By James K. Stoller, MD, MS
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For patients with chronic obstructive pulmonary disease (COPD), supplemental oxygen has been shown to be life-prolonging for individuals with severe resting room air hypoxemia. Specifically, the time-honored Nocturnal Oxygen Treatment Trial (NOTT) and the Medical Research Council study showed that supplemental oxygen used continuously (i.e., as close to 24 hours per day as possible) was significantly associated with enhanced survival for individuals whose resting room air PaO2 was ≤ 55 mm Hg or 56-59 mm Hg with accompanying polycythemia or cor pulmonale. On the basis of these studies, the Centers for Medicare and Medicaid Services (CMS) currently supports and funds prescribing supplemental oxygen for individuals with COPD who satisfy the following indications:
- Resting room air PaO2 < 55 mm Hg or SaO2 < 88%
- Resting room air PaO2 56-59 mm Hg with “P” pulmonale on electrocardiogram, polycythemia > 55%
- Exercise desaturation to SaO2 < 88% or sleep desaturation not corrected by CPAP
In this context, supplemental oxygen currently accounts for a $2 billion expenditure in the United States.
Addressing the question
In contrast to the clarity that supplemental oxygen benefits COPD patients with severe resting hypoxemia, the role of supplemental oxygen in COPD patients with moderate resting hypoxemia or with isolated exercise desaturation remains unclear. Indeed, small studies by Gorecka et al and by Chaouat et al have failed to demonstrate that supplemental oxygen confers benefit for COPD patients whose resting room air PaO2 were 56-65 mm Hg and 56-69 mm Hg, respectively.
To address this common and naggingly unclear issue for clinicians, the National Heart, Lung, and Blood Institute and CMS have sponsored the recently published Long-Term Oxygen Treatment Trial (LOTT), which was an unblinded, randomized controlled trial of supplemental oxygen for COPD patients with moderate resting hypoxemia and/or exercise desaturation. The LOTT trial was conducted in 42 centers throughout the United States, including Cleveland Clinic.
LOTT recruited 738 COPD patients whose resting SpO2 was 89-93% and/or who desaturated with activity (defined as desaturating to SpO2 < 90% for > 10 seconds but remaining > 80% SpO2 for > 5 minutes on a 6-minute walk test). Participants were randomized to a control group (which received no supplemental oxygen) versus an intervention group, which received either supplemental oxygen at rest and during sleep for patients with resting moderate hypoxemia, or supplemental oxygen with activity and sleep alone for those patients whose resting room air SpO2 values exceeded 93% but who satisfied desaturation criteria as outlined above.
The primary outcome measure of LOTT was time to death or first hospitalization, with patient follow-up for one to six years (median follow-up 18.4 months). In a time-to-event analysis, no significant difference between the supplemental oxygen group and the control group was observed in time to death or first hospitalization. Similarly, no difference between groups was observed in rates of all hospitalizations, COPD exacerbations or COPD-related hospitalizations. A variety of other measures of quality of life, lung function, and distance walked in 6 minutes were also assessed (e.g., the St. George’s Respiratory Questionnaire, the Quality of Well-Being scale, the SF36, the Hospital Anxiety and Depression scale, the Pittsburgh Sleep Quality index, etc.). Notably, in secondary analysis of pre-specified groups, the only groups who demonstrated a benefit from using supplemental oxygen were those who experienced a COPD exacerbation between one and three months before enrollment into LOTT and patients > 71 years old at the time of study enrollment.
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 receive long-term supplemental oxygen (supplemental-oxygen group) and 120 assigned to receive no long-term supplemental 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 hospitalization). 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 values were derived from log-rank tests. 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 adjustment for multiple comparisons. Figures and legends reproduced with permission from the Massachusetts Medical Society.
Figure 2. Primary Composite Outcome of Death or First Hospitalization for Any Cause and Composite Events in the Intention-to-Treat Population]
The LOTT trial is among the landmark studies in COPD because it addresses a critically important, everyday clinical question that had remained unanswered for many years until LOTT. To the extent that LOTT showed no benefit of supplemental oxygen in most of the COPD patients studied, we expect that the results of this trial will change prescribing patterns for patients with COPD and moderate resting hypoxemia or isolated exercise desaturation; specifically, clinicians may no longer prescribe supplemental oxygen for stable COPD patients who desaturate to the level studied in LOTT.
Several important caveats must be considered in interpreting the results of this landmark trial. First, the results do not reliably apply to COPD patient groups who were not included in the study, e.g., those who severely desaturate with activity (i.e., to < 80% SpO2 on exercise for > one minute). Similarly, as all LOTT patients were stable for at least one month, the results do not apply to COPD patients who desaturate on being discharged from the hospital after a COPD exacerbation.
As with so many other important NIH-sponsored clinical trials or observational studies in which Cleveland Clinic Respiratory Institute has participated (e.g., the Registry for Individuals with Severe Deficiency of Alpha-1 Antitrypsin, the Lymphangioleiomyomatosis Registry, the Severe Asthma Research Network and the ARDSNet trial), LOTT presents another powerful example of how Cleveland Clinic Respiratory Institute is fulfilling its tripartite mission of “better care of the sick, investigation of their problems, and more teaching of those who serve.”
Dr. Stoller is Chair of Cleveland Clinic’s Education Institute and a practicing pulmonologist.