1. Primary Thromboprophylaxis in Ambulatory Cancer Patients: Current Guidelines and Updated Evidence
Taylor Butler, PharmD, BCOP
Decentralized Clinical Pharmacist
Department of Veteran Affairs
Tennessee Valley Healthcare System

2. Presentation Objectives
Review and contrast the American Society of Clinical Oncologist (ASCO), European Society of Medical Oncologist (ESMO), and National Comprehensive Cancer Network (NCCN) guidelines for venous thromboembolism (VTE) prophylaxis in the ambulatory setting
Discuss the current evidence of VTE prophylaxis in the ambulatory setting

3. Why is VTE important in cancer?
VTE risk in the ambulatory setting is 8-19% in cancer, depending on the cancer type, while a matched cohort without cancer was only 1.4%
In pancreatic cancer, symptomatic VTE was significant for a worse response rate, progression-free survival, and overall survival
Other studies report a 2-6 fold increase in mortality
Something else that complicates this clinical scenario is that we would have to use anticoagulant or antithrombotic therapy to prevent VTE and these agents increase the risk of bleeding and we already know that these patients are at a higher risk of bleeding
Source: 1 Khorana AA, Dalal M, Lin J, et al. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013; 119:
2 Mandala M, Reni M, Cascinu S, et al. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncol 2007; 18:

4. ASCO Guidelines
Routine thromboprophylaxis not recommended (Strength of recommendation: evidence-based, strong)
Consider with “highly select high-risk patients” (evidence-based, weak)
Multiple myeloma patients with antiangiogenesis therapy should receive prophylaxis with LMWH or low-dose aspirin based on risk (evidence-based, strong)
Source: Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guidelines update. J Clin Oncol 2013; 31(17):

5. ASCO Guidelines Other pertinent recommendations
Assess patients periodically for VTE risk (informal consensus, strong)
Oncology professionals should educate patients about the s/sx of VTE (informal consensus, strong)
Includes “uncertainty regarding benefit and harms as well as dose duration of prophylaxis”
Source: Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guidelines update. J Clin Oncol 2013; 31(17):

6. ESMO Guidelines
Patient receiving palliative chemotherapy for locally advanced or metastatic disease
Not recommended (Level of evidence and grade of recommendation: II,C)
Consider in high risk patients (II, C)
Consider aspirin, LMWH, or adjusted-dose warfarin for multiple myeloma patients receiving thalidomide plus dexamethasone or chemotherapy (II, B)
Patient receiving adjuvant chemotherapy and/or hormone therapy (including with central venous catheters)
Not recommended (I, A)
Source: Mandala M, Falanga A, and Rolia F. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22(Suppl 6): vi85-92.

7. NCCN Guidelines Ambulatory patients with cancer
No routine px recommended outside clinical trial (category 2A)
Multiple Myeloma receiving immunomodulators (IMiDs)
High risk: Recommend anticoagulant VTE prophylaxis (category 2A)
Low risk: Recommend aspirin (category 2A)
Provider/patient discussion
Disclaimer
Source: National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease. Version Updated 7/22/2016.

8. Khorana Predictive Model
Site of primary cancer
Very High Risk (2 points) – stomach, pancreas
High Risk (1 pt) – lung, lymphoma, gynecologic, genitourinary except prostate
Pretreatment platelet count ≥ 350 x 109/L (1 pt)
Hgb < 10 g/dL or use of erythropoietin-stimulating agents (1 pt)
Pretreatment leukocyte count > 11 x 109/L (1 pt)
BMI ≥ 35 kg/m2 (1 pt)
Source: Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111(10):

9. Khorana Predictive Model
Score/Risk Category
Risk of symptomatic VTE
0 points (Low)
0.3% - 0.8%
1-2 points (Intermediate)
1.8% - 2%
3+ points (High)
6.7% - 7.1%
Source: Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111(10):
Intermediate in other studies has gone up to 8.4% and up to 41% for high risk

10. Multiple Myeloma Risk Factors
Individual Risk Factors
Obesity (BMI of 30 kg/m2 or greater)
Surgery, including trauma or any anesthesia
History of VTE
Use of erythropoietin-stimulating agents
Central venous catheter or pacemaker
Blood clotting disorders
Increased risk diseases (cardiac, chronic kidney disease, diabetes, acute infection, immobilization)
Myeloma Risk Factors
Diagnosis
Hyperviscosity
Myeloma therapy
IMiD in combo with dexamethasone (≥480 mg), doxorubicin, or multiagent chemotherapy
Source: Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22:

11. Multiple Myeloma Risk Assessment
Low
0-1 risk factors
Aspirin mg once daily
High
≥ 2 individual/myeloma risk factors
Prophylactic dose enoxaparin or full-dose warfarin (target INR = 2-3)
Source: Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22:

12. Overview of Guidelines
ASCO
ESMO
NCCN
Last updated
February 2015
March 2011
July 2016
1° VTE px (excluding myeloma)
Consider for highly select high-risk patients
Consider for high risk
Only for clinical trial
1° VTE px in myeloma
Recommend
Consider
Risk Assessment
Yes
Patient Discussion No
Source: 1 Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guidelines update. J Clin Oncol 2013; 31(17):
2 Mandala M, Falanga A, and Rolia F. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22(Suppl 6): vi85-92.
3 National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease. Version Updated 7/22/2016.
Of note, ASCO and ESMO specifically only comments on patients receiving chemotherapy, NCCN is more general but patients who receive chemotherapy are at a higher risk. Patients with pancreatic cancer are included and tend to be the more controversial patients. NCCN  MD judgment, clinical trial push

13. Literature Review Review parameters from January 2015 – May 2017
PubMed
ASCO, MASCC, and ESMO abstracts
Lustig DB, Rodriguez R, and Wells PS. Implementation and validation of a risk stratification method at The Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis. Thromb Res 2015; 136(6):
Cella CA, Di Minno G, Carlomagno C, et al. Preventing venous thromboembolism in ambulatory cancer patients: The ONKOTEV study. Oncologist 2017; 22(5):

14. Meta-analysis – Pancreatic Cancer (2016)
Tun NM, Guevara E, and Oo TH
N = 738 ambulatory advanced pancreatic cancer patients
VTE incidence was 2.1% with LMWH versus 11.2% in the control group (P<0.0001)
Bleeding risk was non-significantly higher
NNT to prevent one symptomatic VTE was 11
Source: Tun NM, Guevara E, and Oo TH. Benefit and risk of primary thromboprophylaxis in ambulatory patients with advanced pancreatic cancer receiving chemotherapy: a systematic review and meta-analysis of randomized controlled trials. Blood Coagul Fibrinolysis 2016; 27(3):

15. Meta-analysis – Lung Cancer (2017)
Fuentes HE, Oramas DM, Paz LH, et al.
N = 5107 with lung cancer
Treatment groups included LMWH, UFH, and warfarin
50% decrease in VTE with LMWH
No increased risk of bleeding
Mortality benefit when ALL VTE prevention modalities were combined
Higher bleeding incidence when all VTE modalities were combined
11 studies included
Source: Fuentes HE, Oramas DM, Paz LH, et al. Meta-analysis on anticoagulation and prevention of thrombosis and mortality among patients with lung cancer. Thromb Res 2017; 154:

16. New Oral Anticoagulants (NOACs)
Guideline
Recommendation
ASCO
Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE
ESMO
Not mentioned
NCCN
Direct oral anticoagulants are not recommended
Source: 1 Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guidelines update. J Clin Oncol 2013; 31(17):
2 Mandala M, Falanga A, and Rolia F. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22(Suppl 6): vi85-92.
3 National Comprehensive Cancer Network. Cancer-associated venous thromboembolic disease. Version Updated 7/22/2016.

17. Upcoming Trials Title Projected Completion
A New Clinic-Genetic Risk Score for Predicting Venous Thromboembolic Events in Cancer Patient (ONCOTHROMB)
November 2016
Evaluation of the Use of Apixaban in Prevention of Thromboembolic Disease in Patients with Myeloma Treated with iMiDs (MYELAXAT)
July 2017
Effects of Anticoagulant Preventive Injection in Patients with Blood Cancer (METRO B)
A Study to Evaluate the Efficacy and Safety of Rivaroxaban Venous Thromboembolism Prophylaxis in Ambulatory Cancer Patients
July 2018
Apixaban for Primary Prevention of Venous Thromboembolism in Patients with Multiple Myeloma
December 2019
Apixaban for the Prevention of Venous Thromboembolism in Cancer Patients (AVERT)
Prophylaxis of Venous Thromboembolism in Advanced Lung Cancer (PROVE)
January 2021
Source: Clinicaltrials.gov. Accessed on May 6th, 2017.
Also, studies evaluating biomarkers, etc. to help better determine risk (thrombin generation marker, fibrin structure marker,)

18. Conclusion
ASCO, ESMO, and NCCN guidelines have similar recommendations regarding VTE prophylaxis in ambulatory cancer patients
General consensus recommends against routine prophylaxis outside of patients diagnosed with multiple myeloma who are receiving antiangiogeneic agents
Periodic risk assessments and patient discussions are vital in the decision-making process
New evidence is needed, including a validated risk assessment adopted into clinical practice