The association between race and venous thromboembolism risk after initiation of chemotherapy: An analysis of the <scp>SAVE</scp>‐<scp>ONCO</scp> trial control arm
Authors: Yu‐Wei Chen, Alok A. Khorana
Journal: American Journal of Hematology (2017)

Venous thromboembolism (VTE) risk varies across the races and ethnicities in the general population1 and VTE has been reported to be the leading cause of death in outpatients receiving chemotherapy.2 However there is paucity of data comparing the risk of VTE between races in the setting of initiation of chemotherapy. Our study analyzed publicly available SAVE-ONCO trial3 control arm (N = 1604) from Project Data Sphere website4 to investigate the effect of race on VTE risk in patients initiating chemotherapy. The SAVE-ONCO trial3 investigated the efficacy of semuloparin in preventing venous thromboembolism in patients with solid organ tumors receiving chemotherapy. The SAVE-ONCO trial was a placebo-controlled trial: the experimental arm (N = 1608) received semuloparin (20 mg once daily) and the comparator arm (N = 1604) received placebo starting on the first day of the chemotherapy and continuing on the duration of the chemotherapy course with an intention to be administered for at least three months. No other anticoagulants were allowed in this trial. The institutional review board approved this study. Patient baseline characteristics were retrieved including race, sex, age, cancer site, cancer stage, and factors associated with VTE as defined in the original SAVE-ONCO trial.3 Khorana risk score for VTE as previously published5 was calculated for patient baseline VTE risk adjustment. Patients whose chemotherapy agents have been reported to be associated with VTE risk were identified: they were cisplatin, bevacizumab, sunitinib, cetuximab, pantinumumab, and tamoxifen. The outcomes of interest included any events of symptomatic deep-vein thrombosis in lower or upper extremities, non-fatal pulmonary embolism, or death related to venous thromboembolism during the course of chemotherapy. Descriptive statistics were used to present the patient baseline characteristics. Multivariable Cox proportional hazards model was adopted to estimate the effect of race on developing VTE after adjustment for baseline characteristics. All statistical analyses were performed using SAS® version 9.4. (SAS Institute Inc., Cary, NC, USA). A two-sided P-value < .05 was adopted in all analyses as criteria for statistical significance. The Cox proportional hazards assumption was validated with SAS PROC PHREG procedure with ASSESS statement. Patient baseline characteristics are presented in Supporting Information Table. Among the 1604 patients enrolled to the placebo arm, 1233 (77%) were Whites, 277 (17%) were Asians, 26 (1.6%) were Blacks, 59 (3.7%) were other races, and 9 (0.6%) patients did not have race information. The median follow-up after initiation of chemotherapy was 107 days (interquartile range: 57-150 days). There were 55 VTE or VTE-related death events: 41 were observed in Whites (3.3%), 9 in Asians (3.3%), 4 in Blacks (15.4%), and 1 in patients of unknown race (0.11%) (Supporting Information Figure, chi-square test P-value: .0001). In patients with Khorana low risk, 5 (1.6%) patients developed events; in patients with Khorana intermediate risk, 36(3.54%) patients developed events; in patients with Khorana high risk, 14(5.15%) patients developed events (Supporting Information Figure, Mantel–Haenszel test for trend P-value: .02). In Cox proportional hazards model: compared with Whites, Blacks were associated with increased risk for VTE or VTE-related death (AHR: 3.25, 95% CI: 1.12-9.45, P-value: .03). There was no difference in risk between Whites and Asians (AHR: 0.92, 95% CI: 0.43-1.94, P-value: .82). Patients with Khorana intermediate or high risk, with ECOG score ≥ 2, and patients with ≥2 VTE-associated risk factors had increased risk for VTE or VTE-related death (Table 1). Patient's age, sex, cancer stage, the use of cisplatin or use of any bevacizumab, sunitinib, cetuximab, panitumumba or tamoxifen were not associated with increased VTE risk (Table 1). There are so far few studies conducted in a cancer population which capacitates direct comparisons between Asians and other races outside the United States.6 The SAVE-ONCO trial control arm was an ideal cohort for us to investigate the effect of race on VTE risk in patients receiving chemotherapy given the homogenized follow-up mandated by study procedures and worldwide enrollment. Our results demonstrated that after adjustment for baseline characteristics including the Khorana risk score and chemotherapy agents, there was no difference of VTE risk between Asians and Whites. However Blacks had a significantly threefold increased risk of VTE in patients initiating chemotherapy. Certain limitations included that Blacks were underrepresented and our results were a post-hoc analysis. In conclusion, we found that although Asians might have lower risk of VTE than Whites in the general population,1 this risk might likely be potentiated by chemotherapy agents in cancer population. Physicians should be aware that VTE is the leading cause of death in outpatient chemotherapy.2 Future studies are indicated to address the risk of VTE upon starting chemotherapy among different races and ethnicities. A. A. Khorana reports personal fees from Sanofi, personal fees from Janssen, personal fees from Leo Pharma, personal fees from Bayer, personal fees from Pfizer, personal fees from Halozyme, personal fees from Roche, personal fees from AngioDynamics, outside the submitted work. Conception and Design: Y.W. Chen, A.A. Khorana; Collection and assembly of data: Y.W. Chen, A.A. Khorana; Data Analysis and interpretation: Y.W. Chen, A.A. Khorana; Manuscript writing: Y.W. Chen, A.A. Khorana; Final Approval of manuscript: Y.W. Chen, A.A. Khorana Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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