SHARED CARE GUIDELINES 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)
Background 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). CANCER VTE 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: -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 3 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 Factors that may affect Risk for Cancer-Associated VTE The following factors can impact a patient s risk for cancer-associated VTE. 9,0,3 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 0 9 /L Leukocyte count > x 0 9 /L Hemoglobin <00g/L VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 2 of 0
Symptoms of VTE Symptoms are the same for cancer patients as they are for people without cancer. 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 Assessing Risk for VTE 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 0,000 patients* including a post-hoc analysis within the SAVE-ONCO study.,2 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 0 9 /L Hb <00g/L or use of ESA Leukocyte count > x 0 9 /L BMI 35 kg/m 2 Total 2 RISK OF VTE based on score: Score 0 = 0.5% Score 2 = 2% Score 3 = 7% Beyond the risk factors identified in the Khorana risk assessment model, other potential risk factors that should be considered include: (from ACCP Guidelines 2008) 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 203 Page 3 of 0
Indication for VTE Prophylaxis within Guidelines 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. ASCO 203 3 /ESMO 20 4 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 202 5 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 203 6 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 Canadian Prophylaxis Recommendations 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. Patient Characteristic Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) Platelet Count 350 x 0 9 /L Hb <00g/L or use of ESA Leukocyte count > x 0 9 /L BMI 35 kg/m 2 Total Step : Calculate Risk Score Step 2 Score 2 Consider other VTE Risk Factors Previous venous thrombosis Immobilization Angiogenesis inhibitors (e.g. thalidomide, lenalidomide) Determine Risk High Risk: score 3 &/or other VTE risk factors Non-High Risk: risk score <3 VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 4 of 0
Canadian Prophylaxis Recommendations 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 function 7 Note: There is no clinical data to support the efficacy or safety of the new oral anticoagulant agents (apixaban, dabigatran, rivaroxaban) in oncology patients. Contraindications to Anticoagulation 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 Initiating Anticoagulation 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) VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 5 of 0
Choosing the Appropriate Anticoagulant Always weigh the benefits vs. risks of anticoagulation. Risk for bleeding is increased in patients with: Thrombocytopenia Moderate-severe kidney dysfunction almost /3 of cancer patients have renal insufficiency, with in 5 having normal serum creatinine but low egfr 8 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/min 5. Dosage and Administration 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. 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 40-00 kg 5,000 U SC once daily 40 mg SC once daily 4,500 U SC once daily 0-50 kg 5,000 U SC BID 40 mg SC BID 0,000 U SC once daily 5-200 kg 40 U/kg SC BID 0.40 mg/kg SC BID 4,000 U SC once daily 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 function 9, renal failure 20,2, or on hemodialysis 20,2 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. Monitoring / Follow-Up Anticoagulation monitoring is not needed with LMWHs. However follow-up at specific stages is recommended to reassess the balance of thrombosis, bleeding and anticoagulation, as well as reassessing anticoagulant dose and duration. Patient weight and kidney function should also be reassessed at followup. 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. VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 6 of 0
Patient Education 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 Information to the patient Provide the patient with information about VTE in oncology and their treatment. VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 7 of 0
References. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost. 20;9 Suppl :36-24. 2. Heit JA, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based casecontrol study. Arch Intern Med. 2000;60:809-5. 3. Heit JA, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a populationbased study. Arch Intern Med. 2002;62:245-8. 4. Prandoni P, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;00:3484-8. 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;343:846-50. 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). 999;78:285-9. 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;29:36-20. 0. Khorana AA, Rao MV. Approaches to risk-stratifying cancer patients for venous thromboembolism. Thromb Res. 2007;20 Suppl 2:S4-50.. Khorana AA, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;:4902-7. 2. Agnelli G, SAVE-ONCO Investigators, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 202;366:60-9. 3. 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. 203; accessed online ahead of Print. 4. Mandalà M, et al. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Annals of Oncology 20;22 (Supplement 6): vi85 vi92. 5. 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. 202;4(2 Suppl):e49S-94S. 6. Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN 20;9:74-777; Version 2.203. Updates accessed online at www.nccn.org. 7. Lovenox Product Monograph. Sanofi-aventis Canada Inc. September 28, 200. 8. 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;0:CR209- CR22. 9. 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;97:58-6. 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. 20;364:305-4. 2. 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;43:064-83. VTE Simplified Oncology Outpatient Prophylaxis Protocol Mayt 203 Page 8 of 0
Date: VTE Outpatient Assessment Form and Prophylaxis Recommendations Time: Investigations: o Baseline CBC o Serum creatinine egfr ml/min Patient Weight: (kg) Site of Cancer 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) VTE RISK Patient Characteristic Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) Platelet Count 350 x 0 9 /L Hb <00g/L or use of ESA Leukocyte count > x 0 9 /L BMI 35 kg/m 2 Total RISK SCORE o High Risk (score 3 &/or other VTE risk factors) o Non-High Risk (risk score <3) Considerations Score Step 2: Other Risk Factors o Previous venous thrombosis o Immobilization o Hormonal therapy o Angiogenesis inhibitors (e.g. thalidomide, lenalidomide) Thromboprophylaxis Recommended o Yes o No State Reason 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 Thromboprophylaxis - Low Molecular Weight Heparin egfr >30 ml/min: Weight Dalteparin Dose Enoxaparin Dose Tinzaparin Dose 5-200 kg 40 U/kg SC BID 0.40 mg/kg SC BID 4,000 U SC once daily 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 function 9, renal failure 20,2, or on hemodialysis 20,2 HCP Name (print): Signature: VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 9 of 0 2 <40 kg 2,500 U SC once daily 30 U SC once daily 3,500 U SC once daily 40-00 Tkg 5,000 U SC once daily 40 mg SC once daily 4,500 U SC once daily 0-50 kg 5,000 U SC BID 40 mg SC BID 0,000 U SC once daily
Step Calculate Risk Score Patient Characteristic Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) Platelet Count 350 x 0 9 /L Hb <00g/L or use of ESA Leukocyte count > x 0 9 /L BMI 35 kg/m 2 Total Contraindications to LMWHs Assess patient for VTE risk using Khorana tool plus considerations of other potential VTE risk factors Score 2 Step 2 Consider other VTE Risk Factors 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 Educate patient about VTE risk and prevention options High Risk If risk score 3 &/or other VTE risk factors 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 function,2 Non-High Risk If risk score <3 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 Absolute Contraindications to LMWHs Heparin induced thrombocytopenia Active bleeding Stop LMWH at least 2 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 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.,2. Mahé I, et al. Thromb Haemost. 2007;97:58-6; 2. Lovenox Product Monograph. Sanofi-aventis Canada Inc. September 28, 200 VTE Simplified Oncology Outpatient Prophylaxis Protocol May 203 Page 0 of 0