DW Coyne: Quality of life in the Normal Hematocrit Trial predeﬁned category of ‘other thrombotic events’, which included strokes, peripheral arterial thrombosis, and embo- lism but excluded myocardial infarcts and access thrombosis. According to the ACTR, page 79, patients randomized to the higher target experienced signiﬁcantly more ‘other thrombo- tic events’ (22.4 vs. 17.6%, P ¼ 0.041). The HRQOL was measured at baseline and at 6-month intervals. Approximately 857 patients had data reported at any time point in the HRQOL results tables. In the 1998 publication, there were 961 and 849 patients in the trial at 6 months and 9 months, respectively. The 1998 publication reported the HRQOL changes as follows: ‘The physical- function score on the quality-of-life questionnaire at 12 months increased by 0.6 point for each percentage-point increase in the hematocrit (P ¼ 0.03). For example, an increase in the hematocrit from 30 percent to 42 percent was associated with a clinically meaningful increase of 7.2 points in the score on the physical-function scale. There were no signiﬁcant changes in the scores on the other seven scales.’ The ACTR reports on page 149 the 12-month physical function score as 35.0±27.3 in the high arm and as 35.0±27.5 in the low arm, P ¼ 0.97. Figure 1 graphically presents the ACTR mean scores for ‘physical function’ domain at baseline, 6, 12, and 18 months along with the average hematocrit, epoetin dose, and P-values for group differences at each time point. The ACTR states that (page 70) ‘There were no statistically signiﬁcant changes in quality-of-life scores between groups or over time.’ Table 2 shows table A-11 of the ACTR report, the area under the curve results, which was the primary end-point analysis for HRQOL. Table 3 reproduces the results in the ACTR tables A-12 and A-13, which ‘show the mean scores for the seven scales at each 6-month time point, by treatment group.’ The ACTR summarizes the HRQOL on page 70 as ‘There were no signiﬁcant differences between Group A and Group 100 Hematocrit—mean (s.d.) High 30.5 (3.0) 38.8 (5.0) 40.0 (4.1) Low 30.5 (2.9) 30.9 (3.2) 31.2 (3.0) roe 80 Epoetin dose—mean (s.d.) as units/kg/week in four subgroups ifsce HLoigwh 115417 ((112131)) 145727 ((135140)) 146778 ((137887)) l fyo 60 t i l a u tqed 40 P = 0.99 P = 0.95 P = 0.97 a l e r - h t lea 20 H 40.4 (3.9) 31.5 (3.1) 493 (350) 182 (202) P = 0.56 0 0 6 Months 12 18 Figure 1 | Mean scale scores for physical function domain over time in high (black circle) and low (open circle) target arm, as mean±s.d. Hematocrit values, and mean epoetin doses (from intravenously treated patients), are also from the trial report. From Amgen clinical trial report pages 119, 120, 126, 127, and 149. Kidney International (2012) 82, 235–241 o r i g i n a l a r t i c l e B scores at any time, and scores did not change signiﬁcantly over time.’ According to the ACTR on page 38, differences in hospitalization rates between groups were to be compared using the Kaplan–Meier curve and the log-rank test and ﬁtting Cox proportional hazards regression models. Instead, the 1998 publication reported no difference in hospitalization rates between groups when compared using Fisher’s exact test (Table 1). The ACTR provides hospitalization rates identical to the 1998 publication, but on pages 66 and 67 reports the time to ﬁrst hospitalization results in the following manner: ‘Kaplan-Meier curves for time to ﬁrst hospitalization, show(ed) that Group B (lower hematocrit target) patients experienced higher hospitalization-free ‘survival’ compared to Group A (higher hematocrit target) patients (P ¼ 0.04; log rank test)y’. After adjusting for multiple covariables ‘the RR of hospitali- zationywas 1.14, but the CI spanned 1.00 (0.99 to 1.30).’ DISCUSSION This report documents several differences between the original publication of the NHT trial result in 1998 and the ACTR ﬁled with the FDA in 1996. The NHT was intended to assess the risk/beneﬁt of targeting higher Hgb.1 Unadjusted mortality and the primary end point of mortality plus nonfatal myocardial infarcts were signiﬁcantly higher in the high target arm. These results were not a complete surprise to the company, as the ACTR states on page 21 that a rationale for the trial was an ‘increased risk of mortality (was) considered among the potential adverse effects of full correction of anemia in dialysis patients’. The original publication presented these results as insigniﬁcantly different because of adjustment of the CIs for repeated reviews by the data safety board monitoring, and this was approved by the journal’s editors.1,17 Unadjusted statistical results were not reported in the 1998 publication on the last interim analysis, or in a published letter in 2008, which provided the ﬁnal trial results.16 The FDA now reports in ESA package inserts that the NHT found signiﬁcantly higher relative risk when targeting higher Hgb for both all-cause mortality (1.27, 95% CI 1.04–1.54) and the primary end point (1.28, 95% CI 1.06–1.56). These CIs are not adjusted.15 On the basis of the ACTR results, compared with a Hgb target of 9–11 g/dl, targeting 13–15 g/dl increases the risk of graft and ﬁstula thrombosis (P ¼ 0.001) and other thrombo- tic events (P ¼ 0.04), accelerates the time to ﬁrst hospitaliza- tion (P ¼ 0.04), and tends to increase all-cause mortality (P ¼ 0.0188; HR 1.26, 95% CI 1.02–1.56). The sole beneﬁt was a reduction in the proportion of patients transfused (P ¼ 0.001), whereas HRQOL domains did not improve. The NHT remains the largest ESA trial in the hemodialysis population. The trial population characteristics—42% black, 44% with diabetic nephropathy, and 28% with hypertensive nephropathy, with a mean age of about 65 years, and a mean time on dialysis of 3 years—are comparable to those of the prevalent US dialysis population.1,18 In addition, a majority of the US dialysis patients have cardiac disease, as did all 237