1. VTE PROPHYLAXIS IN
ONCOLOGY OUTPATIENTS
Steering Committee
Marc Carrier, MD, M.Sc., FRCP(C) • Jay Easaw, MD, PhD, FRCP(C)
• Sudeep Shivakumar, MD, M.Sc., FRCP(C)
Oncologists
Scott Berry, B.Sc., MD, MHSc., FRCP(C)
Norman Blais, MD, M.Sc., FRCP(C)
Neil Chua, MD, FRCP(C)
Christine Cripps, MD, FRCP(C)
Robert El-Maraghi, MD, FRCP(C)
Petr Kavan, MD, FRCP(C)
Philip Kuruvilla, MD, FRCP(C)
Dorothy Lo, MD, FRCP(C)
Matilda Ng, MD, FRCP(C)
Yasmin Rahim, MD, FACP, FRCP(C)
Sandeep Sehdev, MD, FRCP(C), BC(ABIM)
Denis Soulieres, MD, FRCP(C)
Catherine Sperlich, MD, FRCP(C)
Srikala Sridhar, MD, FRCP(C)
Elizabeth Strevel, MD, FRCP(C)
Sunil Verma, MD, MSEd, FRCP(C)
Jonathan Wilson, MD, FRCP(C)
Pawal Zalewski, MD, FRCP(C)
Hematologists
Peter Gross, MD , M.Sc., FRCP(C)
Jeannine Kassis, MD, FRCP(C)
Alejandro Lazo-Langner, MD, M.Sc., FRCP(C)
Anne McLeod MD, M.Sc., FRCP(C)
Vicky Tagalakis, MD, M.Sc., FRCP(C)
Axel Tosikyan, MD, FRCP(C)
Oncology Nurses
Kristine Frandsen, RN
Krista Neubauer, RN, BSN
Kelly Savage RN, CNS, LNS, CONC
Oncology Pharmacists
Darryl Boehm, B.Sc. (Pharm)
Amine Bouziane, B. Pharm, M.Sc.
Carlo De Angelis, PharmD
Dominique Duquette, B. Pharm
Kimberly Kuik, B.Sc. (Pharm)
Josee Martineau, B.Pharm, M.Sc. BCPS
Sharon Meeke, B.Sc. (Pharm)
Colleen Olson, B.Sc. (Pharm)
Jack Seki, RPh, B.Sc. (Pharm), PharmD
Laura Wilcock, RPh, B.Sc. (Pharm)
SHARED CARE GUIDELINES

2. Factors that may affect Risk for Cancer-Associated VTE
Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein
thrombosis (DVT), represents one of the most important causes of morbidity and mortality in
cancer patients. Thromboembolism is the 2nd most common cause of death in ambulatory
cancer patients (tied with infections).
The following factors can impact a patient’s risk for cancer-associated VTE.9,10,13
Patient-related factors
• Increased age
• Ethnicity (risk increased in African
Americans)
• Co-morbidities (infection, renal
and pulmonary disease, arterial
thromboembolism, VTE history, inherited
prothrombotic mutations
• Obesity
• Performance status
Cancer-related factors
• Primary site of cancer
• Stage (risk increases with higher stage)
• Comorbid conditions
• Histology
• Time since diagnosis (risk increases during
first 3-6 months)
Treatment-related factors
• Chemotherapy, antiangiogenesis agents,
hormonal therapy
• Radiation therapy
• Surgery ≥ 60 mins
• Erythropoiesis-stimulating agents (ESAs),
transfusions
• Indwelling venous access
Biomarkers
• Platelets ≥ 350 x 109
/L
• Leukocyte count >11 x 109
/L
• Hemoglobin <100g/L
Cancer patients are at a significantly greater risk for developing a blood clot (PE or DVT)
compared with patients without cancer.
Key Facts in Cancer Patients:1-7
• Incidence of VTE ranges from 4-20%
• 4- to 6-fold increased risk for VTE vs. non-cancer patients
• 3-fold increased risk for recurrence of VTE vs. non-cancer patients
• 4 to 13 times higher rate of VTE in those with metastatic disease as compared with those
with localized disease
• Clinical rates may underrepresent burden; at autopsy, VTE rates are as high as 50%
The underlying mechanisms are not completely understood. However, we know that cancer
is a prothrombotic state, with the activation of the coagulation cascade integrally linked to
the processes of tumor growth, metastasis and angiogenesis. Further, chemotherapy can
result in activation of coagulation within a few hours of administration through the induction of
tissue factor (TF) in tumour cells and monocytes, the downregulation of anticoagulant proteins,
damage to vascular endothelium, and platelet activation. Anti-angiogenic agents also contribute
to thrombosis, perhaps through endothelial cell and platelet activation.8
The pathophysiology of cancer-associated thrombosis is likely multifactorial with different
factors assuming lesser or greater degrees of importance depending on the patient, the type of
cancer and the clinical setting.8
Background
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 2 of 10
➠➠CANCER VTE

3. Symptoms of VTE
Assessing Risk for VTE
Symptoms are the same for cancer patients as they are for people without cancer.
Beyond the risk factors identified in the Khorana risk assessment model, other potential risk
factors that should be considered include: (from ACCP Guidelines 2008)
All cancer patients have an increased risk of VTE. However, routine pharmacological
thromboprophylaxis is not indicated in cancer outpatients. Evidence suggests that certain
patients have a higher risk than others. With this knowledge, Dr. Alok Khorana and colleagues
developed a risk assessment tool to assist with identifying cancer patients at the greatest risk of
VTE. This tool was developed from a database of neutropenic patients and has been validated
in almost 10,000 patients* including a post-hoc analysis within the SAVE-ONCO study.11,12
Symptoms of Possible DVT
• Recent swelling of one leg or arm
• Unexplained pain or tenderness of one leg or arm
• Skin may be warm to the touch or is discoloured (red, purple or blue)
Symptoms of Possible PE
• Recent or sudden shortness of breath or breathlessness
• Sharp chest pain or upper back pain, especially when inhaling
• Light-headedness or coughing up blood
• Previous venous thrombosis
• Immobilization
• Hormonal therapy
• Angiogenesis inhibitors (i.e. Avastin, thalidomide, lenalidomide)
* Patient groups included in the risk analysis had cancers of: lung, stomach, pancreas, lymphoma,
gynecological, and GU excluding prostate
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 3 of 10
Patient Characteristic Score RISK OF VTE based on score
Site of Cancer
• Very high risk (stomach, pancreas)
• High risk (lung, lymphoma,
gynecologic, GU excluding prostate)
• Platelet Count ≥ 350 x 109
/L
• Hb <100g/L or use of ESA
• Leukocyte count >11 x 109
/L
• BMI ≥ 35 kg/m2
Total
2
1
1
1
1
1
RISK OF VTE
based on score:
• Score 0 = 0.5%
• Score 1 – 2 = 2%
• Score ≥ 3 = 7%

4. Patient Characteristic Score
Site of Cancer
• Very high risk (stomach, pancreas)
• High risk (lung, lymphoma,
gynecologic, GU excluding prostate)
• Platelet Count ≥ 350 x 109
/L
• Hb <100g/L or use of ESA
• Leukocyte count >11 x 109
/L
• BMI ≥ 35 kg/m2
Total
2
1
1
1
1
1
Determine Risk
• High Risk: score ≥3 &/or other
VTE risk factors
• Non-High Risk: risk score <3
Indication for VTE Prophylaxis within Guidelines
Canadian Prophylaxis Recommendations
Current International Guidelines do provide some recommendations for thromboprophylaxis in
oncology patients some using the Khorana Risk score. However, while there is some consensus
on thromboprophylaxis of inpatients, there is no consensus on thromboprophylaxis in oncology
outpatients despite the fact that the risk of VTE remains increased in some cancer patients,
even when ambulatory.
All cancer patients should be assesed for VTE risk at the time of chemotherapy initiation and
periodically thereafter. In the outpatient setting, risk is best assessed using a validated risk
assessment tool like the Khorana tool. Consideration should also be given to other potential
VTE risk factors.
ASCO 201313
/ESMO 201114
– Routine pharmacologic thromboprophylaxis is not recommended in cancer outpatients
– Clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected
outpatients with solid tumours receiving chemotherapy
– Patients with multiple myeloma receiving lenalidomide- or thalidomide-based regimens
with chemotherapy and/or dexamethasone should receive thromboprophylaxis with
either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients
ACCP 201215
− No routine anticoagulation UNLESS
• Solid tumor
• Presence of risk factors including: previous VTE, hormone therapy, immobilization,
angiogenesis inhibitors, lenalidomide, thalidomide
– If above present, then consider LMWH or unfractionated heparin
NCCN 201316
− Thalidomide/lenalidomide patients, otherwise no routine thromboprophylaxis
− Utilizing Khorana predictive risk model: patients with high risk (≥3) COULD BE considered
for prophylaxis on an individual basis evaluating risk/benefit ratio
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 4 of 10
Consider other VTE Risk
Factors
• Previous venous thrombosis
• Immobilization
• Angiogenesis inhibitors (e.g.
thalidomide, lenalidomide)
Step 1: Calculate Risk Score Step 2

5. Canadian Prophylaxis Recommendations
Contraindications to Anticoagulation
Initiating Anticoagulation
If patient is High Risk (score ≥3 &/or other risk factors)
• Consider prophylaxis with a LMWH at prophylactic dose^
• Decision should be guided by contraindications as well as risk:benefit ratio
Patients should be reassessed periodically, at least every 3 months, after initiation of prophylactic
treatment.
If patient is Non-High Risk (score <3)
• Reassess as appropriate
OR
• Consider thromboprophylaxis if other VTE risk factors exist
^enoxaparin dose adjustment recommended in patients with impaired renal function17
Note: There is no clinical data to support the efficacy or safety of the new oral anticoagulant
agents (apixaban, dabigatran, rivaroxaban) in oncology patients.
It is important to review and understand the patient`s risks and possible contraindications
to anticoagulation.
• Current anticoagulation therapy
• Recent bleeding events – increases risk for further bleeds
• HIT
• Bleeding disorder
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 5 of 10
Prior to initiating any anticoagulant, the following assessments should be done:
• Assess for additional medical conditions
• Determine renal function, body weight, know coagulopathy
• Baseline blood work performed, including serum creatinine and CBC
• Identification of current antiplatelet or anticoagulant use (e.g. ASA, Warfarin)

6. Choosing the Appropriate Anticoagulant
Dosage and Administration
Monitoring / Follow-Up
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 6 of 10
Always weigh the benefits vs. risks of anticoagulation.
Risk for bleeding is increased in patients with:
• Thrombocytopenia
• Moderate-severe kidney dysfunction
− almost 1/3 of cancer patients have renal insufficiency, with 1 in 5 having normal serum creatinine
but low eGFR18
• Current antiplatelet therapy
Choice of anticoagulant should be guided by best practices with consideration to the following
criteria:
• Kidney function
• eGFR <30 mL/min dose adjustment for enoxaparin recommended
no dose adjustment needed for tinzaparin or dalteparin
• eGFR 20-30 mL/min: tinzaparin*
• Provincial reimbursement/cost^
^Outpatient choice may have fewer restrictions as all LMWHs have similar coverage on the majority of provincial
formularies. *tinzaparin clearance was not shown to be correlated with CrCl, even when the CrCl was as low as
20 mL/min15
.
LMWH ​is the therapy of choice​ except ​in the case of severe kidney failure for VTE prevention for inpatients
and outpatients. Thromboprophylaxis should​ continue for a minimum of 3 months, it may be extended
if clinically warranted.
In patients with impaired renal function (<30 mL/min):
• Dalteparin: no dose adjustment is required
• Enoxaparin: a dosage adjustment is recommended since enoxaparin appears to accumulate
in this patient group and may increase risk of bleeding.
• Tinzaparin: no dose adjustment of tinzaparin at prophylaxis doses is needed in patients with
impaired renal function19,
renal failure20,21
, or on hemodialysis20,21
LMWH:
Weight Dalteparin Dose Enoxaparin Dose Tinzaparin Dose
<40 kg 2,500 U SC once daily 30 U SC once daily 3,500 U SC once daily
40-100 kg 5,000 U SC once daily 40 mg SC once daily 4,500 U SC once daily
101-150 kg 5,000 U SC BID 40 mg SC BID 10,000 U SC once daily
151-200 kg 40 U/kg SC BID 0.40 mg/kg SC BID 14,000 U SC once daily
Note: There is insufficient clinical data to support the efficacy and safety of the new oral anticogulant​ agents
(apixaban, dabigatran, rivaroxaban) as primary thromboprophylactic agents in oncology patients.
Anticoagulation monitoring is not needed with LMWHs. However follow-up at specific stages is
recommendedtoreassessthebalanceofthrombosis,bleedingandanticoagulation,aswellasreassessing
anticoagulant dose and duration. Patient weight and kidney function should also be reassessed at follow-
up.
Follow-up recommendations:
• Bring patient back, if possible, in the first week to ensure self-injections are properly administered,
and to assess for bleeding complications
• Monitor as part of standard chemotherapy protocol
• Review injection technique at each visit. Provide patients with tips to maximize injection success
Patients should be reassessed as appropriate, and at a minimum of 3 months after initiation of prophylactic
treatment.

7. Patient Education
Information to the patient
VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 7 of 10
Patients/carers need to be educated about VTE risk and the available options to lower the risk.
If thromoboprophylaxis is initiated then education about this new therapy must also be done.
Review benefits/requirements for thromboprophylaxis as well as restrictions/risks. Have patient
or carer do the first injection in the clinic with the assistance of clinic nurse or physician.
Items that should be reviewed with the patient/carer:
• Patient’s VTE risk and options to lower their risk
• Explain why injection vs. oral medication (note currently no indication or data for new
oral agents in oncology). Patients should be reassessed as appropriate, and at a
minimum of 3 months after initiation of prophylactic treatment
• Symptoms of a blood clot, particularly DVT or PE
• What to do if symptoms are suspected
• Seek medical attention ➝ provide clear direction including phone numbers etc.
• Purpose of anticoagulation medication
• Anticoagulants reduce the amount of clotting taking place in the blood allowing the
blood to flow more freely. They also prevent the formation of blood clots or prevent
existing blood clots from growing
• Therapy will need to continue for several months to reduce the risk of developing a
clot
• Restrictions when on anticoagulation medication
• No dietary restrictions with LMWHs
• Alcohol in moderation only
• Risks of using/taking anticoagulation medication
• Increased risk of bleeding – exercise caution with sharp objects, avoid contact and
high-risk physical activities, and avoid using ASA & NSAIDs without your doctor’s
permission
• Inform other Healthcare Professionals/providers including dentists that they are using
anticoagulation. There may be a concern with dental extractions, but really only if
there are 4 or more extractions
• Bleeding on an anticoagulant/blood thinner is a medical emergency
• Blood clot prevention
• Stay active
• Don’t smoke or stop smoking
• Maintain a normal body weight, if possible
• Drink plenty of liquids
• When travelling wear compression stockings and/or get up and walk frequently
Provide the patient with information about VTE in oncology and their treatment.

8. References
VTE Simplified Oncology Outpatient Prophylaxis Protocol Mayt 2013 Page 8 of 10
1. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost.
2011;9 Suppl 1:316-24.
2. Heit JA, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-
control study. Arch Intern Med. 2000;160:809-15.
3. Heit JA, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-
based study. Arch Intern Med. 2002;162:1245-8.
4. Prandoni P, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant
treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484-8.
5. White RH, et al. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical
procedures. Thromb Haemost. 2003;90:446-55.
6. Sørensen HT, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med.
2000;343:1846-50.
7. Levitan N, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus
those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore). 1999;78:285-91.
8. Khorana AA, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient
chemotherapy. J Thromb Haemost. 2007;5:632-4.
9. Sousou T, Khorana AA. New insights into cancer-associated thrombosis. Arterioscler Thromb Vasc Biol.
2009;29:316-20.
10. Khorana AA, Rao MV. Approaches to risk-stratifying cancer patients for venous thromboembolism. Thromb
Res. 2007;120 Suppl 2:S41-50.
11. Khorana AA, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis.
Blood. 2008;111:4902-7.
12. Agnelli G, SAVE-ONCO Investigators, et al. Semuloparin for thromboprophylaxis in patients receiving
chemotherapy for cancer. N Engl J Med. 2012;366:601-9.
13. Lyman GH, et al. Venous thromboembolism (VTE) prophylaxis and treatment in patients with cancer: American
Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2013; accessed online ahead of
Print.
14. Mandalà M, et al. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice
Guidelines. Annals of Oncology 2011;22 (Supplement 6): vi85–vi92.
15. Kearon C, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e419S-94S.
16. Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN
2011;9:714-777; Version 2.2013. Updates accessed online at www.nccn.org.
17. Lovenox®
Product Monograph. Sanofi-aventis Canada Inc. September 28, 2010.
18. Launay-Vacher V, et al. Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug
management: the renal insufficiency and anticancer medications (IRMA) study. Med Sci Monit 2004;10:CR209-
CR212.
19. Mahé O, et al. Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients
with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost. 2007;97:581-6.
20. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand
Intensive Care Society Clinical Trials Group, et al. Dalteparin versus unfractionated heparin in critically ill
patients. N Engl J Med. 2011;364:1305-14.
21. Nutescu EA, et al. Low-molecular-weight heparins in renal impairment and obesity: available evidence and
clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43:1064-83.

9. VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 9 of 10
HCP Name (print):____________________________ Signature:____________________________________
Date:
Time:
VTE Outpatient Assessment Form and Prophylaxis Recommendations
Patient Weight: (kg) ____________ Site of Cancer ____________________________________________
o Baseline CBC o Serum creatinine eGFR_____mL/min
Current Cancer Therapy
o Angiogenesis inhibitors (e.g. Avastin, thalidomide, lenalidomide)
o Biological response modifiers (e.g. interferon, Rituxan, Herceptin)
o Nonspecific immunomodulating agents (e.g. 5-fluorouracil)
Current Anticoagulant Therapy
• Anticoagulant therapy o Yes Type and dose: __________________________________ o No
• Oral Anticoagulant therapy (e.g. warfarin, dabigatran, rivaroxaban, apixaban):
o Yes Type and dose: __________________________________ o No
eGFR >30 mL/min:
In patients with impaired renal function (<30 mL/min):
• Dalteparin: no dose adjustment is required
• Enoxaparin: a dosage adjustment is recommended since enoxaparin appears to accumulate in this patient
group and may increase risk of bleeding.
• Tinzaparin: no dose adjustment of tinzaparin at prophylaxis doses is needed in patients with impaired renal
function19
, renal failure20,21
, or on hemodialysis20,21
Step 2: Other Risk Factors
o Previous venous thrombosis
o Immobilization
o Hormonal therapy
o Angiogenesis inhibitors (e.g.
thalidomide, lenalidomide)
Investigations:
Thromboprophylaxis Recommended
o Yes o No – State Reason
VTE RISK
Considerations
Thromboprophylaxis - Low Molecular Weight Heparin
RISK SCORE
o High Risk (score ≥3 &/or other VTE risk factors)
o Non-High Risk (risk score <3)
Patient Characteristic Score
Site of Cancer
• Very high risk (stomach, pancreas)
• High risk (lung, lymphoma,
gynecologic, GU excluding prostate)
• Platelet Count ≥ 350 x 109
/L
• Hb <100g/L or use of ESA
• Leukocyte count >11 x 109
/L
• BMI ≥ 35 kg/m2
Total
2
1
1
1
1
1
➠
Weight Dalteparin Dose Enoxaparin Dose Tinzaparin Dose
<40 kg 2,500 U SC once daily 30 U SC once daily 3,500 U SC once daily
40-100 Tkg 5,000 U SC once daily 40 mg SC once daily 4,500 U SC once daily
101-150 kg 5,000 U SC BID 40 mg SC BID 10,000 U SC once daily
151-200 kg 40 U/kg SC BID 0.40 mg/kg SC BID 14,000 U SC once daily

10. VTE Simplified Oncology Outpatient Prophylaxis Protocol May 2013 Page 10 of 10
Contraindications to LMWHs
• In the prophylaxis setting, mechanical thromboprophylaxis should be provided to all patients with a
contraindication to LMWHs
*Use clinical judgment to weigh the risk of venous thromboembolism versus the risk of bleeding
^enoxaparin dose adjustment recommended in patients with impaired renal function.1,2
1. Mahé I, et al. Thromb Haemost. 2007;97:581-6; 2. Lovenox®
Product Monograph. Sanofi-aventis Canada Inc. September 28, 2010
Patient Characteristic Score
Site of Cancer
• Very high risk (stomach, pancreas)
• High risk (lung, lymphoma,
gynecologic, GU excluding prostate)
• Platelet Count ≥ 350 x 109
/L
• Hb <100g/L or use of ESA
• Leukocyte count >11 x 109
/L
• BMI ≥ 35 kg/m2
Total
2
1
1
1
1
1
• Previous venous thrombosis
• Immobilization
• Hormonal Therapy
• Angiogenesis inhibitors (e.g.
thalidomide, lenalidomide)
Risk
• High Risk: score ≥3 &/or other
VTE risk factors
• Non-High Risk: risk score <3
Step 1
Calculate Risk Score
Step 2
Consider other VTE Risk Factors
Assess patient for VTE risk using Khorana tool plus
considerations of other potential VTE risk factors
Educate patient about VTE risk and prevention options
➠
➠
Consider Pharmacologic Prophylaxis
Any LMWH at prophylactic dose^
Decision should be guided by contraindications
Assess risk:benefit ratio*:
thrombocytopenia, mod-severe renal
dysfunction, antiplatelet therapy
^enoxaparin dose adjustment is recommended
in patients with impaired renal function1,2
Reassess as appropriate
Or
Consider thromboprophylaxis
if other VTE risk factors exist
Reassess as appropriate, and at a minimum
of 3 months after initiation of prophylactic
treatment
➠
➠
High Risk
If risk score ≥3 &/or other VTE risk factors
➠
➠➠
Absolute Contraindications to LMWHs
• Heparin induced thrombocytopenia
• Active bleeding
• Stop LMWH at least 12 hours before spinal invasion;
Next dose should be held at least 2 hours after spinal
invasion
Relative Contraindications to LMWHs
• Severe thrombocytopenia
• Severe coagulopathy
• High bleeding risk
Non-High Risk
If risk score <3