The n e w e ng l a n d j o u r na l of m e dic i n e

C or r e sp ondence

Long-Term Outcomes of the ADRENAL Trial

To the Editor: We recently reported the pri-
mary results of the Adjunctive Corticosteroid
Treatment in Critically Ill Patients with Septic
Shock (ADRENAL) trial, which tested the hypoth-
esis that hydrocortisone would result in lower
mortality than placebo among patients with
septic shock.1 Further analysis of the trial data
has been conducted according to a previously
published statistical analysis plan, which desig-
nated death 6 months after randomization as a
secondary end point.2 These data are now avail-
able and are reported here.
Among patients for whom trial data were
available, data on death at 90 days after random-
ization were obtained for 1832 of 1853 patients
(98.9%) assigned to hydrocortisone and 1826 of
1860 (98.2%) assigned to placebo. At 6 months,
we obtained data on vital status (alive or dead)
for 1812 patients (97.8%) and 1803 patients
(96.9%), respectively.
At 6 months, among the patients for whom
data on vital status were available, 571 of 1812
(31.5%) assigned to hydrocortisone and 574 of
1803 (31.8%) assigned to placebo had died (odds

P Value for
Subgroup Hydrocortisone Placebo Odds Ratio (95% CI) Interaction
no. of patients with event/total no. of patients (%)
Sex 0.74
Male 351/1091 (32.2) 364/1106 (32.9) 0.96 (0.80–1.15)
Female 220/721 (30.5) 210/697 (30.1) 1.01 (0.80–1.27)
Admission type 0.48
Surgical 140/560 (25.0) 156/575 (27.1) 0.90 (0.69–1.18)
Medical 431/1252 (34.4) 418/1227 (34.1) 1.01 (0.86–1.20)
Catecholamine dose 0.49
≤15 µg/min 258/957 (27.0) 261/977 (26.7) 1.01 (0.83–1.24)
>15 µg/min 306/841 (36.4) 305/801 (38.1) 0.92 (0.75–1.12)
Site of sepsis 0.25
Pulmonary 269/787 (34.2) 263/817 (32.2) 1.07 (0.87–1.32)
Other 302/1025 (29.5) 311/986 (31.5) 0.91 (0.75–1.10)
APACHE II score 0.15
≥25 356/832 (42.8) 318/779 (40.8) 1.05 (0.86–1.29)
<25 214/978 (21.9) 256/1022 (25.0) 0.85 (0.69–1.05)
Time from shock onset to randomization 0.37
<6 hr 117/347 (33.7) 105/337 (31.2) 1.10 (0.80–1.53)
6 to <12 hr 143/506 (28.3) 160/486 (32.9) 0.80 (0.61–1.05)
12 to <18 hr 133/432 (30.8) 124/411 (30.2) 1.03 (0.76–1.38)
≥18 hr 176/521 (33.8) 181/562 (32.2) 1.07 (0.83–1.39)
0.5 1.0 2.0

Hydrocortisone Placebo
Better Better

Figure 1. Subgroup Analysis of Death at 180 Days.

The odds ratio of death at 180 days in the six prespecified subgroups is shown. The size of the square representing the odds ratio re-
flects the relative numbers in each subgroup, and horizontal bars represent 95% confidence intervals. P values are for heterogeneity of
the effect of the trial regimen on the primary outcome in each subgroup. Scores on the Acute Physiology and Chronic Health Evaluation
(APACHE) II are assessed on a scale from 0 to 71, with higher scores indicating a higher risk of death (a score of ≥25 has been used as
a cutoff point to identify patients at a higher risk for death). Data on admission type were missing for 1 patient in the placebo group; on
the catecholamine dose for 14 in the hydrocortisone group and for 15 in the placebo group; on the APACHE II score for 2 and 2, respec-
tively; and on the time from shock onset to randomization for 6 and 7, respectively.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

ratio, 0.99; 95% confidence interval, 0.86 to Jeremy Cohen, M.D., Ph.D.

1.13; P = 0.83). The results were not altered by University of Queensland
adjustment for stratification variables or addi- Brisbane, QLD, Australia
tional covariates, as described in our original Laurent Billot, M.Sc., M.Res.
article1 (Table S1 in the Supplementary Appen- George Institute for Global Health
dix, available with the full text of this letter at Sydney, NSW, Australia
Supported by project grants from the National Health and
NEJM.org). There was no significant heterogene- Medical Research Council of Australia (grant nos., 1004108 and
ity in the effect of the trial regimen on the risk 1124926) and the Health Research Council of New Zealand
of death at 6 months in the six prespecified (grant no., 12/306), by indirect funding from the National Institute
subgroups (Fig. 1), nor were there geographic of Health Research in the United Kingdom, and by Practitioner
Fellowships from the National Health and Medical Research
differences (Fig. S1 in the Supplementary Ap- Council of Australia (to Drs. Venkatesh, Finfer, and Myburgh).
pendix). We conclude that in adult patients with Disclosure forms provided by the authors are available with
septic shock, hydrocortisone did not affect mor- the full text of this letter at NEJM.org.
tality at 6 months after randomization; these This letter was published on April 25, 2018, at NEJM.org.
findings are in concert with the 90-day mortal-
1. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocor-
ity results published earlier in the Journal. ticoid therapy in patients with septic shock. N Engl J Med 2018;​
Balasubramanian Venkatesh, M.D. 378:​797-808.
2. Billot L, Venkatesh B, Myburgh J, et al. Statistical analysis
Simon Finfer, M.D. plan for the Adjunctive Corticosteroid Treatment in Critically Ill
John Myburgh, M.D., Ph.D. Patients with Septic Shock (ADRENAL) trial. Crit Care Resusc
2017;​19:​183-91.
George Institute for Global Health
Sydney, NSW, Australia DOI: 10.1056/NEJMc1803563
bvenkatesh@georgeinstitute.org.au Correspondence Copyright © 2018 Massachusetts Medical Society.

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