Use of Statins, Survival and Incidence of Thrombosis Among Older Adults with Essential Thrombocythemia: A Population-Based Study
Authors: Podoltsev Nikolai , Zhu Mengxin , Wang Rong , Zeidan Amer M. , Wang Xiaoyi , Huntington Scott F , Giri Smith , Davidoff Amy J. , Gore Steven D. , Ma Xiaomei 
Published: October 2019

Abstract
Introduction: Studies of various solid tumors have suggested a potential for statins to modify cancer risks/outcomes. Statins can induce apoptosis and inhibit JAK2-V617F-dependent cell growth in vitro, as well as inhibit erythropoietin-independent erythroid colony formation of primary cells from patients with myeloproliferative neoplasms. JAK2-V617F mutation occurs in about 60% of patients with essential thrombocythemia (ET). It is unknown whether the use of statins influences the outcomes of ET patients.
Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we assembled a population-based cohort of older adults who were diagnosed with ET during 2007-2013 and fulfilled the following eligibility criteria: 1) aged 66-99 years at diagnosis; 2) had continuous Medicare Parts A and B coverage and not enrolled in health maintenance organizations from 12 months before diagnosis to death or the end of study (12/31/2014), whichever was earlier (i.e., the end of follow up); and 3) continuously enrolled in Medicare Part D from 6 months before diagnosis to end of follow up. Patients were identified as statin users if they had any prescription for statins (rosuvastatin, atorvastatin, pitavastatin, simvastatin, lovastatin, pravastatin, or fluvastatin) in Part D claims from their ET diagnosis to end of follow up. For both statins and hydroxyurea (HU, a commonly used treatment for ET), percentage of days covered (PDC) was defined as the percentage of days from diagnosis to the end of follow-up covered by respective prescriptions. We further classifed statins as lipophilic (atorvastatin, lovastatin, simvastatin, pitavastatin and fluvastatin) or hydrophilic (pravastatin and rosuvastatin).
Log-rank tests were used to compare Kaplan-Meier (K-M) curves between statin users and non-users with regard to overall survival and risk of thrombosis after ET diagnosis. Multivariate Cox proportional hazards models were used to assess the relationship between statin PDC and overall survival. Multivariate competing risk models with death as a competing risk were utilized to evaluate the relationship between statin PDC and risk of thrombosis after ET diagnosis. All multivariate models adjusted for HU PDC, age, sex, race, state buy-in, influenza vaccination 12 months prior to ET diagnosis (as a marker for healthcare access), disability status, modified Elixhauser score for comorbidities, and previous thrombosis. All statistical tests were two-sided and conducted with SAS (Version 9.4).
Results: Of the 876 ET patients included in this study (median age = 78 years, interquartile range [IQR]: 72-84 years), a majority were female (67.8%) and white (86.4%) (Table 1). Approximately half of the patients (n=412, 50.5 %) used statins after ET diagnosis with a median statin PDC of 56% (IQR: 24%-87%). Of the 412 statin users, 75.8% (n=335) already used statins before ET diagnosis; 306, 76, and 60 patients used exclusively lipophilic statins, exclusively hydrophilic statins, and both types, respectively.
With a median follow-up of 2.79 years, 35.8% (n=158) of statin users and 48.2% (n=209) of non-users died; K-M curves showed that statin users (median: 6.01 years) had a significantly better overall survival than non-users (median: 4.00 years; Log rank test, p<.01) (Figure 1). Adjusting for covariates, every 10% of statin PDC after ET diagnosis was associated with a 14% lower risk of all-cause mortality (hazard ratio [HR]=0.86, 95% confidence interval [CI]: 0.82-0.89; p<.01). Increases in lipophilic and hydrophilic statin PDC had similarly positive effects on overall survival.
Thrombosis after diagnosis was recorded in 301 (34.4%) patients, including 230 arterial thromboses. The percentages of statin users and non-users who had thrombosis were similar (33.8% vs. 34.8%). Risk of thromosis was not significantly different between statin users and non-users based on Log-rank test (p=.27) or multivariate competing risk model (p=.68) (Figure 2). No association with thrombosis was observed in users of lipophilic or hydrophilic statins.
Sensitivity analyses that only included patients who started using statins after ET diagnosis revealed similar findings pertaining to both survival and thrombosis.
Conclusions: In this large population-based cohort study of older adults with ET, use of statins improved patient survival but did not have significant impact on incidence of thrombosis.

Disclosures
Podoltsev: CTI biopharma: Research Funding; Astellas Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Research Funding; Celator: Research Funding. Zeidan:Agios: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Huntington:Janssen: Consultancy; Celgene: Consultancy; Bayer: Consultancy. Davidoff:Celgene: Research Funding. Gore:Celgene: Consultancy, Research Funding. Ma:Celgene: Consultancy, Research Funding; Incyte: Consultancy.