http://www.kidney-international.org & 2012 International Society of Nephrology see commentary on page 135 The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial Daniel W. Coyne1 1Washington University School of Medicine, Renal Division, St Louis, Missouri, USA o r i g i n a l a r t i c l e The Normal Hematocrit Trial (NHT) was the largest trial of epoetin randomizing 1265 hemodialysis patients with cardiac disease to lower (9–11 g/dl) or higher (13–15 g/dl) hemoglobin (Hgb), hypothesizing that higher Hgb would reduce mortality, and improve survival and quality of life. The trial was terminated early, and a 1998 publication reported that targeting higher hematocrit levels led to an insignificant increase in the primary end points (death or myocardial infarct), or risk ratio 1.3, 95% confidence interval (CI), 0.9–1.90, but the P-value was not given, and all-cause death risk was not reported. A higher target reportedly did not increase hospitalization rates, but did significantly improve the ‘physical function’ domain of quality of life. Comparing the 1996 Food and Drug Administration (FDA)-filed clinical trial report to the 1998 publication, however, found several discrepancies. Among these, the 1998 article reported interim trial results with only the adjusted CI but did not state that the unadjusted CIs were 99.912th percentile, and despite being a secondary end point, reported only the association of achieved Hgb with higher quality of life score. Randomization to the higher target had actually increased the risk for the primary end point (risk ratio 1.28, 95% CI ¼ 1.06–1.56; P ¼ 0.0112; 99.92% CI ¼ 0.92–1.78), the risk of death (risk ratio 1.27, 95% CI ¼ 1.04–1.54), non-access thrombotic events (P ¼ 0.041), and hospitalization rate (P ¼ 0.04), while ‘physical function’ did not improve (P ¼ 0.88). Hence, disclosure of these results in the 1998 publication or access to the FDA- filed report on the NHT in the late 1990s would likely have led to earlier concerns about epoetin safety and greater doubts about its benefits. Kidney International (2012) 82, 235–241; doi:10.1038/ki.2012.76; published online 21 March 2012 KEYWORDS: anemia; epoetin; hemodialysis; quality of life Correspondence: Daniel W. Coyne, Washington University School of Medicine, Renal Division, 660 S. Euclid Avenue, Campus Box 8129, St Louis, Missouri 63110, USA. E-mail: DCoyne@dom.wustl.edu Received 18 October 2011; revised 22 December 2011; accepted 3 January 2012; published online 21 March 2012 Kidney International (2012) 82, 235–241 There has been controversy over the risks and beneﬁts of erythropoietic-stimulating agent (ESA) therapy since the completion of the Normal Hematocrit Trial (NHT) in 1996 and its publication in 1998.1 The NHT remains the largest randomized trial of ESA in hemodialysis patients. It treated patients with clinical evidence of heart failure or ischemic heart disease with epoetin (an ESA) to a target hematocrit of 30±3% vs. 42±3%. Hematocrit was calculated by multi- plying the measured hemoglobin (Hgb) level by three. A majority of the US dialysis patients have ischemic heart disease or heart failure.2–4 Therefore, the NHT represented an important assessment of the risks and beneﬁts of higher Hgb for the majority of dialysis patients. The NHT was stopped early because of a trend toward increased deaths and nonfatal MI in the high-Hgb target arm.1 Although the NHT trial results demonstrated satisfac- tory outcomes with a Hgb target of 9–11 g/dl, subsequent nephrology anemia guidelines in 1997 and 2001 recom- mended a Hgb target of 11–12 g/dl when prescribing an ESA.5,6 This was largely based on studies suggesting other beneﬁts from somewhat higher Hgb, including improvements in health-related quality of life (HRQOL). The NHT publication stated that higher Hgb had signiﬁcantly increased scores in the ‘physical function’ domain of HRQOL. As the NHT is the largest trial of ESAs in hemodialysis, the report of improvements in physical function via higher Hgb had a great impact on clinical guidelines that attempted to balance the risks and beneﬁts of ESA therapy. By 2006, the improvement in HRQOL observed in the NHT was of central importance, as the US and European Renal guidelines recommended that all patients with chronic kidney disease (CKD) should have Hgb maintained at 11 g/dl or higher.7,8 The 2006 US Kidney Disease Outcome Quality Improvement (KDOQI) guideline group concluded that ‘yQOL (quality of life) is a sufﬁcient and, apparently, the sole determinant of treatment beneﬁt.’7 Also in 2006, trials in non-dialysis CKD and other populations reported increased thrombovascular and cardio- vascular events and death with ESA use, especially when targeting higher Hgb.9–12 Consequently, the US regulatory authorities recommended lower Hgb goals and far more caution when using ESA.12,13 In 2009, the TREAT trial, which 235