Articles
Home oxygen for moderate hypoxaemia in chronic obstructive pulmonary disease: a systematic review and meta-analysis

https://doi.org/10.1016/S2213-2600(22)00179-5Get rights and content

Summary

Background

Long-term oxygen therapy (LTOT) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia. However, the best method of management of moderate hypoxaemia not qualifying for LTOT (including isolated nocturnal desaturation) is uncertain. We examined the effect of home oxygen (either LTOT or nocturnal oxygen therapy) on overall survival in patients with COPD and moderate hypoxaemia.

Methods

In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINHAL, and Web of Science from database inception to Jan 13, 2022, for parallel-group randomised trials of long-term or nocturnal oxygen in patients with COPD and moderate daytime hypoxaemia or isolated nocturnal desaturation, or both. Control groups received usual care or ambient air through sham concentrators (placebo) throughout the study period. The primary outcome of interest was 3-year mortality. Crossover trials and trials of oxygen in severe hypoxaemia were excluded. Two reviewers applied inclusion and exclusion criteria to titles and abstracts and screened the full-text articles and reference lists of relevant studies. Aggregate data were extracted manually in duplicate using structured data collection forms. Methodological quality was assessed using the Cochrane Risk of Bias tool. Random-effects meta-analysis was used to pool individual studies. We considered the minimal clinically important difference for home oxygen to be a relative risk reduction in mortality at 3-year follow-up of 30–40%. The meta-analysis is registered on PROSPERO, CRD42021225372.

Findings

We identified 2192 studies and screened 1447 after removal of duplicates, of which 161 were subjected to full-text screening, and six were identified as being eligible for inclusion. These six randomised trials were published between 1992 and 2020 and the quality of evidence was high. In the primary meta-analysis (five trials; 1002 patients), we found the effect of home oxygen in reducing 3-year mortality to be small or absent (relative risk 0·91 [95% CI 0·72–1·16]; τ2 = 0·00), hence the lower limit of the 95% CI did not meet the prespecified minimal clinically important difference.

Interpretation

The results of our meta-analysis suggest that home oxygen probably makes little or no difference to 3-year mortality in patients with COPD and moderate hypoxaemia. The data do not support the widespread use of home oxygen in this patient population.

Funding

None.

Introduction

Two landmark trials conducted in the 1970s and published in the 1980s laid the scientific foundation of home oxygen therapy in chronic obstructive pulmonary disease (COPD) and severe daytime hypoxaemia.1, 2 These two trials, the British Medical Research Council (BMRC) trial1 and the Nocturnal Oxygen Therapy Trial (NOTT),2 in total included only 290 patients. Both trials and, thereafter, their meta-analysis showed that long-term oxygen therapy (LTOT) used for at least 15–18 h per day improves survival, with a large treatment effect.3

Results of the BMRC trial and NOTT, and emerging technologies of oxygen concentrators and liquid oxygen, stimulated administration of home oxygen to patients with COPD with less severe hypoxaemia than included in these foundational studies (ie, moderate hypoxaemia), often under the recommendation of influential societies.4, 5 Use of LTOT in patients with moderate hypoxaemia is widespread. For instance, in the National Emphysema Treatment Trial,6 the proportion of LTOT prescriptions that were for patients with moderate hypoxaemia was 41%, and in the Genetic Epidemiology of COPD (COPDGene) study,7 this proportion was 68%. Yet, the most recent randomised trials of LTOT in patients with moderate daytime hypoxaemia and of nocturnal oxygen therapy in patients with isolated nocturnal desaturation did not find a survival benefit from supplemental oxygen.8, 9 Both the Long-Term Oxygen Treatment Trial (LOTT)8 and the International Nocturnal Oxygen (INOX) trial9 examined the effect of home oxygen on a primary composite outcome (death or first hospitalisation in LOTT and death or progression to LTOT in INOX) and did not have the power to assess the effect of home oxygen on the separate outcome of mortality.

Research in context

Evidence before this study

Home oxygen prescribed for at least 15–18 h per day (ie, long-term oxygen therapy [LTOT]) improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia. However, the effect of home oxygen delivered as LTOT or only during sleep time (ie, nocturnal oxygen therapy) in patients with moderate hypoxaemia is still uncertain. The proportion of LTOT prescriptions that are for patients with moderate hypoxaemia is approximately 50%. The two most recent and largest randomised trials of LTOT or nocturnal oxygen therapy in patients with moderate hypoxaemia did not find a survival benefit of home oxygen. Both the Long-Term Oxygen Treatment Trial (LOTT) and the International Nocturnal Oxygen (INOX) trial examined the effect of oxygen on a primary composite outcome (death or first hospitalisation in LOTT and death or progression to LTOT in INOX) and did not have the power to assess the effect of oxygen on the separate outcome of mortality. We aimed to determine the common effect of LTOT and nocturnal oxygen therapy on the primary outcome of survival through a systematic review and meta-analysis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, CINHAL, and Web of Science from database inception to Jan 13, 2022, for original articles published in any language using terms as well as title, abstract, and text words related to COPD and oxygen therapy.

Added value of this study

This systematic review and meta-analysis adds new evidence regarding the effect of supplemental oxygen in moderate hypoxaemia. We identified six trials of LTOT or nocturnal oxygen therapy published between 1992 and 2020. The primary meta-analysis (five trials; 1002 patients) indicated that home oxygen had little or no effect on survival at 3-year follow-up. The results were homogeneous across trials and remained consistent when LTOT and nocturnal oxygen therapy were analysed separately. Treatment effect excluded clinically important benefit. Similarly, we found no evidence of benefit of LTOT or nocturnal oxygen therapy on the rates of exacerbations and hospitalisations for respiratory conditions, and on changes in quality of life at 3-year follow-up. Quality of evidence was high for the primary outcome of mortality and moderate or low for all secondary outcomes.

Implications of all the available evidence

This meta-analysis provides no indication that home oxygen improves survival after 3 years of intervention and suggests that it probably has little or no beneficial effect on important outcomes such as rates of exacerbations and hospitalisations or quality of life in patients with COPD and uncomplicated moderate hypoxaemia. LTOT or nocturnal oxygen therapy might still be considered in the rare and poorly studied circumstances of moderate hypoxaemia complicated by end-organ dysfunction (polycythaemia, pulmonary hypertension, or cerebral dysfunction). Because home oxygen is the second most expensive health-care expenditure associated with clinical care for COPD in high-income countries after hospitalisation, guidelines should be reviewed to reflect these findings.

Similarities in baseline characteristics, daytime oxygen saturation, and 3-year mortality (18–20%) of patients with moderate daytime hypoxaemia who participated in the LOTT and those with isolated nocturnal desaturation who engaged in the INOX trial indicate that the two populations cannot be clearly distinguished.8, 9 Moderate daytime hypoxaemia is also a strong predictor of nocturnal desaturation.10 Therefore, these two populations overlap to a very large extent and could be considered as a whole as having moderate hypoxaemia. Our objective was to determine the effect of LTOT and nocturnal oxygen therapy in patients with COPD and moderate hypoxaemia on the primary outcome of mortality through a systematic literature review and meta-analysis. Secondary outcomes included rates of exacerbation and hospitalisation, quality of life, and progression to LTOT in patients who only received nocturnal oxygen therapy.

Section snippets

Search strategy and selection criteria

In this systematic review and meta-analysis, with assistance of a registered librarian, we searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINHAL, and Web of Science from database inception until Jan 13, 2022, for original articles published in any language using Medical Subject Headings (known as MeSH) terms as well as title, abstract, and text words related to COPD and oxygen therapy. The complete search strategy was independently reviewed by a second librarian and

Results

We identified 2192 records from our initial database search, of which 745 were duplicates. 1447 separate publications were then screened, of which 1286 were excluded after screening the title and abstract, and 161 were subjected to full-text screening and their reference lists were searched for potentially eligible studies (figure 1). From full-text screening, 14 reports of eight trials were identified that met inclusion criteria, and from reference list screening another 22 potentially

Discussion

We found no effect of LTOT or nocturnal oxygen therapy on survival after 3 years of intervention in patients with COPD and moderate hypoxaemia. Also, home oxygen probably has little or no effect on exacerbation and hospitalisation rates, quality of life, and, in the case of nocturnal oxygen therapy, progression to LTOT. These findings support the arguments against the widespread recommendation of home oxygen in this population.

Our interpretation of the primary meta-analysis of mortality is from

Data sharing

This meta-analysis is based on data extracted from previously published research. Most of the data and study materials are available in the public domain. Additional data from the LOTT were obtained from the Repository Information Coordinating Center of the National Heart, Lung and Blood Institute. These data will not be made publicly available.

Declaration of interests

YL reports participation in Innovair—a company that holds shares in OxyNov, the owner of FreeO2, an automated oxygen delivery system. RC reports grants to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Genentech, and Regeneron; personal fees for serving on speaker bureaus and consultation panels from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, Regeneron, Genentech, Abbott, and Respinova; and holding stock in Inogen—a company that manufactures portable oxygen

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