Beruflich Dokumente
Kultur Dokumente
DOI: 10.1111/jth.12070
ORIGINAL ARTICLE
To cite this article: Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N,
Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, Prins MH, Qari MH, Streiff
MB, Syrigos K, Bounameaux H, Buller HR. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism
in patients with cancer. J Thromb Haemost 2013; 11: 5670.
Correspondence: Dominique Farge, Assistance Publique- Hopitaux de
Paris, Saint-Louis Hospital, Internal Medicine and Vascular Disease
Unit, 1 avenue Claude-Vellefaux, 75010 Paris, France and Sorbonne
Paris Cite, INSERM U 796, Paris 7 Diderot University, Paris, France.
Tel.: +33 1 42 49 97 64/67; fax: +33 1 42 49 94 78.
E-mail: dominique.farge-bancel@sls.aphp.fr
1
These authors contributed equally to this work. The role of each author is
specied in the Addendum. Reviewers are listed in the Acknowledgement
section.
These international guidelines were elaborated on the initiative of the
Groupe Francophone Thrombose et Cancer (GFTC) with the
collaboration of the Academic Medical Center (AMC) and the
University Medical Center Groningen (UMCG), the Netherlands, and
the methodological support of the French Institute of Cancer (INCa).
Received 25 July 2012, accepted 5 November 2012
Summary. Background: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are
heterogeneous and their implementation has been suboptimal
worldwide. Objectives: To establish a common international
consensus addressing practical, clinically relevant questions in
this setting. Methods: An international consensus working
group of experts was set up to develop guidelines according to
an evidence-based medicine approach, using the GRADE
system. Results: For the initial treatment of established VTE:
low-molecular-weight heparin (LMWH) is recommended [1B];
fondaparinux and unfractionated heparin (UFH) can be also
used [2D]; thrombolysis may only be considered on a case-bycase basis [Best clinical practice (Guidance)]; vena cava lters
(VCF) may be considered if contraindication to anticoagulation
or pulmonary embolism recurrence under optimal anticoagu 2012 International Society on Thrombosis and Haemostasis
lation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed
when safe; VCF are not recommended for primary VTE
prophylaxis in cancer patients [Guidance]. For the early
maintenance (10 days to 3 months) and long-term (beyond
3 months) treatment of established VTE, LMWH for a
minimum of 3 months is preferred over vitamin K antagonists
(VKA) [1A]; idraparinux is not recommended [2C]; after 3
6 months, LMWH or VKA continuation should be based on
individual evaluation of the benet-risk ratio, tolerability,
patient preference and cancer activity [Guidance]. For the
treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA
to LMWH when treated with VKA; (ii) increase in LMWH
dose when treated with LMWH, and (iii) VCF insertion
[Guidance]. For the prophylaxis of postoperative VTE in
surgical cancer patients, use of LMWH o.d. or low dose of
UFH t.i.d. is recommended; pharmacological prophylaxis
should be started 122 h preoperatively and continued for at
least 710 days; there are no data allowing conclusion that one
type of LMWH is superior to another [1A]; there is no evidence
to support fondaparinux as an alternative to LMWH [2C]; use
of the highest prophylactic dose of LMWH is recommended
[1A]; extended prophylaxis (4 weeks) after major laparotomy
may be indicated in cancer patients with a high risk of VTE and
low risk of bleeding [2B]; the use of LMWH for VTE prevention
in cancer patients undergoing laparoscopic surgery may be
recommended as for laparotomy [Guidance]; mechanical
methods are not recommended as monotherapy except when
pharmacological methods are contraindicated [2C]. For the
prophylaxis of VTE in hospitalized medical patients with cancer
and reduced mobility, we recommend prophylaxis with
LMWH, UFH or fondaparinux [1B]; for children and adults
with acute lymphocytic leukemia treated with L-asparaginase,
depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients
receiving chemotherapy, prophylaxis is not recommended
routinely [1B]; primary pharmacological prophylaxis of VTE
may be indicated in patients with locally advanced or metastatic
pancreatic [1B] or lung [2B] cancer treated with chemotherapy
and having a low risk of bleeding; in patients treated with
thalidomide or lenalidomide combined with steroids and/or
chemotherapy, VTE prophylaxis is recommended; in this
setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar eects;
however, the ecacy of these regimens remains unclear [2C].
Special situations include brain tumors, severe renal failure
(CrCl < 30 mL min)1), thrombocytopenia and pregnancy.
Guidances are provided in these contexts. Conclusions: Dissemination and implementation of good clinical practice for the
management of VTE, the second cause of death in cancer
patients, is a major public health priority.
Keywords: Anticoagulant, Bleeding, Cancer, Clinical practice
guidelines, GRADE system, Venous thromboembolism.
Introduction
Cancer is an independent and major risk factor for venous
thromboembolism (VTE) [1,2]. VTE, dened as deep-vein
thrombosis (DVT) or pulmonary embolism (PE), is reported in
up to 20% of patients with cancer [3]. Although the association
between cancer and thrombosis has been known since Trousseaus rst report [4], cancer care providers now have increased
awareness of the impact of thrombotic complications in their
patients. Several factors have contributed to this heightened
awareness. First, cancer-associated VTE is increasingly prevalent. In an analysis of more than one million hospitalized
patients with cancer, the rate of VTE increased by 28% from
1995 to 2003 (P < 0.0001) [5]. Second, the consequences of
VTE are better understood. Thrombosis is the second leading
cause of death in patients with cancer [6]. Furthermore, VTE is
an independent prognostic factor of mortality in cancer
patients. Cancer patients with VTE have a shorter overall
survival than cancer patients without VTE at the same tumor
stage and receiving the same anti-cancer treatment [1,3]. In
addition, patients with cancer who also suffer from VTE have
an increased risk of recurrent VTE, bleeding complications,
morbidity, and utilization of health care resources [7,8].
Therefore, the prevention and treatment of VTE in cancer
patients represent major challenges in daily practice. As cancer
patients often present with a variety of risk factors and comorbidities, specic oncology guidelines on the subject have
been established using various methodological approaches.
Several national and international guidelines for the prevention and treatment of VTE in cancer patients have been
published in the past [918]. Their methodological quality
varies widely. In addition, underuse of VTE prophylaxis
represents a major problem in daily life, and use of adequate
prophylaxis is even less frequent among cancer patients [19]. In
view of these issues, an international multidisciplinary working
group was set up, following the initiative of the Groupe
Francophone Thrombose et Cancer (GFTC), with the
collaboration of the Academic Medical Centre (AMC) and
the University Medical Center Groningen (UMCG), the
Netherlands, to develop harmonized guidelines for cancer
patients, using the GRADE system, an up-to-date evidencebased clinical practice guideline development approach, with
the methodological support of the French Institute of Cancer
(INCa). In this article, we present the results and conclusions
of this working group on the prevention and treatment of VTE
in cancer patients.
Methods
Working group
58 D. Farge et al.
Literature review and analysis
Table 1 Denition of levels of evidence according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) scale
[GUYATT2008] [GUYATT2008A]
Level
Denition
High (A)
Moderate (B)
Further research is very unlikely to change our condence in the estimate of eect
Further research is likely to have an important impact on our condence in the estimate of eect and may change the
estimate
Further research is very likely to have an important impact on our condence in the estimate of eect and is likely to
change the estimate
Any estimate of eect is very uncertain
Low (C)
Very low (D)
Denition
Strong (Grade 1)
Weak (Grade 2)
The panel is condent that the desirable eects of adherence to a recommendation outweigh the undesirable eects
The panel concludes that the desirable eects of adherence to a recommendation probably outweigh the
undesirable eects, but is not condent
In the absence of any clear scientic evidence and because of undetermined balance between desirable and
undesirable eects, judgment was based on the professional experience and consensus of the international experts
within the working group
Best clinical
practice (Guidance)
60 D. Farge et al.
Table 3 LMWH used in studies comparing early maintenance treatment (10 days to 3 months) and long-term (beyond 3 months) treatment by LMWH
alone with short-term heparin followed by VKA
Drug
Enoxaparin
Dalteparin
Tinzaparin
Idraparinux
Study
)1
CANTHANOX [MEYER2002]
CLOT [LEE2003]
LITE [HULL2006]
VANGOGH subgroup [VANDOORMAAL2010]
Table 4 Dosage regimen evaluated in clinical trials of thromboprophylaxis in surgical cancer patients
LMWH
Factor Xa inhibitors
LMWH extended use
3
1
1
3
1
1
1
1
1
1
1
1
2
1
1
studies
study
study
studies
study
study
study
study
study
study
study
62 D. Farge et al.
64 D. Farge et al.
Recommendations.
1 We recommend prophylaxis with LMWH, UFH or
fondaparinux in hospitalized medical patients with cancer
and reduced mobility [Grade 1B].
Values and preferences: subcutaneous injections.
Costs: In some countries price differences between LMWH,
UFH or fondaparinux may inuence the choice.
2 For children with ALL treated with L-asparaginase, depending on local policy and individual patient characteristics
(platelet count, kidney function, brinogen and antithrombin III levels, etc.), prophylaxis may be considered in some
patients; the same therapeutic option can be considered for
adults [Best clinical practice, based on evidence of very low
quality and a balance between desirable and undesirable
effect depending on individual patient characteristics].
Values and preferences: subcutaneous injections.
3 In patients receiving chemotherapy, prophylaxis is not
recommended routinely [Grade 1B].
Values and preferences: subcutaneous injections.
4 Primary pharmacological prophylaxis of VTE may be
indicated in patients with locally advanced or metastatic
pancreatic cancer treated with chemotherapy and having a
low bleeding risk [Grade 1B].
Values and preferences: subcutaneous injections.
Special situations
8 In pregnant cancer patients, standard treatment for established VTE and standard prophylaxis should be implemented [Best clinical practice, in the absence of data and
based on the contraindication of VKA during pregnancy].
Addendum
DF and HRB conceived and coordinated all the processes
and the working group. PD and MB evaluated the quality of
the studies in a double-blind manner using GRADE
appraisal grids and provided the rst draft of the supplemental tables. All authors participated in the working group,
and contributed to data extraction and analysis, issue of
recommendations and writing of a comprehensive technical
report [Treatment of Venous Thromboembolism in Patients
with Cancer. Copyright 1093790 (OPIC 28/02/2012)],
which served as the basis for the present manuscript. DF,
PD, MB, HB, HRB and all the co-authors contributed to the
elaboration of the guidelines. DF and PD elaborated the rst
draft of the manuscript, which was reviewed by HB and
HRB.
Acknowledgements
Financial support was provided by the Groupe Francophone
Thrombose et Cancer (http://www.thrombose-cancer.com),
the Paris 7 Institut Universitaire dHematologie (IUH St Louis
Hospital), the International Society of Thrombosis and Haemostasis (ISTH) 2007 Presidential Fund, the Societe Medicale
des Amis de Desgenettes du Service de Sante des Armees and
the French National Cancer Institute (INCa).The authors wish
to thank the following reviewers: I. Alhejji, Hamad Medical
Corporation, Qatar; R. Alikhan, University Hospital of Wales,
United Kingdom; T. Andre, Hopital La Pitie Salpetrie`re, Paris,
France; E. Andres, CHRU de Strasbourg, Strasbourg, France;
M-T. Barrelier, CHU Hopital Cote de Nacre, Caen, France; C.
Bennett, London, United Kingdom; N. Blais, CHUM Hopital
Notre-Dame, Montreal, Canada; D. Braguer, Centre de
Recherche en Oncologie Biologique et Oncopharmacologie,
Marseille, France; K. Carter, Portsmouth Hospitals NHS
Trust, Portsmouth, United Kingdom; A. Croft, University
Hospital of Wales, United Kingdom; E. Dimakakos, Sotiria
Hospital, Athe`nes, Greece; M. Duchosal, Centre Hospitalier
Universitaire Vaudois, Lausanne, Switzerland; A. Elias, Hopital Font-Pre, Toulon, France; M. Ellis, Meir Medical Center,
Kfar Saba, Israel; M. Espie, Hopital Saint-Louis, Paris,
France; N. Espie, Paris, France; V. Georgoulias, University
General Hospital of Heraklion, Greece; P. Girard, Institut
Mutualiste Montsouris, Paris, France; E. Gonzales-Billalabeitia, Hospital J. M. Morales Meseguer, Murcia, Spain; K.
Hamulyak, University of Maastricht, Maastricht, the Netherlands; R. Hoffman, Rambam Health Care Campus, Haifa,
Israel; R. Hull, University of Calgary, Calgary, Canada; M.
Johnson, Hull York Medical School, York, United Kingdom;
P.W. Kamphuisen, University Medical Center, Groningen, the
Netherlands; A. Kleinjan, Academisch Medisch Centrum,
66 D. Farge et al.
References
1 Levitan N, Dowlati A, Remick SC, Tahsildar HI, Sivinski LD, Beyth
R, Rimm AA. Rates of initial and recurrent thromboembolic disease
among patients with malignancy versus those without malignancy.
Risk analysis using Medicare claims data. Medicine (Baltimore) 1999;
78: 28591.
2 Heit JA, Silverstein MD, Mohr DN, Petterson TM, OFallon WM,
Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary
embolism: a population-based case-control study. Arch Intern Med
2000; 160: 80915.
3 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of
venous thromboembolism and its eect on survival among patients
with common cancers. Arch Intern Med 2006; 166: 45864.
4 Trousseau A. Plegmasia alba dolens. Lectures on clinical medicine,
delivered at the Hotel-Dieu, Paris 1865; 5: 281332.
5 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH.
Frequency, risk factors, and trends for venous thromboembolism
among hospitalized cancer patients. Cancer 2007; 15: 110.
6 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH.
Thromboembolism is a leading cause of death in cancer patients
receiving outpatient chemotherapy. J Thromb Haemost 2007; 5:
6324.
7 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami
B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A.
Recurrent venous thromboembolism and bleeding complications
during anticoagulant treatment in patients with cancer and venous
thrombosis. Blood 2002; 100: 34848.
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
68 D. Farge et al.
38 Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny
P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of lowmolecular weight heparin and warfarin for the secondary prevention
of venous thromboembolism in patients with cancer: a randomized
controlled study. Arch Intern Med 2002; 162: 172935.
39 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M,
Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized
Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Lowmolecular-weight heparin versus a coumarin for the prevention of
recurrent venous thromboembolism in patients with cancer. N Engl J
Med 2003; 349: 14653.
40 Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J;
ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone
versus initial enoxaparin followed by warfarin for a 180-day period.
Clin Appl Thromb Hemost 2006; 12: 38996.
41 Romera A, Cairols MA, Vila-Coll R, Mart X, Colome E, Bonell A,
Lapiedra O. A randomised open-label trial comparing long-term subcutaneous low-molecular-weight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis. Eur J
Vasc Endovasc Surg 2009; 37: 34956.
42 Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep
venous thrombosis with low-molecular-weight heparins, a metaanalysis. Arch Intern Med 1995; 155: 6017.
43 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of
patients with acute venous thromboembolism: results of a metaanalysis. Am J Med 1996; 100: 26977.
44 Hettiarachchi R, Prins M, Lensing A, Buller HR. Low molecular
weight heparin versus unfractionated heparin in the initial treatment of venous thromboembolism. Curr Opin Pulm Med 1998; 4:
2205.
45 Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM.
Low-molecular-weight heparins compared with unfractionated
heparin for treatment of acute deep venous thrombosis. A metaanalysis of randomized, controlled trials. Ann Intern Med 1999; 130:
8009.
46 Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A
meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism:
examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160:
1818.
47 Rocha E, Mart nez-Gonzalez MA, Montes R, Panizo C. Do the low
molecular weight heparins improve ecacy and safety of the treatment of deep venous thrombosis? A meta-analysis. Haematologica
2000; 85: 93542.
48 Quinlan D, McQuillan A, Eikelboom JW. Low-molecular-weight
heparin compared with intravenous unfractionated heparin for
treatment of pulmonary embolism: a meta-analysis of randomized,
controlled trials. Ann Intern Med 2004; 140: 17583.
49 Mismetti P, Quenet S, Levine M, Merli G, Decousus H, Derobert E,
Laporte S. Enoxaparin in the treatment of deep vein thrombosis with
or without pulmonary embolism: an individual patient data metaanalysis. Chest 2005; 128: 220310.
50 Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, Muti P, Bdair F,
Schunemann HJ. Anticoagulation for the initial treatment of venous
thromboembolism in patients with cancer: a systematic review. Cancer
2008; 113: 168594.
51 Akl EA, Vasireddi SR, Gunukula S, Barba M, Sperati F, Terrenato I,
Muti P, Schunemann H. Anticoagulation for the initial treatment of
venous thromboembolism in patients with cancer (Review). Cochrane
Database Syst Rev 2011; 6: CD006649.
70 D. Farge et al.
100 Dahan R, Houlbert D, Caulin C, Cuzin E, Viltart C, Woler M,
Segrestaa JM. Prevention of deep vein thrombosis in elderly medical
in-patients by a low molecular weight heparin: a randomized doubleblind trial. Haemostasis 1986; 16: 15964.
101 Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A,
Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG,
Weisslinger N. A comparison of enoxaparin with placebo for the
prevention of venous thromboembolism in acutely ill medical patients.
N Engl J Med 1999; 341: 793800.
102 Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT,
Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study
Group. Randomized, placebo-controlled trial of dalteparin for the
prevention of venous thromboembolism in acutely ill medical patients
Circulation 2004; 110: 8749.
103 Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH,
Tomkowski W, Turpie AG, Egberts JF, Lensing AW; ARTEMIS
Investigators. Ecacy and safety of fondaparinux for the prevention
of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006; 332: 3259.
104 Meister B, Kropshofer G, Klein-Franke A, Strasak AM, Hager J,
Streif W. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic
leukemia. Pediatr Blood Cancer 2008; 50: 298303.
105 Mitchell L, Andrew M, Hanna K, Abshire T, Halton J, Wu J,
Anderson R, Cherrick I, Desai S, Mahoney D, McCusker P, Chait P,
Abdolell M, de Veber G, Mikulis D. Trend to ecacy and safety using
antithrombin concentrate in prevention of thrombosis in children
receiving l-asparaginase for acute lymphoblastic leukemia. Thromb
Haemost 2003; 90: 23544.
106 Riess H, Pelzer U, Deutschino G. PROSPECT-CONKO 004: a
prospective, randomized trial of simultaneous pancreatic cancer
treatment with enoxaparin and chemotherapy. ASCO 2009, abstract
LBA4506.
107 Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros
J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G. Gemcitabine
versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic
cancer. Eur J Cancer 2012; 48: 128392.
108 Haas SK, Freund M, Heigener D, Heilmann L, Kemkes-Matthes B,
von Tempelho GF, Melzer N, Kakkar AK; TOPIC Investigators.
Low-molecular-weight heparin versus placebo for the prevention of
venous thromboembolism in metastatic breast cancer or stage III/IV
lung cancer. Clin Appl Thromb Hemost 2012; 18: 15965.
109 Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala` M, Cavanna
L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S,
Gasparini G, Lorusso V, Bonizzoni E, Tonato M; PROTECHT
Investigators. Nadroparin for the prevention of thromboembolic
events in ambulatory patients with metastatic or locally advanced
solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10: 9439.
110 Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR,
Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S, Finch T,
Levine MN. PRODIGE: a randomized placebo-controlled trial of
dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost
2010; 8: 195965.
111 Verso M, Gussoni G, Agnelli G. Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy:
a combined analysis of the PROTECHT and TOPIC-2 studies. J
Thromb Haemost 2010; 8: 164951.
112 Zangari M, Barlogie B, Anaissie E, Saghafar F, Eddlemon P, Jacobson J, Lee CK, Thertulien R, Talamo G, Thomas T, van Rhee F,
Fassas A, Fink L, Tricot G. Deep vein thrombosis in patients with
113
114
115
116
117
118
119
120
121
122
123
124
125
126