Supplementary Material for: Mortality and Cardiovascular Morbidity Associated with Haemoglobin Levels: A Pooled Analysis of Randomised Controlled Trials

Background/Aims: Several randomised controlled trials
(RCTs) have raised concerns about potential harm associated with
erythropoiesis-stimulating agents (ESAs) in chronic kidney disease
patients, especially when haemoglobin (Hb) levels above 13 g/dl were
targeted. We report the relationship between Hb levels and outcomes in
the methoxy polyethylene glycol-epoetin beta RCT programme. Methods:
We assessed the association between Hb and a composite end point, as
well as its components [all-cause mortality, myocardial infarction (MI)
or cerebrovascular events (CVE)], in multiple post hoc analyses of 9
prospective RCTs (3,405 chronic kidney disease patients). Mean Hb levels
over time and deviation from target were analysed using a Cox
regression model. Time-adjusted average Hb, deviation from target, the
last Hb, Hb slope and within-patient Hb variability preceding an event
were analysed using a time-dependent Cox model. Hazard ratios and 95%
confidence intervals were calculated. Results: Average Hb
<10 g/dl, decrease from stable baseline Hb >1 g/dl, last Hb <10
g/dl, Hb decline >1.5 g/dl/4 weeks and increased Hb variability were
associated with a higher risk of the composite end point and all-cause
mortality. An increased risk for CVE and MI was found with a last Hb
<10 g/dl and with a decrease from baseline >1 g/dl in the
preceding month. Conclusion: In multiple analyses from a
large programme of prospective clinical trials of ESA treatment, risk of
all-cause mortality and cardiovascular morbidity risk was consistently
higher at Hb <10 g/dl and in patients whose Hb fell below target.