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Policy changes and impact rises: Erythropoietin Payment Policy on Cardiovascular Outcomes of Peritoneal Dialysis Patients CURRENT

The by Taiwan National Health Insurance (NHI) system provided a natural experimental venue to examine whether cardiovascular risk differs while keeping hematocrit (Hct) below 30% or over 30%. This study intended to analyze the impact of loosening erythropoietin payment criteria for PD patients on their cardiovascular outcomes. Methods Two cohorts of incident PD patients before and after the relaxation of NHI’s erythropoietin payment criteria were identified as Cohort 1 and Cohort 2, respectively, and further matched by propensity scores and then followed up for cardiovascular events. There were 1,759 patients in Cohort 1 and 2,981 patients in Cohort 2. After propensity score matching, 1,754 subjects were selected from each cohort. The outcome measures were cardiovascular events and were analyzed through Cox regressions.

2 Abstract Background and Purposes The change in reimbursement policy of erythropoietin application to peritoneal dialysis (PD) patients by Taiwan National Health Insurance (NHI) system provided a natural experimental venue to examine whether cardiovascular risk differs while keeping hematocrit (Hct) below 30% or over 30%. This study intended to analyze the impact of loosening erythropoietin payment criteria for PD patients on their cardiovascular outcomes.

Methods
Two cohorts of incident PD patients before and after the relaxation of NHI's erythropoietin payment criteria were identified as Cohort 1 and Cohort 2, respectively, and further matched by propensity scores and then followed up for cardiovascular events. There were 1,759 patients in Cohort 1 and 2,981 patients in Cohort 2. After propensity score matching, 1,754 subjects were selected from each cohort. The outcome measures were cardiovascular events and were analyzed through Cox regressions.

Findings and Conclusion
For the composite cardiovascular endpoint, Cohort 2 patients had significantly lower risk than Cohort 1. The risk reduction was observed only in diabetic patients. After loosening erythropoietin payment criteria, less cardiovascular risks were observed, particularly for diabetic patients. It is concluded that for diabetic PD patients, maintaining a Hct level higher than 30% is crucial for reducing the cardiovascular risk.

Introduction
Erythropoietin is a major regulatory hormone of erythrocyte production that is produced from kidney.
For chronic kidney disease (CKD) patients, erythropoietin production from kidney decreases. In addition, shorten erythrocyte survival and chronic inflammatory status contribute to anemia.
Administration of exogenous erythropoietin for CKD patients, especially who receive dialysis, is the standard treatment of anemia.
In the past, with the use of erythropoietin, the practice tended to increase hematocrit (Hct) target to 3 "normal level" (i.e., 40.5% for male and 36% for female). However, more recent large, randomized outcome trials [1][2][3] show that elevated Hct to more than 36% compared to 30-36% is associated with higher cardiovascular risk for CKD patients. These findings led to the limitation of Hct upper bound. However, what is an optimal Hct target is still debatable. The recommendations from National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative [4] and Taiwan's nephrology professionals [5] both suggest keeping the level of Hct between 33 and 36%.
The public statement of the European Medical Agency in 2007 concluded that a target Hct range is 30-36% [6]. U.S. Food and Drug Administration recommended to reduce or interrupt erythropoietin if hematocrit approaches or exceeds 33% for dialysis patients in 2011 safety announcement [7]. The recommendation from Kidney Disease Improving Global Outcome in 2012 was to maintain Hct below 34.5% [8]. Accordingly, a range from 30-36% might be considered the least bandwidth to accommodate these recommendations.
In order to reduce the cost of providing end-stage renal disease (ESRD) treatments while maintaining or preferably improving patient care, the U.S. Center for Medicare and Medicaid (CMS) recently implemented the ESRD Prospective Payment System, known as the "expanded ESRD bundle" on January 1, 2011 [9]. In response to a quality incentive program (QIP) required by the Congress, two quality measures of anemia management were established to identify poor performance, patients with a hemoglobin (Hb) level less than 10 g/dL and a Hb level greater than 12 g/dL. [9] These Hb levels are equivalent to the levels of Hct less than 30% and beyond 36% since conversion between Hb and Hct is that 1 g/dL in Hb is equal to 3% in Hct. However, the CMS retired the Hb less than 10 g/dL measure in its later QIP requirements [10,11]. The dialysis facilities would receive no penalties for Hb levels lower than 10 g/dL, and patients with Hb level lower than 10 g/dL might be spotted more often in the future. The elimination of penalties for lower bound of Hb levels has indeed removed the financial incentives to provide costly erythropoietin and raised some concerns about patient care [12].
Nevertheless, whether patients with a Hb level lower than 10 g/dL or Hct level lower than 30% will be associated with lower or higher risk of adverse events will be a logical inquiry warranted for investigation.

4
Limited studies had reported cardiovascular events or mortality associated with Hct levels lower than 30%. By comparing dialysis patients maintaining Hct below 30% to those with 30-36%, no significant difference was found [13][14][15]. While more recent studies [1][2][3] comparing the risk of pushing Hct levels over 36% with that of between 30-36% had a large sample size of more than twelve hundreds with a follow-up period more than fourteen months, these early studies had a relatively small sample size of 152 patients or less and a short follow-up period of six to nine months. Moreover, their research emphases were not specifically designed and dedicated to this research issue. Recently, the change in reimbursement policy of erythropoietin application to peritoneal dialysis patients by Taiwan National Health Insurance (NHI) system provided a natural experimental venue for examining this clinical research issue.
The incidence and prevalence rates of ESRD in Taiwan have been ranked at the top internationally since 2001 [16], and this has put immense burdens of caring and funding for ESRD patients on its NHI system. The low renal transplant rate, less than 1% annually [17] results in nearly all of Taiwan's ESRD patients on dialysis treatments to prolong their lives, and more than 93.5% undergo hemodialysis treatments in 2004 [18]. In order to increase peritoneal dialysis (PD) utilization, Subsequent to the introduction of the erythropoietin criteria relaxation, the Hct levels for both prevalent and incident PD patients were observed an increase from 28-29% to 30-31%. The [19][20][21] main purpose of our study is to analyze the impact of loosening erythropoietin application criteria for PD patients to understand if less cardiovascular events may occur when maintaining Hct between 30-31% as compared to 28-29%.

2.1 Ethics statement
Data resource was based on the National Health Insurance Research Database (NHIRD). [22] Researchers can access NHIRD data after ethical and scientific review processes. Prior to applying, the study has been approved by the ethical review board of National Taiwan University Hospital (NTUH-REC No.201406018W). There are 27 institutional review boards capable of issuing approvals, and all are supervised and regulated by the Taiwan Ministry of Health and Welfare. To protect individuals' confidentiality, all datasets in the Data Science Centre are pseudonymized. Personal ID, birth date, and names are encrypted, and this de-identification process was approved by an independent third party. We performed data analysis in the branches of the Data Science Centre. The analyzed results were also examined by the Data Science Centre before exporting. The Institutional Review Board had verified the anonymity of data analysis performed in this study. All research procedures followed the directives of the Declaration of Helsinki.

Study Design
This is an observational study to compare the cardiovascular events of two cohorts of the newly treated (incident) PD patients before and after the relaxation of NHI's erythropoietin payment criteria.
Cohort 1 included dialysis patients who started to receive maintenance PD treatments during a specified period of 28 months before the relaxation of NHI's erythropoietin payment criteria. To ensure an adequate observation period, this cohort was followed up for additional 14 months after the month of the cohort's last patient enrollment. Cohort 2 included incident dialysis patients who started to receive maintenance PD treatments within a 28-month time interval after the relaxation of NHI's erythropoietin payment criteria. Additional 14-month follow-up observations were also made after the month of the cohort's last patient enrollment. We set a 6-month time lag between the initiation of relaxing erythropoietin payment criteria and the time that the first enrollment of patients in Cohort 2 in order to accommodate possible adaptation of physician prescribing practices to the new policy.
Because the potential imbalances in the distributions of many measured and unmeasured baseline covariates exist between the two cohorts, researchers have to employ the propensity score (PS) analysis, developed by Rosenbaum et al. [23] Thus, the influence of any potential enrollment biases 6 between these two cohorts was attenuated through a PS matching approach and identification of patients with comparable characteristics in the two cohorts. This study defined PS as the probability of a patient having experienced a cardiovascular event. Patients in Cohort 1 and 2 were matched with PS scores estimated by age, sex and a comorbidity index with the nearest neighbor-greedy approach.
The comorbidity index was developed by Liu et al. [24] specifically for U.S. Medicare dialysis population and had been validated in Taiwanese dialysis patients [25].
After matching with PS, patients were followed up till experiencing either one of the following three Finally, in addition to administering erythropoietin, because the patient Hct level could also be affected by the usages of iron and red-cell transfusion, iron and red-cell transfusion for patients in the two cohorts were examined to determine if differences in the usages of iron and red-cell transfusion existed between the two cohorts.

Patient selection
Incident PD patients were identified from the claim data of entire beneficiaries covered by

Statistical Analyses
The primary outcome measure is a composite cardiovascular endpoint, defined as myocardial infarction, heart failure hospitalization, stroke or death. Myocardial infarction was defined by in both cohorts were followed up to the occurrence of myocardial infarction, heart failure hospitalization, stroke or death, whichever occurred earlier. Secondary outcomes include myocardial infarction, heart failure hospitalization, stroke and death. Each patient was followed up to the occurrence of each cardiovascular event. Data on patients who did not have an event were censored 8 at the data cut-off point or transition to hemodialysis, whichever occurred earlier.
The selection and analyses of primary and secondary endpoints of cardiovascular risk in our study were the same as previous large-scale studies [1][2][3]. In addition to cardiovascular events, death was also considered an important clinical endpoint in the evaluation of cardiovascular risk because reducing mortality is an ultimate goal of reducing cardiovascular risk. Using a composite primary endpoint with each component evaluated as the secondary endpoint analysis is commonly adopted by many clinicians [2,3]  Cox proportional hazards model was employed to estimate the cardiovascular risk between the two cohorts. Estimated hazard ratios (HRs) for Cohort 2 relative to Cohort 1 and 95% confidence intervals (CIs) were calculated. In order to obtain more insightful results, patients were further stratified by diabetic status. Cox regression analyses for diabetic and non-diabetic patients were performed separately. All analyses were performed using SAS software, version 9.1. Table 1     patients, significant risk reduction was found not only in composite cardiovascular endpoint, but also in secondary endpoints including stroke and heart failure hospitalization. Since similar percentages of patients in matched Cohort 1 and Cohort 2 received oral and intravenous iron, and the oral and intravenous iron dosage was also comparable between these two cohorts, it is reasonable to assume that higher Hct in matched Cohort 2 might result from higher erythropoietin dosage. And the reduction in cardiovascular risk in matched Cohort 2 may be related to higher erythropoietin dosage and adequate Hct range.

Results
While the findings demonstrating that pushing Hct to more than 36% compared to 30-36% tend to increase cardiovascular risk [1][2][3]7] have been widely accepted and recommended, lack of sufficient evidences to present whether there exist differences in cardiovascular risk by maintaining Hct levels below 30% relative to 30-36%. A few studies with a small sample and a short follow-up period showed no significant difference in cardiovascular risk or mortality for patients maintaining Hct below 30% compared to those maintaining 30-36%. [13][14][15] Thus, these limitations prevent investigators to detect the potential difference in cardiovascular risk. On the contrary, our national study showed that lower cardiovascular risk is associated with increasing Hct from 28-29% to 30-31% for incident PD patients. The number of subjects in our study was 3508, and the median follow-up duration was 23 months. The sample size and follow up duration were comparable to those more recent large-scale studies [1][2][3], where the sample sizes were between 1265 and 4038 and the median follow-up durations between 14 and 29 months.
Although no Hct data reported in the NHI beneficiaries claim database had led to no direct
In our study, the median erythropoietin dosage in Cohort 2 (12,739U) was significantly higher than that in Cohort 1 (10,588U), that is, more than 20% increase after loosening the erythropoietin reimbursement criteria. Given that the usages of iron supplements (both oral and intravenous) and red-cell transfusions were comparable in both cohorts, increased erythropoietin usage supports the assumption that the Hct of incident PD patients also increased after loosening the erythropoietin payment criteria.
Because the reduction in cardiovascular risk was observed only in diabetic patients, the difference in cardiovascular event risk reduction between diabetic and non-diabetic patients might not be the

Conclusions
While the findings demonstrating that pushing Hct to more than 36% compared to 30-36% tend to increase cardiovascular risk [1][2][3]7] have been widely accepted and recommended, lack of sufficient evidences to present whether there exist differences in cardiovascular risk by maintaining Hct levels below 30% relative to 30-36%. Our study provided a natural experiment to answer this question.
Matched Cohort 1 and Cohort 2 had comparable baseline characteristics. This suggests that both cohorts had similar cardiovascular risk factors. After loosening erythropoietin payment criteria, significant lower risk of cardiovascular events, stroke and heart failure hospitalization was observed in matched Cohort 2, in particular those with diabetes mellitus. The risk reduction may be related to 16 higher erythropoietin dosage and adequate Hct range. Further research is needed to investigate why PD patients with DM are more sensible to the increase in erythropoietin dosage and Hct levels. Our findings support that, for PD patients with DM, maintaining a Hct level higher than 30% is crucial for reducing cardiovascular risk. This provides implication for policy makers how to use healthcare resources cost-effectively while reducing potential cardiovascular risk for PD patients.

Ethics Approval and Consent to Participate
The study has been approved by the ethical review board of National Taiwan University Hospital