PICOT Question:    Use of Oxygen to help with Hypoxia and Organ Failure in patients with COPD.    1) Students will be placed into groups by the end of the second week of the s

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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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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

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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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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- subg