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Originally published as JCO Early Release 10.1200/JCO.2005.12.901 on March 14 2005 © 2005 American Society of Clinical Oncology.
Catheter-Associated Thrombosis: Thromboprophylaxis or Not?1 McMaster University, Juravinski Cancer Centre, Hamilton, Ontario, Canada
2 Barts and The London, Queen Mary School of Medicine and Dentistry, London, United Kingdom Long-term indwelling central venous catheters are commonly used in cancer patients for the administration of chemotherapy, parenteral nutrition, and blood products and for the facilitation of the drawing of blood. Despite their important role in the delivery of quality patient care, central venous catheters can be associated with morbidity. One of the most common complications is catheter-related venous thrombosis. The extent of thrombosis associated with a central vein catheter can involve the catheter tip (ball-valve clot), the length of the catheter (fibrin sheath), or the catheterized vessel in the upper limb, with or without the central vasculature of the neck or mediastinum.1 In the 1990s, with the increasing use of central venous catheters in cancer patients, there was a clinical impression that catheter thrombosis was a common occurrence, associated with considerable morbidity. The results of two randomized trials provided evidence to support the use of prophylactic antithrombotic agents to prevent catheter-associated thrombosis. In a trial conducted by Monreal et al,2 patients with a long-term subclavian venous catheter were randomly assigned either to 2,500 U of dalteparin low molecular weight heparin subcutaneously once daily for 90 days or to no prophylaxis. Upper limb venography was performed at 90 days or sooner if symptoms appeared. The trial was stopped early, after upper extremity thrombosis developed in one (6%) of 16 patients treated with low molecular weight heparin compared with eight (62%) of 13 control patients (P = .002). Six of the 29 thrombotic events were symptomatic. There was no increased risk of bleeding associated with the low molecular weight heparin. Bern et al3 randomly assigned cancer patients with indwelling central venous catheters to either 1 mg of warfarin for 90 days or no treatment. This dosage regimen was based on the demonstrated efficacy of postoperative prophylaxis with 1 mg of warfarin in patients undergoing gynecologic surgery.4 Venography was performed at 90 days. One hundred twenty-one patients were randomly assigned, but only 80 patients completed the trial. Fifteen (37.5%) of 40 control patients developed thrombosis compared with four (9.5%) of 42 patients on warfarin (P = .001). Seventeen of the thrombotic episodes were symptomatic. In most cases, the prothrombin time was not prolonged, and there was no increase in bleeding associated with warfarin. After the publication of these studies, although there was lack of consensus on whether patients with central vein catheters should routinely receive thromboprophylaxis, low-dose warfarin was used in some clinical practices. In some patients, the prothrombin time was prolonged excessively because of interactions with chemotherapy drugs.5 This issue contains two well-conducted randomized controlled trials by Verso et al6 and Couban et al7 evaluating thromboprophylaxis in cancer patients with central venous catheters. Both of these trials were double blind and, hence, provide higher quality evidence than the earlier published randomized trials that were not double blind. The two trials in this issue used different approaches in the choice of outcome for their studies. Verso et al6 used mandatory venography of the upper limb at 42 days, whether the patient had symptoms or not. The use of this screening technique for venous thrombosis was adopted from prophylactic studies in patients undergoing orthopedic surgery,8 with venography of the lower limbs at 7 to 10 days after surgery as the standard outcome measure used in clinical trials evaluating antithrombotics in this setting. Asymptomatic thrombosis in the deep veins of the lower limbs is considered a reasonable surrogate for the development of symptomatic venous thromboembolism because 20% of thrombi in the calf veins extend to the proximal deep veins and 50% of patients with proximal deep vein thrombosis have associated pulmonary embolism. Unfortunately, the natural history of catheter-associated thrombosis is not nearly as well defined as postoperative thrombosis. There is substantial variation among studies in the reported rates of pulmonary embolism.1,9 In the Verso et al6 trial, patients received either enoxaparin low molecular weight heparin once daily for 6 weeks or placebo. Upper limb venography was performed at 6 weeks. Thrombosis was observed in 22 (14.1%) of 155 patients in the low molecular weight heparin group compared with 28 (18%) of 155 patients in the placebo group (P = .35). The rate of symptomatic thrombosis was just 2.1%. The authors had originally postulated a much higher event rate of 30% in the control group and that there would be a 50% relative reduction in thrombosis with treatment; instead of a 30% event rate, the observed rate was approximately half that rate. With a lower baseline event rate, a much larger sample size would be required to detect a relative risk reduction of the same magnitude. There is the possibility that the low molecular weight heparin is efficacious, but another trial with much larger power would be required; this could be achieved by including more patients and by treating patients for a longer duration. Verso et al6 speculate that the dosage regimen of low molecular weight heparin used in the trial might have been ineffective and a higher dosage regimen might have resulted in a positive result. Although this is plausible, the 40-mg daily dose of enoxaparin low molecular weight heparin is the effective prophylactic dose used after orthopedic surgery, a highly thrombogenic stimulus. However, increasing the dose could be associated with an increased risk of bleeding, which was not observed in this trial. Couban et al7 chose to use clinical outcome, rather than venography, as the primary outcome measure. The choice of two different outcomes in the trials by Verso et al6 and Couban et al7 (venography v clinical outcome, respectively) is reminiscent of the controversy of end points used in trials evaluating antithrombotics in orthopedic surgery.8,10 Although the standard in orthopedic surgery has been mandatory postoperative venography, there are those who argue that the only appropriate end point is symptomatic venous thromboembolism. It may be that, in trials evaluating antithrombotic prophylaxis in patients with central vein catheters, symptomatic thrombosis is a better outcome because the natural history of an asymptomatic thrombus on a screening venogram is unclear. In the Couban et al7 trial, patients received 1 mg of warfarin or placebo for 9 weeks. The rate of symptomatic thrombosis in the warfarin patients was 4.6% compared with 4.0% in the placebo patients (hazard ratio, 1.20; 95% CI, 0.37 to 3.94). The authors postulated a baseline event rate of 37.5% in placebo patients, with an expected 50% relative risk reduction with 1 mg of warfarin. Once again, the event rate was much lower than postulated, and with a baseline event rate of 4%, any future trial would require a much larger sample size to detect a 50% reduction in thrombosis. More than half of the patients had an interruption of study medication for at least 7 days. Although this may have contributed to the lack of efficacy of warfarin, it would not have influenced the low incidence of thrombosis in the control group. Both of these prospective trials show that the rate of catheter-associated thrombosis is relatively low, whether measured clinically or radiographically. This observation is supported by recent cohort studies11,12 and a randomized trial evaluating low molecular weight heparin.13 Is it possible to explain the difference in event rates of contemporary studies compared with the earlier studies? There are three possible reasons for this observation. First, earlier trials may have overestimated the event rate; because they were not double blind, they were subject to diagnostic suspicion bias. Second, undoubtedly, improvements in biocompatibility and insertion and maintenance techniques for central vein catheters may be responsible for the lower thrombosis rate in recent years. Third, are the populations in the earlier trials different than those in the contemporary trials? This is a possibility, but there are limitations to cross-study comparisons. All four trials studied patients of similar age. In three of the trials, most of the patients had solid tumors,2,3,6 but in contrast, 80% of the patients in the trial by Couban et al7 had hematologic malignancies. A comparison of the trials for chemotherapy cannot be made because only the trial by Verso et al6 provided such information. So what is the bottom line? On the basis of the results of contemporary trials, it is difficult to recommend routine antithrombotic prophylaxis in cancer patients with central venous catheters. Institutions should assess their rates of catheter-associated thrombosis. If they seem to be higher than the rates in contemporary trials, then the institutions need to examine how the catheters are inserted and maintained. Central venous catheters are a mainstay of chemotherapy administration, and thousands of catheters are inserted annually in the United States. When symptomatic thrombosis occurs in association with a catheter, it definitely complicates the clinical care of the patient because of the need for anticoagulant therapy and because often the catheter has to be removed. Although given the current evidence, routine prophylaxis is not recommended, large-scale trials using symptomatic thrombosis as an outcome measure need to be carried out. Both low molecular weight heparin and low-dose warfarin are reasonable agents to study, but low molecular weight heparin is administered subcutaneously, and warfarin requires laboratory monitoring. As we look to the future, novel antithrombotic agents that can be administered orally and do not require laboratory monitoring will be available to be studied in this condition.14 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Bona RD: Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Hemost 25:147-155, 1999[Medline] 2. Monreal M, Alastrue A, Rull M, et al: Upper extremity deep venous thrombosis in cancer patients with venous access device: Prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 75:251-253, 1996[Medline] 3. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: A randomized prospective trial. Ann Intern Med 112:423-428, 1990 4. Poller L, McKernan A, Thomson JM, et al: Fixed mini-dose warfarin: A new approach to prophylaxis against venous thrombosis after major surgery. BMJ 295:1309-1312, 1987
5. Masci G, Magagnoli M, Zucali PA, et al: Minidose warfarin prophylaxis for catheter-associated thrombosis in cancer patients: Can it be safely associated with fluorouracil-based chemotherapy? J Clin Oncol 21:736-739, 2003
6. Verso M, Agnelli G, Bertoglio S, et al: Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: A double-blind, placebo-controlled, randomized study in cancer patients. J Clin Oncol 23:4057-4062, 2005
7. Couban S, Goodyear M, Burnell M, et al: Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter–associated thrombosis in patients with cancer. J Clin Oncol 23:4063-4069, 2005
8. Geerts WH, Heit JA, Clagett GP, et al: Prevention of venous thromboembolism. Chest 119:132S-175S, 2001 (suppl 1)
9. Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665-3675, 2003
10. Hull R, Pineo G, Stein PD: Extended out-of-hospital low molecular weight heparin prophylaxis against deep vein thrombosis in patients after elective hip arthroplasty. Ann Intern Med 135:858-869, 2001 11. Lee AY, Webb C, Guo Q, et al: Prospective cohort study of the incidence, risk factors and long-term sequelae of symptomatic catheter-related thrombosis in adults with cancer. Blood 14:604, 2004
12. Walshe LJ, Malak SF, Eagan J, et al: Complication rates among cancer patients with peripherally inserted central catheters. J Clin Oncol 20:3276-3281, 2002 13. Reichardt P, Kretzschmar A, Biakhov M, et al: A phase III double-blind, placebo-controlled study evaluating the efficacy and safety of daily low-molecular-weight heparin (dalteparin sodium, fragmin) in preventing catheter-related complications in cancer patients with central venous catheters. Proc Am Soc Clin Oncol 21:396a, 2002 (abstr 1474) 14. Weitz JI, Hirsh J, Samama M: New anticoagulant drugs: The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:265S-286S, 2004 (suppl)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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