Annals of Oncology Advance Access originally published online on November 29, 2005
Annals of Oncology 2006 17(2):289-296; doi:10.1093/annonc/mdj059
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© 2005 European Society for Medical Oncology
Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial
1 Evang. Johannes-Krankenhaus, Medizinische Klinik, Bielefeld; 2 Robert-Rössle-Klinik, HELIOS-Klinikum Berlin-Buch, Charité Campus Buch, Berlin; 3 Krankenhaus Altstadt, Klinik für Hämatologie/Onkologie, Magdeburg, Germany; 4 Central Clinical Hospital, Moscow, Russia; 5 Alta Bates Comprehensive Cancer Center, Berkeley, CA, USA; 6 Onkologische Schwerpunktpraxis, Freiburg, Germany; 7 Mary Potter Oncology Centre, Little Company of Mary Medical Centre, Pretoria, South Africa; 8 AHEPA Hospital, Aristotele University of Thessaloniki, Thessaloniki, Greece; 9 Cancer Research Center Department of Clinical Pharmacology, Moscow, Russia; 10 Instituto Português de Oncologia Francisco Gentil Centro Regional de Lisboa, Lisbon, Portugal; 11 Klinikum Chemnitz, Germany; 12 Department of Internal Medicine I, University of Vienna, Austria; 13 Department of Internal Medicine, Knappschaftskrankenhaus Ruhr University Bochum; Germany; 14 Pharmacia, Gruppo Pfizer Inc., Milano, Italy
* Correspondence to: Prof M. Karthaus, Evang. Johannes-Krankenhaus, Med. Klinik II, Hematology/Oncology and Palliative Care, Schildescher Strasse 99, D-33611 Bielefeld, Germany. Tel: +49-52180102; Fax: +49-5218014307; E-mail: Meinolf.Karthaus{at}evkb.de
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Abstract |
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Background: Cancer patients receiving chemotherapy experience thromboembolic complications associated with the use of long-term indwelling central venous catheters (CVCs). This prospective, double-blind, placebo-controlled, multicenter study evaluated whether prophylactic treatment with a low molecular weight heparin could prevent clinically relevant catheter-related thrombosis.
Patients and methods: Patients with cancer undergoing chemotherapy for at least 12 weeks (n = 439) were randomly assigned, in a 2:1 ratio, to receive either dalteparin (5000 IU) or placebo, by subcutaneous injection, once daily for 16 weeks. Patients underwent upper extremity evaluation with either venography or ultrasound at the time of a suspected catheter-related complication (CRC) or upon completion of study medication. The primary end point, as determined by a blinded adjudication committee, was the occurrence of a CRC, defined as the first occurrence of any one of the following: clinically relevant catheter-related thrombosis that was symptomatic or that required anticoagulant or fibrinolytic therapy; catheter-related clinically relevant pulmonary embolism; or catheter obstruction requiring catheter removal.
Results: There was no significant difference in the frequency of CRCs between the dalteparin arm (3.7%) and the placebo arm (3.4%; P = 0.88), corresponding to a relative risk of 1.0883 (95% confidence interval 0.37–3.19). No difference in the time to CRC was observed between the two arms (P = 0.83). There was no significant difference between the dalteparin and placebo groups in terms of major bleeding (1 versus 0) or overall safety.
Conclusions: Dalteparin prophylaxis did not reduce the frequency of thromboembolic complications after CVC implantation in cancer patients. Dalteparin was demonstrated to be safe over 16 weeks of treatment in these patients.
Key words: cancer therapy, catheter-related complication, prophylaxis, venous thrombosis
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Thromboembolic complications occur commonly in cancer patients. The pathogenesis is multifactorial, including a release of procoagulants by tumor cells and anticancer drugs. This association between cancer and thromboembolic disease has been recognized for over a century [1
]. Recent advances in biochemistry, cell biology and molecular biology have helped to provide a better understanding of the complex interactions between tumor cells and the hemostatic system [2]. In addition to the procoagulant properties of tumor cells, many treatment interventions for patients with cancer, including surgery, chemotherapy and hormonal therapy are known to increase the risk of venous thromboembolism [3].
The use of central venous catheters (CVCs) is well established for the delivery of cytotoxic agents, blood components or parenteral nutrition in patients with cancer. However, an increased risk of thromboembolic complications associated with long-term, indwelling CVCs have been recognized as a serious problem, leading to significant morbidity, catheter malfunction and treatment delays [4, 5]. While the majority of catheter-related complications (CRCs) are related to the local effects of catheter thrombosis (clinical signs and symptoms of upper limp thrombosis, malfunctioning catheter), pulmonary embolism has been reported to occur in 
5–12% of patients [6–8].
The incidence of catheter-related thrombosis (CRT) reported in studies conducted in cancer patients is highly variable. Some studies have reported frequencies ranging from 37% to 66%, while other studies have described lower rates ranging from 4% to 13% [4, 9–14]. Several reasons may account for these variations including variable definitions of CRT, methods of CRT assessment, heterogeneity of study population, and differences of the catheter in length, diameter and material.
The interpretation of published literature on prevention of CVC thrombosis and other CRCs is, however, limited by a relative lack of randomized trial data. In fact, only two randomized trials evaluating the role of anticoagulation in CVC thrombosis were published when this study started [10, 15].
In a trial conducted by Bern et al. [15], the administration of 1 mg warfarin as thromboprophylaxis in 40 cancer patients with CVC was examined versus 42 cancer patients who received no treatment. Warfarin significantly reduced the thrombotic event rate related to the CVC as compared with the control group (9.5% versus 37.5%).
Monreal et al. [10] randomized a total of 29 cancer patients to dalteparin administered at a dosage of 2500 IU once daily versus a control group without treatment. However, the study was stopped early owing to the high incidence of thrombosis in the control group of patients (eight out of 13 patients; 62%). In the dalteparin-treated group only one out of 16 patients developed CRT (6%).
Although these two trials suggested that anticoagulants might be beneficial in preventing CRTs, unequivocal conclusions could not be drawn from these small studies.
The current study is the first large multinational, double-blind, placebo-controlled, prospective study to evaluate the efficacy and safety of dalteparin in the prevention of clinically relevant or symptomatic CRT in patients with cancer receiving chemotherapy via CVCs.
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end points
The primary end point was the occurrence of a CRC, defined as the first occurrence of any one of the following: clinically relevant CRT that was symptomatic or that required anticoagulant therapy or therapeutic infusion of a fibrinolytic agent with or without catheter removal; catheter-related clinically relevant pulmonary embolism with or without catheter removal; or catheter obstruction requiring catheter removal.
Secondary end points were: the incidence of CRCs per day of exposure to the study drug; the incidence of asymptomatic CRT not requiring any intervention during the study period; the time to the first clinically relevant CRC; the time to catheter removal; the use of bolus injections of fibrinolytic agents for CRT or catheter obstruction (with or without catheter removal); catheter-related infection (with or without catheter removal) or a positive catheter-tip culture; the incidence of clinically relevant and objectively verified non-catheter-related venous or arterial thromboembolic event (TEE); and clinical and laboratory adverse events.
study design
This study was a phase III, randomized, double-blind, prospective, placebo-controlled trial carried out in 48 different centers in the following countries; Austria, Canada, France, Germany, Greece, Portugal, the Russian Federation, the Slovak Republic, South Africa, Sweden, the UK and the USA. Consecutive eligible patients with documented cancer were randomly assigned, within 5–7 days of catheter placement, to receive either dalteparin (5000 IU) or placebo (0.2 ml saline), injected subcutaneously once daily. Patients were enrolled between August 1999 and June 2001. The randomization favored dalteparin at a 2:1 ratio. Patients were allocated to the treatment arm based on whether catheter insertion was proximal or distal to the axilla and by institutional site by centralized interactive voice processing system. Study medication continued for 16 weeks or until the occurrence of a CRC, catheter removal, a non-catheter-related thrombosis, death, an adverse event leading to cessation of treatment, other unacceptable toxicity, development of clinically relevant prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT). Catheter flushing with UFH (500 IU)/saline bolus flushes were allowed during catheter use. During periods of chemotherapy- or radiotherapy-induced thrombocytopenia, study medication was withheld until the platelet count rose to at least 30 000/mm3.
All patients had assessments for primary and secondary end points at weeks 1, 2, 4, 8, 12 and 16. All patients underwent upper extremity evaluation [venography, ultrasound or computed tomography (CT) scan] upon the suspected occurrence of a CRC, removal of the catheter (planned or premature) or at 16 weeks from the start of study medication. Ventilation-perfusion (VQ) scan or spiral CT scan were used to verify pulmonary embolism occurrence. A central adjudication committee reviewed all venograms, CT scans, angiograms, compression ultrasonography examinations, VQ scans and other procedures obtained for a suspected CRC and made final judgement, blinded to patient treatment assignment.
Laboratory assessments of coagulation profile (PT, aPTT), complete blood count (hemoglobin, hematocrit, white blood cell count, absolute neutrophil count, platelet count) and chemistry profile [creatinine, aspartate aminotransferase (AST), total bilirubin, potassium] were performed. A major bleeding event was defined as a fall in hemoglobin of 2 g/dl or more or a 6% or greater reduction in hematocrit with manifest hemorrhage, any intraocular, intraspinal or intracranial hemorrhage, bleeding requiring blood transfusion, or fatal hemorrhage.
patients
Patients requirements for inclusion were as follows: histologically confirmed malignancy; placement of a CVC for chemotherapy within 5–7 days prior to randomization and treatment; an expected length of catheter use of at least 12 weeks; age 
18 years; weight 40 kg; an Eastern Cooperative Oncology Group performance status of 0,1 or 2; a life expectancy of at least 16 weeks; adequate pretreatment organ function as demonstrated by a platelet count of at least 100 000/mm3; an absolute neutrophil count of at least 1500/mm3; total bilirubin and serum creatinine of up to 2x the upper limit of normal; AST up to 3x (patients without liver metastasis) or 5x (patients with liver metastasis) the upper limit of normal; and a PT/aPTT up to 1.5x the upper limit of normal. Positive local ethics votes were obtained from all participating centers. All patients gave written informed consent to inclusion in the study.
Patients were excluded from the study for the following reasons: known hypersensitivity (including heparin-induced thrombocytopenia) to dalteparin, other low molecular weight heparins (LMWHs) or unfractionated heparin (UFH); active gastrointestinal or genitourinary tract bleeding; known coagulopathy; requirement for aspirin, dipyridamole, UFH, other LMWHs, warfarin or other anticoagulation therapy (heparin flushing allowed); active uncontrolled infection, including suspected catheter-related infection; known HIV positivity or AIDS-related illness; eye, ear or CNS surgery or a CNS trauma within the past 3 months; intracranial or intraocular hemorrhage (within 1 year) or retinal detachment (within 6 months); mental incapacitation or psychiatric illness that would prevent the provision of informed consent; uncontrolled hypertension, unstable angina, symptomatic congestive heart failure, myocardial infarction (within previous 6 months) or uncontrolled cardiac arrhythmia; severe concurrent disease; leukemia requiring induction/consolidation chemotherapy during the 16-week study period; requirement of high-dose chemotherapy and stem cell transplantation during the 16-week study period; use of investigational or unapproved catheter devices; and pregnancy, breastfeeding or likelihood of pregnancy.
statistics
The sample size was based on the assumption that the incidence of clinically significant CRCs would be 30% with placebo and 12% with dalteparin during the 16-week study period. To detect this reduction in CRC incidence in a two-sided comparison with alpha = 0.001, 80% power and a 2:1 randomization, a total of 435 patients would be sufficient, 290 patients in the dalteparin arm and 145 patients in the placebo arm. This calculation included a 15% increase in sample size to account for patients not adequately evaluable for the primary end point.
The primary end point was compared between the two treatment groups using the 
2-test. Statistical testing on secondary end points was based only on two-sided Fisher's exact test. Intention-to-treat and as-treated study populations were evaluated.
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patient characteristics
The patient characteristics are given in Table 1. Patients were well matched for age, gender, weight and race. Significantly more patients in the dalteparin arm had solid tumors (92.9%) compared with the placebo arm (86.2%; P = 0.048). The percentage of patients randomized but not receiving study medication was low and comparable in each arm (3.1% and 3.4% dalteparin and placebo, respectively). From 145 patients randomized to the placebo arm, 140 received at least one dose and from 294 patients randomized to the dalteparin arm, 285 received at least one dose. Early termination rates were comparable in each treatment arm. Of those treated, 67% and 67.1% in the dalteparin and placebo groups, respectively, completed the 16-week treatment. The reasons for early termination were similar in both treatment groups (Table 2). Adverse events, most related to the underlying cancer, withdrawal of consent and other reasons related to cancer accounted for
80% of withdrawals. The majority of patients underwent an off-treatment evaluation of the catheter to detect asymtomatic thrombosis. End of treatment evaluation by venography was carried out in 61.3% (n = 179) and 59.3% (n = 86) of patients in the dalteparin and placebo treatment arms, respectively. In the remaining patients compression ultrasound was used for patency evaluation of the upper limp.
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end point evaluations
The frequency of CRCs in the dalteparin arm was 3.7% compared with 3.4 in the placebo arm (P = 0.88), corresponding to a relative risk of 1.0883 [95% confidence interval (CI) 0.37–3.19; see Table 3]. In addition, there was no difference in the time to onset of CRC (P = 0.83) between patients on dalteparin or placebo (Figure 1). The overall event rate (3.6%) was substantially lower than the assumed rate used to calculate the sample size. The rate of CRCs was comparable between solid tumor patients and patients with hematological malignancies. Fifteen out of these 16 patients with CRCs had solid tumor diagnosis (CRC rate 3.8%) and one patient had a hematological tumor (CRC rate 2.3%).
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The secondary end point analyses of non-catheter-related venous TEE and asymptomatic CRT are shown in Table 4. There were no significant differences in any of these events between the dalteparin and placebo group. Catheter-related infection data (including cases of positive catheter-tip culture) have been reported elsewhere [16
].
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safety data
The majority of patients had at least one adverse event. Most were due to non-study medication treatment or the underlying cancer. Overall, the adverse event profile was characteristic of an advanced cancer patient population.
Most of the reactions at the injection site occurred when dalteparin, and not placebo, was injected. These reactions consisted mainly of bruising (6.3% of patients), pain (2.8%) or hemorrhage (2.5%), but also edema, irritation and pruritus at the injection site (0.4% each). In only one patient skin ulceration was observed (0.4%). The proportion of patients who reported at least one of those reactions during the study was 9.5% with dalteparin and 2.9% with placebo. All the observed local reactions, however, were mild or moderate in severity (Table 5).
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The frequency and analysis of bleeding is shown in Table 6. Bleeding events consisted of any type of hemorrhagic events including local events, such as hemorrhage or bruising at the injection site. The frequency of patients who had at least one hemorrhagic event during the study was comparable between the two arms (17.5% in the dalteparin group versus 15% in placebo-treated patients), corresponding to a relative risk of 1.20 (95% CI 0.69–2.10). Few of these events were of grade 3–4 and only two were described as major bleeding by the adjudication committee: one grade 4 gastric hemorrhage in the dalteparin arm and one grade 4 subarachnoid hemorrhage in the placebo arm.
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discussion |
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The population entered in this phase III trial was recognized to be at high risk for thrombosis owing to the advanced stage of solid tumors in the majority of the patients, the placement of a CVC and the tumor treatment the patients were receiving [17
–19].
Dalteparin administered 5000 IU subcutaneously once daily, a dose approved in many countries in high-risk patients undergoing surgical procedures [20], did not prove to be effective in reducing the frequency of CRCs in this study. Notably, the overall number of thromboembolic complications both catheter- and non-catheter-related that have been observed in this trial was unexpectedly low in both treatment arms.
The results of this trial are relevant. The strengths of this trial were a double-blind placebo-controlled study design, a the large sample size as well as a multinational recruitment of patients. The rate of CVC-related thrombosis reported in cancer patients is highly variable [21]. This may depend upon different patient populations as well the methodology used to assess the presence of a thrombus, and whether or not asymptomatic events were included [22–27]. However, rates of CRT in these studies were usually substanticially higher than demonstrated in our trial.
One possible explanation for the difference in the rate of thromboembolic complications between our trial and other studies is that many of the published trials were retrospective reviews. Some other trials were conducted in an open fashion, or were limited by a small number of patients included. In our trial, all the thrombotic events that could meet the criteria for the primary end point were reviewed in a blinded fashion by an independent adjudication committee. Under these strict trial conditions, the catheter-related thrombotic event rate was low and there was no difference between the two study arms. The same results were observed with the secondary variables, i.e. the rate of asymptomatic CRTs, catheter-related infections and non-catheter-related TEEs. The rate of each variable in the placebo arm, however, was so low that meaningful differences could not be detected. Based on statistical design the study was underpowered to detect smaller differences. Therefore, it would now be necessary to have a much larger sample size for further trials.
In accordance with our results, Biffi et al. [27] reported a comparable incidence of CRT with a rate of 1.06% in cancer patients receiving LMWH as prophylaxis in a monocentric trial. Furthermore, very similar rates of catheter-related thrombosis were recently reported by Couban et al. [28], who investigated the prophylatic use of warfarin (1 mg daily fixed dose). In their randomized study, which included 255 patients, the frequency of symptomatic CVC-associated thrombosis in the placebo and coumadin arm was 4% and 4.6%, respectively. In another trial, Verso et al. [29] randomly assigned cancer patients scheduled for insertion of CVC to receive either subcutaneous enoxaparin 40 mg once a day or placebo. They started treatment 2 h before CVC insertion and continued for 6 weeks only. In this smaller study the rate of CRT was somewhat higher. Thus, deep venous thrombosis was observed in 22 patients (14.1%) treated with enoxaparin and in 28 patients (18%) treated with placebo, again without a significant difference between the two arms (P = 0.35). Taken together, in accordance to our study, all recently published randomized multicenter trials using LMWH or low-dose warfarin for prevention of venous thromboembolism associated with CVC failed to prove efficacy, as illustrated in Table 7. With respect to these data, anticoagulation is no longer recommended for routine prophylaxis of catheter-related thromboembolic complications in cancer patients [30].
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Another concurrent explanation of the low rate of thromboembolic complications might be the type of the implanted catheter. In fact, most of the catheters placed in the present study were subcutaneous ports, which have been associated with fewer thrombotic events as compared with external catheters. Eastridge and Lefor [31
] prospectively evaluated 209 and 113 cancer patients who had received external catheters or subcutaneous ports, respectively. In the cohort of patients with external catheters a higher frequency of thrombosis (10% versus 6% in the cohort of patients with ports) was demonstrated. Data reported in patients who had implanted subcutaneous ports were confirmed by Lyon et al. [32]. These authors retrospectively evaluated 195 venous access devices implanted in cancer patients, and observed a catheter-related thrombosis rate and an infection rate of 5%. In another small study, 100 cancer patients were randomized to receive an external catheter or subcutaneous port, and were monitored for catheter-related complications for 6 months [33]. Although the difference was not statistically significant, thrombotic complications (9% versus 2% of patients with ports) occurred in more often patients with external catheters. However, thus far, an older meta-analysis on limited patient numbers could not establish an effect of the type of catheter on CRC [34].
The low frequency of CRCs might also be discussed as a consequence of routine flushing of the catheter to maintain its patency. As pointed out in Table 7, port flushing was carried out in most clinical trials. In some trials, however, there was no statement on the practice of port flushing. Another point to be considered is the shorter hospitalization and the outpatient treatment that has become more common practice in the last 15 years. More frequent and longer admissions to the hospital seem to be associated with a higher frequency of thrombosis [35, 36].
In this trial dalteparin was well tolerated and there were no important differences in terms of overall safety when dalteparin was compared with placebo. Bleeding complications with a daily dose of 5000 IU administered for prophylaxis were observed less often when compared with LMWH or coumadin for treatment of thromboembolic events in cancer patients [29, 34, 37–39]. In particular, major bleeding occurred in only one dalteparin-treated (0.4%) and one placebo-treated patient, and dalteparin-related thrombocytopenia was also infrequent (0.7%). Regarding the adverse event analyses dalteparin appeared to be nearly as safe as placebo.
In conclusion, our results suggest that the actual risk for cancer patients carrying CVC to developing thrombotic events is overestimated and is not as high as suggested in earlier reports. In our study, dalteparin failed to reduce the low risk of thromboembolic complication in this study population but was well tolerated at a dose of 5000 IU daily.
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Acknowledgements |
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This trial was supported by Pfizer Inc. This work was presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, USA, 18–21 May 2002.
Received for publication August 3, 2005. Revision received September 26, 2005. Accepted for publication September 27, 2005.
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1. Trousseau A. Plegmasia alba dolens. In Trousseau A (ed.): Lectures on Clinical Medicine, delivered at the Hotel-Dieu, Paris. Cormack JR, trans. London: New Syndenham Society 1872: 281–295.
2. Rickles F, Falanga A. Molecular basis for the relationship between thrombosis and cancer. Thromb Res 2001; 102: 215–224.
3. Lee A, Levine M. The thrombophilic state induced by therapeutic agents in the cancer patient. Semin Thromb Hemost 1999; 25: 137–145.[Web of Science][Medline]
4. Bona R. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Hemost 1999; 25: 147–155.[Web of Science][Medline]
5. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003; 21: 3665–3675.
6. Boraks P, Seale J, Price J et al. Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haematol 1998; 101: 483–486.[CrossRef][Web of Science][Medline]
7. Allen A, Megargell J, Brown D et al. Venous thrombosis associated with the placement of peripherally inserted central catheters. J Vasc Interv Radiol 2000; 11: 1309–1314.[Web of Science][Medline]
8. Diebold J, Lohrs U. Venous thrombosis and pulmonary embolism. A study of 5039 autopsies. Pathol Res Pract 1991; 187: 260–266.[Web of Science][Medline]
9. Balestreri L, De Cicco M, Matovic M et al. Central venous catheter-related thrombosis in clinically asymptomatic oncologic patients: a phlebographic study. Eur J Radiol 1995; 20: 108–111.[CrossRef][Web of Science][Medline]
10. Monreal M, Alastrue A, Rull M et al. Upper extremity deep venous thrombosis in cancer patients with venous access devices—prophylaxis with a low molecular weight heparin (Fragmin). Thromb Haemost 1996; 75: 251–253.[Web of Science][Medline]
11. DeCicco M, Matovic M, Balestreri L et al. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study. Thromb Res 1997; 86: 101–113.[CrossRef][Web of Science][Medline]
12. Ray S, Stacey R, Imrie M, Filshie J. A review of 560 Hickman catheter insertions. Anaesthesia 1996; 51: 981–985.[Web of Science][Medline]
13. Nightingale CE, Norman A, Cunningham D et al. A prospect analysis of 949 long-term central venous access catheters for ambulatory chemotherapy in patients with gastrointestinal malignancy. Eur J Cancer 1997; 33: 398–403.[CrossRef][Web of Science][Medline]
14. Schwarz RE, Groeger JS, Coit DG. Subcutaneously implanted central venous access devices in cancer patients. A prospective analysis. Cancer 1997; 79: 1635–1640.[CrossRef][Web of Science][Medline]
15. Bern M, Lokich J, Wallach S et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Intern Med 1990; 112: 423–428.
16. Karthaus M, Suedhoff T, Reichardt P et al. Frequency of central venous catheter (CVC)-related infections in cancer patients (CP) treated on a double-blind Phase III trial of dalteparin versus placebo for the prevention of catheter-related complications (CRC). Procceedings of the 42nd ICAAC, San Diego, CA, USA: American Society for Microbiology, 27–30 September 2002. Abstract K667.
17. Monreal M, Lafoz E, Ruiz J et al. Upper-extremity deep venous thrombosis and pulmonary embolism. A prospective study. Chest 1991; 99: 280–283.
18. Kakkar AK, Williamson RCN. Prevention of venous thromboembolism in cancer using low molecular-weight heparins. Haemostasis 1997; 27 (Suppl 1): 32–37.
19. Rickles FR, Levine MN. Venous thromboembolism in malignancy and malignancy in venous thromboembolism. Haemostasis 1998; 28: 43–49.
20. Fragmin®. In: Physicians' Desk Reference, 53rd edition. Montrale, NJ: Medical Economics Company, 1999; 2486–2488.
21. Male C, Chait P, Andrew M et al. PARKAA Investigators Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood 2003, 101: 4273–4278.
22. Valente M, Ponte E. Thrombosis and cancer. Minerva Cardioangiol 2000; 48: 117–127.[Medline]
23. Bona RD. Thrombotic complications of central venous catheters in cancer patients. Semin Thromb Haemost 1999; 25: 147–155.
24. Johnson MJ, Sproule MW, Paul J. The prevalence and associated variables of deep venous thrombosis in patients with advanced cancer. Clin Oncol 1999; 11: 105–110.[CrossRef][Web of Science]
25. Kakkar AK. Venous thromboembolism and cancer. Baillieres Clin Haematol 1998; 11: 675–687.[CrossRef][Medline]
26. Monreal M, Salvador R, Soriano V, Sabrina M. Cancer and deep venous thrombosis. Arch Intern Med 1988; 148: 485.
27. Biffi R, Pozzi S, Agazzi A et al. Use of totally implantable central venous access ports for high-dose chemotherapy and peripheral blood stem cell transplantation: results of a monocentre series of 376 patients. Ann Oncol 2004; 15: 296–300.
28. Couban S, Goodyear M, Burnell M, Dolan S. A randomized double-blind placebo-controlled study of low dose warfarin for the prevention of symptomatic central venous catheter-associated thrombosis in patients with cancer. J Clin Oncol 2005; 23: 4063–4069.
29. 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 2005; 23: 4057–4062.
30. Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 Suppl): 338–400.
31. Eastridge BJ, Lefor AT. Complications of indwelling venous access devices in cancer patients. J Clin Oncol 1995; 13: 233–238.
32. Lyon RD, Griggs KA, Johnson AM, Olsen JR. Long-term follow-up of upper extremity implanted venous access devices in oncology patients. J Vasc Interv Radiol 1999; 10: 463–471.[Medline]
33. Mueller BU, Skelton J, Callender DPE et al. A prospective randomized trial comparing the infectious and noninfectious complications of an externalized catheter versus a subcutaneously implanted device in cancer patients. J Clin Oncol 1992; 10: 1943–1948.[Abstract]
34. Klerk CP, Smorenburg SM, Buller HR. Thrombosis prophylaxis in patient populations with a central venous catheter: a systematic review. Arch Intern Med 2003; 163: 1913–1921.
35. Kelly C, Dumenko L, McGregor E, McHutchion E. A change in flushing protocols of central venous catheters. Oncol Nurs Forum 1992; 19: 599–605.[Medline]
36. White RH, Zhou H, Romano PS. Length of hospital stay for treatment of deep venous thrombosis and the incidence of recurrent thromboembolism. Arch Intern Med 1998; 158: 1005–1010.
37. Massicotte P, Julian JA, Gent M et al. PROTEKT Study Group. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003; 109: 101–108.[CrossRef][Web of Science][Medline]
38. Massicotte P, Julian JA, Gent M et al. REVIVE Study Group. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109: 85–92.[CrossRef][Web of Science][Medline]
39. Meyer G, Marjanovic Z, Valcke J et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729–1735.
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 W. H. Geerts, D. Bergqvist, G. F. Pineo, J. A. Heit, C. M. Samama, M. R. Lassen, and C. W. Colwell Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 381S - 453S. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
A. Falanga, A. Y. Y. Lee, M. B. Streiff, and G. H. Lyman Anticoagulation in the Treatment of Venous Thromboembolism in Patients with Cancer ASCO Educational Book, January 1, 2008; 2008(1): 258 - 268. [Abstract] [Full Text] [PDF]
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 A. Chan, A. Iannucci, and W. E Dager Systemic Anticoagulant Prophylaxis for Central Catheter-Associated Venous Thrombosis in Cancer Patients Ann. Pharmacother., April 1, 2007; 41(4): 635 - 641. [Abstract] [Full Text] [PDF]
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D Fagnani, R Franchi, C Porta, P Pugliese, K Borgonovo, A Bertolini, M Duro, A Ardizzoia, V Filipazzi, L Isa, et al. Thrombosis-related complications and mortality in cancer patients with central venous devices: an observational study on the effect of antithrombotic prophylaxis Ann. Onc., March 1, 2007; 18(3): 551 - 555. [Abstract] [Full Text] [PDF]
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 H. C. Kwaan Double Hazard of Thrombophilia and Bleeding in Leukemia Hematology, January 1, 2007; 2007(1): 151 - 157. [Abstract] [Full Text] [PDF]
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