High-flow nasal cannula compared with non-invasive ventilation for acute hypercapnic respiratory failure in patients with acute exacerbations of COPD: a systematic review and meta-analysis of comparative studies

High-flow nasal cannula (HFNC) is increasingly used as an alternative to non-invasive ventilation (NIV) in acute exacerbations of COPD (AECOPD) with acute hypercapnic respiratory failure, but its comparative effectiveness remains uncertain, particularly in patients with mild-to-moderate respiratory acidosis. To compare HFNC with NIV as initial non-invasive respiratory support for treatment failure, endotracheal intubation, all-cause mortality, and treatment switch, while distinguishing randomized evidence from complementary observational evidence. Five databases were searched through February 2026 for randomized controlled trials (RCTs) and comparative observational studies of adults with AECOPD and acute hypercapnic respiratory failure, predominantly with arterial pH 7.25–7.35. Random-effects meta-analysis was the primary approach. Treatment failure was a composite endpoint that variably included intubation, treatment switch, and, in some studies, death. Study-design subgroup analyses and sensitivity analyses were used to examine heterogeneity. Risk of bias was assessed with RoB 2 and ROBINS-I. Ten studies (6 RCTs, 4 observational; n = 1,061) were included. In the combined random-effects analyses, there was no statistically significant difference in all-cause mortality (OR 0.91, 95% CI 0.60–1.38; I²=0%) or endotracheal intubation (OR 0.98, 95% CI 0.64–1.49; I²=12%). Treatment switch was more frequent with HFNC (OR 3.34, 95% CI 1.14–9.77; I²=68%). Composite treatment failure was numerically higher with HFNC but was not statistically significant in the primary random-effects analysis (OR 1.39, 95% CI 0.80–2.41; I²=61%). In RCT-only analyses, mortality (OR 0.99, 95% CI 0.59–1.66) and intubation (OR 1.18, 95% CI 0.68–2.05) remained inconclusive, whereas treatment switch (OR 4.14, 95% CI 1.50-11.47) and composite treatment failure (OR 1.98, 95% CI 1.22–3.22) were higher with HFNC. Excluding the study with an asymmetric treatment-failure definition attenuated the combined treatment-failure estimate (OR 1.17, 95% CI 0.71–1.94; I²=48%). In selected patients with AECOPD and predominantly mild-to-moderate hypercapnic respiratory acidosis, the available evidence does not demonstrate a statistically significant difference in mortality or intubation between initial HFNC and NIV; however, the confidence intervals do not establish equivalence or non-inferiority. HFNC is associated with a greater need for crossover to NIV, and randomized evidence also indicates a higher composite treatment-failure rate. HFNC should therefore be considered a potential alternative for selected patients, particularly when NIV is poorly tolerated, only where close monitoring, early reassessment, and prompt rescue NIV are available.