In which oxygen is necessary, but not sufficient for life: A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation

Oxygen: You’re probably using it. But is it helping you? Ok, yes, fine, but: Who would be better off with more? The Long-Term Oxygen Treatment Trial Research Group, whose expertise in descriptive naming is surpassed only by their hunger for oxygen-related knowledge, set out to more exactly answer that question in A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation.

Patients, Intervention, Comparator, and Outcomes

738 patients at 47 centers with stable COPD and moderate resting desaturation (SpO2 89-93% at rest) or desaturation on ambulation (SpO2 > 80% but 90% for use with exertion, as well as 2L during sleep. The primary outcome was time to death or first hospitalization for any cause.  There were an array of secondary outcomes, including incidence of COPD exacerbation and performance on 6-minute walk testing. Median follow up was 18.4 months.

To clarify, this both is and is not a different group of patients than currently qualifies for oxygen prescription. Currently Medicare (and as a result most private insurance) requires resting sat < 88% to qualify for O2, lower than the resting threshold for this study. However, the threshold for desats with ambulation was identical to current requirements. So this study is simultaneously addressing two questions: Are there patients whose resting saturation does not currently qualify them for oxygen who might benefit from it? And are the patients whose desaturations with exertion already qualify them for oxygen actually deriving any benefit?

A Bit of Context

As this 2010 review in Chest by the same group summarizes, there has been quite a bit of work on supplemental oxygen for COPD. First, way back in 1981 we learned that people with severe desaturations (PaO2 17 hours/day rather than continuous) in that population; however, the total number of patients enrolled was 153, and the length of follow up 3 years.

With regard to exercise-induced desaturations, it’s well established that these are bad news. Multiple both retrospective and cohort studies have established that desaturation during exercise is predictive of mortality. A few studies have shown an improvement in exercise tolerance with oxygen, but no study has assessed a mortality benefit for long-term supplemental oxygen in this population. The fact that Medicare pays for oxygen in that population anyway is probably driven by the well-documented mortality increase, as well as an increase in exercise capacity, rather than mortality benefit.

The authors note that Medicare spent $1.4 billion on home oxygen and related supplies in 2015 (they choose to quote a more impressive but out of date 2011 number of > $2 billion), but the impact of home oxygen (and other DME, for that matter) on the medicare budget should not be presented without context.  For some perspective, they spent $31.3 billion on skilled nursing facility care and $139.1 billion on inpatient hospitalization all of which is best viewed as a tiny sliver of the almost $600 billion annual Medicare budget (take a look at all of these figures here with your copious free time). Additionally, it might reasonably be posited that if it improves mortality or decreases the frequency of hospitalizations, these might be very cost effective dollars, and as such that we should be spending more of them and not less.

Results

Man those Kaplan-Meier curves are really good friends. One might even say… inseparable. Ahem. There was no difference in time-to-event analysis for the primary outcome in the study population as a whole, nor when broken down by desat at rest versus ambulation. (For the record, 18% of patients had resting desats alone and 43% had ambulatory desats alone, with the remaining 49% meeting both criteria.) In an “as-treated” analysis, patients who used oxygen for > 16 hours per day had outcomes no better than their less adherent counterparts. And as a real kick in the pants, oxygen did not increase quality of life, exercise capacity, or mean time to COPD exacerbations.

So it’s a negative study, but note that the authors set themselves a high bar: They powered the study to have 90% detection for a HR of 0.60. That’s right, they went looking for a 40% mortality reduction, knowing full well they might miss smaller effect sizes due to type II error. And to look for this over only 18.4 months of median follow up is asking for a large effect in a relatively short time. However, note that the benefit in patients with severe desaturations was found within the first 12 months.

So maybe 88% is the magic cutoff! The authors note that oxygen desaturations have non-linear effects on physiology, and the difference between 88 and 90% might reasonably be important. Regardless of why, this study does make it fairly difficult to justify paying for oxygen for people who do not desat below 88% at rest. Without at least a tangible exercise tolerance or quality of life benefit, it’s unclear how this could be worth it.

Bottom Line

While supplemental oxygen has previously been shown to improve mortality in patients with severe resting desaturations (PaO2 < 55), it was found not to have an effect on mortality, time to hospitalization, 6-minute walk test performance, or quality of life for patients with moderate resting desaturations (SpO2 89-93%) or desaturations with exercise only.

Read the study here.

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