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E. Grilz et al.
scarce, we conducted a study to describe the incidence of ATE, explore clinical risk factors, and investigate the impact of ATE on mortality in patients with cancer.
Methods
Study design
This study was performed within the framework of the Vienna Cancer and Thrombosis Study (CATS), which started in 2003 at the Medical University of Vienna. CATS is a single-center prospec- tive observational cohort study, approved by the ethics committee (number: 126/2003, ethik-kom@meduniwien.ac.at), and conducted in accordance with the Declaration of Helsinki. Detailed information about the study design and procedures have been reported previ- ously.13 Briefly, adult patients (≥18 years) with a newly diagnosed malignancy or progression of disease after complete or partial remission were eligible for inclusion. Patients were not included if they had received radiotherapy or surgery within the last two weeks or chemotherapy within the last three months before study inclusion. Furthermore, all patients with a thromboembolic event within the last three months or an overt bacterial or viral infection within the last six weeks before study inclusion were excluded. Patients with an indication for long-term prophylactic or thera- peutic anticoagulation were excluded, but temporary treatment with low molecular heparin (e.g. for hospitalized patients) was allowed. Furthermore, patients on acetylsalicylic acid or other platelet inhibitors were not excluded.13,14 All patients gave their written informed consent and were prospectively followed for a maximum duration of two years, until the occurrence of VTE, loss of follow up, withdrawal of consent, or death.
Until October 2013, 2004 patients were included in this study. After re-evaluation of the inclusion and exclusion criteria, 124 patients had to be excluded, because: 1) they did not fulfill inclu- sion (n=35) or exclusion criteria (n=60); 2) no follow up was avail- able (n=20); 3) no material for laboratory analyses was available (n=7); or 4) patients withdrew consent (n=2). Thus, overall 1880 patients with active cancer between 17th October 2003 and 28th October 2013 were included in this analysis.
Outcome measurement
Venous thromboembolism is the pre-defined primary outcome of CATS. Data on ATE were collected as a comorbid condition during the observation time. To verify diagnosis of ATE, we com- piled data from: 1) the CATS database; 2) patients' follow-up let- ters; 3) telephone records with patients, their family members, treating oncologists/hemato-oncologists and general practitioners during follow up; 4) digital information systems of the General Hospital of Vienna and the Vienna Urban Health Care Providers; and 5) the Austrian death registry.
The primary end point of this analysis was objectively con- firmed symptomatic ATE, which was defined as a composite of acute myocardial infarction (ST-elevation myocardial infarction and non-ST-elevation myocardial infarction), peripheral arterial occlusion, if treated with an interventional procedure (i.e. a catheter-based or open surgical procedure to improve arterial blood flow in non-cardiac arteries, except the intracranial vessels), and ischemic stroke. Both minor (National Institute of Health Stroke Score ≤ 3) and major (National Institute of Health Stroke Score > 3) stroke were included.15,16 A panel of experts in cardiolo- gy, neurology, and vascular medicine adjudicated all events based on objective evidence. Objective evidence for diagnosis included: 1) computed tomography (CT); magnetic resonance imaging (MRI) and autopsy report for ischemic stroke; 2) Doppler-sonogra- phy, digital subtraction angiography, CT-angiography, and MR-
angiography for peripheral arterial occlusion; 3) electrocardiogra- phy, echocardiography (e.g. hypokinetic/akinetic and hypotrophic myocardial section without any other existing reason), cardiac biomarkers, identification of an intracoronary thrombus by angiography, and autopsy evidence for myocardial infarction. No routine screening for ATE was carried out during the study. Asymptomatic arterial thrombosis (e.g. incidentally detected stroke on restaging CT scans) was considered an event if it was considered clinically significant by members of the adjudication committee. In cases where objective diagnostic evidence based on imaging or lab results was missing, the adjudication committee decided on the basis of documented clinical evidence. The adjudi- cation committee also classified mortality into fatal ATE and death-from-any-cause-other-than-fatal-ATE, which was the sec- ondary end point.
Statistical analysis
Continuous variables were summarized as medians (25th-75th percentile), and count data as absolute frequencies (%). The reverse Kaplan-Meier method was used to estimate median fol- low-up time.17
The cumulative incidence of ATE was calculated using a com- peting risk estimator with 95% confidence intervals (95%CI).18 ATE incidences between groups were compared with Gray’s tests.19 We assume that cancer patients are not only at risk of ATE, but are also at risk of dying from cancer. If patients die from their underlying malignancy, the risk of ATE occurrence is instantly reduced to zero. Therefore, death represents a competing risk sce- nario.20,21 To address this issue, univariable and multivariable Fine & Gray competing risk regression models were used to analyze the subdistribution hazards of ATE.22 Overall survival was ana- lyzed with Kaplan-Meier estimators, and hazards of death were modeled with uni- and multivariable Cox models. VTE and death- from-any-cause-other-than-fatal-ATE were considered competing events in all statistical analyses concerning the primary end point.20 Relative risks of ATE between patients with breast cancer and other tumor types could not be estimated because the risk of ATE was 0.0% in breast cancer patients. Thus, modeling for this comparison was performed with a generalized linear model from the Bernoulli family with an identity link.23
To quantify the impact of ATE occurring during follow up on mortality, we used Cox models treating ATE as a time-dependent variable (controlling for immortal time bias), and performed a landmark analysis. In the time-dependent Cox model, one day of survival time was added in one patient who developed ATE and died on the same day.
Stata 14.0 (Stata Corp., Houston, TX, USA) and SPSS 24 (SPSS Inc., Chicago IL, USA) were used to perform all statistical analyses.
Results
Patients’ and follow-up characteristics
The study cohort included 1880 patients with a wide range of different cancer types (Table 1). The majority of patients (n=1385, 73.7%) had newly diagnosed cancer, while 495 (26.3%) patients had a progressive disease after complete or partial remission. The median follow-up time was 723 days [25th-75th percentile (Q1-Q3): 308-731, range: 1-731]. During the observation time 157 (8.4%) VTE events were observed and 754 (40.1%) patients died.
Risk of ATE in patients with cancer
Forty-eight (2.6%) patients developed ATE during the observation time. Among those patients, 19 (39.6%) non-
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haematologica | 2018; 103(9)