Erythropoietin Stimulating Agents and Risk of Cardiovascular Events in Older Patients with Myelodysplastic Syndromes

Introduction:

Since the widespread adoption of Erythropoietin-Stimulating Agents (ESA) to ameliorate anemia in Myelodysplastic Syndromes (MDS), several studies demonstrated their safety with regards of venous thrombosis, but it is not clear whether ESA are associated with increases risk of ischemic cardiovascular disease (CVD) in MDS, as they are in other scenarios as solid tumor or kidney disease). We previously demonstrated that MDS is associated with increased risk of CVD in older adults from SEER-Medicare. Here, we examined if the use of ESA was associated with CVD in patients with MDS.

Methods:

We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare, using published methods. We abstracted age, sex, race/ethnicity, rurality, socioeconomic quintile, marital status, geographic region, and baseline CVD risk factors including hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS risk was defined using a validated claim-based risk score (SMMRS), including histology codes. Transfusion burden and use of hypomethylating agents (HMA), lenalidomide, or ESA were defined as time-varying variables from HCPCS codes and prescription records. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke after MDS diagnosis. Subjects with an acute CVD event within 1 year before MDS diagnosis were excluded. We controlled for confounding using 2 complementary analytic approaches. First, we determined the association between ESA use and CVD using propensity score adjusted cause-specific Cox hazard models with death from any cause as a competing risk. Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month ESA treatment window and a control period of 6 months prior to the incident event.

Results:

We analyzed a total of 14,102 patients with MDS which met study criteria. The study cohort had a median age of 82 years (IQR 77 - 86) and was predominantly male (53.8%) and non-Hispanic white (88.6%). Rurality (13.8%) and low socioeconomic status (13.4%) were represented. Pre-existing CVD and prevalence of CVD risk factors at time of MDS diagnosis were common, with estimated cardiovascular risk being low, intermediate, and high in 11.1%, 32.3%, and 56.6% of subjects, respectively. SMMRS risk was low, intermediate-1, intermediate-2, and high in 26.6%, 25.2%, 25.4%, and 22.8%, respectively, and 28.6% were transfusion dependent. ESA use was documented in 23.7%. A total of 2,874 (20.4%) subjects had an ischemic CVD event at any time in follow-up, with cumulative incidences of MI and ischemic stroke being 11.3% and 10.6%, respectively. The propensity score (PS) for conditional probability of ESA utilization included demographic variables, CVD risk factors, MDS risk scores and transfusion dependence, and the PS model adequately predicted ESA use (AUC 0.77). Cause-specific regression with death as competing risk, adjusted for PS and other MDS treatments (HMA and lenalidomide), showed no association between ESA and the risk of MI (adjusted hazard ratio [aHR]=0.86, 95% confidence interval [95%CI] 0.67 - 1.11), ischemic stroke (aHR = 1.07, 95%CI 0.87 - 1.33), or composite CVD (aHR = 0.97, 0.82 - 1.15). Adjusting for exposure to other MDS therapies, conditional logistic regression in the case-crossover analysis showed the odds ratio (OR) for ESA did not vary between event and control period and was not associated with MI (OR = 1.01, 95%CI 0.51 - 2.01), ischemic stroke (OR = 1.63, 95%CI 0.87 - 3.03), or composite CVD (OR = 1.26, 0.83 - 1.91).

Conclusions:

Few studies have previously investigated the safety of ESA therapy in MDS in terms of increased risk of ischemic CVD despite increasing interest on cardiovascular outcomes in MDS. In this observational study an older Medicare population with high baseline cardiovascular risk, we demonstrate that use of ESA is not associated with incident CVD events in patients with MDS. The lack of an association provides evidence of that ESA are potentially safe in MDS while the high burden of CVD highlights the need for therapeutic strategies targeting cardiovascular health.