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E. Grilz et al.
smoking history (SHR=2.0, 1.1-3.7; P=0.022), and a known arterial cardiovascular disease (e.g. history of stroke, peripheral arterial disease, coronary heart disease) at study entry (SHR=3.7, 1.9-7.2; P<0.001) were associat- ed with a higher ATE risk.
The body mass index (SHR=1.0, 1.0-1.1; P=0.115), and a prior history of VTE (SHR= 0.8, 0.2-3.5; P=0.814) were not associated with risk of ATE. Furthermore, dyslipi- demia, which was defined as having at least one of the fol- lowing diagnoses: 1) hypertriglyceridemia; 2) hyperlipi- demia; or 3) hypercholesterolemia, was also not associat- ed with the risk of ATE in patients with cancer (SHR=1.5, 0.7-3.2; P=0.302). Treatment with lipid lowering agents (SHR=2.9, 1.5-5.3; P<0.001) or platelet aggregation inhibitors (SHR=5.0, 2.8-8.8; P<0.001) at study entry was associated with ATE occurrence. Cancer stage was not associated with an increased risk of ATE occurrence (SHR=0.7, 0.4-1.5; P=0.398). Lung cancer (SHR=2.3, 1.2- 4.2; P=0.009), and kidney cancer (SHR=3.8, 1.4-10.5; P=0.012) were associated with an increased risk of ATE. Cumulative incidences of ATE separated by cancer type are shown in Figure 3. In multivariable competing risk regression analyses, age [adjusted (adj.) SHR per 10 year increase=1.4, 95%CI: 1.2-1.7; P<0.001], male sex (adj. SHR=2.6, 1.3-5.2; P=0.006), and smoking (adj. SHR=2.1, 1.1-3.9; P=0.026) emerged as independently associated with the risk of ATE in patients with cancer when correct- ed for each other. After correction for age, male sex, and smoking, the association between hypertension (adj. SHR=2.4, 1.3-4.5; P=0.005), a known arterial cardiovascu- lar disease (adj. SHR=2.6, 1.3-5.3; P=0.007), treatment with lipid lowering agents (adj. SHR=2.2, 1.2-4.4; P=0.013), and the use of platelet aggregation inhibitors (adj. SHR=3.7, 2.1-6.7; P<0.001) at study entry and ATE remained statistically significant. Diabetes did not reach statistical significance in this multivariable analysis (adj. SHR=1.8, 0.9-3.5; P=0.093). Furthermore, the association between ATE and kidney cancer prevailed (adj. SHR=3.7, 1.3-10.6; P=0.016), whereas it did not for lung cancer (adj.
SHR=1.6, 0.8-3.4; P=0.193). None of the 276 patients with breast cancer developed ATE during follow up (crude risk=0.0%). In contrast, 48 ATE events occurred in the 1604 patients with other tumor entities (crude risk=3.0%), for an absolute risk difference of 3.0% (95%CI: 1.0-5.0; P=0.004). However, breast cancer patients were signifi- cantly younger than patients with other tumors (median age 59 vs. 62 years; P<0.001). Nonetheless, breast cancer remained associated with a lower risk of ATE even after adjusting for age (adjusted absolute risk difference=2.8%, 95%CI: 0.7-4; P=0.007), and also after exclusion of male patients and adjustment for age (adjusted absolute risk dif- ference=1.7%, 95%CI: 0.1-3.3; P=0.035).
We also investigated the cumulative impact of cardio- vascular risk factors on ATE risk in patients with cancer (Figure 4). We assigned one point for each of the following cardiovascular risk factors: hypertension, diabetes, known arterial cardiovascular disease, and dyslipidemia. Assuming a linear relationship between the number of risk factors and ATE risk, the SHR was 1.8 (1.4-2.2; P<0.001) per point increase. This association prevailed after adjustment for age and sex (SHR=1.6, 1.2-2.0; P=0.001). The 2-year cumulative incidence of ATE in patients with 0, 1, 2, 3, and 4 points was 1.4% (0.8-2.3), 2.7% (1.5-4.3), 5.8% (3.3-9.3), 5.6% (1.8-12.7), and 12.5% (2.1-32.8), respectively.
Association between ATE and survival of patients with cancer
The 3-, 6-, 12-, and 24-month overall survival estimates of the study cohort were 94.0% (95%CI: 92.8-95.0), 87.5% (85.9-88.9), 74.8% (72.7-76.7), and 57.9% (55.5- 60.2), respectively. In multistate modeling the occurrence of ATE was associated with a 3.2-fold relative increase in the risk of death from any cause [hazard ratio (HR)=3.2, 95%CI: 2.2-4.8; P<0.001). This association prevailed after adjusting for age (adj. HR=2.9, 2.0-4; P<0.001), as well as age and lung cancer as an indicator for a cancer type with poor prognosis (adj. HR=2.5, 1.7-3.7; P<0.001). In a land-
Figure 1. Cumulative incidence of arterial thromboembolism (ATE) in patients with cancer. For estima- tion we used a competing risk cumulative incidence estimator. Venous thromboembolism (VTE) and death-from-any-cause were considered as competing risk events. The dashed line represents 95% confidence bands.
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haematologica | 2018; 103(9)