DW Coyne: Quality of life in the Normal Hematocrit Trial o r i g i n a l a r t i c l e Table 4 | Results from high-quality trials assessing effect of hemoglobin target on HRQOL Trial Population, patient characteristics Numbera High vs. low hemoglobin Positive HRQOL Support 2006 hemoglobin target (g/dl) differences between arms target of 11 g/dl or higher? Besarab et al.1 Hemodialysis, all had heart 1233 9–11 vs. 13–15 None (improved physical No failure or CAD function according to 1998 No significant difference publication) between groups CanEPO21 b Hemodialysis, all had LVD or 78 9.5–11 vs. 11.5–13 None No LVH Foley et al.23 Hemodialysis, free of marked 94 9.5–10.5 vs. 13–14 Fatigue, depression, Possibly in healthier subjects comorbidity relationships Parfrey et al.19 Hemodialysis, no CAD or LVD 324 9.5–11.5 vs. 13.5–14.5 Vitality Possibly; significantly increased risk of stroke Roger et al.22 CKD stage 3 and 4, excluded 155 9–10 vs. 12–13 None No uncontrolled angina, class III or IV HF, severe chronic respiratory disease, symptomatic peripheral vascular disease, or fistula placement Abbreviations: CAD, coronary atherosclerotic disease; CKD, chronic kidney disease; HF, heart failure; HRQOL, health-related quality of life; LVD, left ventricular dilation; LVH, left ventricular hypertrophy. aData are extracted from the 2006 KDOQI Anemia guideline evidence tables 13 and 17. Data from only high-quality trials are shown. bThis trial had a 40-patient third arm, which received placebo; both treatment arms had improvements in HRQOL compared with placebo. the patients in the NHT.2–4 As higher Hgb associates with improved survival, lower cardiac event rates, and higher HRQOL, it was hypothesized that raising Hgb would lead to improved outcomes. The NHT was designed to test this hypothesis.1 The surprising results suggesting harm from targeting higher Hgb represented the ﬁrst major evidence of safety problems with the use of ESAs. In 1997, following early termination of the NHT but before publication of the results, the National Kidney Foundation’s Dialysis Outcomes Quality Initiative (DOQI, now KDOQI) guidelines recommended a Hgb goal of 11–12 g/dl when using an ESA in CKD patients, with physicians determining which patients warranted treatment.5 The 1997 KDOQI workgroup was aware that the NHT had been terminated early because the high target arm ‘was experiencing a greater incidence of nonfatal myocardial infarcts or death’ than the control arm.5 The 1997 KDOQI guideline and 2001 update did not have the formal evidence rules and rigid evaluation techniques that are now commonly used to develop guidelines.5,6 Consequently, both observational data and trials of varying quality were considered in support of guidelines. There was also no substantive emerging evidence of safety problems with ESAs in patients with renal disease or other populations until later. In addition, there was a prevailing viewpoint that higher Hgb was conferring distinct beneﬁts in cardiovascular health and patient stamina based on observational data and small trial results. Similarly, the January 2001 updated guidelines used very similar logic and cited almost identical strands of evidence to again recommend a Hgb target of 11–12 g/dl when using epoetin.6 The 2001 update additionally cited a lower rate of hospitalization when targeting higher Hgb, which would have been undermined by publication of the ACTR results noted here.6 Regardless, it is unlikely that knowledge of the results outlined in this paper would have signiﬁcantly altered either the 1997 or the 2001 KDOQI guidelines because of the lack of corroborating evidence of harm from ESAs. Kidney International (2012) 82, 235–241 In contrast, by 2006, there was evidence that ESAs increased thrombovascular risks and increased deaths in some cancer trials.9 In addition, some of the earlier proposed beneﬁts from targeting normal Hgb, such as further regression of left ventricular hypertrophy, had failed to materialize in randomized trials.19 Most importantly, the 2006 KDOQI Anemia guidelines were far more rigorous evaluations of evidence.7 Only clinical trials were considered evidence, the quality of each trial was assessed, and pertinent results were collected into evidence tables. On the basis of review of the evidence tables, the 2006 workgroup wrote a Clinical Practice Guideline that ‘In patients with CKD, Hb (hemoglobin) should be 11.0 g/dl or greater.’7 This was a substantive change from previous guidelines, which had physicians determine whether anemia warranted treatment. A Clinical Practice Guideline, unlike practice recommendations, can form the basis for clinical performance measures to evaluate physicians.20 The work- group stated that ‘In developing the statement Hb level should be 11.0 g/dl or greater, the Work Group concluded that— when comparing higher with lower Hb targets—QOL is a sufﬁcient and, apparently, the sole determinant of treatment beneﬁt’ (italics in the original).7 The 2006 KDOQI Hgb target guideline was based solely on review of interventional trial results. The workgroup cited ﬁve high-quality trials in support of HRQOL claim; by far the largest was the 1998 NHT publication (Table 4).7 The NHT results were described as ‘Physical: þ (better with higher Hgb), Increased by 0.6 point for each percentage point increase in Hct’, as quoted from the 1998 publication.7 Two of the other trials reported no signiﬁcant improvement in HRQOL when targeting higher vs. lower Hgb.21,22 The other two high-quality trials, limited to healthier hemodialysis patients, had conﬂicting results regarding improvement in HRQOL.19,23 One found no improvement in any SF-36 measure with higher Hgb targets, but did ﬁnd improvements 239