o r i g i n a l a r t i c l e DW Coyne: Quality of life in the Normal Hematocrit Trial Table 1 | Comparison of 1998 and 2008 New England Journal articles to the FDA-filed NHT Clinical Trial Report 1998 New England Journal of Medicine publication FDA-filed Clinical Trial Report Data reported Primary end point (death+nonfatal MI) All-cause deaths The last interim analysis performed on March 30, 1996 on 1233 patients RR 1.3; (95% CI 0.9–1.9). (P-value not given) 95 % CI adjusted for the previous interim analyses Not reported Hospitalization rate 72% vs. 69% P=0.29 by Fisher’s exact test Quality of life Thrombotic events Physical function domain ‘at 12 months increased by 0.6 point for each percentage-point increase in the hematocrit (P=0.03).’ Vascular access 39% vs. 29%, P=0.001 Other thrombotic events, listed individually, P=NS The last interim analysis performed on March 30, 1996 on 1233 patients RR 1.3 (99.912% CI=0.92–1.85) (P=0.0119)*,a Kaplan–Meier, log-rank test P=0.0188* RR 1.26 (95% CI=1.02–1.56)*,a 72% vs. 69% P=0.04 by Kaplan–Meier curve, log-rank test. Adjustment for covariables, RR 1.14, 95% CI 0.994–1.30 (P=0.06) None of seven domains showed any significant improvement over time or between groups Vascular access 39% vs. 29%, P=0.001 Other thrombotic events, grouped, 22% vs. 18%, P=0.041 Final trial results 2008 New England Journal of Medicine Letter to the Editor FDA-filed Clinical Trial Report Data reported Data reflect the final results on 1265 patients following trial termination on June 24, 1996. Primary end point RR 1.28 (CI 0.92–1.78); P-value not given. The 95% CI were (death+nonfatal MI) adjusted for the previous interim analyses with the use of the method of repeated confidence intervals. Abbreviations: CI, confidence interval; FDA, Food and Drug Administration; MI, myocardial infarct; NS, not significant; RR, relative risk. *The P-value required for significance at this interim analysis was set at 0.00088. **The P-value required for significance at this analysis was set at 0.0008. aThe final trial result for relative risk for the primary end point was 1.28, 95% CI 1.06–1.56, and for all-cause death was 1.27, 95% CI 1.04–1.54. Data reflect the final results on 1265 patients following trial termination on June 24, 1996. Kaplan–Meier log-rank P=0.01138. Unadjusted OR 1.28 (99.92% CI=0.92–1.78) (0.0112)**,a compared placebo treatment to ESA therapy targeting a Hgb goal of 13 g/dl, demonstrated that ESA therapy afforded no reduction in cardiac events or deaths, a marginal improve- ment in quality of life, and an increased risk of strokes and arterial and venous thromboembolic events.14 Recently, the Food and Drug Administration (FDA) concluded that ‘Using ESAs to target a Hgb level of greater than 11 g/dl increases the risk of serious adverse cardiovas- cular events and has not been shown to provide additional patient beneﬁt.’15 This is in conﬂict with the NHT results from 1998, which reported that a higher Hgb target improved HRQOL and insigniﬁcantly increased deaths. I sought to determine whether the results of the NHT published in 1998 were complete and supported the recom- mendations in renal anemia guidelines. I obtained the NHT report ﬁled by Amgen (Thousand Oaks, CA) with the FDA in 1996 through a Freedom of Information Act request, and compared the primary and secondary predeﬁned HRQOL end-point results in the Amgen clinical trial report (ACTR) with the 1998 publication. RESULTS The trial randomized 1265 patients, although the 1998 publication and most of the ACTR analyzed data on the 1233 patients who were part of the last interim analysis performed by the data safety monitoring board.1,16 The clinical trial report states on page 4 that analyses on the entire 1265 patients did not change the results. The primary end-point results on the entire 1265-patient cohort were reported in a letter published in 2008.16 236 The differences in the major primary and secondary end points and adverse events between the 1998 publication and the ACTR are shown in Table 1. Table 1 also compares the ACTR and the FDA safety announcement on ESAs released in June 2011 with the 2008 letter containing ﬁnal NHT information. The major differences regarding the primary end point are owing to the 1998 report and the 2008 letter exclusively reporting adjusted 95% conﬁdence intervals (CIs), and not providing the P-value for the analysis, which would have been o0.05.1,16 As shown in the ACTR on pages 54 and 58, the unadjusted CIs required for signiﬁcance were 99.912% at the last interim analysis (P ¼ 0.00088) and 99.92% (P ¼ 0.0008) at study termination. As described in the methods of the original publication, these CIs were adjusted to account for repeated testing by the data safety monitoring board. Differences between the treatment groups with respect to both the primary end point and all-cause death are statistically signiﬁcant by the unadjusted CIs, but fail to reach signiﬁcance using the boundary rules adopted by the data safety monitoring board. Stopping the trial early before reaching the prescribed signiﬁcance threshold created an insigniﬁcant difference between arms. In 2007 and 2011, the FDA reported only the unadjusted 95% CIs, and now classiﬁes the trial results as showing signiﬁcant harm.15 The 1998 publication states that ‘There were no differences between groups in the incidence of cerebrovas- cular accidents, transient ischemic attacks, peripheral gang- rene, (or) intestinal ischemiay.’ Because of the concern that epoetin dosed to correct anemia could increase throm- botic events, the ACTR states on page 78 that there was a Kidney International (2012) 82, 235–241