Curr Oncol, Vol. 22, pp. 144-155; doi: http://dx.doi.org/10.3747/co.22.2587

CANADIAN RECOMMENDATIONS FOR VTE TREATMENT IN CANCER

PR AC T I C E G U I D E L I N E

Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2: treatment J.C. Easaw md phd,* M.A. Shea–Budgell msc,* C.M.J. Wu md,* P.M. Czaykowski md,† J. Kassis md,‡ B. Kuehl phd,§ H.J. Lim md phd,|| M. MacNeil md,# D. Martinusen pharmd,|| P.A. McFarlane md phd,§ E. Meek rn,* O. Moodley md,** S. Shivakumar md,# V. Tagalakis md,‡ S. Welch md,§ and P. Kavan md ‡ ABSTRACT

1. INTRODUCTION

Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy is used to treat vte; however, patients with cancer have unique clinical circumstances that can often make decisions surrounding the administration of therapeutic anticoagulation complicated. No national Canadian guidelines on the management of established cancer-associated thrombosis have been published. We therefore aimed to develop a consensus-based, evidence-informed guideline on the topic. PubMed was searched for clinical trials and meta-analyses published between 2002 and 2013. Reference lists of key articles were hand-searched for additional publications. Content experts from across Canada were assembled to review the evidence and make recommendations. Low molecular weight heparin is the treatment of choice for cancer patients with established vte. Direct oral anticoagulants are not recommended for the treatment of vte at this time. Specific clinical scenarios, including the presence of an indwelling venous catheter, renal insufficiency, and thrombocytopenia, warrant modifications in the therapeutic administration of anticoagulation therapy. Patients with recurrent vte should receive extended (>3 months) anticoagulant therapy. Incidental vte should generally be treated in the same manner as symptomatic vte. There is no evidence to support the monitoring of anti–factor Xa levels in clinically stable cancer patients receiving prophylactic anticoagulation; however, levels of anti–factor Xa could be checked at baseline and periodically thereafter in patients with renal insufficiency. Follow-up and education about the signs and symptoms of vte are important components of ongoing patient care.

Complex cancer treatments and the presence of comorbidities can complicate the treatment of venous thromboembolism (vte) in patients with cancer. Guidelines on the management of vte in the oncology setting have been developed by the American Society of Clinical Oncology1 and CancerControl Alberta (part of Alberta Health Services)2, but fail to address several key issues concerning the monitoring of anticoagulation and the use of anticoagulants in specific subpopulations. Other guidelines are broader in scope, and their discussion of treatment for vte is therefore limited to a subsection3–5. No national guidelines specifically focus on the treatment of cancer-associated vte. We therefore aimed to develop national recommendations that are evidence-based (or consensus-based where evidence is lacking) on the treatment of vte in cancer patients. The resulting recommendations provide guidance to physicians, nurses, and other frontline medical professionals involved in the management of patients with cancer. The recommendations address the preferred therapy and dosing for established vte; duration of therapy; management of incidental vte, of vte related to a central venous catheter (cvc), and of established vte in special clinical scenarios; patient education; and the monitoring of anticoagulation therapy.

KEY WORDS Low molecular weight heparin, venous thromboembolism, pulmonary embolism, deep vein thrombosis, clots, anticoagulation, practice guideline

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2. METHODOLOGY 2.1 Literature Search Strategy The U.S. National Library of Medicine’s PubMed database was searched for relevant articles published between 2002 and March 2013. Search terms included “neoplasm” or “cancer” and “thrombosis prophylaxis” or “vte prophylaxis,” and results were limited to randomized controlled trials (rcts) and meta-analyses published between 2008 and March 2013. Trials that did not report outcomes related to the treatment of vte were excluded. In addition, the U.S.

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EASAW et al.

National Guidelines Clearinghouse was searched for guidelines published between 2007 and March 2013. Updated results of relevant clinical trials published after March 2013 were also included. Because of a lack of translation services, non-English-language articles were excluded from the review of the evidence.

2.2 Development of Recommendations The development and review process for the recommendations was modelled after these sources: the U.K. National Institute for Health and Clinical Excellence6, the Archives of Pediatrics and Adolescent Medicine 7, and the agree collaboration8. Clinical questions and initial recommendations were developed by two medical oncologists (JCE and PK) and a cancer research methodologist (MAS), based on the literature review and clinical experience treating patients with cancer and vte. The University of Oxford Centre for Evidence-Based Medicine grading system was used to grade the recommendations9. The resulting recommendations were reviewed by an expert panel of medical oncologists, hematologic oncologists, hematologists, and an internist, representing the provinces of Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan, Alberta, and British Columbia. A total of 11 specialists contributed directly to the development of all recommendations. Recommendations pertaining to renal insufficiency were further reviewed by a nephrologist and a pharmacist with expertise in renal insufficiency. Recommendations were initially reviewed using a Web-based survey to capture the level of agreement with each statement on a 5-point scale ranging from “strongly agree” to “strongly disagree” and including an option of “unsure.” An evidence summary accompanied each statement, and panelists were instructed to consider the level of evidence when rating each statement. In addition to the rating scales, panelists were given the opportunity to comment on each statement. Based on panelist responses, recommendations were categorized as “consensus” (that is, statements with which most panelists agreed, with no more than 3 “neutral” or “unsure” responses allowed) or “non-consensus” (that is, statements with which at least 1 panelist disagreed or those that had 4 or more “neutral” or “unsure” responses). Nonconsensus statements were reviewed once with the entire panel via webinar (Cisco WebEx, San Jose, CA, U.S.A.) to better understand the rationale for any disagreement or uncertainty and to determine where additional discussion was needed to reach consensus. The non-consensus statements were divided into two categories: “monitoring and dosing” and “special populations.” Panel members were assigned to a working group to address statements in one of the two categories. Working groups met a final time via webinar to discuss and revise the statements; consensus methods were used.

3. RESULTS The literature review identified fifty-six publications, including three clinical practice guidelines. Metaanalyses and rcts were considered to be strong or higher-level evidence in developing the recommendations. Several relevant retrospective case series were also included in the discussion, but were considered to be weak or lower-level evidence. Based on the Web survey responses, consensus was reached immediately on 25 of the 34 final recommendation statements (74%). The remaining 9 recommendations were further discussed by the assigned panel members to reach consensus. Consensus was eventually reached for all 34 recommendation statements (Table i).

4. DISCUSSION 4.1 Therapy Types and Dosing for the Treatment of Established VTE 4.1.1 Low Molecular Weight Heparin For cancer patients on active treatment who develop vte , therapy with low molecular weight heparin (lmwh) is more effective than therapy with warfarin in preventing recurrent blood clots10. The clot trial—which included 672 cancer patients with acute symptomatic proximal dvt, pulmonary embolism ( pe), or both—compared lmwh with warfarin. All patients were initially treated for 6 months with either subcutaneous dalteparin (200 IU/kg daily for 1 month, followed by 150 IU/kg daily for 5 months) or warfarin [bridged with lmwh until the patient’s international normalized ratio (inr) reached 2–3]. Recurrent vte occurred in 8% of the dalteparin group and in 16% of the warfarin group [hazard ratio (hr): 0.48; p = 0.002]. The groups did not differ in their rates of major bleeding and any bleeding (6% vs. 4% and 14% vs. 19% respectively)11. Data from the catch rct, which compared tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily overlapped and followed by dose-adjusted warfarin (target inr: 2.0–3.0) for 6 months in cancer patients with symptomatic vte, demonstrated lower rates of recurrent vte with tinzaparin [hr: 0.65; 95% confidence interval (ci): 0.41 to 1.03; p = 0.07]; however, that difference was not statistically significant. Clinically relevant non-major bleeding was lower with tinzaparin than with warfarin [50 patients (11%) and 73 patients (16%) respectively, p = 0.03]12. Importantly, catch (conducted more than a decade after the clot study) showed that tinzaparin use was associated with clot recurrence at rates similar to those seen with other lmwhs, but that the clot recurrence rate for warfarintreated patients was less frequent than expected. One possible explanation for those findings is that physicians or anticoagulation monitoring services (or both) are doing a more effective job of preventing Current Oncology—Volume 22, Number 2, April 2015

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CANADIAN RECOMMENDATIONS FOR VTE TREATMENT IN CANCER

table i

Guideline questions and recommendations related to the treatment of venous thromboembolism (vte)

Category

Question

Recommendations

Strength of evidence Grade Consensus category

Is there a preferred anticoagulation therapy for cancer patients with established vte? In patients with established vte, low molecular weight heparin (lmwh) is the treatment of choice because of decreased recurrence rates on treatment. 2. When should warfarin be used in cancer patients with established vte? Warfarin (inr 2–3), although less favoured, can be used in situations in which lmwh is contraindicated or the patient refuses lmwh. 3. Can direct oral anticoagulation agents (that is, apixaban, dabigatran, rivaroxaban) be used for the treatment of cancer-associated thrombosis? Direct oral anticoagulant agents (that is, apixaban, dabigatran, rivaroxaban) have not yet been proved to be efficacious or safe in oncology patients and are currently not recommended for the treatment of cancer-associated thrombosis. 4. What is the appropriate dosing for dalteparin in cancer patients with vte? For cancer-associated vte, dalteparin is used subcutaneously at 200 U/kg daily for the first month, followed by 150 U/kg daily for the subsequent 5 months. The evidence is insufficient to support subcutaneous dosing of dalteparin at 200 U/ kg daily without dose reduction; however, this regimen is used in clinical practice. 5. What is the appropriate dosing for enoxaparin in cancer patients with vte? There is evidence to support subcutaneous dosing of enoxaparin at 1 mg/kg twice daily or 1.5 mg/kg once daily in the general population, but cancer-specific data are limited. Consider using the twice-daily dosing regimen in high-risk populations such as those with cancer. 6. What is the appropriate dosing for tinzaparin in cancer patients with vte? Tinzaparin should be dosed at 175 U/kg daily subcutaneously. 7. Should patients with recurrent vte while receiving therapeutic anticoagulation receive a dose increase? If so, by how much? Patients with recurrent vte while on lmwh should receive a dose increase of 20%–25%. 8. Are there special considerations for the administration of anticoagulation therapy in obese cancer patients with established vte? Administration of lmwh should be based on actual body weight rather than on ideal body weight. Dose capping is not recommended.

Preferred therapy 1.   and dosing

Duration   of therapy

9.

Incidental vte

10. How should incidental vte be managed in cancer patients? Incidental vte should generally be treated in the same manner as symptomatic vte; however, dosing in proximal deep vein thrombosis (dvt) and pulmonary embolism ( pe) has not been studied.

Central venous  catheter–  related vte

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Should anticoagulant therapy be extended in patients with recurrent vte? Patients with recurrent vte should receive extended (>3 months) anticoagulation therapy.

11. Should cancer patients with upper-extremity dvt in whom the central venous catheter (cvc) has not been removed receive anticoagulation therapy? Anticoagulation therapy for the duration of the cvc is recommended for cancer patients with upper-extremity dvt in whom the cvc has not been removed. 12. How long should cancer patients with upper-extremity dvt and cvc removal receive anticoagulation? Anticoagulation therapy for at least 3 months is recommended for cancer patients with upper-extremity dvt in whom the cvc has been removed.

1A

Immediate

1A

Immediate

2C

Immediate

1A

After discussion After discussion

5D

2B

After discussion

5D

After discussion

1A

Immediate

4D

Immediate

2C

Immediate

2B

Immediate

4D

Immediate

1A

Immediate

1B

Immediate

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EASAW et al.

table i Continued

Category

Question

Recommendations

Strength of evidence Grade Consensus category

Inferior vena cava 13. Should an inferior vena cava (ivc) filter be used in combination with anticoagulation therapy in cancer?   filter The addition of an ivc filter to anticoagulation therapy is not recommended; however, in patients with an ivc filter, anticoagulation therapy can be used in the absence of contraindications. Patients   with renal   insufficiency

Patients with   low platelet  counts

Cirrhosis

14. Are there special considerations for elderly patients with cancer receiving anticoagulation therapy for established vte? Elderly patients more than 70 years of age with reduced creatinine clearance could be at greater risk of lmwh-induced complications such as bleeding. 15. Is there a preferred anticoagulation therapy for elderly cancer patients with established vte? There is no high level evidence to recommend one lmwh or unfractionated heparin (ufh) over another in elderly patients with active malignancy. Tinzaparin might have a favourable biologic profile using therapeutic dosing in the setting of renal insufficiency. 16. Is there a preferred anticoagulation therapy for cancer patients with impaired renal function with established vte? There is no high-level evidence to recommend one lmwh or ufh over another in patients with impaired renal function. Enoxaparin might have a less favourable biologic profile than tinzaparin and dalteparin in patients with impaired renal function. 17. Can cancer patients with established vte undergoing hemodialysis receive lmwh? In patients with active malignancy who are undergoing hemodialysis, lmwh should not routinely be used and should be administered only after consultation with a nephrologist. 18. Should cancer patients with persistent or severe thrombocytopenia receive anticoagulation therapy for established vte? Patients with persistent or severe thrombocytopenia should be referred to a hematologist or thrombosis expert where possible. In patients with significant thrombocytopenia, lmwh or ufh is preferred over vitamin K agonist if anticoagulation is necessary. 19. Should cancer patients with a platelet count below 20,000/μL receive anticoagulation for established vte? For acute clot (

Canadian consensus recommendations on the management of venous thromboembolism in patients with cancer. Part 2: treatment.

Patients with cancer are at increased risk of venous thromboembolism (vte). Anticoagulation therapy is used to treat vte; however, patients with cance...
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