Incidence and Risk Factors of Arterial Thromboembolism in Non-Small Cell Lung Cancer
Authors: Leader Avi , Icht Oded , Batat Erez , Rozovski Uri , Joseph Lilach , Shochat Tzippy , Goldstein Daniel A , Dudnik Elizabeth , Brenner Baruch , Raanani Pia , Spectre Galia , Ariel Hammerman , Zer Alona 
Published: November 2019

Introduction
It is well established that patients with advanced non-small cell lung cancer (NSCLC) have an increased risk of venous thromboembolism (VTE). VTE risk in cancer outpatients can be stratified using risk scores such as the Khorana score. Recently, studies have also shown an increased risk of arterial thromboembolism (ATE) in cancer patients, especially from 6 months prior cancer diagnosis until 12 months after (Navi B et al, JACC 2017; Navi B et al, Blood 2018). Importantly, lung cancer (LC) emerged as a high risk group in some studies. It is unknown what the risk factors of ATE in LC are, and whether ALK-rearrangement is a risk factor, as with VTE (Zer A, Clin Lung Cancer 2017).
Objectives: 1) Evaluate the incidence of NSCLC-associated ATE; 2) Determine risk factors for NSCLC-associated ATE; 3) Compare ATE and VTE incidence and risk factors in NSCLC.
Methods: A historical population-based cohort study was performed utilizing the Clalit Health Services (CHS) database. CHS is both a healthcare payer and provider, covering &gt; 50% of the Israeli population, with &lt;1%/year turnover. CHS individual patient data are recorded in a centralized electronic database. The current study included all CHS patients diagnosed with NSCLC between 1/2012-6/2019. Patients were indexed 6 months prior NSCLC and were followed for 18 months or until death or June 30th 2019, whatever came first. Demographics, cardiovascular (CV) risk factors and cancer-related data were extracted at NSCLC diagnosis. Patients with ≥1 ALK-inhibitor (crizotinib or alectinib) prescriptions were classified as ALK-LC, since these medications require pre-authorization, granted only in ALK-LC.
The primary outcome was first cancer-associated ATE, defined as a hospital admission with a primary diagnosis of acute myocardial infarction or stroke within 18 months of study index (i.e. from 6 months prior NSCLC diagnosis until 12 months after), using ICD-9 codes. Cancer-associated VTE (within the above timeframe) was a secondary outcome, using codes for deep vein thrombosis or pulmonary embolism. The cumulative incidence of each outcome [95% CI] at 18 months was calculated with death as a competing risk. Associations between preselected baseline variables and outcomes were determined using multivariate cox regression. The Fine & Gray model incorporated the competing risk of death in all analyses.
Results: 4752 NSCLC patients were included. Patient characteristics are shown in Table 1, stratified by ATE during follow up. 172 (3.6%) were classified as ALK-LC and 1308 (27.5%) had prior cerebrovascular or cardiovascular (CV) disease. At 18 months, 3004 (63.2%) were alive without ATE, 1637 died (34.4%) and 111 had an ATE (2.34%). Figure 1 shows the cumulative incidence of ATE, which was 1% [95% CI: 0.76-1.3%] at 12 months and 3% [2.57-3.66%] at 18 months. The corresponding VTE cumulative incidences were 7.91% [7.13-8.77] and 10.11% [9.28-11.02%]. Table 2 shows a multivariate cox regression analysis of associations between baseline variables and ATE or VTE.
Conclusions:
ATE is a clinically relevant problem in newly-diagnosed NSCLC patients, especially in the year following diagnosis, in males (2.9%) and patients with CV disease (4.3%; HR 2.36). Accordingly, increased awareness in high risk patients is warranted. VTE occurs 4-5 times more than ATE in NSCLC and is associated with different factors. While ALK-rearrangement appears to be a risk factor for VTE, more ATE events and a larger sample size are needed to rule out an association between ALK-rearrangement and ATE. The long-term burden of ATE in this cohort is currently under analysis and being compared to a non-NSCLC cancer population.

Disclosures
Spectre: Pfizer: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boeringer ingelheim: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees.