The three key clinical trials which guide the current use of ESA therapy are CHOIR, CREATE and TREAT. Each of these trials assessed the optimal haemoglobin in patients with CKD stages III-V, and the associated cardiovascular outcomes of higher and lower haemoglobin targets. The trials are summarised below (click name to download paper):
The results of the Correction of Hemoglobin in Outcomes and Renal Insufficiency (CHOIR) trial were reported in 2006. This open-label randomised, controlled, clinical trial enrolled 1432 patients with anemia (all with haemoglobin below 11 g/dL at enrollment, and naïve to ESAs) and CKD III-IV (GFR between 15–50 mL/minute/1.73 m2), and compared cardiovascular and renal outcomes for two groups randomized to receive Epoetin Alfa to achieve mean haemoglobin of 11.3 g/dL (N = 717) versus 13.5 g/dL (N = 715).
The primary end point was the time to the composite of death, myocardial infarction, hospitalisation for congestive heart failure, or stroke. Secondary outcomes included the time to renal replacement therapy, hospitalisation for cardiovascular reasons or any other cause, and quality of life. Patients with uncontrolled hypertension, active gastrointestinal bleeding, iron overload, history of frequent red cell transfusions, refractory iron deficiency anemia, active malignancy, angina pectoris, or previous ESA treatment were excluded.
At baseline, patients in both groups were similar with respect to their demographics with few exceptions. All 1432 patients were included in the final analysis in an intention to treat model. Median followup was 16 months. At 3 months, a difference in haemoglobin values between the two arms were observed. Although the low haemoglobin group was largely able to achieve the pre-specified target haemoglobin (11.3g/dL), fewer patients in the high haemoglobin group were able to reach their target (13.5g/dL).
The trial was terminated early at the recommendation of the data and safety monitoring board after recording 125 adverse events in the higher haemoglobin group versus 97 events in the lower haemoglobin group (HR, 1.34; 95% confidence interval, 1.03–1.74; P = .03). These adverse events included death, myocardial infarction, stroke, and hospitalisation for congestive heart failure. The authors concluded that the likelihood of showing a benefit in the higher haemoglobin group was negligible. Interestingly, quality of life scores were similar among the two groups.
The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta trial (CREATE), was also published in 2006. It is a randomised controlled trial enrolling 603 patients to study the cardiovascular benefit of Epoetin Beta in patients with aneamia (Hb level 11–12.5 g/dL) with stages III-IV CKD (GFR 15–35 mL/minute/1.73 m2). Patients were randomly assigned to a target hameoglobin in the normal range (13–15 g/dL, n = 301) versus a sub-normal level (10.5–11.5 g/dL, n = 302).
The primary endpoint was a composite of eight cardiovascular events which included: sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, angina pectoris, or cardiac arrhythmia resulting in hospitalisation, and complication of peripheral vascular disease. Patients who were expected to require renal replacement therapy within six months, had advanced cardiovascular disease, were recently transfused, or had non-renal causes of anemia were excluded.
The majority of patients in the normal haemoglobin group received Epoietin beta (98%). In the sub-normal haemoglobin group, 32% received Epoietin Beta in year one, 52% in year two, and 76% in year three. At the end of study, the haemoglobin levels between the two groups differed by 1.5 g/dL.
Compared to the normal haemoglobin group, the sub-normal haemoglobin group did not experience significantly more cardiovascular events or decline in GFR. In total, 105 primary cardiovascular events occurred during the trial, 58 in the higher haemoglobin group versus 47 in the sub-normal haemoglobin (p = not significant). Time to initiation of dialysis after 18 months of the trial was significantly shorter among those treated to a normal haemoglobin (p = 0.03), and general health and physical function were significantly improved relative to the subnormal haemoglobin group (p = 0.003 and p < 0.001, respectively).