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Arterial thromboembolism in patients with cancer
mark analysis with the landmark set at three months after baseline, 2-year predicted overall survival was 62.3% in patients who did not develop ATE during the first three months of follow up, and 24.8% in patients who did develop ATE during the first three months (Mantel-Byar P<0.001) (Figure 5). The median survival time of patients with cancer after ATE was only 63 days (Q1-Q3: 36-233).
Discussion
We analyzed the cumulative incidence of ATE, identi- fied clinical risk factors, and evaluated the impact of ATE on mortality in patients with cancer in this prospective observational cohort study. During a follow-up period of up to two years, 2.6% of patients developed ATE, defined as the composite of myocardial infarction, stroke and peripheral artery disease, which was less common than VTE. The risk of ATE was increased in patients with high- er age, male sex, hypertension, and a positive smoking history. In addition, the risk of ATE varied by cancer type with lung and kidney cancer having the highest, and breast cancer having the lowest risk. We also observed that the occurrence of ATE is associated with a 3-fold increased risk of mortality. The negative impact of ATE on cancer patients’ prognosis indicates an unmet need for better understanding of the burden of ATE in cancer, the identification of patients at risk of ATE, and improved strategies to prevent, treat and manage ATE in patients with cancer.
An increased risk of stroke and coronary heart disease in patients with cancer has been reported in previous studies.24-30 In a recent retrospective analysis of a Surveillance, Epidemiology, and End Results (SEER) and Medicare linked dataset of patients with a primary cancer diagnosis between 2002 and 2011 in the USA, the 6- month cumulative incidence of myocardial infarction and ischemic stroke was 4.7% compared to 2.2% in a
Figure 2. Time-dependent rates of arterial thromboembolism (ATE) and venous thromboembolism (VTE) over two years of follow up. While the rate of VTE was highest during the first six months of follow up and then declined, the risk of ATE did not have a peak and remained relatively constant during follow up. The curves were predicted with a flexible parametric regression model on the log- cumulative-hazard scale (Stata routine stpm2).
matched control group without cancer.31 The cumulative incidence of ATE in this study was higher than in our study (4.7% vs. 2.6%). However, increasing age is an important cardiovascular risk factor and patients in this retrospective study were older than in our study, where outcome data were prospectively collected (median age 74 vs. 61 years). It is likely that an increased rate of ATE may be attributable to some degree to differences in age and also to the presence of classical cardiovascular risk factors in the studied populations. In general, estimating the true risk of ATE may be challenging in cancer patients. Non- specific ATE symptoms such as dyspnea and chest pain are highly prevalent in cancer patients and oncologists may attribute such symptoms often to the underlying can- cer, which may lead to an under-diagnosis of ATE. On the other hand, cardiologists may be reluctant to schedule cancer patients for diagnostic coronary angiographies when cancer patients have a poor performance status or are deemed to have a poor prognosis, leading to a further underestimation of the ATE burden in cancer patients. Thus, oncologists and cardiologists should maintain a rel- atively high index of suspicion for ATE when dealing with cancer patients with ATE-related symptoms.
The relative risk of ATE according to the cancer type in our study was similar to that of previous studies. Patients with lung and kidney cancer had the highest relative risk of ATE.29-31 The difference in ATE risk between cancer types may be driven by general risk factors that increase risk of both cancer and ATE, such as smoking, or by spe- cific anti-cancer treatments, such as platinum-based com- bination chemotherapy, vascular endothelial growth fac- tor (VEGF) / vascular endothelial growth factor receptor (VEGFR) inhibitors, which have been associated with increased risk of ATE.12,32-37 Prior studies also suggested an association between metastasis and the risk of ATE occur- rence, which was not confirmed in our study.29-31
The risk of VTE in patients with cancer varies during the course of the cancer disease. It is highest during the first
Figure 3. Cumulative incidence of arterial thromboembolism (ATE) according to cancer type. A competing risk cumulative incidence estimator was used. For clarity, only selected tumor entities are compared. A Gray’s test was used to test for differences between cancer types (P<0.001), venous thromboembolism and death-from-any-cause were considered as competing risk event.
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