Effect of Erythropoietin Stimulating Agents on Cardiovascular Events in Chronic Kidney Disease Patients on Hemodialysis

Objectives: Patients with chronic kidney disease (CKD) develop anemia which is treated with erythropoietin-stimulating agents (ESAs). However, ESAs do not reduce the risk of cardiovascular mortality. Furthermore, this is unclear whether ESAs therapy has any association with adverse cardiovascular events. Methods: After an informed consent 275 male and female patients, between ages 35 to 75 years, with CKD stage V on ESAs undergoing twice weekly hemodialysis were enrolled. The dose of ESAs was calculated according to weight as 50mg/kg with target hemoglobin being 11 – 12 g/dl. Dose adjustments were made in the patients who failed to achieve target hemoglobin. The patients were followed for a year with the primary end point being new evidence of acute myocardial infarction (MI) diagnosed through ECG or echocardiography. Safety outcomes included stroke or death. Results: The data was entered and analyzed in Statistical Package for Social Sciences (SPSS) version 18. 1 Senior Registrar, Department of North Medicine Mayo Hospital, Lahore 2 Assistant Professor of Medicine, KEMU/ Mayo Hospital, Lahore 3 Medical Officer, Dept of Medicine, Mayo Hospital, Lahore 4 Professor of Medicine, KEMU/ Mayo Hospital, Lahore 5 Provincial Data Analyst Date of Submission: 01-02-2017 Date of Acceptance for Publication: 04-05-2017 Conflict of Interest: None Funding Source: None


Introduction
Chronic kidney disease (CKD), caused by diabetes mellitus, hypertension and other diseases, is characterized by a progressive decline in the estimated glomerular filtration rate (eGFR); the diagnosis is confirmed via a reduced GFR for a minimum of 3 months often accompanied by albuminuria. 1,2][4] The decrease in the production of erythropoietin, caused by renal insufficiency and the antiproliferative effects of the uremic toxins being accumulated in the body, results in anemia of chronic kidney disease. 56][7][8] The present study was designed to find out the risk of adverse cardiovascular events associated with ESAs therapy.

Patients and Methods
During this descriptive case series study, CKD stage V patients, aged between 35 -75 years (both males and females) who were receiving ESA therapy for partial correction of hemoglobin, were enrolled after an informed consent.These patients were undergoing hemodialysis twice a week (each session lasting for 4 hours) for a period of less than 1 year.
The patients who had been on maintenance hemodialysis for a longer duration than a year, had a known coronary artery disease as evidenced by Coronary Angiography, previous episode of Myocardial Infarction established through fresh and previous ECG recordings or with the help of echocardiography or a known case of Left Bundle Branch Block (LBBB) were excluded.Pregnancy and Diabetes Mellitus were considered as additional criteria for excluding the patients from our study.
Patients were given human recombinant erythropoietin intravenously twice a week after every dialysis.The dose was initiated according to the weight as 50 mg/kg to achieve partial correction of hemoglobin however dose adjustments were made in those cases who failed to achieve target hemoglobin as per KDO-QI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease by National Kidney Foundation.Target hemoglobin was set at 11 -12 g/dl with a monthly increase in hemoglobin between 0.66 to 1 g/dl.The dose was reduced in cases where the rise in hemoglobin was beyond the monthly target.
The patients were routinely investigated for hemoglobin level at monthly interval and dose adjustments were made where necessary.Electrocardiogram (ECG) was routinely recorded at specified monthly intervals and at random intervals to record any active or recent ischemic changes.Echocardiography was routinely performed at 3 monthly intervals to look for signs of new onset segmental wall motion abnormalities.
The patients were followed up for a year with the primary end point being new evidence of acute myocardial infarction (MI).The secondary end point was evidence of echocardiographic changes of new segmental wall motion abnormality, intolerance to ESA therapy or drug related side effects leading to discontinuation of therapy.Safety outcomes included evidence of new episode of stroke, pericarditis or mortality.

Discussion
The incidence of anemia of chronic disease or iron deficiency anemia is high considering the fact that these patients are erythropoietin or iron deficient.The landmark study by Obrador et al showed that among predialysis patients, 68% of those with advanced chronic kidney disease who required renal replacement therapy had a hematocrit less than 30 mg/dL; of these, 51% of patients had a hematocrit less than 28 mg/dL. 9his warrants the use of ESA in most of these patients for partial correction of hemoglobin. 10,11he descriptive case series of 275 patients showed that 164 (59.6%) patients were males and 111 (40.4%) were females.The patients who were enrolled had their ages varying from 35 to 75 years with the mean age of the patients being 51.52 with the standard deviation of ± 5.73.Only 52 (18.9%) patients were reported with Myocardial Infarction and 223 (81.1%) patients did not have any evidence of Myocardial Infarction.It was also observed that out of 52 patients who had Myocardial Infarction, 37 (71%) were males and 15 (29%) patients were female.It means 18.9% of the total study population had myocardial infarction while receiving erythropoietin stimulating agents during a one year follow up period with a higher risk of myocardial infarction in male patients.
Literature review shows that The Normal Hematocrit Study tested the hypothesis that normalization of the hematocrit as compared to partial correction would improve cardiovascular outcomes.The Normal Hematocrit Study enrolled a total of 1233 patients between October 27, 1993, and March 31, 1996; 618 were assigned to the normal-hematocrit group, and 615 to the low-hematocrit group.After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among the patients in the low-hematocrit group. 12hen compared with our study, the results show a relatively similar trend of myocardial infarction albeit with a higher incidence since we recorded 52 incidences of myocardial infarction with 37 of those being males and 15 females (71% and 29% respectively).4][15] Regular screening protocols need to be established for this patient population with a careful selection of patients for these treatments. 16 limitation of our study was that we did not rule out other causes of coronary artery disease in the patients who were reported to have myocardial infarction during the observation period like atheroscleorsis caused by dyslipidemia or advanced atherosclerosis due to any cause. 17,18

Conclusion
We found that the use of ESA in end stage renal disease patients who are on regular maintenance hemodialysis is adversely related with myocardial infarction.The use of ESA should therefore be carefully monitored to avoid potentially fatal outcomes.Whether this is the only contributing factor in this population or there are other factors related to this finding should be further investigated through a multi-centre study that includes other causes of myocardial infarction as part of the study design.