion attempt (OR = 5.5; 95% CI, 1.2 to 24.6; P = .03); ovarian cancer versus other sites (OR = 4.8; 95% CI, 1.5 to 15.1; P = .01); and previous versus no previous CVC (OR = 3.8; 95% CI, 1.4 to 10.4; P = .01). Symptomatic CRT developed in 3.3% of those who received any anticoagulant therapy, compared with 5.2% who did not receive any anticoagulant therapy (P = .36, Fisher’s exact). However, the use of anticoagulant therapy was not controlled in this study. During follow-up, development of catheter blockage was associated with CRT (OR = 14.7; 95% CI, 5.5 to 40; P < .0001). A total of 50 catheters developed blockage of which 12 also developed CRT; seven of these cases presented with blockage and CRT at the same time. Sixteen of 500 insertions had evidence of infection at the catheter insertion site but none had documented systemic infection related to the catheter. Only one episode of catheter occlusion was treated with 1 mg of alteplase and it had a successful outcome. Nine of the 19 patients with CRT were treated with anticoagulant therapy alone, eight patients received anticoagulant therapy and had their catheters removed, one patient was treated with catheter removal alone, while one patient did not receive any treatment. Of the 17 patients who received anticoagulant therapy, eight patients received low molecular weight heparin (LMWH) alone, eight patients received initial therapy with a LMWH followed by warfarin, which was dosed to achieve a target international normalized ratio of 2.0 to 3.0, and one patient was treated with intravenous heparin. At 24 weeks after a diagnosis of CRT, 15 of 19 patients were alive, of whom two patients had residual symptoms in the affected arm. By 52 weeks, 10 patients with CRT were still alive and only one patient reported minor discomfort in the affected arm without any swelling. There were no cases of recurrent CRT, symptomatic, or fatal PE. Development of CRT did not appear to influence overall mortality (P = .12, Fisher’s exact). During the study follow-up period, 460 catheters were removed. The three most common reasons for catheter removal were: catheter was no longer needed (222 patients); patient died (120 patients); catheter pulled or fell out accidentally (25 patients).
Our study is the first prospective study that was designed with rigorous methodology to determine the incidence of symptomatic CRT, identify risk factors, and document the long-term outcomes of CRT in patients with cancer. We found a low incidence of symptomatic CRT at 4.3% or 0.3 per 1,000 catheter-days, and that having more than one attempt at insertion, a previous catheter, or ovarian cancer is associated with a higher risk of CRT. We also observed that catheter blockage is significantly associated with CRT. We also did not find a difference in the life span of catheters between those with and without CRT. Lastly, long-term complications such as postphlebitic syndrome and PE were infrequent. The low incidence of symptomatic CRT confirms the results from recent studies.2 A prospective study following cancer patients with PICCs reported 3.4% of the catheters were removed as a result of thrombosis.7 However, symptomatic CRT was not the primary end point of this study and the methods for documenting CRT were unclear. A randomized trial comparing open-ended versus valved catheters connected to an implanted port also reported a low incidence of both symptomatic (2%) and asymptomatic (3.6%) CRT.8 This study routinely performed ultrasonography at 1 and 4 months to screen for CRT so that the true incidence of symptomatic CRT might have been underestimated. In addition, three placebo-controlled randomized trials assessing the efficacy of low-dose anticoagulant therapy for prophylaxis also reported a 3% to 4% incidence of symptomatic CRT in patients who received placebo.9-11 We found three baseline risk factors that predicted for a higher risk of symptomatic CRT. Two of the risk factors, having previous central venous catheterization and more than one attempt at insertion, suggest that vessel wall trauma or endothelial damage predisposes to CRT. Other studies have made similar observations, and one study reported that 42% of patients with a history of long-term central venous access had evidence of thrombosis on duplex scanning.16 We found that having ovarian cancer was a risk factor for CRT, but this has not been reported previously. On review of these cases, there was no evidence that histologic subtype influenced the risk of CRT, and many of the patients needed a CVC because of a lack of peripheral venous access, following many courses of chemotherapy. This suggests that vessel injury from multiple venipunctures or cytotoxic chemotherapy, rather than tumor biology, is the cause of CRT in this group of patients also. We did find that catheter occlusion is strongly associated with CRT. This likely indicates that thrombus development in the lumen of the catheter and the catheterized vein frequently occurs together. Like the recently published randomized trials,9-12 our study also did not find that prophylaxis with anticoagulants reduced the risk of symptomatic CRT; however, our study was not designed to address this question. A recently completed multicenter randomized trial comparing prophylaxis with fixed dose 1-mg warfarin, dose-adjusted warfarin (international normalized ratio targeted between 1.5 and 2.0), or no prophylaxis also failed to find a reduction in symptomatic CRT with warfarin therapy. In fact, dose-adjusted warfarin was associated with an increased risk of bleeding.12 On the basis of the results of these studies, routine anticoagulant prophylaxis is no longer recommended by the seventh American College of Chest Physicians Consensus Guidelines.17 The lack of difference in the catheter life span between catheters without CRT and those with CRT that were treated with anticoagulants alone shows that anticoagulation can preserve the life span of a catheter with CRT. We also found a low incidence of long-term complications in patients with CRT. These findings suggest that anticoagulant therapy is a safe and effective treatment for CRT. Nonetheless, our results should be interpreted with caution because there were few patients with symptomatic CRT. Clinical trials with long-term follow-up are needed to determine the optimal treatment of CRT and the true long-term complication rates. Our study has several strengths. We had broad eligibility criteria, included consecutive, unselected patients, and had no loss to follow-up. We used a prospective design with scheduled assessments, rather than rely on patient self-reporting alone, which could lead to underreporting. Using objective investigations to diagnose CRT and strict definitions of symptomatic CRT helped to minimize misdiagnosis. Asymptomatic thrombotic events were not included so our findings are clinically relevant. There are limitations with our study. This was a single center study so the results may not be applicable to other institutions, especially if the types of catheter used, the insertion techniques, and maintenance catheter care differ from our protocol. Recently, guidelines were introduced by the Society of Interventional Radiology to provide standardized definitions and uniform reporting requirements to assist in study design and outcomes reporting on central venous access devices.18 Adherence to these guidelines by future studies will facilitate comparison among studies from different institutions. The low incidence of symptomatic CRT and the lack of control for cancer therapy, anticoagulant prophylaxis, and treatment of CRT limited our ability to identify independent risk factors and long-term complications with confidence. Finally, bias could have been introduced if there were any systematic differences between patients who participated and those who refused informed consent. Further studies are needed to confirm our findings, identify other risk factors, and address prevention and treatment of CRT.
The authors indicated no potential conflicts of interest.
We thank Deborah Marcellus, MD, Robin Snelling, Anita York, and Leslie Gauthier, and all the nurses and staff of the Radiology Department of the Henderson Hospital, the Juravinski Cancer Centre, and the Community Care Access Centre for their support of this project.
Supported by the Hamilton Regional Cancer Centre Foundation, Juravinski Cancer Centre, Hamilton, Ontario, Canada. Presented in part at the American Society of Hematology Annual Meeting, San Diego, CA, December 4-7, 2004. Agnes Y.Y. Lee, MD, is a recipient of a New Investigator Award from the Canadian Institutes of Health Research Research and Development Program. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
