The heart and science of medicine. Enhancing the

The heart and science of medicine. Enhancing the

The heart and science of medicine. Enhancing the Khorana score: traditional VTE risk factors are important in predicting long term VTE risk inMDcancer outpatients initiating American Society of Hematology Daniel Douce Conference Atlanta, Georgia Steven Ades MD, MSc December 10 , 2017 chemotherapy Chris Holmes MD, th PhD Mary Cushman MD, MSc Charles MacLean MD Neil Zakai MD, MSc UVMHealth.org/CancerCenter

Disclosures No disclosures to report Background Individuals with cancer are at risk of Venous Thromboembolism (VTE) One fifth of all VTE occurs in patients with cancer Second leading cause of death in patients with cancer Khorana et al were instrumental in publishing a prediction model for VTE but has several limitations: 6 month VTE risk only Targeted enrollment of specific tumor types, chemotherapy Convenience sample 1. Lee, A. Y. (2005). "Management of thrombosis in cancer: primary prevention and secondary prophylaxis." Br J Haematol 128(3): 291-302. 2. Sorensen, H. T., et al. (2000). "Prognosis of cancers associated with venous thromboembolism." N Engl J Med 343(25): 1846-1850. 3. Khorana, A. A., et al. (2008). "Development and validation of a predictive model for chemotherapy-associated thrombosis." Blood 111(10): 4902- 4907. Khorana score Patient characteristic Points

Very high risk cancer (stomach, pancreas) 2 High risk (lung, lymphoma, gynecologic, bladder, testicular 1 Pre-chemotherapy platelet count 350 x10/L or more 1 Hemoglobin level less than 10 g/dl, or use of red cell growth factors 1 Pre-chemotherapy leukocyte count more than 11 x10/L 1 BMI 35 kg/m or more

1 Score 3=high risk, 2=intermediate risk, 0-1=low risk Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907 Aims 1. Are age, sex, prior VTE and hospitalization risk factors for VTE in people with cancer? 2. Do traditional factors enhance the Khorana Score? Methods All individuals starting chemotherapy at University of Vermont Cancer Center from 2012-2014 Included internal jugular vein & portal vein thromboses, as well as superficial thrombophlebitis treated with full anticoagulation Prior history of VTE defined as occurring more than 90 days prior to starting chemotherapy Case ascertainment: VTE screened for using ICD-9 codes and confirmed by clinical chart review by a physician. Analysis Traditional VTE risk factors (Age, Sex, VTE history) assessed in univariate analysis

Logistic regression: 6 month interval since starting chemotherapy Cox proportional hazard ratios over the 3 year observation period Khorana score assessed using both Logistic regression and Cox models Traditional VTE risk factors adjusted for covariates derived from the Khorana score Hospitalizations assessed using time-varying covariates using Cox models Results 1583 patients in the cohort 187 (11.8%) VTE events 64% of VTE events occurred within 6 months of starting chemotherapy 40% with lower extremity DVT 37% with PE 11% with both PE and DVT 6% with upper extremity DVT

5% with Portal Vein or IVC thrombus Results Patient characteristic Developed VTE No VTE Mean age (SD) 61 (12) 60 (14) Sex (% male) 52.3 47.3 Mean Baseline BMI (SD) 32.6 (12.3)*

30.8 (11.4)* Hospitalizations (per person-year) 1.408** 0.829** Lung 26 (13.9) 160 (11.5) Breast 12 (6.4)** 217 (15.5)** Gastrointestinal (colorectal, pancreas, biliary, stomach, esophagus, liver) 49 (26.2)** 221 (15.8)**

Genitourinary (prostate, kidney, urothelial, bladder, testicular) 20 (10.7) 102 (7.3) Gynecologic (ovarian, uterine, cervical) 13 (7.0) 92 (6.6) Hematologic (leukemia, lymphoma, myeloma, myelodysplastic syndrome) 41 (22) 387 (27.8) Other (includes head & neck, brain, melanoma, sarcoma) 26 (13.9) 212 (15.2)

Type of cancer (%): * P < 0.05 ** P< 0.01 Traditional Risk Factors Odds Ratio (OR) and Hazard Ratios (HR) 95% Confidence interval (CI) Risk Factors for 6Month Rate of VTE (129 VTE) OR (95% CI) Risk Factors for Incidence of VTE over 3 year period (187 VTE) HR (95% CI) Age (per 10 years older) 1.08 (0.95, 1.24) 1.04 (0.95, 1.15)

Male Sex 1.36 (0.95, 1.96) 1.59 (1.21, 2.08) Prior history of VTE 1.46 (0.76, 2.82) 2.17 (1.44, 3.25) Factors in Khorana Score Risk Factors for 6Month Rate of VTE OR (95% CI) Risk Factors for Incidence of VTE over 3 year period HR (95% CI) High risk cancer type

1.61 (1.22, 2.11) 1.43 (1.16, 1.76) Platelets 350 x 109/L 1.09 (0.67, 1.78) 0.88 (0.59, 1.31) Hgb <10 g/dL 1.44 (0.91, 2.27) 1.78 (1.28, 2.47) WBC 11 x 109/L 1.16 (0.76, 1.78) 1.17 (0.85, 1.63) BMI 35 kg/m2 1.73 (1.16, 2.59)

1.21 (0.89, 1.65) Hospitalizations Unadjusted Hazard Ratio HR (95% CI) Adjusted for Khorana Risk Factors HR (95% Cl) Hospitalization only 1.75 (0.72, 4.28) 1.30 (0.47, 3.51) Hospitalization +30 days 3.09 (2.12, 4.51) 2.87 (1.97, 4.20) Hospitalization + 90 days

2.87 (2.06, 4.00) 2.69 (1.92, 3.75) Addition of Traditional Risk Factors to Khorana Score Risk Factors for 6Month VTE Risk, Adjusting for Khorana Score OR (95% CI) Risk Factors for Incidence of VTE over 3 year period, Adjusting for Khorana Score Age (per 10 years older) 1.08 (0.94, 1.24) 1.05 (0.95, 1.16) Male Sex 1.36 (0.94, 1.96)

1.57 (1.21, 2.07) Prior history of VTE 1.41 (0.73, 2.75) 2.12 (1.41, 3.18) HR (95% CI) Does adding male sex and prior VTE enhance the Khorana score? C-Statistic for Khorana score in first 6 months: 0.61 (95% CI 0.56, 0.65) C-index for Khorana score over 3 years: 0.59 C-index for Khorana score + male sex and VTE history: 0.61 Conclusions Addition of traditional VTE risk factors to the Khorana score does not improve predictive accuracy in the first 6 months of therapy Traditional risk factors of male sex and prior VTE history significantly impact VTE incidence after the first 6 months Recent hospitalizations were a stronger predictor of VTE risk than any other variable evaluated

Risk of cancer-related VTE varies over time, risk needs to be reevaluated over the course of a patients treatment Limitations Retrospective Data: Administrative database using ICD-9 codes: chance of misclassification Limited to patients starting chemotherapy, not all cancer patients Could not adjust for performance status VTE events at outside hospitals may have been missed Single institution study Acknowledgements Jeffords Institute for Quality, The UVM Medical Center Supported in part by an educational grant from the Lake Champlain Cancer Research Organization Inc. Risk Factors for 6-Month Incidence of VTE Unadjusted Odds Ratio Odds Ratio

adjusted for Khorana Risk Factors 129 VTE events within 6 months Khorana Score Components High risk cancer type Platelets 350 x 109/L Hgb <10 g/dL WBC 11 x 109/L BMI 35 kg/m2 Traditional Risk Factors Age (per 10 years older) Male Sex Prior history of VTE Hospitalization Hospitalization + 90 days Hospitalization +30 days Hospitalization only 1.61 (1.22, 2.11) 1.09 (0.67, 1.78) 1.44 (0.91, 2.27) 1.16 (0.76, 1.78) 1.73 (1.16, 2.59)

1.08 (0.95, 1.24) 1.36 (0.95, 1.96) 1.46 (0.76, 2.82) Risk Factors for Incidence of VTE over 3 year observation period Unadjusted Hazard Ratio Hazard ratio Adjusted for Khorana Risk Factors 187 VTE events over 3 years 1.43 (1.16, 1.76) 0.88 (0.59, 1.31) 1.78 (1.28, 2.47) 1.17 (0.85, 1.63) 1.21 (0.89, 1.65) 1.08 (0.94, 1.24) 1.36 (0.94, 1.96) 1.41 (0.73, 2.75)

1.04 (0.95, 1.15) 1.59 (1.21, 2.08) 2.17 (1.44, 3.25) 1.05 (0.95, 1.16) 1.57 (1.21, 2.07) 2.12 (1.41, 3.18) 2.87 (2.06, 4.00) 3.09 (2.12, 4.51) 1.75 (0.72, 4.28) 2.69 (1.92, 3.75) 2.87 (1.97, 4.20) 1.30 (0.47, 3.51)

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