Long-term oxygen therapy may not reduce mortality in patients with stable COPD and non-severe resting hypoxemia or exercise-induced hypoxemia

EBM Focus - Volume 11, Issue 46

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Reference – N Engl J Med 2016 Oct 27;375(17):1617 (level 2 [mid-level] evidence)

  • Long-term oxygen therapy (LTOT) is recommended for patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia, but efficacy of LTOT for patients with COPD and non-severe hypoxemia is uncertain.
  • The recent Long-Term Oxygen Treatment Trial randomized 738 adults ≥ 40 years old with stable COPD and non-severe resting hypoxemia or exercise-induced hypoxemia to LTOT vs. no oxygen therapy for 1-6 years.
  • LTOT in these patients did not significantly reduce mortality (in 17.9% with LTOT vs. 19.7% with no oxygen therapy) or improve other clinical outcomes, though a meaningful reduction in mortality cannot be excluded.

For patients with COPD and severe resting hypoxemia, LTOT increases survival (Ann Intern Med 1980 Sep;93(3):391, Lancet 1981 Mar 28;1(8222):681) and is recommended by professional organizations (Global Initiative for Chronic Obstructive Lung Disease 2016, Ann Intern Med. 2011 Aug 2;155(3):179-91). However, for patients with non-severe hypoxemia, LTOT has not been shown to increase survival (Eur Respir J 1999 Nov;14(5):1002, Thorax 1997 Aug;52(8):674, Am Rev Respir Dis 1992 May;145(5):1070), though all of these trials were small. Based on this evidence, recommendations regarding LTOT for patients with non-severe hypoxemia have not been made. The recent Long-Term Oxygen Treatment Trial randomized 738 adults ≥ 40 years old with stable COPD and resting oxygen SpO2 89%-93% or exercise-induced SpO2 80%-89% to LTOT vs. no oxygen therapy for 1-6 years. Patients were excluded for recent COPD exacerbations requiring antibiotics or systemic corticosteroids, recent thoracic surgery or other possible causes of pulmonary instability, serious comorbidities that may lead to death during the trial, other conditions that may affect oxygenation, and

< 10 pack-years of cigarette smoking history. Patients in the LTOT group received either 24-hour therapy or oxygen during sleep and exercise, depending on their specific condition. Patients in the no oxygen therapy group received supplemental oxygen if they developed severe hypoxemia; these patients were reevaluated after 30 days.

There was not a statistically significant difference between groups in mortality, with death occurring in 17.9% with LTOT vs. 19.7% with no oxygen therapy (hazard ratio of 0.9 [95% CI 0.64-1.25]). There was also no significant difference in the combined outcome of death or first hospitalization for any cause (in 67.4% vs. 67.6%, with consistent results in most subgroup analyses based on demographics and clinical characteristics). Finally, there were no significant differences between groups in rates of COPD exacerbations, changes in quality of life, or other clinical outcomes. Adverse events related to oxygen therapy were reported in 8.6% and included 6 fires or heat-induced burns, 4 liquid oxygen-induced burns, 23 instances of tripping or falling over the oxygen therapy equipment (2 of which resulted in hospitalization), and additional minor events.

The results of this trial show that, in patients with stable COPD and non-severe resting hypoxemia or exercise-induced hypoxemia, long-term oxygen therapy (LTOT) does not clearly reduce mortality or improve clinical outcomes, consistent with results of smaller trials. However, this trial was originally designed to assess the effect of LTOT only on mortality and only in patients with stable COPD and non-severe resting hypoxemia. After 7 months and 34 enrolled participants, a lower than projected mortality rate instigated a redesign to also include patients with exercise-induced hypoxemia and to assess the combined outcome of times to death or first hospitalization as the primary outcome. Hence, this trial may be underpowered to detect differences between groups in mortality alone, and this is reflected in the 95% confidence interval for the hazard ratio (0.64-1.25), which includes the possibility of a meaningful reduction in mortality with LTOT. It is also worth keeping in mind that this trial does not address the use of oxygen for short-term reasons or in individuals with particular clinical characteristics that may warrant oxygen therapy. Nevertheless, this trial provides evidence from a large trial suggesting that careful consideration should be used before recommending LTOT in patients with stable COPD and non-severe resting hypoxemia or exercise-induced hypoxemia.

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