Comparing standard treatment of moderate to severe obstructive sleep apnoea to add-on acetazolamide treatment: An open-label randomised controlled trial

Dear Editor, I am writing to share my thoughts on the article titled “Comparing standard treatment of moderate to severe obstructive sleep apnoea to add-on acetazolamide treatment: An open-label randomised controlled trial” by Tripathi et al., published in Lung India, Volume 42, Issue 1, January–February 2025. The study provides valuable insights into the potential benefits of combining acetazolamide with continuous positive airway pressure (CPAP) therapy for moderate to severe obstructive sleep apnea (OSA). The authors present a well-designed methodology, including a randomised controlled trial, and the results highlight a significant reduction in the apnea-hypopnea index (AHI) and improvements in sleep architecture and oxygen desaturation index (ODI). The findings suggesting that acetazolamide enhances CPAP effectiveness are compelling, especially given the common challenge of patient non-compliance with CPAP therapy. Moreover, the study emphasises safety, with minimal and comparable side effects between the treatment groups, suggesting the feasibility of combining acetazolamide with CPAP for OSA management. Despite the positive findings, several important points need to be addressed. PREVIOUS CPAP USE It would be crucial to clarify whether the patients recruited for this study were already on CPAP therapy before enrollment into the study, and if so, for how long the patient received CPAP therapy. The duration of prior CPAP therapy could significantly affect the reduction in AHI, as patients who have been using CPAP for a longer period may already have some degree of symptom improvement. This variable should be accounted for in the analysis to prevent confounding factors from influencing the outcomes. BODY MASS INDEX (BMI) AS A POTENTIAL CONFOUNDING FACTOR Although the average baseline BMI of the patients was statistically comparable in the two groups, the data was skewed in the BMI subgroup of 25–29.9 and 30–34.9 kg/m2. There is a noticeable imbalance in the distribution of BMI between the two groups, with the CPAP-only group having a higher percentage of participants in the BMI categories of 25–29.9 kg/m2 (17.8% vs. 28%) and 30–34.9 kg/m2 (35.6% vs. 38%) compared to the combination therapy group. Statistical comparison between these BMI subgroups is not provided in the paper. Given that BMI is a known confounder for higher AHI in OSA, its potential impact on the study’s results should be addressed. The authors should consider performing a subgroup analysis or adjusting for BMI in their statistical models. STATISTICAL ANALYSIS AND CLINICAL RELEVANCE While the study reports statistically significant improvements in AHI and other parameters, the clinical significance of these findings should be considered. For instance, the mean reduction in total AHI from 45.47 to 34.69 events/hour, while statistically significant, may not be substantial enough to result in clinically meaningful improvements in patient outcomes. Further discussion on the clinical relevance of these changes, in the context of patient quality of life and symptom improvement, would strengthen the interpretation of the results. ADDITION OF A PLACEBO-CONTROLLED ARM To further strengthen the conclusions of this study, we believe it is essential to address the absence of a placebo control for acetazolamide. While the study suggests that acetazolamide may offer benefits in combination with CPAP therapy, the absence of a placebo-controlled arm (CPAP + PLACEBO) raises concerns about the potential for placebo effects. Without a placebo control, it is difficult to determine whether the observed improvements were truly due to the pharmacological effects of acetazolamide or whether they resulted from participant expectations or other non-specific factors. As few study parameters like ESS and STOPBANG score used in this trial are subjective, the inclusion of placebo-controlled term is vital. CONCERNS REGARDING LONG-TERM USE OF ACETAZOLAMIDE Another important consideration is the unknown long-term safety of acetazolamide for the treatment of OSA. Chronic use of acetazolamide may lead to metabolic disturbances, such as electrolyte imbalances and acidosis, which could significantly limit its practical use as a long-term therapy. The study does not provide sufficient data on the potential risks of prolonged acetazolamide administration, making it difficult to assess whether its benefits outweigh these potential harms. Further investigation into the long-term safety and tolerability of acetazolamide is critical before considering its widespread use in managing OSA. COMPLIANCE AND ADHERENCE The study mentions that the compliance-adjusted AHI was significantly lower in the combination therapy group, suggesting better treatment adherence. However, no specific details about the methods used to assess compliance were provided. It would be important to clarify whether compliance was objectively monitored (e.g., via CPAP usage data logs) or based on patient self-reporting. Additionally, adherence to acetazolamide was not clearly discussed, and this could impact the results of the study. CONCLUSION In conclusion, while the study by Tripathi et al. offers valuable data on the potential benefits of combining acetazolamide with CPAP, the points raised above suggest that additional considerations and refinements are needed to fully validate the combination therapy as a treatment option for OSA. We would encourage the authors to address these issues in future studies and potentially consider modifications to the current trial design to improve the robustness of the findings. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.