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JOURNAL OF CLINICAL ONCOLOGY Venous Thromboembolism Prophylaxis and Treatment inPatients With Cancer: American Society of Clinical Gary H. Lyman, Nicole M. Kuderer, and Oncology Clinical Practice Guideline Update Jeffrey M. Clarke, Duke University and Gary H. Lyman, Alok A. Khorana, Nicole M. Kuderer, Agnes Y. Lee, Juan Ignacio Arcelus, Edward P. Balaban, Duke Cancer Institute, Durham; Nigel S.
Key, Lineberger Comprehensive Cancer Jeffrey M. Clarke, Christopher R. Flowers, Charles W. Francis, Leigh E. Gates, Ajay K. Kakkar, Nigel S. Key, Mark N. Levine, Center, University of North Carolina, Chapel Howard A. Liebman, Margaret A. Tempero, Sandra L. Wong, Ann Alexis Prestrud, and Anna Falanga Hill, NC; Alok A. Khorana, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; Agnes Y. Lee, University of British Colum- bia, Vancouver, British Columbia; Mark N.
Levine, McMaster University, Hamilton, To provide recommendations about prophylaxis and treatment of venous thromboembolism (VTE) Ontario, Canada; Juan Ignacio Arcelus, in patients with cancer. Prophylaxis in the outpatient, inpatient, and perioperative settings was Hospital Universitario Virgen de las Nieves, considered, as were treatment and use of anticoagulation as a cancer-directed therapy.
University of Granada, Granada, Spain; Edward P. Balaban, University of Pittsburgh Cancer Centers Network, Pittsburgh, PA; A systematic review of the literature published from December 2007 to December 2012 was Christopher R. Flowers, Emory University completed in MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed School of Medicine and Winship Cancer evidence to determine which recommendations required revision.
Institute, Atlanta, GA; Charles W. Francis, James P. Wilmot Cancer Center and University of Rochester, Rochester, NY; Forty-two publications met eligibility criteria, including 16 systematic reviews and 24 randomized Leigh E. Gates, patient representative, controlled trials.
Denver, CO; Ajay K. Kakkar, Thrombosis Research Institute, London, United King- dom; Howard A. Liebman, Keck School of Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thrombopro- Medicine, University of Southern California, phylaxis is not routinely recommended for outpatients with cancer. It may be considered for selected Los Angeles; Margaret A. Tempero, high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy University of California–San Francisco and/or dexamethasone should receive prophylaxis with either low–molecular weight heparin (LMWH) or Pancreas Center, San Francisco, CA; low-dose aspirin. Patients undergoing major cancer surgery should receive prophylaxis, starting before Sandra L. Wong, University of Michigan, Ann Arbor, MI; Ann Alexis Prestrud, Ameri- surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered can Society of Clinical Oncology, Alexan- in those with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep dria, VA; and Anna Falanga, Hospital Papa vein thrombosis and pulmonary embolism as well as for long-term (6 months) secondary prophylaxis. Use Giovanni XXIII, Bergamo, Italy.
of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE.
Published online ahead of print at Anticoagulation should not be used for cancer treatment in the absence of other indications. Patients with www.jco.org on May 13, 2013.
cancer should be periodically assessed for VTE risk. Oncology professionals should provide patient Clinical Practice Guidelines Committee education about the signs and symptoms of VTE.
Approval: Pending Editor's note: This American Society of J Clin Oncol 31:2189-2204. 2013 by American Society of Clinical Oncology Clinical Oncology Clinical Practice Guideline Update provides recommendations with 2. Should ambulatory patients with cancer re- comprehensive discussion of the relevant ceive anticoagulation for VTE prophylaxis literature for each recommendation. The during systemic chemotherapy? Data Supplement, including evidence The American Society of Clinical Oncology (ASCO) 3. Should patients with cancer undergoing sur- tables, is available at first published an evidence-based clinical practice gery receive perioperative VTE prophylaxis? guideline on prophylaxis and treatment of venous 4. What is the best method for treatment of pa- Authors' disclosures of potential conflicts thromboembolism (VTE) in 2007.1 ASCO guide- tients with cancer with established VTE to pre- of interest and author contributions are found at the end of this article.
lines are updated at intervals determined by an Up- 5. Should patients with cancer receive anticoagu- lants in the absence of established VTE to im- Corresponding author: American Society of date Committee; this is a full guideline update. Table Clinical Oncology, 2318 Mill Rd, Suite 800, 1 provides a summary of the 2007 and 2012 guide- 6. What is known about risk prediction and Alexandria, VA 22314; e-mail: awareness of VTE among patients with cancer? 2013 by American Society of Clinical 1. Should hospitalized patients with cancer re- An Update Committee was formed (Appendix Table ceive anticoagulation for VTE prophylaxis? A1, online only) to review data published since the initial 2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Lyman et al
guideline and update recommendations, as warranted, considering evidence ASCO believes that cancer clinical trials are vital to inform medical identified by the systematic review.
decisions and improve cancer care and that all patients should have the oppor-tunity to participate.
Guideline Development Process
The Update Committee met in July 2012 and had a second meeting via teleconference. During those meetings, the Update Committee reviewed evi- The goal of this update was to review evidence available since publication dence identified by the systematic review and revised guideline recommenda- of the original guideline and to revise recommendations, as needed, about the tions. Additional work on the guideline was completed electronically. The prevention and treatment of VTE among patients with cancer. One new steering committee and lead ASCO staff person prepared an updated guideline clinical question, regarding risk, was added, and a separate systematic review to share with the Update Committee members for review. As per standard was completed to address this issue.
practice, the guideline was submitted to Journal of Clinical Oncology for review.
Literature Review and Analysis
The VTE Update Committee and the ASCO Clinical Practice Guideline Com- Literature search strategy. The effectiveness search included the MED- mittee reviewed and approved this guideline document before publication.
LINE, Cochrane Database of Systematic Reviews, and Cochrane Central Reg- ister of Controlled Trials databases. Conference proceedings from annual The practice guideline is not intended to substitute for the independent meetings of ASCO, the American Society of Hematology, the European Soci- professional judgment of the treating physician. Practice guidelines do not ety of Medical Oncology, and the International Society of Thrombosis and account for individual variation among patients and may not reflect the most Hemostasis were searched through 2012 or the most recent year available. The recent evidence. This guideline does not recommend any particular product or risk assessment search was completed in MEDLINE.
course of medical treatment. Use of the practice guideline is voluntary. The Reference lists from seminal articles, guidelines from other organiza- Additional information is available at tions, and recent review articles were hand searched for additional citations.
THE BOTTOM LINE
Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer
Pharmacologic anticoagulation Medical oncologists, surgical oncologists, hospitalists, oncology nurses Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization Thromboprophylaxis is not routinely recommended for ambulatory patients with cancer; it may be considered for very select high-risk patients Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive pro- phylaxis with either low molecular–weight heparin (LMWH) or low-dose aspirin to prevent venous thromboembolism (VTE) Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 Extending postoperative prophylaxis up to 4 weeks should be considered in those with high-risk features LMWH is recommended for the initial 5 to 10 days of treatment for patients with established deep vein thrombosis and pulmo- nary embolism, as well as for long-term (6 months) secondary prophylaxis Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE Anticoagulation should not be used to extend survival in patients with cancer in the absence of other indications Patients with cancer should be periodically assessed for VTE risk Oncology professionals should provide patient education about the signs and symptoms of VTE An Expert Panel was convened to develop clinical practice guideline recommendations based on a review of evidence provided by a systematic review of the medical literature This guideline was published in Journal of Clinical Oncology. The Data Supplement, including evidence tables, and clinical tools and
resources, can be found at
2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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VTE Prophylaxis and Treatment: ASCO Guideline Update
Table 1. VTE Prophylaxis and Treatment Recommendations
Strength of Evidence Type and 2013 Recommendation Strength of Recommendation 2007 Recommendation 1.1 Hospitalized patients who have active malignancy with Hospitalized patients with cancer should be considered acute medical illness or reduced mobility should receive candidates for VTE prophylaxis with anticoagulants in pharmacologic thromboprophylaxis in the absence of Recommendation type, strength: the absence of bleeding or other contraindications to bleeding or other contraindications.
evidence based, strong 1.2 Hospitalized patients who have active malignancy without Evidence: moderate additional risk factors may be considered for pharmacologicthromboprophylaxis in the absence of bleeding or other Recommendation type, strength: evidence based, strong 1.3 Data are inadequate to support routine thromboprophylaxis Evidence: insufficient in patients admitted for minor procedures or shortchemotherapy infusion or in patients undergoing stem-cell/ Recommendation type, strength: bone marrow transplantation.
informal consensus, moderate 2.1 Routine pharmacologic thromboprophylaxis is not Evidence: moderate Routine prophylaxis with an antithrombotic agent is not recommended in cancer outpatients.
Recommendation type, strength: evidence based, strong 2.2 Based on limited RCT data, clinicians may consider LMWH Evidence: moderate prophylaxis on a case-by-case basis in highly selected Recommendation type, strength: outpatients with solid tumors receiving chemotherapy.
evidence based, weak Consideration of such therapy should be accompanied by adiscussion with the patient about the uncertainty concerningbenefits and harms as well as dose and duration ofprophylaxis in this setting.
2.3 Patients with multiple myeloma receiving thalidomide- or Evidence: moderate Patients receiving thalidomide or lenalidomide with lenalidomide-based regimens with chemotherapy and/or chemotherapy or dexamethasone are at high risk for Recommendation type, strength: dexamethasone should receive pharmacologic thrombosis and warrant prophylaxis. Until such time evidence based, strong thromboprophylaxis with either aspirin or LMWH for lower- as data are available from RCTs, LMWH or adjusted- risk patients and LMWH for higher-risk patients.
dose warfarin (INR approximately 1.5) isrecommended in patients with myeloma receivingthalidomide plus chemotherapy or dexamethasone.
This recommendation is based on extrapolation fromstudies of postoperative prophylaxis in orthopedicsurgery and a trial of adjusted-dose warfarin in breastcancer. RCTs evaluating antithrombotic agents areneeded in patients with multiple myeloma receivingthalidomide or lenalidomide plus chemotherapy and/ordexamethasone. Research identifying better markersof ambulatory patients with cancer most likely todevelop VTE is urgently needed.
3.1 All patients with malignant disease undergoing major All patients undergoing major surgical intervention for surgical intervention should be considered for malignant disease should be considered for Recommendation type, strength: pharmacologic thromboprophylaxis with either UFH or thromboprophylaxis. Patients undergoing laparotomy, evidence-based, strong LMWH unless contraindicated because of active bleeding or laparoscopy, or thoracotomy lasting greater than 30 high bleeding risk.
minutes should receive pharmacologicthromboprophylaxis with either low-dose UFH orLMWH unless contraindicated because of high risk ofbleeding or active bleeding.
3.2 Prophylaxis should be commenced preoperatively.
Evidence: moderate Prophylaxis should be commenced preoperatively or as early as possible in the postoperative period.
Recommendation type, strength: evidence based, moderate 3.3 Mechanical methods may be added to pharmacologic Evidence: moderate Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy methods but should not be used as monotherapy for Recommendation type, strength: for VTE prevention unless pharmacologic methods are VTE prevention unless pharmacologic methods are evidence based, strong contraindicated because of active bleeding or high bleeding contraindicated because of active bleeding.
3.4 A combined regimen of pharmacologic and mechanical Evidence: moderate A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest- prophylaxis may improve efficacy, especially in the Recommendation type, strength: risk patients.
informal consensus, moderate 3.5 Pharmacologic thromboprophylaxis for patients undergoing Prophylaxis should be continued for at least 7 to 10 days major surgery for cancer should be continued for at least 7 postoperatively. Prolonged prophylaxis for up to 4 Recommendation type, strength: to 10 days. Extended prophylaxis with LMWH for up to 4 weeks may be considered in patients undergoing evidence based, strong to weeks postoperatively should be considered for patients major abdominal or pelvic surgery for cancer with undergoing major abdominal or pelvic surgery for cancer high-risk features such as residual malignant disease who have high-risk features such as restricted mobility, after operation, obese patients, and those with a obesity, history of VTE, or with additional risk factors as history of VTE.
listed in Table 3. In lower-risk surgical settings, the decisionon appropriate duration of thromboprophylaxis should bemade on a case-by-case basis considering the individualpatient.
(continued on following page) 2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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Lyman et al
Table 1. VTE Prophylaxis and Treatment Recommendations (continued)
Strength of Evidence Type and 2013 Recommendation Strength of Recommendation 2007 Recommendation Treatment and secondary prophylaxis 4.1 LMWH is preferred over UFH for the initial 5 to 10 days of LMWH is the preferred approach for the initial 5 to 10 anticoagulation for the patient with cancer with newly days of anticoagulant treatment of the patient with Recommendation type, strength: diagnosed VTE who does not have severe renal impairment cancer with established VTE.
evidence based, strong (defined as creatinine clearance ⬍ 30 mL/min).
4.2 For long-term anticoagulation, LMWH for at least 6 LMWH given for at least 6 months is also the preferred months is preferred because of improved efficacy over approach for long-term anticoagulant therapy. VKAs Recommendation type, strength: VKAs. VKAs are an acceptable alternative for long-term with a targeted INR of 2 to 3 are acceptable for long- evidence based, strong therapy if LMWH is not available.
term therapy when LMWH is not available.
4.3 Anticoagulation with LMWH or VKA beyond the initial 6 Evidence: insufficient After 6 months, indefinite anticoagulant therapy should months may be considered for select patients with active be considered for selected patients with active Recommendation type, strength: cancer, such as those with metastatic disease or those cancer, such as those with metastatic disease and informal consensus, weak to those receiving chemotherapy. This recommendation is based on Panel consensus in the absence of clinicaltrials data.
4.4 The insertion of a vena cava filter is only indicated for Evidence: weak to moderate The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy (see patients with contraindications to anticoagulant Recommendation type, strength: Table 4). It may be considered as an adjunct to therapy and in those with recurrent VTE despite informal consensus, moderate anticoagulation in patients with progression of thrombosis adequate long-term therapy with LMWH.
(recurrent VTE or extension of existing thrombus) despiteoptimal therapy with LMWH.
4.5 For patients with primary CNS malignancies, Evidence: moderate For patients with CNS malignancies, anticoagulation is anticoagulation is recommended for established VTE as recommended for established VTE as described for Recommendation type, strength: described for other patients with cancer. Careful monitoring other patients with cancer. Careful monitoring is informal consensus, strong is necessary to limit the risk of hemorrhagic complications.
necessary to limit the risk of hemorrhagiccomplications. Anticoagulation should be avoided inthe presence of active intracranial bleeding, recentsurgery, preexisting bleeding diathesis such asthrombocytopenia (platelet count ⬍ 50,000/␮L), orcoagulopathy.
4.6 Use of novel oral anticoagulants for either prevention or Evidence: insufficient treatment of VTE in patients with cancer is not Recommendation type, strength: recommended at this time.
informal consensus, strong 4.7 Based on consensus, incidental PE and DVT should be Evidence: insufficient treated in the same manner as symptomatic VTE.
Recommendation type, strength: Treatment of splanchnic or visceral vein thrombi diagnosed informal consensus, moderate incidentally should be considered on a case-by-case basis,considering potential benefits and risks of anticoagulation.
Anticoagulation and survival 5.1 Anticoagulants are not recommended to improve survival Evidence: weak to moderate Anticoagulants are not recommended to improve survival in patients with cancer without VTE.
in patients with cancer without VTE. Patients with Recommendation type, strength: cancer should be encouraged to participate in clinical informal consensus, moderate trials designed to evaluate anticoagulant therapy as anadjunct to standard anticancer therapies.
5.2 Patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapyas an adjunct to standard anticancer therapies.
6.1 Based on consensus, the Panel recommends that patients Evidence: moderate New for 2012 Update with cancer be assessed for VTE risk at the time of Recommendation type, strength: chemotherapy initiation and periodically thereafter. Individual informal consensus, strong risk factors, including biomarkers or cancer site, do notreliably identify patients with cancer at high risk of VTE. Inthe outpatient setting, risk assessment can be conductedbased on a validated risk assessment tool (Table 5).
6.2 Based on consensus, the Panel recommends that Evidence: insufficient oncologists educate patients regarding VTE, particularly in Recommendation type, strength: settings that increase risk such as major surgery, informal consensus, strong hospitalization, and while receiving systemic antineoplastictherapy.
Abbreviations: INR, international normalized ratio; LMWH, low–molecular weight heparin; PE, pulmonary embolism; RCT, randomized controlled trial; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.
The Update Committee reviewed the list of included reports for completeness.
Inclusion and exclusion criteria. Articles for the efficacy systematic Subject headings and keywords used in the efficacy literature search included review were selected for inclusion if they were RCTs or systematic reviews four major categories: VTE, anticoagulation, malignancy, and randomized of RCTs that assessed the efficacy and safety of anticoagulation in controlled trials (RCTs). The full search string is available in the Data Supple- patients with cancer and included at least 50 patients per arm. Only data ment. The risk literature search also included four major categories: risk from conference proceedings available as full presentations or posters assessment, VTE, cancer, and cohort studies.
were included.
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VTE Prophylaxis and Treatment: ASCO Guideline Update
For the risk systematic review, studies from the ambulatory setting that either developed or validated risk models were included. Only reports that GUIDELINE RECOMMENDATIONS: CLINICAL QUESTION 1
included multivariate analyses were eligible. Risk assessment models limited to Should hospitalized patients with cancer receive anticoagulation for single cancer types were excluded.
Data extraction. Eligible reports for both reviews were preliminarily identified after the literature search. Full-text copies were obtained to furtherassess eligibility. Articles that met eligibility for the efficacy search underwent data extraction by ASCO staff for study design and quality, patient character- Hospitalized patients who have active malignancy with istics, outcomes, and adverse events. Outcomes of interest included symptom- acute medical illness or reduced mobility should receive phar- atic and asymptomatic thrombotic events found on screening, major and macologic thromboprophylaxis in the absence of bleeding or minor bleeding, early and overall mortality, sudden death, and adverse events.
For the risk review, data extraction included study characteristics, quality, and risk assessment model development and evaluation. Outcomes of interestincluded factors incorporated into the risk assessment model, model equation, and outcomes according to risk.
Hospitalized patients who have active malignancy without addi- Evidence summary tables (Data Supplement) were reviewed for accu- tional risk factors may be considered for pharmacologic thrombopro- racy and completeness by an ASCO staff member who was not involved in dataextraction. Disagreements were resolved through discussion; the Steering phylaxis in the absence of bleeding or other contraindications.
Committee was consulted if necessary.
Study quality. Trial characteristics from the RCTs were extracted to evaluate the potential for bias. Study quality was also assessed for the reports in Data are inadequate to support or oppose thromboprophy- the risk systematic review.
laxis in patients admitted for minor procedures or short chemo- Guideline and Conflicts of Interest
therapy infusion or in patients undergoing stem-cell/bone The Update Committee was assembled in accordance with ASCO's Con- flict of Interest Management Procedures for Clinical Practice Guidelines("Procedures," summarized at http://www.asco.org/guidelinescoi). Membersof the Update Committee completed ASCO's disclosure form, which requires Literature Update and Analysis 1
disclosure of financial and other interests that are relevant to the subject matter Three randomized trials were identified by the systematic review: of the guideline, including relationships with commercial entities that are CERTIFY (Certoparin for Thromboprophylaxis in Medical Patients), reasonably likely to experience direct regulatory or commercial impact as the CERTAIN (Certoparin Versus Unfractionated Heparin for the Pre- result of promulgation of the guideline. Categories for disclosure include vention of Thromboembolic Complications in Acutely Ill Medical employment relationships, consulting arrangements, stock ownership, hono- Patients), and EXCLAIM (Extended Prophylaxis for Venous Throm- raria, research funding, and expert testimony. In accordance with the Proce-dures, the majority of the members of the Update Committee did not disclose boEmbolism in Acutely Ill Medical Patients with Prolonged any such relationships.
Immobilization).2-4 EXCLAIM evaluated extended prophylaxis.2 Onesystematic review and meta-analysis of inpatient thromboprophylaxis At intervals, the Update Committee co-chairs and two Update Commit- was also identified.5 Dosing information is provided in Table 2.
tee members designated by the co-chairs will determine the need for guidelinerevisions based on the available literature. If necessary, the Update Committee will be reconvened. When appropriate, the Update Committee will suggest Both new primary prophylaxis trials in medically ill patients, revised recommendations to the Clinical Practice Guideline Committee.
CERTAIN and CERTIFY, compared a low molecular–weight heparin(LMWH), certoparin, with unfractionated heparin (UFH). The primary outcome for both trials was the composite of symptomaticor asymptomatic deep vein thrombosis (DVT), symptomatic pul- monary embolism (PE), or VTE-related death. Among the 172 The efficacy literature search yielded a total of 380 citations patients randomly assigned in the CERTAIN trial, 8.0% and 9.2% from MEDLINE, 531 citations from conference proceedings, and in the UFH and LMWH groups, respectively, had active or previ- 18 from hand searching. Forty-two reports provisionally met in- ous cancer (not significant).3 The primary end point was reported clusion and exclusion criteria and were selected for full-text review.
in 18% of patients receiving UFH and 10.7% of patients receiving Of those, reports from 30 trials and systematic reviews were se- certoparin (not significant).
lected for data extraction. The QUOROM diagram is available in Patients with cancer were eligible to participate in CERTIFY, but the Data Supplement.
the percentage was not reported.4 Among the 3,244 patients randomly For the risk systematic review, the MEDLINE literature search assigned in this trial, the primary outcome of DVT or PE occurred in yielded 664 citations. Of those, 54 provisionally met eligibility criteria 3.9% in the certoparin arm compared with 4.5% receiving UFH (not and were selected for full-text review. Six articles were identified for significant). Both trials included an older patient population; the data extraction.
mean age in CERTIFY was ⬎ 78 years,4 and in CERTAIN, it was ⬎ 70years.3 Neither trial reported data for cancer subgroups. Bleeding rates Study Quality and Limitations of the Literature
were higher with UFH compared with LMWH. Sudden death was not Publications identified by the systematic review varied with re- reported for either trial.
spect to potential for bias, ranging from low to high. A majority of the The systematic review examined pharmacologic thrombopro- trials were of moderate quality. Specific quality issues are discussed phylaxis with LMWH, UFH, fondaparinux, and placebo.5 DVT rates within the section for the relevant clinical question.
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Table 2. Dosing Regimens for Prophylaxis/Treatment of VTE in Patients With Cancer
Pharmacologic (anticoagulant) prophylaxis Hospitalized medical patientsb Unfractionated heparin 5,000 U once every 8 hoursc 5,000 U once daily 2.5 mg once daily Surgical patientsbe Unfractionated heparin 5,000 U 2-4 hours preoperatively and once every 8 hoursc thereafter or 5,000 U 10-12 hours preoperatively and 5,000 U once daily thereafter 2,500 U 2-4 hours preoperatively and 5,000 U once daily thereafter or 5,000 U 10-12 hours preoperatively and 5,000 U once daily thereafter 20 mg 2-4 hours preoperatively and 40 mg once daily thereafter or 40 mg 10-12 hours preoperatively and 40 mg once daily thereafter 2.5 mg qd beginning 6-8 h postoperatively Treatment of established VTEf Unfractionated heparing 80 U/kg IV bolus, then 18 U/kg per hour IV; adjust dose based on aPTTh 100 U/kg once every 12 hours; 200 U/kg once daily 1 mg/kg once every 12 hours; 1.5 mg/kg once daily 175 U/kg once per day ⬍ 50 kg, 5.0 mg once daily; 50-100 kg, 7.5 mg once daily; ⬎ 100 kg, 10 mg once daily 200 U/kg once daily for 1 month, then 150 U/kg once daily 1.5 mg/kg once daily; 1 mg/kg once every 12 hours 175 U/kg once daily Adjust dose to maintain INR 2 to 3 Abbreviations: aPTT, activated partial thromboplastin time; FDA, US Food and Drug Administration; INR, international normalized ratio; IV, intravenous; LMWH, low–molecular weight heparin; VTE, venous thromboembolism.
aAll doses are administered as subcutaneous injections except as indicated.
bDuration for medical patients is length of hospital stay or until fully ambulatory; for surgical patients, prophylaxis should be continued for at least 7 to 10 days.
Extended prophylaxis for up to 4 weeks should be considered for high-risk patients.
cUnfractionated heparin 5,000 U every 12 hours has also been used but appears to be less effective.
dThis drug is not approved by the FDA for this indication.
eWhen neuraxial anesthesia or analgesia is planned, prophylactic doses of once-daily LMWH should not be administered within 10 to 12 hours before the procedure/instrumentation (including epidural catheter removal). After the surgery, the first dose of LMWH can be administered 6 to 8 hours postoperatively. Aftercatheter removal, the first dose of LMWH can be administered no earlier than 2 hours afterward. Clinicians should refer to their institutional guidelines and theAmerican Society of Regional Anesthesia Guidelines for more information.6 fContraindications to therapeutic anticoagulation are listed in Table 4.
gParenteral anticoagulants should overlap with warfarin for 5 to 7 days minimum and continued until INR is in the therapeutic range for 2 consecutive days.
hUnfractionated heparin infusion rate should be adjusted to maintain the aPTT within the therapeutic range in accordance with local protocol to correspond with a heparin level of 0.3 to 0.7 U/mL using a chromogenic Xa assay.
iDependent on significant renal clearance; avoid in patients with creatinine clearance ⱕ 30 mL/minute or adjust dose based on anti–factor Xa levels.
jOptimal dose unclear in patients ⬎ 120 kg.
kTwice-daily dosing may be more efficacious than once-daily dosing for enoxaparin based on post hoc data.
lThis drug is not available in the United States.
mTotal duration of therapy depends on clinical circumstances. See Clinical Question 4, section entitled "Initial and Long-Term Treatment Up to 6 Months," for more nThis is the only LMWH with FDA approval for extended therapy to prevent recurrent thrombosis in patients with cancer.
ratio [OR], 0.60; 95% CI, 0.47 to 0.75) but similar between LMWH 16.0% in the placebo arm. The primary outcomes were VTE defined as and UFH (OR, 0.92; 95% CI, 0.56 to 1.52). No differences in the rate of a composite of symptomatic or asymptomatic proximal DVT, symp- death or PE were noted between patients who were treated with tomatic PE, and fatal PE, and major bleeding. The proportion of VTE LMWH/fondaparinux, UFH, or placebo. Major bleeding rates were events was greater with placebo: 4.0% versus 2.5% for an absolute risk similar across all treatment arms considered. Minor bleeding rates difference of ⫺1.53% (95% CI, ⫺2.54% to ⫺0.52%). Major bleeding were similar with LMWH and UFH and greater than in placebo- was uncommon but significantly greater with active therapy: 0.8% treated patients. Cancer-specific rates were not provided for either versus 0.3%. The early mortality rate was similar across trial arms VTE or bleeding.
(hazard ratio [HR], 0.93; 95% CI, 0.65 to 1.32).2 Cancer-specific datawere not reported.
In an RCT, 6,085 acutely ill medical patients were assigned to extended prophylaxis with enoxaparin or placebo for 28 days (⫾ 4 days) after receiving open-label enoxaparin for an initial 10 days (⫾ 4 The inpatient trials enrolled mixed populations including pa- days).2 Of the patients in the LMWH arm, 14.1% had cancer, as did tients with cancer as well as general medical patients. To date, no trials 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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VTE Prophylaxis and Treatment: ASCO Guideline Update
Table 3. Risk Factors and Biomarkers for Cancer-Associated Thrombosis
Treatment Related Platelet count (ⱖ 350,000/␮L) Stage (higher for advanced stage) Antiangiogenic agents (eg, Race (higher in African Americans; Leukocyte count (⬎ 11,000/␮L) lower in Asians/PacificIslanders) Cancer histology (higher for Medical comorbidities (infection, Hemoglobin (⬍ 10 g/dL) adenocarcinoma than renal disease, pulmonary Time after initial diagnosis (highest in first 3 to 6 months) Indwelling venous access devices Diminished performance status Radiation therapy Inherited prothrombotic mutations Surgery ⬎ 60 min Abbreviation: VTE, venous thromboembolism.
have evaluated inpatient thromboprophylaxis in a cancer-only popu- uncertainty concerning benefits and harms as well as dose and dura- lation. These recommendations were formulated by extrapolating the tion of prophylaxis in this setting.
best available data. All RCTs included reduced mobility as an eligibilitycriterion, but the definitions of immobility were not explicit or con- sistent. This limits generalizability of these data to all hospitalized Patients with multiple myeloma receiving thalidomide- or patients with cancer and tempered the willingness of the Update lenalidomide-based regimens with chemotherapy and/or dexameth- Committee to recommend thromboprophylaxis for all inpatients asone should receive pharmacologic thromboprophylaxis with either with malignancy.
aspirin or LMWH for lower-risk patients and LMWH for higher- The extended thromboprophylaxis trial, CERTAIN, indicates risk patients.
that prolonging anticoagulation reduces VTE event rates but increasesthe risk of bleeding. Importantly, a midstudy amendment narrowedthe eligible patient population after interim analysis noted limited Literature Update and Analysis 2
efficacy in patients without reduced mobility.2 Findings from this trial The updated systematic review identified three systematic must be interpreted with this narrow patient population in mind.
reviews15-17 considering the ambulatory setting and nine RCTs.18-25Two RCTs, SAVE-ONCO (Evaluation of AVE5026 in the Prevention Risk Among Inpatients
of Venous Thromboembolism in Cancer Patients Undergoing Chem- A vast majority of hospitalized patients with cancer are at otherapy),18 and PROTECHT (Prophylaxis of Thromboembolism moderate to high risk for thromboembolic events, because active During Chemotherapy)19 included patients with a variety of solid cancer is a strong risk factor.7-13 Most patients have additional risk tumors. Two others, FRAGEM (Gemcitabine With or Without Dalte- factors, including comorbid conditions such as infection, immo- parin in Treating Patients With Locally Advanced or Metastatic Pan- bility, or advanced age.14 The benefit of prophylaxis increases with creatic Cancer)21 and PROSPECT-CONKO 004 (Chemotherapy the risk of VTE. Table 3 includes a list of risk factors that can be With or Without Enoxaparin in Pancreatic Cancer)24,25 included only used to evaluate risk in oncology inpatients. Risk is further ad- patients with pancreatic cancer. The PRODIGE (Dalteparin Low dressed in Clinical Question 6.
Molecular Weight Heparin for Primary Prophylaxis of VenousThromboembolism in Brain Tumour Patients) trial examined antico-agulation for patients with glioma.23 Two recent trials evaluated CLINICAL QUESTION 2
thromboprophylaxis in multiple myeloma.20,22 Final publications oftwo trials discussed in the previous guideline are also discussed.26 Should ambulatory patients with cancer receive anticoagulation forVTE prophylaxis during systemic chemotherapy? Two systematic reviews identified RCTs comparing LMWH pro- Routine pharmacologic thromboprophylaxis is not recom- phylaxis in the outpatient setting with placebo or no prophylaxis.
mended in cancer outpatients.
Estimated risk ratios (RRs) across trials indicated decreases in symp-tomatic VTE events with LMWH thromboprophylaxis of 0.53 (95% CI, 0.39 to 0.72) and 0.54 (95% CI, 0.31 to 0.95), respectively.16,17 Based on limited RCT data, clinicians may consider LMWH Neither meta-analysis noted a statistically significant increase in bleed- prophylaxis on a case-by-case basis in highly selected outpatients with ing with LMWH. Of note, the second report included only trials of solid tumors receiving chemotherapy. Consideration of such therapy patients with advanced lung cancer from two RCTs.16 The relative risk should be accompanied by a discussion with the patient about the for symptomatic VTE was 0.58 (95% CI, 0.28 to 1.06).
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Lyman et al
A recent Cochrane review compared the efficacy and safety of Pancreatic cancer. The FRAGEM and PROSPECT-CONKO LMWHs, vitamin K antagonists (VKAs), and direct thrombin inhib- 004 trials enrolled patients with advanced pancreatic neoplasms.21,25 itors with no intervention or placebo in ambulatory patients with The FRAGEM trial was a phase IIb RCT of 123 patients with advanced cancer.15 Fewer symptomatic VTEs occurred with LMWH throm- pancreatic cancer receiving gemcitabine-based chemotherapy com- boprophylaxis in the pooled analysis of ⬎ 2,400 patients (RR, 0.62; paring thromboprophylaxis with therapeutic doses of dalteparin up to 95% CI, 0.41 to 0.99). Rates of major and minor bleeding were not 12 weeks, following a schedule similar to that of the CLOT (Random- consistently increased with anticoagulation compared with placebo.
ized Comparison of Low Molecular–Weight Heparin Versus Oral Four trials specifically considered the LMWH dalteparin, allowing a Anticoagulant Therapy for the Prevention of Recurrent Venous subgroup analysis of that agent. No difference in VTE event rates was Thromboembolism in Patients with Cancer) trial, with no throm- noted between dalteparin and placebo (RR, 0.75; 95% CI, 0.42 boprophylaxis.21 VTE over the course of the study was reduced from 28% to 12%, with a relative risk of 0.42 (95% CI, 0.19 to 0.94; P ⫽ The absolute differences in symptomatic VTE event rates be- .039). No differences in rates of major bleeding or mortality between tween treated and control patients were ⬍ 5% in most trials. Among study arms were observed.
the three systematic reviews, the absolute risk differences in VTE were The PROSPECT-CONKO 004 trial was presented as an oral 1.5%, 2.8%, and 1.7% with estimates of the number needed to treat presentation but has not yet been published.25 In this trial, 312 patients (NNT) of 67, 36, and 59, respectively, to prevent one symptomatic with stage IV pancreatic cancer being treated with gemcitabine-based VTE event across the included trials. Importantly, individual patient chemotherapy were randomly assigned to enoxaparin at half the data were not evaluated, limiting the assessment of patients with therapeutic dose for 3 months or no thromboprophylaxis. VTE different cancers, often receiving different cancer therapies and anti- was reduced from 15% to 5%, with a relative risk of 0.35 (95% coagulants, and with varying degrees of VTE risk.
CI, 0.16 to 0.75; P ⫽ .007). Again, no significant difference inrates of major bleeding was reported.
Glioma. The PRODIGE trial included 186 patients with newly Recent Clinical Trials
diagnosed grade 3 or 4 glioma and was terminated early.23 Patients Mixed solid tumors. The PROTECHT and SAVE-ONCO trials were randomly assigned to dalteparin or placebo for 6 months, and evaluated thromboprophylaxis in ambulatory patients with cancer therapy could continue for an additional 6 months. VTE events oc- receiving chemotherapy for locally advanced or metastatic solid tu- curred in nine patients (9%) in the dalteparin arm compared with 13 mors.18,19 These double-blind trials compared anticoagulation with patients (15%) in the placebo arm (HR, 0.51; 95% CI, 0.19 to 1.40; P ⫽ either the LMWH nadroparin or the ultra-LMWH semuloparin with .29). Five patients in the dalteparin arm experienced intracranial placebo. Semuloparin is not available and has been withdrawn from bleeding by 12 months compared with one in the control arm (HR, marketing worldwide. The primary end point for PROTECHT was a 4.2; 95% CI, 0.48 to 36; P ⫽ .22).
composite of symptomatic VTEs and arterial thromboembolic events Overall, the Panel concluded that offering all patients with solid during treatment and follow-up.19 In PROTECHT, 3.9% of patients malignancies anticoagulation for thromboprophylaxis in the ambula- in the control arm experienced events compared with 2.0% of patients tory setting is not justified based on the available clinical trial data and treated with nadroparin for an NNT of 53 (one-tailed P ⫽ .02). Major the heterogeneity of this patient population.
bleeding rates were not different between the arms. In an exploratory Multiple myeloma. Two RCT substudies assessed different subgroup analysis, thromboembolic event rates were greater in pa- thromboprophylaxis strategies in patients with newly diagnosed mul- tients who received thromboprophylaxis compared with controls: tiple myeloma receiving lenalidomide- or thalidomide-based treat- 8.3% versus 5.9%. In SAVE-ONCO, fewer symptomatic VTE events ment.20,22 Palumbo et al22 stratified patients on the basis of age and occurred in patients who received semuloparin (1.2%) compared transplantation eligibility and then randomly assigned them to one with placebo (3.4%; HR, 0.36; 95% CI, 0.21 to 0.60; P ⬍ .001).18 The of two chemotherapy regimens. Patients who received thalidomide- absolute risk difference for VTE events was 2.2% for an NNT of 45.
based regimens were eligible for random assignment to warfarin, Major bleeding was similar across arms (HR, 1.05; 95% CI, 0.55 to low-dose aspirin, or enoxaparin. Of 659 analyzed patients, serious thromboembolic events, acute cardiovascular events, or sudden death Two double-blind RCTs of ambulatory patients with metastatic during the first 6 months occurred in 6.4% in the aspirin group, 8.2% breast carcinoma (TOPIC-1) or stage III/IV non–small-cell lung car- in the warfarin group, and 5.0% in the LMWH group. Compared with cinoma (TOPIC-2) compared certoparin 3,000 IU subcutaneously LMWH, the absolute differences were 1.3% (95% CI, 3.0% to 5.7%; once daily with placebo for 6 months.26 The primary outcome was P ⫽ .544) with aspirin and 3.2% (95% CI, 1.5% to 7.8%; P ⫽ .183) symptomatic or asymptomatic VTE. TOPIC-1 randomly assigned with warfarin. Three major bleeding episodes occurred with aspirin 353 patients but was stopped after an interim analysis revealed no (1.4%) compared with none in the other arms.22 No difference in the difference between treatment arms. VTE occurred in 4% from both risk of VTE was found when comparing aspirin with LMWH (HR, study arms, resulting in an OR of 1.02 (95% CI, 0.30 to 3.48). TOPIC-2 1.13; 95% CI, 0.59 to 2.17).
randomly assigned 547 patients, 4.5% of whom experienced VTE in In the other study from the same group, 342 patients with newly the certoparin arm and 8.3% in the placebo arm (OR, 0.52; 95% CI, diagnosed multiple myeloma treated with lenalidomide-based chem- 0.23 to 1.12). Major bleeding in the certoparin and control arms was otherapy were randomly assigned to either prophylactic low-dose 1.7% and 0% in TOPIC-1 and 3.7% and 2.2% in TOPIC-2, respec- aspirin (100 mg per day) or enoxaparin during induction and consol- tively, neither of which was statistically significant. A post hoc explor- idation chemotherapy.20 Symptomatic VTE was reported in 2.3% of atory analysis demonstrated a reduction in VTE in stage IV lung patients receiving aspirin and 1.2% receiving LMWH for an absolute carcinoma in the certoparin arm (3.5% v 10.2%; P ⫽ .032).
difference of 1.07% (95% CI, ⫺1.69 to 3.83; P ⫽ .452). No major 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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VTE Prophylaxis and Treatment: ASCO Guideline Update
bleeding was reported in either arm, and minor bleeding was noted in Sakon et al34 trial, 164 patients with cancer undergoing abdominal one patient receiving enoxaparin.
laparotomy were randomly assigned to enoxaparin or intermittentpneumatic compression (IPC). The incidence of symptomatic VTEwas 1.2% (95% CI, 0.03 to 6.53%) in the enoxaparin group and 19.4% CLINICAL QUESTION 3
(95% CI, 7.45 to 37.47%) in the IPC group. Major bleeding wasreported in 4.6% (95% CI, 1.5% to 10.4%) in the enoxaparin group Should patients with cancer undergoing surgery receive perioperative and 2.6% (95% CI, 0.1% to 13.8%) in the IPC group. The SAVE- ABDO (Evaluation of AVE5026 as Compared to Enoxaparin for thePrevention of Venous Thromboembolism in Patients Undergoing Major Abdominal Surgery)33 and Simonneau et al35 trials compared All patients with malignant disease undergoing major surgical two different LMWH regimens. SAVE-ABDO was a randomized, intervention should be considered for pharmacologic thrombopro- double-blind, phase III trial of 4,414 patients undergoing major ab- phylaxis with either UFH or LMWH unless contraindicated because dominal surgery, of whom 81% underwent surgery for malignant of active bleeding or high bleeding risk.
disease. Patients were randomly assigned to either ultra-LMWHsemuloparin starting before surgery or enoxaparin starting after sur- gery. The primary outcome of any VTE and all-cause mortality oc- Prophylaxis should be commenced preoperatively.
curred in 5.5% of those receiving enoxaparin and 6.3% receivingsemuloparin (OR, 1.16; 95% CI, 0.84 to 1.59). There were fewer events of major bleeding with semuloparin (OR, 0.63; 95% CI, 0.46 to 0.87).
Mechanical methods may be added to pharmacologic throm- In the double-blind Simonneau et al study, patients with colorectal boprophylaxis but should not be used as monotherapy for VTE pre- cancer were randomly assigned to nadroparin or enoxaparin, both vention unless pharmacologic methods are contraindicated because starting before surgery.35 Of 1,288 patients randomly assigned, only of active bleeding or high bleeding risk.
950 (73.8%) were analyzed, with symptomatic and asymptomaticVTE rates of 15.9% with nadroparin and 12.6% with enoxaparin for a relative risk of 1.27 (95% CI, 0.93 to 1.74; not significant). Major A combined regimen of pharmacologic and mechanical prophy- bleeding was reported in 11.5% of patients receiving enoxaparin and laxis may improve efficacy, especially in the highest-risk patients.
7.3% receiving nadroparin (RR, 0.64; 95% CI, 0.45 to 0.91; P ⫽ .012).
These surgical studies were conducted in patients with GI, gyne- cologic, or urologic malignancies undergoing major cancer surgeries Pharmacologic thromboprophylaxis for patients undergoing and examined thromboprophylaxis administered for approximately 7 major surgery for cancer should be continued for at least 7 to 10 days.
to 10 days. This duration was established in historical trials of primary Extended prophylaxis with LMWH for up to 4 weeks postoperatively prophylaxis in the surgical setting.36-44 There are no studies assessing should be considered for patients undergoing major abdominal or shorter durations or limiting thromboprophylaxis during the hospi- pelvic surgery for cancer who have high-risk features such as restricted talization for lower risk cancer surgery.
mobility, obesity, history of VTE, or with additional risk factors aslisted in Table 3. In lower-risk surgical settings, the decision on appro-priate duration of thromboprophylaxis should be made on a case-by- case basis considering the individual patient.
Three systematic reviews of extended prophylaxis, for 4 weeks postoperatively with LMWH in mixed cancer and noncancer popula- Literature Update and Analysis 3
tions, were reported.28,30,31 The meta-analysis by Bottaro et al28 in- Six meta-analyses27-32 and three RCTs33-35 of perioperative pro- cluded three trials involving 1,104 patients, 70.6% of whom had phylaxis in patients with cancer were identified by the updated system- cancer. A decrease in asymptomatic and symptomatic VTE among atic review. Three of the meta-analyses28,30,31 and one of the RCTs patients with cancer was noted in a subgroup analysis (RR, 0.46; 95% considered extended perioperative thromboprophylaxis.33 CI, 0.28 to 0.77). Major bleeding was not significantly different in thetreatment groups overall (RR, 0.83; 95% CI, 0.22 to 3.12), although no cancer-specific rates were reported. Akl et al31 included three trials or A Cochrane meta-analysis comparing prophylactic LMWH with subgroups of trials representing patients with cancer and reported a UFH in the cancer perioperative setting found little difference in rates decrease in the risk of asymptomatic DVT with extended LMWH of PE and DVT.32 Major bleeding was also similar with the two prophylaxis versus untreated control or placebo (RR, 0.21; 95% CI, anticoagulants (RR, 0.84; 95% CI, 0.52 to 1.36). A systematic review 0.05 to 0.94). No significant difference in the risk of major bleeding limited to patients undergoing surgery for gynecologic cancer com- was reported (RR, 2.94; 95% CI, 0.12 to 71.85). Rasmussen et al30 pared UFH, LMWH, or sequential compression devices with either included one additional trial in their meta-analysis but did not present untreated controls or one another.29 A reduction in DVT with UFH results specifically among patients with cancer undergoing surgery.
compared with untreated controls was observed (RR, 0.58; 95% CI, The incidence of asymptomatic and symptomatic VTE after major 0.35 to 0.95), but there was no difference between UFH and LMWH abdominal or pelvic surgery was 14.3% among controls and 6.1% (RR, 0.91; 95% CI, 0.38 to 2.17). Bleeding rates were not reported.
among those receiving extended prophylaxis with LMWH (OR, 0.41; The three RCTs that assessed primary perioperative prophylaxis 95% CI, 0.26 to 0.63; P ⬍ .001). Although major bleeding events were included patients undergoing abdominal or pelvic surgery. In the not presented separately, all bleeding events in the control and LMWH 2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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groups were 3.7% (95% CI, 2.4% to 5.5%) and 4.1% (95% CI, 2.7% to6.0%), respectively (OR, 1.11; 95% CI, 0.62 to 1.97; P ⫽ .73).
Table 4. Contraindications and Other Considerations to Withhold Therapeutic
Anticoagulant Therapy in Patients With Cancer and VTEⴱ The more recent CANBESURE (Cancer, Bemiparin, and Surgery Evaluation) study randomly assigned 626 patients undergoing ab-dominal or pelvic cancer surgery to either extended thromboprophy- Active major, serious, or potentially life-threatening bleeding not laxis with bemiparin (28 days) or bemiparin (8 days) in a double-blind reversible with medical or surgical intervention, including but not fashion.45 The primary outcome of asymptomatic or symptomatic limited to any active bleeding in a critical site (ie, intracranial,pericardial, retroperitoneal, intraocular, intra-articular, intraspinal) DVT, nonfatal PE, or all-cause mortality during the double-blind Severe, uncontrolled malignant hypertension period occurred in 10.1% of patients receiving bemiparin and 13.3% Severe, uncompensated coagulopathy (eg, liver failure) of those in the placebo group, and the primary end point was not met Severe platelet dysfunction or inherited bleeding disorder (RR, 0.75; 95% CI; 0.46 to 1.24; P ⫽ .26). Major bleeding was reported Persistent, severe thrombocytopenia (⬍ 20,000/␮L) in two patients (0.6%) receiving bemiparin and one (0.3%) in the Surgery or invasive procedure, including but not limited to lumbar placebo arm (not significant). While the study was underway, but puncture, spinal anesthesia, and epidural catheter placement before unblinding, a secondary outcome of major VTE was defined as Intracranial or spinal lesion at high risk for bleeding asymptomatic proximal or symptomatic proximal DVT, nonfatal PE, Active peptic or other GI ulceration at high risk of bleeding and VTE-related death. At the end of the double-blind period, major Active but non–life-threatening bleeding (eg, trace hematuria) VTE was reported in two (0.8%) and 11 (4.6%) patients, respectively Intracranial or CNS bleeding within past 4 weeks (RR, 0.18; 95% CI; 0.04 to 0.78; P ⫽ .010).
Major surgery or serious bleeding within past 2 weeks Persistent thrombocytopenia (⬍ 50,000/␮L) Patients for whom anticoagulation is of uncertain benefit CLINICAL QUESTION 4
Patient receiving end-of-life/hospice care Very limited life expectancy with no palliative or symptom reduction What is the best method for treatment of patients with cancer with Asymptomatic thrombosis with concomitant high risk of serious established VTE to prevent recurrence? Patient characteristics and values Preference or refusal Nonadherence to dosing schedule, follow-up, or monitoring LMWH is preferred over UFH for the initial 5 to 10 days of Abbreviation: VTE, venous thromboembolism.
anticoagulation for the patient with cancer with newly diagnosed VTE ⴱThese criteria are specific for therapeutic doses of anticoagulation and who does not have severe renal impairment (defined as creatinine should not be applied to prophylactic doses of anticoagulation.
†Absolute contraindications are situations in which anticoagulation should clearance ⬍ 30 mL/min).
not be administered because the risk of harm associated with bleeding is likelyto exceed the potential benefit from anticoagulation.
‡Relative contraindications are situations in which anticoagulation may be administered if the risk of recurrent or progressive thrombosis is estimated to For long-term anticoagulation, LMWH for at least 6 months is exceed the risk of bleeding.
preferred because of improved efficacy over VKAs. VKAs are an ac-ceptable alternative for long-term therapy if LMWH is not available.
Anticoagulation with LMWH or VKAs beyond the initial 6 Based on consensus, incidental PE and DVT should be treated months may be considered for select patients with active cancer, such in the same manner as symptomatic VTE. Treatment of splanchnic as those with metastatic disease or those receiving chemotherapy.
or visceral vein thrombi diagnosed incidentally should be consid-ered on a case-by-case basis, considering potential benefits and risks of anticoagulation.
The insertion of a vena cava filter is only indicated for patients with contraindications to anticoagulant therapy (Table 4). It may be Literature Update and Analysis 4
considered as an adjunct to anticoagulation in patients with progres- Three systematic reviews relevant to VTE treatment and second- sion of thrombosis (recurrent VTE or extension of existing thrombus) ary prophylaxis were identified.46-48 No new RCTs that met inclusion despite optimal therapy with LMWH.
criteria were identified.
For patients with primary CNS malignancies, anticoagulation is Data on the relative efficacy and safety of LMWH and UFH for recommended for established VTE as described for other patients with initial treatment in patients with cancer come from post hoc subgroup cancer. Careful monitoring is necessary to limit the risk of hemor- analysis of large RCTs.48 Differences in recurrent thrombosis and bleeding were not observed. However, a reduction in mortality withLMWH compared with UFH at 3 months of follow-up was estimated (RR, 0.71; 95% CI, 0.52 to 0.98). A systematic review and meta- Use of novel oral anticoagulants for either prevention or treat- analysis comparing LMWH and VKAs for long-term anticoagulation ment of VTE in patients with cancer is not recommended at this time.
was reported by the Cochrane Collaboration.47 The rate of recurrent 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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thromboembolism was lower with LMWH (RR, 0.49; 95% CI, 0.34 to complications, altered metabolism in those with liver or renal impair- 0.70), but the rates of mortality and bleeding were similar.
ment, drug interaction with hormonal and chemotherapeutic agents, Romera-Villegas et al46 assessed LMWH dose (full, intermediate, inability to measure the anticoagulant activity using standard assays, or prophylactic) compared with VKAs for long-term VTE treatment.
and lack of an antidote. In a placebo-controlled pilot study of primary LMWH at full (RR, 0.37; 95% CI, 0.19 to 0.74) or intermediate (RR, prophylaxis with apixabain for 3 months in patients with advanced or 0.52; 95% CI, 0.35 to 0.79) dose was superior to a VKA. No difference metastatic cancer, Levine et al59 reported major bleeding in only 2.2% between prophylactic doses of LMWH and VKA was found based on of patients. Nonetheless, adequately powered RCTs are needed to small numbers of patients. Indirect comparison revealed no differ- examine the efficacy and safety of these drugs in patients with cancer.
ences in major bleeding between the LMWH doses.
Initial and Long-Term Treatment Up to 6 Months
Patients with recurrent VTE despite standard doses of anti- For initial therapy in patients with established VTE without renal coagulant therapy should be assessed for treatment compliance, impairment (creatinine clearance ⬎ 30 mL/min), a Cochrane meta- heparin-induced thrombocytopenia, or any evidence of mechanical analysis found improved survival with LMWH over UFH in patients compression resulting from malignancy. Otherwise, management op- with cancer.48 However, a small RCT in elderly patients with renal tions include treatment with an alternate anticoagulant regimen, in- insufficiency (only 6% with cancer) reported higher mortality with creasing the dose of LMWH, or adding a vena cava filter to LMWH. In tinzaparin compared with UFH (see Special Populations).49 For treat- patients for whom standard doses of LMWH fail, higher doses should ment up to 6 months, meta-analyses and RCTs validate superiority of be considered and are generally well tolerated in those without an LMWH over VKAs.47,50-52 increased risk of bleeding. In a retrospective study of patients with Data on other anticoagulants for patients with cancer are limited.
cancer and recurrent thrombosis, increasing the LMWH dose by 20% Fondaparinux has been used for initial53 and extended therapy for to 25% was effective in preventing further recurrence.60 VTE54 in patients with cancer. The numbers of patients in thesereports were small. Nonetheless, although fondaparinux may be analternative for patients with heparin-induced thrombocytopenia, it does not have a US Food and Drug Administration indication in Incidental findings of PE and/or DVT during routine staging this setting.
with computed tomography scans of abdomen and pelvis as well assplanchnic or visceral vein thrombi are frequently reported. In a recent Treatment Beyond 6 Months
large systematic review and meta-analysis of 12 studies including ⬎ No published studies address optimal anticoagulation beyond 10,000 patients, those had a weighted mean prevalence of incidental the first 6 months in patients with cancer. However, it is the consensus PE of 3.1% (95% CI, 2.2 to 4.1%).61 In a retrospective cohort analysis of the Panel, based on extrapolation from patients with idiopathic by Moore et al,62 44% of all thromboembolic events were incidental.
VTE, that continuing anticoagulation beyond 6 months should be In a cohort study by Singh,63 50% of DVTs and ⬎ 35% of PEs were considered for selected patients because of the persistent high risk of incidentally discovered. The pulmonary distribution of incidental em- recurrence in those with active cancer. The decision to continue anti- boli is no different from that of symptomatic emboli, with nearly half coagulation must be balanced against the risk of bleeding, cost of occurring in major pulmonary vessels.64,65 Importantly, rates of VTE therapy, quality of life, life expectancy, and patient preference.
recurrence, bleeding, and mortality seem to be similar in patients withcancer and incidental VTE compared with those with symptom- Novel Oral Anticoagulants
Novel anticoagulants that target thrombin (direct thrombin in- hibitor dabigatran) or activated factor X (antifactor Xa inhibitors Vena Cava Filter
rivaroxaban, apixaban, and edoxaban) are now approved for selected The role of inferior vena cava (IVC) filters remains uncertain and indications in VTE prevention and treatment. However, RCTs evalu- controversial because of the paucity of trials. In an 8-year follow-up ating these drugs for VTE treatment included few patients with malig- report from the only RCT of permanent IVC filters, the addition of nant disease: RECOVER (Dabigatran Versus Warfarin in the IVC filters to standard anticoagulation for at least 3 months compared Treatment of Acute Venous Thromboembolism) study of dabigatran, with anticoagulation alone reduced the risk of PE but increased the 5%55; EINSTEIN trials of rivaroxaban, 6.8% (DVT; Oral Direct Factor incidence of DVT and had no effect on survival.69 Patients with cancer Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep constituted 16% and 12% of those with and without filters, respec- Vein Thrombosis), 4.7% (PE; Oral Direct Factor Xa Inhibitor Rivar- tively. In a small RCT comparing fondaparinux alone for 90 days with oxaban in Patients With Acute Symptomatic Pulmonary Embolism), fondaparinux and IVC filter placement, no difference in recurrent and 4.7% (Extended Treatment; Once-Daily Oral Direct Factor Xa VTE, bleeding, or mortality was found.54 Cohort studies in patients Inhibitor Rivaroxaban in the Long-Term Prevention of Recurrent with cancer suggest much higher rates of recurrent VTE and no sur- Symptomatic Venous Thromboembolism in Patients With Symp- vival advantage with filters.70 It remains unclear whether permanent tomatic Deep-Vein Thrombosis or Pulmonary Embolism)56,57; and or retrievable filters are preferable in the cancer setting. It is reasonable AMPLIFY-EXT (Apixaban After Initial Management of PE and VTE to select a retrievable filter when the contraindication to anticoagula- With First-Line Therapy–Extended Treatment) trial of apixaban, tion is expected to be transient. The safety, however, of retrievable 1.8% (2.5 mg) and 1.1% (5 mg).58 Additional concerns with using filters has raised serious concerns. In 2010, the US Food and Drug these agents in patients with cancer include: unpredictable absorption Administration released a safety alert for optional recovery filters in and higher risk of GI bleeding in those with mucositis or other GI response to the high number of adverse events reported.71 2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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Literature Update and Analysis 5
Patients with intracranial tumors are at increased risk for throm- The updated systematic review identified three systematic botic complications and intracranial hemorrhage. However, presence reviews84-86 and one RCT.87 All included patients who did not have of an intracranial tumor or brain metastasis is not an absolute contra- any indication for anticoagulation.
indication to anticoagulation. Limited data support use of antithrom- The systematic review and meta-analysis from Kuderer et al84 botic therapy in patients with primary or metastatic brain tumors who evaluated the impact of anticoagulation on survival. The general com- develop concurrent venous thrombosis.72-77 A high failure rate has parison of any anticoagulation with no therapy—as well as the more been reported with IVC filters, without improved overall survival or specific LMWH or warfarin versus no therapy— demonstrated a reduced intracranial hemorrhage in small retrospective series.74,75,77 lower mortality risk at 1 year with anticoagulation. Bleeding rates werehigher with any anticoagulation (RR, 2.31; 95% CI, 1.93 to 2.76).
Two Cochrane reviews were published on this topic; one evalu- Evidence on LMWH and other anticoagulants in special patient ated survival with oral anticoagulation and the other with parenteral populations comes largely from patients without cancer. Most studies agents.85,86 Comparisons of warfarin with no therapy showed no were retrospective, had small samples, and did not include appropri- significant differences in mortality or the incidence of VTE. As ex- ate control groups. Although increasing age is a risk factor for bleed- pected, warfarin was associated with increased bleeding. In the com- ing, anticoagulant therapy should be offered to elderly patients who parisons of UFH or LMWH versus placebo, a decrease in mortality have no contraindications. Caution and close monitoring are neces- was noted at 2 years (RR, 0.92; 95% CI, 0.88 to 0.97). This decrease was sary in those with renal impairment, cognitive decline, and without also noted in the small subgroup of patients with small-cell lung family or nearby support.
cancer (RR, 0.86; 95% CI, 0.75 to 0.98).
The elderly. The IRIS (Innohep in Renal Insufficiency Study) One RCT included patients with advanced lung, hormone- trial comparing tinzaparin with UFH for initial therapy in patients refractory prostate, or pancreatic cancer and life expectancy ⬍ 6 age ⱖ 70 years with renal impairment was terminated early because of months.87 Patients were randomly assigned to 6 weeks of LMWH or an excess number of deaths in the tinzaparin group.49 Poor prognosis no treatment. No benefit in overall survival was noted (HR, 0.94; 95% factors, including cancer, were over-represented in the tinzaparin CI, 0.75 to 1.18). This trend was consistent in the subgroup analysis by arm. Because of early termination, the study was underpowered to cancer type.
detect differences in clinically relevant bleeding and recurrent VTE.
Renal impairment. Bleeding risk is high in patients with renal CLINICAL QUESTION 6
impairment and likely even higher in those with concurrent cancer.
Limited data suggest that LMWH can accumulate when therapeutic What is known about risk prediction and awareness of VTE among doses are administered to patients with creatinine clearance ⬍ 30 patients with cancer? mL/min and that the risk of bleeding in these patients is at leasttwo-fold higher than in patients with normal creatinine clearance.78 Studies indicate that enoxaparin requires dose reduction, but tinza-parin does not.79-81 Data on dalteparin at therapeutic doses in patients Based on consensus, the Panel recommends that patients with with renal impairment are lacking. Anti-Xa monitoring is recom- cancer be assessed for VTE risk at the time of chemotherapy initiation mended if LMWH is used in patients with moderate to severe renal and periodically thereafter. Individual risk factors, including biomark- impairment. If this is not available, UFH and VKAs are safer options ers and cancer site, do not reliably identify patients with cancer at high for initial and long-term treatment, respectively.
risk of VTE. In the outpatient setting, risk assessment can be con- Obesity. In obese patients, LMWH dosing has not been well ducted based on a validated risk assessment tool (Table 5).
studied. Cohort studies using enoxaparin and dalteparin suggest thatLMWH dose should be based on a patient's actual body weight.82,83 Bleeding risk does not seem to be higher in obese patients.
Based on consensus, the Panel recommends that oncologists educate patients regarding VTE, particularly in settings that increaserisk such as major surgery, hospitalization, and while receiving sys- CLINICAL QUESTION 5
temic antineoplastic therapy.
Literature Update and Analysis 6
Should patients with cancer receive anticoagulants in the absence of The risk systematic review identified five cohort studies.62,88-91 established VTE to improve survival? Two reported development of new risk assessment models,88,89 andthree evaluated existing models.62,90,91 The International Myeloma Working Group proposed a consensus-based risk assessment algo- Anticoagulants are not recommended to improve survival in rithm to categorize risk among patients with myeloma; validation is patients with cancer without VTE.
awaited.92 Several VTE risk assessment tools have been developed andvalidated in the perioperative setting, but none has specifically focused on patients with cancer.93 Patients with cancer should be encouraged to participate in clin- Multiple cancer-, treatment-, and patient-related risk factors for ical trials designed to evaluate anticoagulant therapy as an adjunct to VTE relevant to various cancer populations are summarized in Table standard anticancer therapies.
3.91,94-96 Although patients with brain, pancreatic, stomach, kidney, 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
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VTE Prophylaxis and Treatment: ASCO Guideline Update
phylactic LMWH. Many patients reported improved quality of life Table 5. Predictive Model for Chemotherapy-Associated VTE in the
secondary to a feeling of safety and reassurance.108 Ambulatory Setting Communicating with patients about the signs, symptoms, and Patient Characteristic risk of VTE is crucial. Oncologists, along with other health care pro- fessionals on the oncology team, should assure, at minimum, that Very high risk (stomach, pancreas, primary patients have a basic recognition of VTE warning signs. Nurses are in High risk (lung, lymphoma, gynecologic, an ideal position to educate patients.109 Resources, including informa- bladder, testicular, renal tumors) tion sheets and symptom checklists, are available to facilitate such Prechemotherapy platelet count ⱖ 350,000/␮L Hemoglobin level ⬍ 10 g/dL or use of red-cell conversations. Respondents to the qualitative survey who were given educational materials or directed to such (15% of the sample) found Prechemotherapy leukocyte count ⬎ 11,000/␮L those materials "very useful."106 Body mass index ⱖ 35 kg/m2 Further education can help patients distinguish between symp- Calculate total score, adding points for each criterion in the model toms secondary to their underlying disease, treatment, and other potential causes. Patients may not report new symptoms, unless que- High risk ⱖ 3 points ried directly, because they mistakenly assume symptoms are manifes- Intermediate risk, 1 to 2 points tations of their cancer or adverse effects of therapy. A good patient Low risk, 0 points history, along with ongoing communication with the health care NOTE. Data adapted.88 Abbreviation: VTE, venous thromboembolism.
team, can help ensure effective communication as well as facilitatepatient understanding.
ovarian, or lung cancer are commonly considered at high risk for VTE,patients with hematologic malignancies are also at elevated risk.97,98Hospitalization or major surgery can lead to a transient increase in Rates of VTE are higher among African Americans than in the general risk.2,3,27-32,34,35,45,99 Specific therapeutic agents such as thalidomide,22 population overall.110,111 Rates are lower in the Asian population than lenalidomide,20 and cisplatin62,100 can also increase VTE risk. Al- in other ethnicities.111 A nationwide analysis of nearly 500,000 patients though a number of biomarkers have been evaluated, neither solitary with cancer in Taiwan recently described risk factors and a scoring risk factors nor individual biomarkers reliably identify high-risk system for this population.112 Applicability of these findings to North American and European patients is unknown.
A multivariable clinical risk assessment model for VTE was de- Although ASCO clinical practice guidelines represent expert rec- veloped and internally validated in a cohort of ambulatory patients ommendations on best practices to provide the highest level of cancer with cancer receiving systemic chemotherapy (Table 5).88 This model care, it is important to note that many patients have limited access to has now been externally validated for predicting risk of VTE by several medical care. Racial and ethnic disparities in health care contribute investigators.90,91 The balance of benefit and harm with thrombopro- significantly to this problem in the United States. Minority racial/ phylaxis for high-risk patients identified by the model is under study.
ethnic patients with cancer suffer disproportionately from comorbidi- Therefore, routine thromboprophylaxis in this setting is not cur- ties, experience more substantial obstacles to receiving care, are more rently recommended.
likely to be uninsured, and are at greater risk of receiving care of poorquality than other Americans.113-116 Many other patients lack access tocare because of geography or distance from appropriate treatment PATIENT AND CLINICIAN COMMUNICATION
facilities. Awareness of these disparities in access to care should beconsidered in the context of this clinical practice guideline, and health Despite the well-known association of VTE and cancer, patients are care providers should strive to deliver the highest level of cancer care to woefully unaware of that risk and of warning signs and symptoms.
these vulnerable populations.
Two patient surveys found that fewer than half of patients were awareof the increased risk of VTE associated with malignancy.105,106 In asurvey of hospitalized patients receiving thromboprophylaxis, re- sponders reported hearing about VTE more frequently from friends,family, or the media than from health care providers.107 A differentsurvey indicates that inpatients knew more about VTE than outpa- These recommendations are based on data identified by a systematic tients: 36% versus 15%.106 review of the literature. Some key questions are, as yet, unanswered.
The need for increased patient education and awareness is clear.
The potential benefits and harms of thromboprophylaxis in patients Educated patients are more likely to report symptoms that could lead with cancer receiving chemotherapy in the outpatient setting and the to early intervention.107 In addition, aware and educated patients are utility of risk assessment require additional research. Future throm- more likely to accept efforts such as anticoagulation or early mobility boprophylaxis trials in outpatients receiving chemotherapy may ben- after surgery. In fact, a qualitative survey of patients with cancer noted efit from the identification of high-risk groups in whom the balance of that increased awareness of VTE led to increased acceptance of pro- benefits and harms favors prophylaxis.
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(C), sanofi-aventis (C), LEO Pharma (C), Bristol-Myers Squibb (C),
The Data Supplement, including evidence tables, and clinical tools Genentech (C), Eli Lilly (C); Agnes Lee, Bristol-Myers Squibb (C); and resources can be found at Patient Charles W. Francis, Eisai (C); Ajay K. Kakkar, Bayer HealthCare information is also available there and at Pharmaceuticals (C), Boehringer Ingelheim (C), Eisai (C),GlaxoSmithKline (C), Pfizer (C), sanofi-aventis (C); Howard A.
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OF INTEREST
Eli Lilly, sanofi-aventis, Daiichi Sankyo, Johnson & Johnson, Eisai, LEOPharma, Bristol-Myers Squibb, Genentech; Agnes Lee, Bayer HealthCare Although all authors completed the disclosure declaration, the following Pharmaceuticals, Boehringer Ingelheim, LEO Pharma, Pfizer, author(s) and/or an author's immediate family member(s) indicated a sanofi-aventis; Juan Ignacio Arcelus, Bayer HealthCare Pharmaceuticals, financial or other interest that is relevant to the subject matter under Bristol-Myers Squibb, Pfizer, sanofi-aventis Research Funding: *Gary H.
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dence and Mortality Data. 87. van Doormaal FF, Di Nisio M, Otten HM, et
Plasma tissue factor may be predictive of venous 115. Mead H, Cartwright-Smith L, Jones K, et al:
al: Randomized trial of the effect of the low molec- thromboembolism in pancreatic cancer. J Thromb Racial and Ethnic Disparities in U.S. Health Care: A ular weight heparin nadroparin on survival in patients Haemost 6:1983-1985, 2008 Chartbook. New York, NY, Commonwealth Fund, with cancer. J Clin Oncol 29:2071-2076, 2011 102. Thaler
88. Khorana AA, Kuderer NM, Culakova E, et al:
Microparticle-associated tissue factor activity, ve- 116. Howlader N, Noone AM, Krapcho M, et al:
Development and validation of a predictive model nous thromboembolism and mortality in pancreatic, SEER Cancer Statistics Review, 1975-2009 (Vintage for chemotherapy-associated thrombosis. Blood gastric, colorectal and brain cancer patients. J 2009 Populations), National Cancer Institute. 111:4902-4907, 2008 Thromb Haemost 10:1363-1370, 2012 2013 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.
VTE Prophylaxis and Treatment: ASCO Guideline Update
The Update Committee wishes to thank Rose Z. Morrison, Kaitlin Einhaus, Nancy K. Thomasson, Nicholas J. Petrelli MD, Ken Carson, MD, the Journal of Clinical Oncology editorial board and staff, the Clinical Practice Guidelines Committee for its thoughtful reviews of earlier drafts, and the American Society of Clinical Oncology Board of Directors.
Table A1. Panel Composition
Anna Falanga, MD, co-chairⴱ Gary H. Lyman, MD, MPH, co-chairⴱ Hematology and medical oncology Alok A. Khorana, MDⴱ Hematology and medical oncology Nicole M. Kuderer, MDⴱ Hematology and medical oncology Juan Ignacio Arcelus Edward P. Balaban, DO Hematology and medical oncology Jeffrey M. Clarke, MD Christopher R. Flowers, MD, MS Hematology and medical oncology Charles W. Francis, MD Hematology and medical oncology Leigh E. Gates, BA, CPHQ Patient representative Ajay K. Kakkar, MD, BS, PhD Nigel S. Key, MB, ChB, FRCP Hematology and medical oncology Mark N. Levine, MD, MSc Hematology and medical oncology Howard A. Liebman, MD Hematology and medical oncology Margaret A. Tempero, MD Hematology and medical oncology Sandra L. Wong, MD Surgical oncology ⴱSteering Committee member.
2013 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on August 17, 2013. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

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Independently extensible solutions to the expression problem

Independently Extensible Solutions to the Expression Problem Matthias Zenger, Martin Odersky École Polytechnique Fédérale de Lausanne 1015 Lausanne, Switzerland Technical Report IC/2004/33 challenge is now to find an implementation techniquewhich satisfies the following list of requirements: The expression problem is fundamental for the develop-ment of extensible software. Many (partial) solutions to

sajcc.org.za2

Intravascular catheter-related infection – current concepts Department of Medicine, Division of Pulmonology and Critical Care, Johannesburg Hospital and University of the Witwatersrand, Johannesburg Mervyn Mer, MB BCh, Dip PEC (SA), FCP (SA), MMed (Int Med), FRCP (Lond) Intravascular devices are an integral component been completed, show that this topic is of particular