The topic search strategy

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The new england
journal of medicine

n engl j med 375;17 nejm.org October 27, 2016 1617

established in 1812 October 27, 2016 vol. 375 no. 17

The members of the writing committee
(Richard K. Albert, M.D., David H. Au,
M.D., Amanda L. Blackford, Sc.M., Richard
Casaburi, M.D., Ph.D., J. Allen Cooper,
Jr., M.D., Gerard J. Criner, M.D., Philip
Diaz, M.D., Anne L. Fuhlbrigge, M.D.,
Steven E. Gay, M.D., Richard E. Kanner,
M.D., Neil MacIntyre, M.D., Fernando J.
Martinez, M.D., Ralph J. Panos, M.D.,
Steven Piantadosi, M.D., Ph.D., Frank
Sciurba, M.D., David Shade, J.D., Thomas
Stibolt, M.D., James K. Stoller, M.D.,
Robert Wise, M.D., Roger D. Yusen, M.D.,
James Tonascia, Ph.D., Alice L. Stern-
berg, Sc.M., and William Bailey, M.D.) as-
sume responsibility for this article. The
affiliations of the members of the writing
committee are listed in the Appendix. Ad-
dress reprint requests to Dr. Wise at the
Johns Hopkins Asthma and Allergy Cen-
ter, 4B.72, Division of Pulmonary and
Critical Care, 5501 Hopkins Bayview Cir-
cle, Baltimore, MD 21224, or at rwise@
jhmi . edu.

* A complete list of investigators in the
Long-Term Oxygen Treatment Trial
(LOTT) Research Group is provided in
the Supplementary Appendix, available
at NEJM.org.

N Engl J Med 2016;375:1617-27.
DOI: 10.1056/NEJMoa1604344
Copyright © 2016 Massachusetts Medical Society.

BACKGROUND
Long-term treatment with supplemental oxygen has unknown efficacy in patients with
stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced
moderate desaturation.

METHODS
We originally designed the trial to test whether long-term treatment with supplemental
oxygen would result in a longer time to death than no use of supplemental oxygen among
patients who had stable COPD with moderate resting desaturation (oxyhemoglobin satu-
ration as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the ran-
domization of 34 patients, the trial was redesigned to also include patients who had
stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test,
Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the
first hospitalization for any cause into the new composite primary outcome. Patients were
randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-
oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the
supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour
oxygen, and those with desaturation only during exercise were prescribed oxygen during
exercise and sleep. The trial-group assignment was not masked.

RESULTS
A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event
analysis, we found no significant difference between the supplemental-oxygen group and
the no-supplemental-oxygen group in the time to death or first hospitalization (hazard
ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P = 0.52), nor in the rates of all
hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio,
1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI,
0.83 to 1.17). We found no consistent between-group differences in measures of quality
of life, lung function, and the distance walked in 6 minutes.

CONCLUSIONS
In patients with stable COPD and resting or exercise-induced moderate desaturation, the
prescription of long-term supplemental oxygen did not result in a longer time to death or
first hospitalization than no long-term supplemental oxygen, nor did it provide sustained
benefit with regard to any of the other measured outcomes. (Funded by the National
Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services;
LOTT ClinicalTrials.gov number, NCT00692198.)

a bs tr ac t

A Randomized Trial of Long-Term Oxygen for COPD
with Moderate Desaturation

The Long-Term Oxygen Treatment Trial Research Group*

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Two trials that were conducted in
the 1970s showed that long-term treat-
ment with supplemental oxygen reduced

mortality among patients with chronic obstruc-
tive pulmonary disease (COPD) and severe resting
hypoxemia.1,2 These results led to the recommen-
dation that supplemental oxygen be adminis-
tered to patients with an oxyhemoglobin satura-
tion, as measured by pulse oximetry (Spo2), of less
than 89%.3,4 In the 1990s, two trials evaluated
long-term treatment with supplemental oxygen
in patients with COPD who had mild-to-moderate
daytime hypoxemia; neither trial showed a mor-
tality benefit, but both were underpowered to
assess mortality.5,6 The effects of oxygen treat-
ment on hospitalization,7-9 exercise performance,
and quality of life are unclear.10

Medicare reimbursements for oxygen-related
costs for patients with COPD exceeded $2 billion
in 2011.11 If long-term treatment with supple-
mental oxygen reduces the incidence of COPD-
related hospitalizations, increased use could be
cost-effective. Reliable estimates of the number
of prescriptions for supplemental oxygen that
are written for the indication of exercise-induced
desaturation are unavailable. Data suggest that
many patients with advanced emphysema who
are prescribed oxygen may not have severe rest-
ing hypoxemia.12

The Long-Term Oxygen Treatment Trial (LOTT)
was originally designed to test whether the use
of supplemental oxygen would result in a longer
time to death than no use of supplemental oxygen
among patients with COPD and moderate resting
desaturation (Spo2, 89 to 93%). After 7 months
and the randomization of 34 patients, the trial
design was judged to be infeasible owing to lower-
than-projected mortality and the phenotypic
overlap between patients with moderate resting
desaturation and those with exercise-induced de-
saturation. Accordingly, the investigators rede-
signed the trial to include patients with exercise-
induced desaturation and to incorporate the
secondary outcome of hospitalization for any
cause into the new composite primary outcome.
Patients who underwent randomization under the
original design continued in the redesigned trial.

The amended trial tested whether the use of
supplemental oxygen resulted in a longer time to
death or first hospitalization for any cause (com-
posite primary outcome) than no use of supple-

mental oxygen among patients with moderate
resting desaturation or moderate exercise-induced
desaturation. The original and amended trial
protocols are available with the full text of this
article at NEJM.org. Herein we report the pri-
mary and secondary outcomes and 11 of the 14
other outcomes listed in the trial protocol (see the
Supplementary Appendix, available at NEJM.org,
for the reasons that 3 outcomes are not reported).

Me thods

Design

We conducted this parallel-group, randomized
clinical trial of long-term supplemental oxygen
versus no long-term supplemental oxygen in
patients with COPD and moderate resting or
exercise-induced desaturation. Randomization
was performed in a 1:1 ratio, and the trial-group
assignment was not masked. The primary out-
come in the time-to-event analysis, measured
from randomization, was the composite of death
or first hospitalization. The protocol specified
that the consistency of treatment effects would
be tested in subgroups of patients that were de-
fined according to prespecified baseline charac-
teristics. The protocol and amendments were
approved by the data and safety monitoring
board for the trial and by the institutional re-
view board at each center. No materials were
donated to this trial.

Patients

A total of 14 regional clinical centers and their
associated sites (a total of 47 centers) screened
patients who had stable COPD and moderate
resting desaturation (Spo2, 89 to 93%) or moderate
exercise-induced desaturation (during the 6-min-
ute walk test, Spo2 ≥80% for ≥5 minutes and
<90% for ≥10 seconds). All the patients signed
a contract in which they agreed not to smoke
while using oxygen, and they provided written
informed consent. Table S1 in the Supplemen-
tary Appendix lists all the selection criteria.

Interventions

Patients in the supplemental-oxygen group were
prescribed 24-hour oxygen if their resting Spo2
was 89 to 93% and oxygen only during sleep and
exercise if they had desaturation only during ex-
ercise. All the patients in the supplemental-oxygen

A Quick Take
is available at

NEJM.org

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Long-Term Oxygen for COPD with Moder ate Desatur ation

group were prescribed stationary and portable
oxygen systems and 2 liters of oxygen per minute
during sleep. Patients in the supplemental-oxygen
group who had been prescribed 24-hour oxygen
were prescribed 2 liters of oxygen per minute at
rest. The ambulatory dose of oxygen was individu-
ally prescribed and reassessed annually: 2 liters
of oxygen per minute or adjusted higher to main-
tain an Spo2 of 90% or more for at least 2 minutes
while the patient was walking. The protocol
specified that patients in the supplemental-
oxygen group continue the use of supplemental
oxygen regardless of increase in the Spo2 level
and that patients in the no-supplemental-oxygen
group avoid the use of supplemental oxygen un-
less severe resting desaturation (Spo2 ≤88%) or
severe exercise-induced desaturation (Spo2 <80%
for ≥1 minute) developed. If either of these con-
ditions developed, oxygen was prescribed and the
oxygen requirement was reassessed after 30 days.

Each patient in the supplemental-oxygen group
spoke with an adherence educator regularly to
discuss barriers to adherence to the assigned
regimen and to report average daily use. Each
patient in the group that received no long-term
supplemental oxygen (no-supplemental-oxygen
group) spoke with an adherence educator 1 week
after randomization to discuss living without
supplemental oxygen. Every 4 months, all the
patients were asked about supplemental-oxygen
use; those who reported some oxygen use were
asked to estimate the average daily use. Patients
in the supplemental-oxygen group who used
stationary oxygen concentrators also kept logs
of meter readings.

Outcomes

In addition to the composite primary outcome
and its components, outcomes included the inci-
dence of COPD exacerbation, adherence to the
supplemental-oxygen regimen, development of
severe resting desaturation (as assessed by means
of pulse oximetry), development of severe exer-
cise-induced desaturation (as assessed by means
of pulse oximetry), the distance walked in 6 min-
utes, and scores on the Quality of Well-Being
Scale (mean daily scores range from 0 to 1, with
higher scores indicating better quality of life;
minimum clinically important difference, 0.03)13,14
and the St. George’s Respiratory Questionnaire
(total scores range from 0 to 100, with higher

scores indicating worse health-related quality
of life; minimum clinically important difference,
4).15,16 A total of 33 centers elected to obtain spi-
rometric measurements after randomization and
to administer the Medical Outcomes Study 36-Item
Short-Form Health Survey (SF-36; the summary
scores for the physical and mental components
each range from 0 to 100, with higher scores
indicating better function; minimum clinically
important difference, 5),17 the Hospital Anxiety
and Depression Scale (scores on each measure
[anxiety or depression] range from 0 to 21, with
higher scores indicating greater anxiety or de-
pression; minimum clinically important differ-
ence, 1.5),18,19 and the Pittsburgh Sleep Quality
Index (total scores range from 0 to 21, with
higher scores indicating worse sleep quality).20
The protocol lists three additional outcomes
(nutritional status, risk of cardiovascular dis-
ease, and neurocognitive function) that are not
reported here.

Patients attended visits yearly after random-
ization, were interviewed by telephone twice
yearly, and completed mailed questionnaires at
4 months and 16 months (Table S2 in the Sup-
plementary Appendix). Details regarding the as-
certainment of the primary composite outcome
and procedures for measuring resting and exercise-
induced desaturation are provided in the Supple-
mentary Appendix.

Statistical Analysis

Calculation of the final required sample was
based on a time–to–composite event survival
model with the use of the log-rank test statistic.
Assuming 90% power to detect a hazard ratio
for death or first hospitalization of 0.60 in the
supplemental-oxygen group versus the no-supple-
mental-oxygen group, a two-sided type I error
rate of 0.05, an 11.7% overall crossover rate from
the no-supplemental-oxygen group to the supple-
mental-oxygen group, and a 3.1% overall cross-
over rate from the supplemental-oxygen group
to the no-supplemental-oxygen group, we calcu-
lated a sample size of 737 patients. The hazard
ratio of 0.60 corresponds to the smallest differ-
ence in mortality that the investigators judged to
be clinically worthwhile (a 40% lower rate in the
supplemental-oxygen group than in the no-supple-
mental-oxygen group), on the basis of the number
of patients needed to treat. Because supplemen-

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

tal oxygen is expensive and its use is burdensome,
the hazard ratio of 0.60 was also judged to be
appropriate for the composite primary outcome
of death or first hospitalization in the time-to-
event analysis.

Under the original trial design, we assumed
that the crossover rate from the no-supplemental-
oxygen group to the supplemental-oxygen group
would be 21% and the crossover rate from the
supplemental-oxygen group to the no-supple-
mental-oxygen group would be 50%, on the basis
of investigator consensus. In March 2012, the
data and safety monitoring board approved the
use of the observed crossover rates of 11.7%
(from the no-supplemental-oxygen group to the
supplemental-oxygen group) and 3.1% (from the
supplemental-oxygen group to the no-supple-
mental-oxygen group) to refine the sample-size
calculation. Additional details about the sample-
size calculation are provided in the Supplemen-
tary Appendix.

Data were analyzed according to the treatment
group to which the patients were randomly as-
signed (intention-to-treat approach) except as
otherwise noted. A Cox proportional-hazards
model21 with one binary covariate for treatment
group was used to estimate the between-group
hazard ratio for the primary composite outcome
in the time-to-event analysis; the log-rank test
was used for the P value. This method was also
used for each of the secondary outcomes in the
time-to-event analysis.

The consistency of the hazard ratio for the
primary outcome across prespecified subgroups
was assessed by a series of Cox proportional-
hazard models with covariates that included the
treatment-group indicator, indicators for the
levels of the subgroup factor, and treatment-by-
subgroup interaction terms. The P values for
consistency of hazard ratios across subgroups
were determined by Wald chi-square tests. Per the
trial protocol, all reported P values are nominal
and two-sided and were not corrected for mul-
tiple, prespecified comparisons. A P value of less
than 0.05 was considered to indicate statistical
significance for the composite primary outcome,
and a P value of less than 0.01 was considered to
indicate statistical significance for a treatment-
by-subgroup interaction effect on the primary
outcome. Bonferroni corrections were used to
determine the P values that were required for

statistical significance of the trial-group differ-
ences on the secondary and other outcomes and
for statistical significance of the multiple treat-
ment-by-subgroup interaction effects on the pri-
mary outcome that were assessed.22 Additional
details about the statistical analysis are provided
in the protocol and the Supplementary Appendix.

R esult s

Trial Population

From January 2009 through August 2014, a total
of 738 patients at 42 centers underwent random-
ization in the trial: 368 patients were randomly
assigned to the supplemental-oxygen group and
370 to the no-supplemental-oxygen group (Fig. S1
and Table S3 in the Supplementary Appendix). In
the supplemental-oxygen group, 220 patients were
prescribed 24-hour oxygen and 148 were pre-
scribed oxygen during exercise and sleep only.
Of the 738 patients who underwent randomiza-
tion, 133 (18%) had resting desaturation only, 319
(43%) had exercise-induced desaturation only,
and 286 (39%) had both types of desaturation.
The trial groups were similar at baseline except
that the patients in the supplemental-oxygen
group had a lower BODE index (a scoring system
incorporating information on the body-mass in-
dex, airflow obstruction, dyspnea, and 6-minute
walk distance; higher scores indicate a greater
risk of death)23 than those in the no-supplemen-
tal-oxygen group (Table 1, and Table S4 in the
Supplementary Appendix).

Patients were followed for 1 to 6 years; the
last visits occurred during the period from May
through August 2015 (median follow-up, 18.4
months). Vital status as of August 31, 2015, was
ascertained in all patients. A total of 97% of the
patients had at least 1 year of follow-up for hos-
pitalization. Most patients in the supplemental-
oxygen group used 2 liters of oxygen per minute
during exercise throughout follow-up (Table S5
in the Supplementary Appendix).

Primary Outcome

In a time-to-event analysis, we found no signifi-
cant difference between the trial groups in the
composite outcome of death or first hospitaliza-
tion for any cause or in either component (Fig. 1
and Table 2). No significant difference was not-
ed in the subgroups defined according to oxygen

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Long-Term Oxygen for COPD with Moder ate Desatur ation

Characteristic

No Supplemental
Oxygen

(N = 370)

Supplemental
Oxygen

(N = 368)

Age — yr 69.3±7.4 68.3±7.5

Male sex — no. (%) 276 (75) 266 (72)

Race — no. (%)†

Black 34 (9) 46 (12)

White 328 (89) 311 (85)

Other 11 (3) 17 (5)

Medicare coverage — no. (%) 273 (74) 268 (73)

Current tobacco-cigarette smoker — no. (%) 92 (25) 110 (30)

Quality of Well-Being Scale mean daily score‡ 0.56±0.13 0.56±0.13

St. George’s Respiratory Questionnaire total score§ 50.2±17.1 49.8±18.7

Oxygen-desaturation type qualifying the patient for enrollment
— no. (%)

Resting only 60 (16) 73 (20)

Exercise only 171 (46) 148 (40)

Resting and exercise 139 (38) 147 (40)

Spo2 at rest while breathing ambient air — %

All patients 93.5±1.9 93.3±2.1

Resting only 92.3±0.8 92.4±0.9

Exercise only 95.2±1.2 95.4±1.4

Resting and exercise 91.9±1.2 91.7±1.1

Nadir Spo2 during 6-min walk while breathing ambient air
— no./total no. (%)¶

<86% 85/290 (29) 86/292 (29)

86–88% 103/290 (36) 105/292 (36)

>88% 102/290 (35) 101/292 (35)

* Plus-minus values are means ±SD. There were no significant differences at baseline between the group of patients
assigned to receive long-term supplemental oxygen (supplemental-oxygen group) and the group of those assigned to
receive no long-term supplemental oxygen (no-supplemental-oxygen group), except that the patients in the supplemental-
oxygen group had a lower BODE index (a scoring system incorporating information on body-mass index, airflow obstruc-
tion, dyspnea, and 6-minute walk distance; higher scores indicate a greater risk of death)23 than those in the no-supple-
mental-oxygen group (P = 0.007); details of the BODE index values and other characteristics at baseline are provided
in Table S4 in the Supplementary Appendix. Spo2 denotes oxyhemoglobin saturation as measured by means of pulse
oximetry.

† Race was self-reported. Patients were permitted to select more than one race group.
‡ The Quality of Well-Being Scale is a 77-item quality-of-life questionnaire completed by the patient. A score of 0 indicates

death. The mean daily score ranges from 0 to 1, with higher scores indicating better quality of life. The minimum clini-
cally important difference is 0.03.13,14

§ The St. George’s Respiratory Questionnaire is a 51-item questionnaire on the health-related quality of life with regard to
respiratory symptoms that is completed by the patient. The total score ranges from 0 to 100, with lower scores indicat-
ing better health-related qualify of life. The minimum clinically important difference is 4.15,16

¶ The nadir Spo2 is the 10th lowest Spo2 observed during the 6-minute walk. A total of 10 patients (6 patients in the sup-
plemental-oxygen group and 4 in the no-supplemental-oxygen group) either did not attempt or began but did not com-
plete the 6-minute walk. Reasons included being in a wheelchair, amputation of foot or leg, sciatic pain, starting the walk
and stopping because of back pain, or other reason; these 10 participants met the resting hypoxemia criterion. The
nadir Spo2 could not be calculated for 146 patients (70 patients in the supplemental-oxygen group and 76 in the no-
supplemental-oxygen group) owing to loss of their oximetry data file or a technical issue with their oximetry data file
obtained at enrollment.

Table 1. Characteristics of the Patients at Enrollment.*

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Figure 1. Kaplan–Meier Analyses of the Primary Outcome of Death or First Hospitalization for Any Cause
and for the Component Events in the Intention-to-Treat Population.

Panel A shows the results of a time-to-event analysis of the primary outcome, which was a composite of death or first
hospitalization for any cause; the median follow-up was 18.4 months. Data for 120 patients who were assigned to re-
ceive long-term supplemental oxygen (supplemental-oxygen group) and 120 assigned to receive no long-term supple-
mental oxygen (no-supplemental-oxygen group) who neither died nor had a hospitalization were censored at the date
of the last interview. Error bars indicate 95% confidence intervals (assessed every 12 months). For the time-to-event
analysis of the first hospitalization for any cause, the median follow-up was 18.4 months. Data for 139 patients in the
supplemental-oxygen group and 133 in the no-supplemental-oxygen group were censored as of their date of death (if
there was no hospitalization before death) or as of the date of their last interview (if they were alive and had no hospi-
talization). Panel B shows the results of a time-to-event analysis of death; the median follow-up was 41.5 months.
Data for 302 patients in the supplemental-oxygen group and 297 in the no-supplemental-oxygen group who were alive
on August 31, 2015, were censored as of that date. The hazard ratios and 95% confidence limits were derived from
Cox regression models, with supplemental oxygen versus no supplemental oxygen as the single model variable. P val-
ues were derived from log-rank tests. For the components of the composite primary outcome (death and first hospi-
talization), a P value of less than 0.025 (0.05 divided by 2) was considered to indicate statistical significance, with the
use of a Bonferroni adjustment for multiple comparisons.22

B Death

A Primary Outcome (Death or First Hospitalization) or First Hospitalization

C
um

ul
at

iv
e

Pr
ob

ab
ili

ty

1.0

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.0
0 6 12 18 24 30 72

Months since Randomization

P=0.53 by log-rank test

No. at Risk
No supplemental oxygen
Supplemental oxygen

370
368

366
366

362
358

319
321

295
294

242
245

10
8

66

33
33

60

88
88

54

120
116

48

152
149

42

177
184

36

210
216

Supplemental oxygen

No supplemental oxygen

C
um

ul
at

iv
e

Pr
ob

ab
ili

ty

1.0

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.0
0 6 12 18 24 30 72

Months since Randomization

Death or first hospitalization, P=0.52 by log-rank test
First hospitalization, P=0.37 by log-rank test

No. at Risk
No supplemental oxygen
Supplemental oxygen

370
368

304
314

232
243

181
198

139
158

102
125

1
1

66

7
6

60

21
13

54

29
24

48

43
44

42

59
61

36

76
86

Supplemental oxygen, primary outcome
Supplemental oxygen, first hospitalization

No supplemental oxygen, primary outcome
No supplemental oxygen, first hospitalization

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n engl j med 375;17 nejm.org October 27, 2016 1623

Long-Term Oxygen for COPD with Moder ate Desatur ation

prescription, desaturation profile, race, sex,
smoking status, nadir Spo2 during exercise (the
10th lowest Spo2 observed during the 6-minute
walk), forced expiratory volume in 1 second,
BODE index, SF-36 physical-component score,
body-mass index, or history of anemia (Table S6
in the Supplementary Appendix).

Patients in the supplemental-oxygen group
who reported having had a COPD exacerbation
1 to 3 months before enrollment had a longer
time to death or first hospitalization than simi-
lar patients in the no-supplemental-oxygen group
(hazard ratio, 0.58; 95% confidence interval [CI],
0.39 to 0.88; P = 0.007 for interaction), as did
patients who were 71 years of age or older at
enrollment (hazard ratio, 0.75; 95% CI, 0.57 to
0.99; P = 0.03 for interaction) and those who had
a lower quality of life (Quality of Well-Being
Scale score, <0.55) at enrollment (hazard ratio,
0.77; 95% CI, 0.60 to 0.99; P = 0.03 for interac-
tion). However, none of these subgroup-by-
treatment interaction effects were significant
when the analysis was adjusted for multiple

comparisons. In the as-treated analysis, no dif-
ference was found between patients who used
oxygen for at least 16 hours per day and all
others. (Details are provided in Tables S6 and
S7 in the Supplementary Appendix.)

Adherence to Regimen

Histograms of self-reported use of supplemental
oxygen as averaged over follow-up indicate much
longer daily mean (±SD) use in the supplemental-
oxygen group than in the no-supplemental-oxygen
group (13.6±6.1 vs. 1.8±3.9 hours per day) (Fig. 2).
There was a separation of patients in the supple-
mental-oxygen group according to prescription
(15.1±6.2 hours per day in the 24-hour group vs.
11.3±5.0 hours per day in the sleep–exercise
group), but there was considerable overlap. A com-
parison of self-reported stationary concentrator
use with use that was calculated from meter
readings in 100 patients in the supplemental-
oxygen group who had available data showed a
significant linear trend in bias (P<0.001), in
which patients with less-than-average hours of

Outcome

No Supplemental
Oxygen

(N = 370)

Supplemental
Oxygen

(N = 368)
Hazard Ratio

(95% CI) P Value

Primary outcome

Death or first hospitalization for any cause 0.94 (0.79–1.12) 0.52

No. of events 250 248

Composite rate per 100 person-yr 36.4 34.2

Primary-outcome component events

Death 0.90 (0.64–1.25) 0.53

No. of deaths 73 66

Rate per 100 person-yr 5.7 5.2

First hospitalization for any cause 0.92 (0.77–1.10) 0.37

No. of first hospitalizations 237 229

Rate per 100 person-yr 34.5 31.6

* The primary outcome was death or first hospitalization for any cause, whichever came first, in patients randomly as-
signed to receive supplemental oxygen as compared with those assigned to receive no supplemental oxygen. For the
composite-event analysis, data from 120 patients in the supplemental-oxygen group and 120 in the no-supplemental-
oxygen group who neither died nor had a hospitalization were censored as of their last interview. For the analysis of
death, data for 302 patients in the supplemental-oxygen group and 297 in the no-supplemental-oxygen group who were
alive on August 31, 2015, were censored as of that date. For the analysis of the first hospitalization, data for 139 patients
in the supplemental-oxygen group and 133 in the no-supplemental-oxygen group were censored as of their date of death
(if there was no hospitalization before death) or as of the date of their last interview (if they were alive and had no hos-
pitalization). For the components of the composite primary outcome (death and first hospitalization), a P value of less
than 0.025 (0.05 divided by 2) was considered to indicate statistical significance, with the use of a Bonferroni adjust-
ment for multiplicity of comparisons.22 P values were calculated by the log-rank test. CI denotes confidence interval.

Table 2. Primary Composite Outcome of Death or First Hospitalization for Any Cause and Composite Events
in the Intention-to-Treat Population.*

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

daily use tended to overestimate their use and
those with greater-than-average hours of daily
use tended to underestimate their use (Fig. S2 in
the Supplementary Appendix).

Comparison with Design Assumptions

Fewer enrollees than expected were hospitalized
in the year before screening. However, more
patients than expected were hospitalized during
follow-up. Observed mortality rates compared
well with the design assumptions (Table S8 in
the Supplementary Appendix).

Other Outcomes

The two trial groups did not differ significantly
with regard to the rates of all hospitalizations
(rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD
exacerbations (rate ratio, 1.08; 95% CI, 0.98 to
1.19), COPD-related hospitalizations (rate ratio,
0.99; 95% CI, 0.83 to 1.17), or non–COPD-related
hospitalizations (rate ratio, 1.03; 95% CI, 0.90 to
1.18). (Fig. S3 and Table S9 in the Supplemen-
tary Appendix). We found no consistent differ-
ences between groups in the change from base-
line in measures of quality of life, anxiety,

Figure 2. Self-Reported Use of Supplemental Oxygen during Follow-up.

Shown are histograms of total self-reported hours of supplemental-oxygen use per day (sum of stationary use and
portable use) according to randomized assignment and prescription for supplemental oxygen (24-hour use or use
during sleep and exercise). Plus–minus values are means ±SD. The value plotted for a patient is the mean of all the
patient’s self-reports during follow-up. Self-reports were obtained 3 times yearly in the no-supplemental-oxygen
group. In the supplemental-oxygen group, self-reports were more frequent during year 1 (12 times) and were ob-
tained 3 times yearly thereafter. The median number of self-reports for a patient was 20 in the supplemental-oxygen
group (range, 6 to 20) and 8 in the no-supplemental-oxygen group (range, 0 to 18). All the patients in the supple-
mental-oxygen group provided at least one assessment; 363 patients (98%) in the no-supplemental-oxygen group
provided at least one assessment. IQR denotes interquartile range.

N
o.

o
f P

at
ie

nt
s

200

100

150

50

0
0 4 8 12 16 20 24

Hours per Day of Total Oxygen

A No Supplemental Oxygen

Median (IQR), 0 hr/day (0–1.7)
Mean, 1.8±3.9 hr/day

N
o.

o
f P

at
ie

nt
s

35

25

30

20

15

5

10

0
0 4 8 12 16 20 24

Hours per Day of Total Oxygen

B Supplemental Oxygen

Median (IQR), 13.1 hr/day (9.0–19.0)
Mean, 13.6±6.1 hr/day

N
o.

o
f P

at
ie

nt
s

35

25

30

20

15

5

10

0

35

25

30

20

15

5

10

0
0 4 8 12 16 20 24

Hours per Day of Total Oxygen

C Supplemental Oxygen, 24-Hr Prescription

Median (IQR), 15.6 hr/day (10.8–20.8)
Mean, 15.1±6.2 hr/day

N
o.

o
f P

at
ie

nt
s

0 4 8 12 16 20 24

Hours per Day of Total Oxygen

D Supplemental Oxygen, Sleep–Exercise Prescription

Median (IQR), 10.4 hr/day (7.9–14.2)
Mean, 11.3±5.0 hr/day

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n engl j med 375;17 nejm.org October 27, 2016 1625

Long-Term Oxygen for COPD with Moder ate Desatur ation

depression, or in lung function, distance walked
in 6 minutes, or other measures of functional
status (Fig. S4 and Table S10 in the Supplemen-
tary Appendix).

Adverse Events

A total of 51 adverse events were attributed to
the use of supplemental oxygen (Table S11 in the
Supplementary Appendix). There were 23 reports
of tripping over equipment, with two patients
requiring hospitalization. Five patients reported
a total of six instances of fires or burns, with
one patient requiring hospitalization.

Discussion

We found that the prescription of supplemental
oxygen for patients with stable COPD and rest-
ing or exercise-induced moderate desaturation
did not affect the time to death or first hospital-
ization, time to death, time to first hospitaliza-
tion, time to first COPD exacerbation, time to
first hospitalization for a COPD exacerbation,
the rate of all hospitalizations, the rate of all
COPD exacerbations, or changes in measures of
quality of life, depression, anxiety, or functional
status. We found no effect on the primary out-
come in subgroups of patients defined according
to desaturation type, prescription type, or adher-
ence to the regimen. The consistency of the null
findings strengthens the overall conclusion that
long-term supplemental oxygen in patients with
stable COPD and resting or exercise-induced
moderate desaturation has no benefit with regard
to the multiple outcomes measured.

Our data support the conclusions of earlier
studies that among patients with COPD who
have a resting Spo2 of more than 88%, long-term
treatment with supplemental oxygen does not re-
sult in longer survival than no long-term supple-
mental oxygen therapy, regardless of whether
the patients have exercise-induced desaturation.5,6,24
Our findings contrast with the prolonged survival
that was observed among patients with COPD
and severe desaturation who were treated with
supplemental oxygen.1,2 Possible reasons for this
discrepancy are the nonlinear threshold effects
of oxygen saturation on pulmonary vasoconstric-
tion, mediator release, and ventilatory drive,25,26
which occur with an Spo2 of 88% or less and
which may be more important in patients with
chronic hypoxemia.

A systematic review and meta-analysis sug-
gested that oxygen therapy may reduce dyspnea
in patients with COPD and mild or no hypox-
emia.27 We found no consistent benefit of long-
term supplemental oxygen with regard to mea-
sures of quality of life, depression, anxiety, or
functional status.

This trial has some limitations. First, some
patients may not have enrolled in the trial be-
cause they or their providers believed that they
were too ill or that they benefited from oxygen.
Highly symptomatic patients who declined en-
rollment might have had a different response to
oxygen than what we observed in the enrolled
patients. Second, the lack of masking may have
influenced some of the patient-reported out-
comes; however, it is unlikely to have influenced
the primary outcome. Third, we did not use uni-
form devices for oxygen delivery; it is possible
that there was variability in the amount of oxy-
gen delivered. Fourth, the immediate effects of
oxygen on symptoms or exercise performance
were not assessed. We did not measure noctur-
nal oxygen saturation; some patients with COPD
and severe nocturnal desaturation might benefit
from nocturnal oxygen supplementation.28,29 Fifth,
patients’ self-reported adherence may have been
an overestimate of their actual oxygen use. How-
ever, we found good agreement with the use as
measured by means of serial meter readings on
the concentrator. The estimated mean hours per
day of use in the supplemental-oxygen group
(15.1±6.2 hours per day in the 24-hour group
and 11.3±5.0 hours per day in the sleep–exercise
group) (Fig. 2) was similar to the use observed
in the Nocturnal Oxygen Therapy Trial (17.7 hours
per day in the continuous-oxygen group and
12.0 hours per day in the nocturnal-oxygen
group).1 However, we cannot exclude the pos-
sibility that longer exposures to oxygen in the
supplemental-oxygen group might have given
different results. Finally, because hospitalization
was recorded from self-report every 4 months,
it is possible that we underestimated the num-
ber of hospitalizations; however, there did not
appear to be systematic bias in follow-up be-
tween groups.

In conclusion, among patients with stable
COPD and resting or exercise-induced moderate
desaturation, we found that long-term supple-
mental oxygen did not provide any benefit with
respect to the time to death or first hospitaliza-

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T h e n e w e ngl a nd j o u r na l o f m e dic i n e

tion or any sustained benefit with respect to any
other measured outcome.

Supported by the National Heart, Lung, and Blood Institute,
National Institutes of Health and Department of Health and
Human Services (contract nos., HHSN268200736183C, HHSN-
268200736184C, HHSN268200736185C, HHSN268200736186C,
HHSN268200736187C, HHSN268200736188C, HHSN2682007361-
89C, HHSN268200736190C, HHSN268200736191C, HHSN268200-
736192C, HHSN268200736193C, HHSN268200736194C, HHSN-
268200736195C, HHSN268200736196C, HHSN268200736197C,
Y1-HR-7019-01, and Y1-HR-8076-01), in cooperation with the
Centers for Medicare and Medicaid Services, Department of
Health and Human Services.

Dr. Au reports serving on a data monitoring committee for
Novartis; Dr. Casaburi, serving on advisory boards for Boeh-
ringer Ingelheim, AstraZeneca, and Novartis and receiving con-
sulting fees from GlaxoSmithKline and Astellas Pharma, lecture
fees from Boehringer Ingelheim and AstraZeneca, and grant
support to his institution from Boehringer Ingelheim and No-
vartis; Dr. Cooper, receiving grant support from AstraZeneca;
Dr. Fuhlbrigge, serving on an adjudication committee for ICON
Medical Imaging, serving as an unpaid consultant for AstraZen-
eca, and receiving consulting fees from GlaxoSmithKline and
travel support from AstraZeneca; Dr. MacIntyre, receiving con-
sulting fees from Breathe Technologies and Ventec Life Systems;
Dr. Martinez, serving on steering committees for Bayer, Boeh-
ringer Ingelheim, Centocor, Gilead Sciences, Takeda Pharma-
ceuticals (formerly Nycomed), Afferent Pharmaceuticals, Forest
Laboratories, Janssen, GlaxoSmithKline, AstraZeneca, and Pearl
Therapeutics, serving on advisory boards for Boehringer Ingel-

heim, Genentech, Ikaria, Kadmon, Takeda Pharmaceuticals
(formerly Nycomed), Pfizer, Veracyte, Forest Laboratories, Jans-
sen, GlaxoSmithKline, AstraZeneca, Bellerophon Therapeutics
(formerly Ikaria), Novartis, Pearl Therapeutics, Roche, Sunovion
Pharmaceuticals, Theravance Biopharma, and Concert Pharma-
ceuticals, serving on a data and safety monitoring board for
Biogen (formerly Stromedix) and GlaxoSmithKline, and receiv-
ing fees for participating in continuing medical education ac-
tivities from AcademicCME, MedEd Consulting, Continuing
Education, Potomac Center for Medical Education, CME Incite,
Annenberg Center for Health Sciences at Eisenhower, Integritas
Communications, inThought Research, Miller Medical Com-
munications, Paradigm Medical Communications, PeerVoice,
HayMarket Communications, Prime Healthcare, WebMD, and
PeerView Academic Network, consulting fees from Axon Com-
munications, Johnson & Johnson, Clarion Communications,
Adept Field Solutions, Amgen, Proterixbio (formerly Bioscale),
Unity Biotechnology, and Lucid Communique Medical Educa-
tion, and lecture fees from AstraZeneca; Dr. Stoller, receiving
consulting fees from Baxalta, CSL Behring, Grifols, and Arrow-
head Pharmaceuticals; and Dr. Wise, receiving consulting fees
from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,
ContraFect, GlaxoSmithKline, Janssen, Mylan, Novartis, Pfizer,
Pulmonx, Roche, Spiration, Sunovion Pharmaceuticals, Teva
Pharmaceutical Industries, Theravance, Verona Pharma, and
Vertex Pharmaceuticals and grant support from Boehringer
Ingelheim, GlaxoSmithKline, Teva Pharmaceutical Industries,
and Pearl Therapeutics. No other potential conflict of interest
relevant to this article was reported.

Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

Appendix
The affiliations of the members of the writing group are as follows: University of Colorado, Denver (R.K.A.); Veterans Affairs (VA) Puget
Sound Health Care System and University of Washington, Seattle (D.H.A.); Johns Hopkins University School of Medicine (A.L.B., R.W.)
and Johns Hopkins University Bloomberg School of Public Health (D.S., J.T., A.L.S.), Baltimore; Los Angeles Biomedical Research In-
stitute at Harbor–UCLA Medical Center (R.C.) and Cedars–Sinai Medical Center (S.P.) — both in Los Angeles; Birmingham VA Medical
Center (J.A.C.) and the University of Alabama (J.A.C., W.B.), Birmingham; Lewis Katz School of Medicine at Temple University, Phila-
delphia (G.J.C.), and University of Pittsburgh, Pittsburgh (F.S.) — both in Pennsylvania; Ohio State University, Columbus (P.D.), Cincin-
nati VA Medical Center and University of Cincinnati College of Medicine, Cincinnati (R.J.P.), and Cleveland Clinic, Cleveland (J.K.S.)
— all in Ohio; Brigham and Women’s Hospital and Harvard Medical School, Boston (A.L.F.); University of Michigan, Ann Arbor
(S.E.G.); University of Utah Health Sciences Center, Salt Lake City (R.E.K.); Duke University Medical Center, Durham, NC (N.M.);
Weill Cornell Medical Center, New York (F.J.M.); Kaiser Permanente Center for Health Research, Portland, OR (T.S.); and Washington
University School of Medicine, St. Louis (R.D.Y.).

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O R I G I N A L R E S E A R C H

Short-Term Oxygen Therapy Outcomes in COPD
Thibaud Soumagne 1, François Maltais1, François Corbeil2, Bruno Paradis3, Marc Baltzan4,
Paula Simão5, Araceli Abad Fernández6, Richard Lecours7, Sarah Bernard1, Yves Lacasse 1

for the INOX Trial Group

1Quebec Heart and Lung Institute, Laval University, Quebec, Canada; 2Trois-Rivières Affiliated Hospital, Trois-Rivières, Canada; 3Laval Integrated
Center of Health and Social Services, Laval, Canada; 4Mount Sinai Hospital, McGill University, Montreal, Canada; 5Pedro Hispano Hospital,
Matosinhos, Portugal; 6Getafe University Hospital, Getafe, Spain; 7Hôtel-Dieu de Lévis Affiliated Hospital, Lévis, Canada

Correspondence: Yves Lacasse, Quebec Heart and Lung Institute – Laval University, 2725 Ste-Foy Road, Québec, P, Québec, G1V 4G5, Canada,
Tel +1 418-656-4747, Fax +1 418-656-4762, Email [email protected]

Rationale: Short-term oxygen therapy (STOT) is often prescribed to allow patients with chronic obstructive pulmonary disease (COPD)
to be discharged safely from hospital following an acute illness. This practice is widely accepted without being based on evidence.
Purpose: Our objective was to describe the characteristics and outcomes of patients with COPD who received STOT.
Patients and Methods: The study was a secondary analysis of the INOX trial, a 4-year randomised trial of nocturnal oxygen in
COPD. The trial indicated that nocturnal oxygen has no significant effect on survival or progression to LTOT, allowing our merging of
patients who received nocturnal oxygen and those who received placebo into a single cohort to study the predictors and outcomes of
STOT regardless of the treatment received during the trial.
Results: Among the 243 participants in the trial, 60 required STOT on at least one occasion during follow-up. Patients requiring
STOT had more severe dyspnoea and lung function impairment, and lower PaO2 at baseline than those who did not. STOT was
associated with subsequent LTOT requirement (hazard ratio [HR]: 4.59; 95% confidence interval [CI]: 2.98–7.07) and mortality (HR:
1.93; 95% CI: 1.15–3.24). The association between STOT and mortality was confounded by age, disease severity and comorbidities.
Periods of STOT of more than one month and/or repeated prescriptions of STOT increased the probability of progression to LTOT
(OR: 5.07; 95% CI: 1.48–18.8).
Conclusion: Following an acute respiratory illness in COPD, persistent hypoxaemia requiring STOT is a marker of disease
progression towards the requirement for LTOT.
Keywords: oxygen therapy, short-term, long-term, mortality, chronic obstructive pulmonary disease

Plain Language Summary
Short-term oxygen therapy (STOT) is often prescribed to allow patients with COPD to be discharged safely from hospital following an
acute illness. Persistent hypoxaemia after 1 month of STOT or more than 1 episode of STOT increase by 5 folds the probability of
progression to long-term oxygen therapy.

Introduction
Patients with chronic obstructive pulmonary disease (COPD) may temporarily become severely hypoxemic during an
acute exacerbation of the disease requiring hospitalization.1 In such circumstances, oxygen therapy for at least 15 to 18
hours per day may be prescribed for a short period of time (usually up to 3 months before reassessment)2 to allow
patients to be discharged safely from hospital. This is referred to as “short-term oxygen therapy” (STOT)2 and appears to
be a common medical practice, although it is not based on evidence.3,4

Close follow-up of patients who are prescribed STOT is important. Studies in patients with COPD who received STOT in
the course of an acute exacerbation indicate that up to 60% of such individuals will remain severely hypoxemic at 3-month
follow-up and will require that supplemental home oxygen be continued.5–9 STOT then becomes long-term oxygen therapy

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International Journal of Chronic Obstructive Pulmonary Disease Dovepress
open access to scientific and medical research

Open Access Full Text Article

Received: 30 March 2022
Accepted: 21 July 2022
Published: 28 July 2022

(LTOT) delivered in most cases for the remainder of the patient’s life. It is, however, recommended that oxygen be
discontinued upon re-evaluation in those whose partial pressure in oxygen in arterial blood (PaO2) improves to the point
that it exceeds the criteria for LTOT prescription.4 Unfortunately, formal reassessment of these patients is often neglected.
Supplemental home oxygen following hospitalisation for an acute illness is often renewed without assessing patients for
ongoing hypoxaemia.10–12 This situation has been identified by the Choosing Wisely initiative as one of the top five areas of
improvement in adult pulmonary medicine.13

Characteristics of patients who received STOT in convalescence from an exacerbation, predictors of persisting severe
hypoxaemia and long-term prognosis following STOT have not been well studied. This information is important in the
development and testing of strategies to securely discontinue home oxygen in patients who recover sufficiently after an
exacerbation.4 Our objectives were therefore to describe the characteristics and outcomes of patients with COPD who
received STOT and to determine factors associated with the requirement of LTOT after STOT.

Material and Methods
Study Subjects
Patients were recruited from November 2010 to January 2015 in 28 community and university affiliated hospitals in
Canada, Portugal, Spain and France.14 Patients with a diagnosis of COPD (defined by a postbronchodilator forced
expiratory volume in 1 second [FEV1] <70% of the predicted value, a ratio of the FEV1 to the forced vital capacity
[FVC] <0.70, and a total lung capacity as measured by body plethysmography >80% of the predicted value, concurrently
with a history of smoking) were included. All had isolated nocturnal oxygen desaturation (defined on the home oximetry
as ≥30% of the recording time (time in bed) with a transcutaneous arterial oxygen saturation <90%).15 Also, all had
stable disease for at least 6 weeks before enrolment and had not smoked for at least 6 months.

Exclusion criteria were severe daytime hypoxaemia according to the Nocturnal Oxygen Therapy Trial (NOTT)
criteria (PaO2 ≤55 mmHg while breathing ambient air, or a PaO2 56–59 mmHg with evidence of cor pulmonale or
erythrocytosis),16 sleep apnoea (apnoea/hypopnea index of ≥15 events/hour), current use of nocturnal oxygen and
significant respiratory or cardiovascular diseases other than COPD that may influence survival.

Study Design
This study was a secondary analysis of the INOX trial (ClinicalTrials.gov ID: NCT01044628), a 4-year, multi-centre,
randomised, double-blind, placebo-controlled trial assessing nocturnal oxygen therapy in COPD.14,17 The INOX trial
received full approval from the Ethics Committee of the principal investigator’s institution (Institut universitaire de
cardiologie et de pneumologie de Québec; CER-20490) and from the Ethics Committee of all the participating centers.
The INOX trial was conducted in accordance with the Declaration of Helsinki. All participants gave informed consent.
The INOX trial indicated that nocturnal oxygen has no significant effect on the primary outcomes of survival or
progression to LTOT in patients with isolated nocturnal desaturation. These results allowed our merging of patients
who received nocturnal oxygen during the trial and those who received placebo (sham oxygen therapy with a modified
O2 concentrator delivering room air) into a single cohort to study the predictors and outcomes of STOT regardless of the
treatment received during the trial.

Short-Term Oxygen Therapy
As per protocol, STOT could be provided during the course of the trial in case of acute respiratory illness (eg, acute
exacerbation of COPD or pneumonia) necessitating or not hospitalisation. Patients’ evaluation and treatment were then
under the responsibility of the treating physician. STOT prescription criteria were not protocol-based. We assumed that
STOT was only provided to those who were found to be severely hypoxemic during the day (eg, SpO2 ≤88% or paO2 ≤55
mmHg), and that it was prescribed for at least 15–18 hours per day at a flow that increased SpO2 to at least 90%. During
STOT, patients were asked not to use their study concentrator (to avoid those on placebo to receive ambient air) and were
provided with another oxygen concentrator that was effective. However, protocol-based follow-up was mandatory within
90 days following STOT prescription. Upon re-evaluation, patients who remained severely hypoxemic according to the

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NOTT criteria were continued on LTOT. Otherwise, oxygen therapy was discontinued and patients were returned to their
original treatment assignment within the trial (nocturnal oxygen or placebo).

Data Collection and Follow-Up
Baseline clinical measurements included the Charlson comorbidity index,18 spirometry, lung volumes measured by
plethysmography, carbon monoxide diffusion capacity (TLCO) measured by the single-breath method and arterial blood
gas measurements. Patients were followed for 3 to 4 years. They were contacted by telephone every 2 months in order to
collect adverse events. On-site visits took place every 4 months for clinical assessment, including pulse oximetry. Arterial
blood gas and lung function tests were obtained every 12 months or more frequently is required. To describe lung
function at the time of STOT, we used the data obtained in stable condition at the closest point in time. The primary
outcomes of this secondary analysis were mortality and progression to LTOT in the course of the trial.

Statistical Analysis
Data are presented as number (percent) and mean ± standard deviation (or median with interquartile range) for qualitative
and quantitative variables, respectively. Quantitative variables were compared with Student’s t-tests or Wilcoxon tests, as
appropriate whereas qualitative variables were compared using chi-square or Fisher exact tests. In case of multiple
episodes of STOT during the trial, the analysis considered only its first occurrence. The mean numbers of exacerbations
and hospitalisations per patient-year were compared between groups with the use of a Poisson distribution with
overdispersion correction.19 We constructed survival curves using Kaplan–Meier estimates and used the Log rank test
to compare the outcome of those who received STOT during the trial and those who did not. Hazard ratios and 95%
confidence intervals for death or requirement for long-term oxygen therapy were estimated with the use of Cox
regression models. Finally, to identify factors associated with progression to LTOT, multivariate logistic regression
analysis with backward stepwise selection was performed among patients requiring STOT. In this analysis, duration of
STOT was transformed into a dichotomous variable by using receiver-operating characteristics (ROC) analysis to
determine the threshold at which STOT duration best predicted progression to LTOT with minimal false prediction
rate. We also computed the area under the ROC curve to indicate the probability that a random pair of patients, one
progressing to LTOT but not the other, will be correctly classified as to their disease state.20 All variables associated with
progression to LTOT in the univariate analysis with a p value of less than 0.20 were included. Statistical analysis was
performed with R version 4.0.3 and RStudio version 1.4.1103 (R Foundation for Statistical Computing, Vienna, Austria).

Results
Patients
A total of 243 patients were enrolled in the INOX trial; 60 (25%) required STOT on at least one occasion during follow-
up (Figure 1). The main reason for initiating STOT was an acute exacerbation of COPD in 53 patients (88%). Nine
patients received STOT more than once during the trial: STOT was prescribed in 2 and 3 occasions in 7 and 2 patients,
respectively. Baseline characteristics of patients who received STOT are compared with those who did not in Table 1.
Patients requiring STOT during follow-up were significantly older and had higher dyspnoea, more severe lung function
impairment, and lower PaO2 at baseline than those who did not. The proportion of patients who received nocturnal
oxygen or placebo (sham nocturnal oxygen therapy) was similar in the STOT and the non-STOT groups.

Progression to LTOT
During the trial, 84 patients progressed to LTOT, including 42 of the 60 (70%) patients who previously required STOT
and 42 of the 183 (23%) who did not. Among the 42 patients who received STOT and who finally required LTOT, 34
(81%) were prescribed LTOT immediately after STOT (ie, upon re-evaluation while still receiving STOT), and 8 (19%)
had an oxygen-free interval (excluding nocturnal oxygen or placebo) between STOT and LTOT (median interval of 240
days). Survival analysis indicated that STOT was significantly associated with subsequent LTOT requirement

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(Figure 2A). This association remained significant after adjusting for age, FEV1, TLCO, dyspnoea score and PaO2

(adjusted hazard ratio 3.79; 95% CI 2.29–6.27).

Mortality
Sixty-one patients died during follow-up, including 23 of the 60 (38%) patients who previously required STOT and
38 of the 183 (21%) who did not. STOT requirement was significantly associated with mortality (Figure 2B).
However, this association was not significant after adjusting for confounders associated with mortality including
age, Charlson comorbidity index, FEV1, TLCO, dyspnoea score and PaO2 (adjusted hazard ratio 1.57; 95% CI
0.87–2.81).

Factors Associated with LTOT Among Patients Requiring STOT
Patients who progressed to LTOT had a significantly longer duration of STOT and more severe airway obstruction (post-
BD FEV1/FVC) at the time of first STOT prescription (Table 2). Demographics, symptoms, quality of life, exacerbation
rate, and hospitalisation rate did not differ at the time of first STOT prescription between patients who ultimately required
LTOT and those who did not. ROC analysis indicated that a STOT duration of >32 days best predicted progression to
LTOT with an area under curve of 0.69 (95% CI: 0.55–0.83), with a positive predictive value of 83%.

Table 3 shows the results of the univariate and multivariate analyses in the subgroup of patient requiring STOT (n =
60) for the association between LTOT and several selected variables. Multivariate analysis showed that requirement for
LTOT was significantly associated with a duration of STOT > 32 days and/or several prescriptions of STOT and a lower
FEV1/FVC ratio.

Discussion
The results of this study indicate that patients with COPD who required STOT in the course of an acute respiratory illness
had more severe disease than those who did not and progressed more frequently towards LTOT during follow-up. The
association between STOT and increased mortality was confounded by age, poor lung function and comorbidities.
Requirement for STOT for more than one month and/or repeated periods of STOT represent independent predictors for
progression towards LTOT.

Figure 1 Patient flow diagram. See14 for more details.

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The requirement for LTOT should be determined when the patient is in stable condition according to prescription
criteria that are derived from the inclusion criteria of the NOTT and the MRC trial and are well accepted
worldwide.16,21,22 On the contrary, STOT is provided during a period of clinical instability and its prescription criteria
are ill-defined. Most clinicians will consider providing their patients with home oxygen at hospital discharge if severe
resting hypoxaemia persists. Previous studies of STOT used the same prescription criteria as for LTOT (PaO2 ≤55 mmHg
at rest, or a PaO2 <60 mmHg with evidence of cor pulmonale or erythrocytosis).6,10 Although reasonable, these criteria
are not based on evidence.

The prescription of STOT at hospital discharge is first and foremost a matter of safety. Important clinical outcomes
include hospital readmission for respiratory failure, incidence of arrhythmia, myocardial ischemia or heart failure, quality
of life and mortality. The real impact of STOT on these outcomes is unclear however. It is very unlikely that a clinical
trial of STOT will ever be conducted for obvious reasons. Nevertheless, STOT is usually prescribed in the course of acute
exacerbations of COPD that are themselves associated with increased morbidity and mortality, irrespective of the
presence of severe hypoxaemia.23 The one-year mortality rate after a severe exacerbation requiring hospitalisation
ranges from 20% to 43%.24–26 In one study, the most frequent causes of death at 1-year follow-up were respiratory
and cardiovascular disorders.26 Hypoxaemia and requirement for oxygen therapy at discharge have also been reported as
independent predictors of long-term mortality.27–29 We would consider these findings as justifications for STOT when
severe hypoxaemia persists at hospital discharge.

In our opinion, the issue is not to determine whether or not STOT is truly indicated at hospital discharge. Rather, the
question is whether or not STOT should be discontinued, and if so, when is the most appropriate duration of STOT prior

Table 1 Baseline Characteristics of Patients

Short-Term Oxygen
Therapy

No Short-Term Oxygen
Therapy

p value

(n = 60) (n = 183)

Demographics

Age, years 71.0 ± 6.8 68.1 ± 9 0.02
Male sex, n (%) 37 (62) 121 (66) 0.39

BMI, kg/m2 26.1 ± 5.3 26.7 ± 5.3 0.44

Smoking history, pack years 65.2 ± 36.6 58.7 ± 37.3 0.24
Charlson comorbidity index 1.4 ± 0.8 1.4 ± 0.8 0.78

MRC dyspnoea scale (1–5) 3.7 ± 1 3.1 ± 1.1 0.001

Lung function
Post-BD FEV1, L 0.86 ± 0.31 1.06 ± 0.41 <0.001

Post-BD FEV1, % predicted value 37.0 ± 11.9 42.9 ± 14.9 0.005

Post BD FEV1/FVC, % 0.39 ± 0.10 0.42 ± 0.12 0.08
DLCO, mL/min/mmHg 9.9 ± 5.7 12.8 ± 8.3 0.02

DLCO, % predicted value 46.2 ± 23.7 59.1 ± 38 0.02

Inhaled therapy 0.82
LABA, LAMA or both 6 (10) 24 (13)

LAMA + ICS or LABA + ICS 5 (8) 15 (8)

Triple therapy 49 (82) 144 (79)
Arterial blood gas and nocturnal oximetry

pH 7.42 ± 0.03 7.42 ± 0.03 0.25

PaO2, mmHg 65.0 ± 6.4 67.8 ± 7.1 0.009
PaCO2, mmHg 43.6 ± 7.7 41.3 ± 5.6 0.01

Mean nocturnal SpO2, % 88.0 ± 2.4 88.9 ± 2.1 0.003

Percentage of time with nocturnal Spo2 of <90% 79.4 ± 23.4 71.8 ± 22.4 0.02
NOT/placebo group in the INOX trial 31/29 92/91 0.85

Note: Data are presented as mean ± standard deviation or number (percentage).
Abbreviations: BMI, body mass index; BD, bronchodilator; FEV1, forced expiratory volume in one second; FVC, forced vital capacity, diffusing capacity of the
lung for carbon monoxide; LABA, long-acting β2 agonist; LAMA, long-acting muscarinic agents; ICS, inhaled corticosteroids; NOT, nocturnal oxygen therapy.

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to re-evaluation. Several national practice guidelines recommend reassessing the need for oxygen within 2 to 3
months.3,4,30 In previous studies, between 16% and 56% of patients who were prescribed STOT do not recover from
severe hypoxaemia and progress toward LTOT.5–9 In the INOX trial, 70% of those who received STOT ultimately
required LTOT. We also found that periods of STOT of more than one month and repeated prescriptions of STOT
increased by 5 times the probability of progression to LTOT. Since LTOT improves survival,16,21 we submit that LTOT

Figure 2 Kaplan–Meier analyses of LTOT requirement and mortality. (A) Shows the results for the requirement for long-term oxygen therapy (LTOT) according to the
Nocturnal Oxygen Therapy Trial criteria. (B) Shows the results for the separate component of death. Data were censored at the date of dis-continuation of the intervention
or last visit.

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should be considered in patients who remain severely hypoxemic one month after being discharged from hospital or who
have received more than one episode of STOT. Arterial blood gas measurement should be preferred to pulse oximetry to
determine the need for LTOT.31 If severe hypoxaemia persisted, STOT would then become LTOT.

Our study has limitations. First, the prescriptions of STOT were not based on protocol. We assumed that STOT was
only provided to those who were found to be severely hypoxemic (eg, SpO2 ≤88% or paO2 ≤55 mmHg). This practice is
widespread and well accepted.3,4 Second, our study is a secondary analysis of a clinical trial in patients with isolated

Table 2 Characteristics of Patients at the Time of First Short-Term Oxygen Therapy (n = 60)

LTOT No LTOT p value
(n = 42) (n = 18)

Time between baseline and STOT, days 522 ± 339 768 ± 435 0.07

Time between baseline and STOT, days (median, IQR) 508 (219–836) 769 (332–1275)

Duration of first STOT, days 64 ± 62 34 ± 64 0.03
Duration of first STOT, days (median, IQR) 52 (31–73) 30 (21–49)

Demographics

Age, years 72.7 ± 5.6 71.9 ± 6.0 0.83
Charlson comorbidity index 1.2 ± 0.7 1.5 ± 0.7 0.23

Symptoms and quality of life

MRC dyspnoea scale (1–5) 3.6 ± 1.2 3.9 ± 1.1 0.42
SGRQ 55.5 ± 19.0 61.1 ± 16.9 0.46

SF-36 score: physical component 35.8 ± 10.6 31.6 ± 9.8 0.14

SF-36 score: mental component 39.8 ± 13.1 38.2 ± 13.3 0.67
Lung function

Post-BD FEV1, %predicted 34.8 ± 12.7 39.3 ± 13 0.20

Post BD FEV1/FVC, % 37.6 ± 9.4 44.9 ± 9.7 0.009
DLCO, %predicted 41.7 ± 21.2 41.5 ± 18.8 0.98

Events

Acute exacerbations treated at home 95 54
Rate per person-year 1.75 (1.42–2.15) 1.70 (1.30–2.24) 0.88

Hospitalisations for any cause 41 23

Rate per person-year 0.76 (0.55–1.03) 0.73 (0.48–1.10) 0.88
Hospitalisations for respiratory conditions, nb of events 32 14

Rate per person-year 0.59 (0.41–0.84) 0.44 (0.26–0.76) 0.37

NOT/placebo in the INOX trial 20/22 11/7 0.34

Note: Data are presented as mean ± standard deviation or rate (95% confidence interval), unless otherwise specified.
Abbreviations: IQR, interquartile range; for other abbreviations, see Table 1.

Table 3 Risk Factors for LTOT in Patients Requiring STOT (Univariate and Multivariate Analysis)

Variable Univariate p value Multivariate p value

OR 95% CI OR 95% CI

Age 1.02 (0.93–1.11) 0.70

Charlson comorbidity index 0.66 (0.31–1.34) 0.25
Post-BD FEV1, %predicted 0.97 (0.93–1.02) 0.20

Post BD FEV1/FVC, % 0.92 (0.86–0.98) 0.02 0.93 (0.87–0.99) 0.03
DLCO, %predicted 1.00 (0.97–1.03) 0.98

Duration of first STOT, days 1.03 (1.01–1.06) 0.03

Duration of first STOT > 32 days 5.00 (1.58–17.4) 0.008
Number of prescriptions of STOT 0.78 (0.25–2.74) 0.67

More than 1 prescription of STOT 0.83 (0.19–4.35) 0.81

Duration of STOT > 32 days and/or more than 1 prescription of STOT 5.76 (1.79–20.16) 0.004 5.07 (1.48–18.8) 0.01

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nocturnal desaturation. It has been suggested that this phenomenon may represent an independent risk factor for the
development of chronic hypoxaemia in patients with COPD.32 Whether our results apply to all patients with COPD is
uncertain. However, the INOX trial indicated that nocturnal oxygen has no significant effect on survival or requirement to
LTOT.14 In addition, we confirmed that nocturnal oxygen therapy had no effect on the requirement of STOT.

Conclusion
Our study emphasizes the recommendation to closely follow patients discharged from hospital with STOT. Requirement
for STOT at hospital discharge in the course of an acute respiratory illness in COPD is a factor of poor prognosis. We
also identified predictors of progression to LTOT in patients who received STOT. We suggest that continuing LTOT in
patients who remain severely hypoxemic after a period of one month of home oxygen therapy and/or in those who have
more than one episode of STOT may be considered.

Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design,
execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically
reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article
has been submitted; and agree to be accountable for all aspects of the work. A complete list of the investigators in the
International Nocturnal Oxygen (INOX) Trial Group is provided in the Online Supplement.

Funding
Funded by the Canadian Institutes of Health Research (Grant MCT99512). The sponsor was not involved in any of the
stages of this study from the design to the submission of the manuscript for publication.

Disclosure
T Soumagne has no conflict of interest to disclose. F Maltais reports grants from GlaxoSmithKline, AstraZeneca, Sanofi,
Novartis, Boehringer Ingelheim, and Grifols, and personal fees for serving on speaker bureaus and consultation panels
from GlaxoSmithKline, Boehringer Ingelheim, Grifols, and Novartis; he is financially involved with OxyNov, a company
which is developing an oxygen delivery system. F Corbeil, B Paradis, M Baltzan, P Simão, A Abad Fernández,
R Lecours and S Bernard have no conflict of interest to disclose. Y Lacasse reports participation in Innovair,
a company that holds shares in OxyNov, the owner of FreeO2, an automated oxygen delivery system.

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