Abstract
Background
Cancer-associated anemia is commonly managed with erythropoiesis-stimulating agents (ESAs) and red blood cell (RBC) transfusions; however, their relative thrombotic risks remain uncertain.
Methods
We conducted a nationwide population-based case-crossover study using the Korean National Health Insurance Database. Adult patients with newly diagnosed cancer between 2011 and 2020 who developed incident venous thrombosis were included. Exposure to ESAs and other time-varying risk factors was assessed during a 12-week hazard period preceding thrombosis and compared with a matched 12-week control period, separated by a 24-week washout interval. Conditional logistic regression was used to estimate odds ratios (ORs).
Results
Among 710,910 patients with cancer, several clinical exposures occurred more frequently during the hazard period than during the control period, including RBC transfusion (6.85% vs 1.79%), hospitalization (11.79% vs 2.77%), surgery (5.70% vs 2.00%), and central venous catheter insertion (3.34% vs 0.74%) (all p < .001). In unadjusted analyses, both ESA use (OR, 3.14; 95% CI, 2.63–7.75) and RBC transfusion (OR, 3.83; 95% CI, 3.58–4.11) were associated with an increased risk of venous thrombosis. After adjustment for time-varying confounders, ESA use was not significantly associated with thrombosis (adjusted OR, 1.12; 95% CI, 0.93–1.36), whereas RBC transfusion remained independently associated with an increased risk (adjusted OR, 1.44; 95% CI, 1.32–1.58). Sensitivity analyses using 8-week and 4-week exposure windows showed consistent results.
Conclusions
RBC transfusion was associated with an increased risk of venous thrombosis in patients with cancer, whereas ESA therapy was not independently associated with thrombotic complications after adjustment. These findings suggest that RBC transfusion may contribute to thrombotic risk in patients with cancer and highlight the need for careful consideration when managing cancer-associated anaemia.
Keywords: Thrombosis, erythropoiesis-stimulating agents, transfusion, cancer
Introduction
Cancer-associated anemia is a frequent complication in patients with cancer [1]. It is known to be associated with poor clinical outcomes. Erythropoiesis-stimulating agents (ESAs) and red blood cell (RBC) transfusions are commonly used to treat anaemia in patients with cancer. However, the clinical implications of these therapies regarding thrombotic complications remain controversial.
Previous studies have reported the clinical implications of ESA therapy for thrombotic complications. Some studies have shown that ESA therapy is associated with an increased risk of venous thromboembolism in patients with cancer [2–4]. For example, Bennett et al. reported in 2008 a significantly higher incidence of thromboembolic complications among patients receiving ESA therapy compared with placebo or standard of care for the treatment of anaemia [5]. Several other studies have reported similar findings in large meta-analyses [6–7].
RBC transfusion is another commonly used therapy for cancer-associated anaemia. Several studies have evaluated the clinical implications of RBC transfusion for thrombotic complications [8–11]. Some studies have reported that RBC transfusion is associated with an increased risk of venous thromboembolism in patients with cancer [9–11]. For example, a large observational study demonstrated that RBC transfusion was independently associated with a higher risk of venous thromboembolism in patients with cancer [9]. Similar findings have also been reported in other population-based studies [10,11].
Despite growing evidence linking ESA therapy and RBC transfusion to thrombotic complications, their relative risk of venous thromboembolism in patients with cancer remains controversial. Previous studies have reported inconsistent findings regarding whether ESAs or RBC transfusions are more strongly associated with thrombotic complications [12]. Therefore, the present study aimed to evaluate the association between ESA therapy and RBC transfusion in relation to the risk of venous thromboembolism in patients with cancer using a retrospective analysis of a nationwide population-based database.
Methods
Data source
Data on patients with cancer for this study were obtained from the Korean National Health Insurance Research Database. As a public organization, the National Health Insurance covers 97% of the population, whereas the remaining population is covered by the Medical Aid program. The database provides nationwide medical information including details of inpatient and out-patient diagnoses, treatment procedures, drug prescriptions and treatment duration. Diagnoses were defined based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and were considered valid if they were recorded in the discharge reports or at least twice in their outpatient records. This study was approved by the Institutional Review Board of Korea University Medical Center (No. 2021AN0597), which waived the requirement for informed consent because this study used de-identified data obtained from the Korean National Health Insurance Service (NHIS) database, a controlled-access database. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Patient selection
Eligible participants were adults with newly diagnosed cancer between 2011 and 2020 who developed venous thrombosis. Patients who were diagnosed with cancer (ICD-10 code: C00.x-C26.x, C30.x-C34.x, C37.x-C41.x, C45.x-C58.x, C60.x-C76.x, C81.x-C85.x, C88.3, C88.7, C88.9, C90.0, C90.1, C91.x-C93.x, C94.0-C94.3, C94.5, C94.7, C95.x, C96.x) from January 1, 2011, to December 31, 2020 were included in the study. The date of the first cancer code occurrence was considered the index date. The study period began at the index date and ended on December 31, 2020. Patients were censored upon death or loss of NHIS eligibility. We applied several exclusion criteria to reduce potential confounding factors. To include only newly diagnosed patients with cancer, we applied a 6-month washout period; thus, patients with an index date from January 1, 2011, and June 30, 2011 were excluded. To include incident venous thrombosis, patients diagnosed with venous thrombosis prior to the diagnosis of cancer were excluded. Because ESAs are also indicated for anemia related to chronic kidney disease, patients with a history of chronic renal failure within 1 year prior to cancer diagnosis or those who underwent dialysis during the study period were excluded. Finally, patients younger than 18 years were excluded.
Definitions
The primary outcome was incident venous thrombosis, defined using ICD-10 code I80.x, recorded during an outpatient visit or a hospitalization within the study period. The event date was defined as the date of the first occurrence of venous thrombosis following cancer diagnosis. Anemia was defined using the ICD-10 codes of D50, D63.0, and D64.9. The relevant codes used to define comorbidities are listed in eTable 1 in the Supplement.
Study design
This study used a case-crossover design: for each patient, exposure during a predefined hazard period immediately preceding the thrombotic event was compared with exposure during a control period of equal duration. The primary hazard period was defined as the 12 weeks preceding the event date. The control period was defined as a 12-week interval occurring earlier, separated from the hazard period by a 24-week washout interval. To assess the robustness of the findings, sensitivity analyses were performed using alternative exposure windows, including shorter hazard and control periods of 4 weeks, while maintaining the same washout interval. A schematic representation of the study design is provided in eFigure 1 in the Supplement. The primary exposure of interest was ESA use, including erythropoietin alfa, darbepoetin alfa, and methoxy polyethylene glycol–epoetin beta. Exposure was assessed on a weekly basis, and patients were classified as exposed if they had at least one prescription claim during the hazard or control period. Additional analyses evaluated exposure to individual ESA agents. To minimize bias, a case-crossover design was used, allowing each patient to serve as their own control and thereby reducing confounding from time-invariant factors. The study size was determined by the number of eligible patients available in the national database during the study period.
Covariates
Because the case-crossover design inherently controls for time-invariant confounders, only time-varying factors were included in the analysis. These included exposures known or suspected to influence thrombotic risk, such as granulocyte colony-stimulating factor (G-CSF) use, chemotherapy, hospitalization, RBC transfusion, platelet transfusion, central venous catheter insertion, and major surgery. These variables were assessed within both hazard and control periods.
Statistical analysis
The baseline characteristics were summarized descriptively. The proportions of ESA use and other transient exposures during the hazard and control periods were compared using χ2 tests. Conditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ESA use, transfusion, and venous thrombosis. The primary model was adjusted for time-varying variables including RBC transfusion, platelet transfusion, central venous catheter insertion, hospitalization, major surgery, chemotherapy, and G-CSF use. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
Results
Study population
Newly diagnosed patients with cancer from January 1, 2011 to December 31, 2020 were identified (Table 1). After excluding patients newly diagnosed with cancer within the wash-out period, a total of 710,910 patients were included. The most common comorbidities included diabetes (13.3%), chronic pulmonary disease (8.2%), and mild liver disease (5.8%). Metastatic solid tumors were identified in 8.6% of the patients. During the study period, 49.3% of patients were hospitalized and 44.2% underwent surgery.
Table 1.
Baseline characteristics of study population.
| Characteristics | N | % |
|---|---|---|
| Cancer | 710,910 | |
| Anaemia | 120,707 | 16.98 |
| Age | ||
| <65 | 298,113 | 41.93 |
| 65–74 | 189,900 | 26.71 |
| 75–84 | 173,761 | 24.44 |
| ≥85 | 49,136 | 6.91 |
| Gender | ||
| Male | 396,761 | 55.81 |
| Female | 314,149 | 44.19 |
| Year of diagnosis | ||
| 2011 (2011.07 ∼ 2011.12 − 6-month washout period) | 50,669 | 7.13 |
| 2012 | 86,452 | 12.16 |
| 2013 | 81,551 | 11.47 |
| 2014 | 77,345 | 10.88 |
| 2015 | 76,354 | 10.74 |
| 2016 | 76,066 | 10.70 |
| 2017 | 73,178 | 10.29 |
| 2018 | 70,902 | 9.97 |
| 2019 | 66,638 | 9.37 |
| 2020 | 51,755 | 7.28 |
| Comorbidities in the past year | ||
| AIDS/HIV | 66 | 0.01 |
| Cerebrovascular disease | 8,451 | 1.19 |
| Congestive heart failure | 16,599 | 2.33 |
| Chronic pulmonary disease | 58,540 | 8.23 |
| Dementia | 12,612 | 1.77 |
| Diabetes without chronic complications | 94,866 | 13.34 |
| Diabetes with chronic complication | 11,952 | 1.68 |
| Hemiplegia or paraplegia | 3,951 | 0.56 |
| Mild liver disease | 40,874 | 5.75 |
| Moderate or severe liver disease | 5,518 | 0.78 |
| Any malignancy, including leukaemia and lymphoma | 710,910 | 100.00 |
| Metastatic solid tumour | 60,815 | 8.55 |
| Myocardial infarction | 1,908 | 0.27 |
| Peripheral vascular disease | 4,644 | 0.65 |
| Peptic ulcer disease | 11,963 | 1.68 |
| Rheumatologic disease | 5,293 | 0.74 |
| Renal disease | 17,024 | 2.39 |
| Health service utilization | ||
| Hospitalization | 350,419 | 49.29 |
| Surgery | 314,572 | 44.25 |
Comparison of clinical factors during hazard and control periods
In the case-crossover analysis, several exposures occurred more frequently during the hazard period than during the control period (Table 2). RBC transfusion was observed in 6.85% of the hazard period compared to 1.79% of the control period (p < 0.001). Hospitalization (11.79% vs. 2.77%, p < 0.001), surgery (5.70% vs. 2.00%, p < 0.001), and central venous catheter insertion (3.34% vs. 0.74%, p < 0.001) occurred more frequently during the hazard period. Platelet transfusions were performed more frequently during the hazard period than during the control period (1.92% vs. 0.48%, p = 0.003). In contrast, G-CSF use showed a numerical increase (1.90% vs. 0.63%); however, no significant difference was observed between the two periods (p = 0.094). ESA use was infrequent, and no significant difference was observed between the hazard and control periods (0.88% vs. 0.28%, p = 0.477). Similar findings were observed for individual ESA formulations, including epoetin-alfa, darbepoetin-alfa, and methoxy polyethylene glycol–epoetin beta (eTable 2 in the Supplement).
Table 2.
Comparison of time-varying factors during hazard and control periods.
| Hazard period |
Control period |
P Value | |||
|---|---|---|---|---|---|
| N | % | N | % | ||
| ESA use (yes) | 505 | 0.88 | 161 | 0.28 | 0.4766 |
| G-CSF use (yes) | 1,090 | 1.90 | 359 | 0.63 | 0.0944 |
| RBC transfusion (yes) | 3,920 | 6.85 | 1,023 | 1.79 | <0.0001 |
| PLT transfusion (yes) | 1,099 | 1.92 | 273 | 0.48 | 0.0031 |
| Chemotherapy (yes) | 2,218 | 3.87 | 673 | 1.18 | 0.7317 |
| Catheter placement (yes) | 1,910 | 3.34 | 423 | 0.74 | <0.0001 |
| Hospitalization (yes) | 6,751 | 11.79 | 1,587 | 2.77 | <0.0001 |
| Major surgery (yes) | 3,266 | 5.70 | 1,144 | 2.00 | <0.0001 |
Note: 12-week exposure (hazard and control) periods and 24-week gap between the exposure periods.
Abbreviations: ESA, erythropoiesis-stimulating agent; RBC, red blood cell; PLT, platelet.
Association between clinical factors and thrombotic risk
In the unadjusted analysis using the 12-week exposure window, several exposures were associated with thrombotic complications (Table 3). ESA use was associated with an increased risk of thrombosis (OR, 3.14; 95% CI, 2.63–7.75). RBC transfusion was also associated with an increased risk of thrombosis (OR, 3.83; 95% CI, 3.58–4.11). Other exposures, including platelet transfusion, catheterization, hospitalization, and major surgery were also associated with an increased risk of thrombosis in the crude analyses. However, after adjusting for time-varying confounders, including RBC transfusion, platelet transfusion, catheterization, hospitalization, and major surgery, associations were attenuated for several variables. ESA use was no longer significantly associated with thrombosis (adjusted OR 1.12, 95% CI 0.93–1.36), indicating that the crude association was largely explained by concurrent clinical exposures. By contrast, RBC transfusion was independently associated with an increased risk of thrombosis (adjusted OR 1.44, 95% CI 1.32–1.58). Among other variables, hospitalization demonstrated the strongest association (adjusted OR 3.30, 95% CI 3.08–3.54), followed by central venous catheter placement (adjusted OR 1.43, 95% CI 1.27–1.62). After adjustment, platelet transfusions and major surgeries were not significantly associated with thrombosis.
Table 3.
Association between time-varying factors and risk of thrombosis.
| Variables | Crude model |
Adjusted model |
||||
|---|---|---|---|---|---|---|
| ORs | 95% CI | ORs | 95% CI | |||
| ESA use | 3.137 | 2.626 | 7.745 | 1.123 | 0.930 | 1.357 |
| RBC transfusion | 3.832 | 3.577 | 4.105 | 1.443 | 1.316 | 1.582 |
| PLT transfusion | 4.026 | 3.526 | 4.596 | 1.068 | 0.920 | 1.245 |
| Catheter placement | 4.515 | 4.064 | 5.017 | 1.433 | 1.267 | 1.620 |
| Hospitalization | 4.254 | 4.028 | 4.493 | 3.302 | 3.081 | 3.540 |
| Major surgery | 2.855 | 2.669 | 3.054 | 1.051 | 0.969 | 1.141 |
Note: All analyses conducted with a 24-week gap between hazard and control periods.
Abbreviations: ESA, erythropoiesis-stimulating agent; RBC, red blood cell; PLT, platelet.
Sensitivity analyses
Sensitivity analyses using alternative exposure windows of eight and four weeks yielded consistent results (Table 4 and eTable 3 in the Supplement). Across all exposure windows, ESA use remained non-significant after adjustment, with adjusted ORs approaching unity (8-week: 1.04, 95% CI 0.86–1.26; 4-week: 1.04, 95% CI 0.83–1.31). In contrast, RBC transfusion consistently demonstrated a significant association with thrombotic risk, although the magnitude of association decreased with shorter exposure windows (8-week: adjusted OR 1.24, 95% CI 1.13–1.37; 4-week: adjusted OR 1.13, 95% CI 1.01–1.27). Other variables, particularly hospitalization and catheterization, also showed consistent associations across the exposure windows, supporting the robustness of the overall findings.
Table 4.
Sensitivity analyses using alternative exposure windows.
| Exposure window | ESA use |
RBC transfusion |
||||
|---|---|---|---|---|---|---|
| Adjusted OR | 95% CI | Adjusted OR | 95% CI | |||
| 8 weeks | 1.040 | 0.855 | 1.264 | 1.244 | 1.129 | 1.369 |
| 4 weeks | 1.042 | 0.827 | 1.312 | 1.132 | 1.007 | 1.272 |
Note: Adjusted for RBC transfusion, PLT transfusion, central venous catheter insertion, hospitalization, major surgery, and chemotherapy. All analyses were conducted with a 24-week gap between the hazard and control periods.
Abbreviations: ESA: erythropoiesis-stimulating agents; RBC: red blood cell.
Discussion
In this nationwide study, RBC transfusion was significantly associated with an increased risk of thrombotic events, whereas ESA use was not significantly associated with thrombotic complications after adjusting for clinical factors. In contrast to ESA therapy, RBC transfusion was associated with thrombotic complications across multiple exposure windows.
Several clinical exposures, including hospitalization, major surgery, platelet transfusion, and central venous catheter insertion, were more frequently observed during the hazard period. These findings suggest that thrombotic events in patients with cancer may occur in a complex clinical setting in which multiple risk factors coexist. The relatively high hospitalization rate observed in our cohort likely reflects the complexity and severity of cancer care in this nationwide population. Hospitalization may contribute to thrombotic risk through immobilization, invasive procedures, and acute illness. As these factors are known to influence thrombotic risk, we included them in the statistical models to minimize potential confounding effects.
The clinical implications of RBC transfusion in relation to thrombotic complications have been evaluated in several studies; however, the results remain controversial. Two studies have reported that RBC transfusion is associated with an increased risk of thrombotic complications in patients with cancer and other high-risk populations [13,14]. In contrast, two studies have suggested that the observed association between transfusion and thrombosis may be related to underlying disease characteristics and treatment-related factors rather than a direct effect of transfusion [9,15]. Although the relationship between RBC transfusion and thrombotic complications has been investigated in several settings, its clinical significance remains controversial. In contrast to RBC transfusion, ESA therapy was not significantly associated with thrombotic complications in adjusted analyses. Several studies have evaluated the clinical implications of ESA therapy for thrombotic complications [16–18]. A previous study reported that ESA therapy is associated with an increased risk of thromboembolic complications, particularly when higher haemoglobin targets are pursued [16]. However, other studies have suggested that the magnitude of this risk may vary according to the treatment strategy and patient population [17]. In routine clinical practice, ESA therapy is administered according to guideline-based treatment targets, which may reduce the risk of thrombotic complications [18]. Thus, the absence of a significant association between ESA use and thrombotic complications in the present study may reflect the treatment practices and clinical factors.
The biological mechanisms linking RBC transfusion and thrombosis also remain controversial. However, a previous experimental study suggested that the biochemical and structural changes that occur during storage of RBCs may influence coagulation pathways [19]. These changes include alterations in erythrocyte deformability, increased blood viscosity, and generation of extracellular vesicles with procoagulant activity [20,21]. Such changes may contribute to thrombin generation and activation of coagulation pathways following transfusion [22,23]. These mechanisms may be particularly relevant in patients with cancer who are already at an increased risk of thrombosis due to cancer-related hypercoagulability [24].
This study had several strengths. First, we used data from a large nationwide cohort, which allowed us to evaluate relatively uncommon outcomes such as thrombotic events. Second, the case-crossover design allowed each patient to serve as their own control, thereby minimizing confounding due to time-invariant patient characteristics. Sensitivity analyses using different exposure windows yielded consistent results. However, the present study has several limitations. First, this study was conducted using observational data; therefore, residual confounding factors could not be completely excluded. Second, detailed clinical information, including laboratory parameters, cancer characteristics, and treatment-related information, was not available in the database. For example, the NHIS claims database does not provide information on laboratory test results before or after RBC transfusion (e.g. white blood cell, platelet, and haemoglobin levels), cancer stage, chemotherapy regimens, or the clinical indications for RBC transfusion. Therefore, residual confounding related to these unmeasured clinical factors cannot be excluded. Third, the association between transfusion and thrombosis could have been influenced by the disease severity or clinical indications for transfusion, which were not fully captured in the present analysis. The generalizability of these findings may be limited to populations with similar healthcare systems and cancer treatment practices. Fourth, the relatively low proportion of patients with metastatic solid tumours likely reflects the inclusion of all newly diagnosed patients with cancer in this nationwide cohort. In addition, metastatic disease was identified using diagnostic codes at baseline, and patients who developed metastases later during follow-up were not classified as having metastatic disease at study entry. Finally, this study used the most recent NHIS data available at the time of data acquisition. The interval between the study period and data analysis reflects the time required for data availability and the NHIS approval process.
In conclusion, RBC transfusion was significantly associated with thrombotic events in patients with cancer, whereas ESA therapy was not independently associated with thrombosis after adjusting for relevant clinical factors. These findings suggest that RBC transfusion may contribute to thrombotic risk in patients with cancer. Further studies are required to clarify the mechanisms underlying this association and to determine optimal strategies for the management of cancer-associated anaemia.
Supplementary Material
Funding Statement
No Funders.
Disclosure statement
No potential conflict of interest was reported by the authors.
Data availability statement
The data that support the findings of this study are available from the Korean National Health Insurance Service (NHIS) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the NHIS.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the Korean National Health Insurance Service (NHIS) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the NHIS.