Sex-specific efficacy of acetazolamide for acute mountain sickness. A randomised clinical trial

Importance

Acute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated.

Objective

To test the a priori hypothesis that preventive acetazolamide achieves a 20% greater relative risk reduction (RRR) of AMS in female vs male lowlanders ascending to 3600 m.

Design

Randomized, double-blind, placebo-controlled, parallel-group trial conducted from March 2024 to August 2025; participants, outcome assessors, and statistician were blinded until analysis was complete.

Setting

Baseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic.

Participants

Healthy female and male low-altitude residents (age 18-44 years, BMI 18-30 kg/m2, residence <1000 m); females were premenopausal, eumenorrheic, and not using hormonal contraception. Exclusion criteria included pre-existing disease, regular medication, pregnancy, anaemia, and altitude sojourn >2500 m within 4 weeks.

Intervention

Acetazolamide 125 mg or matching placebo twice daily, from 24 hours before ascent and throughout the 2-day, 2-night stay at 3600 m.

Main Outcomes and Measures

Primary outcome was the between-sex difference in RRR of AMS, defined as a 2018 revised Lake Louise Score of 3 or higher including headache. Secondary outcomes included absolute risk reduction (ARR) and drug tolerability.

Results

Of 303 randomized participants (180 females, 123 males; mean [SD] age, 23 [4] years), AMS incidence under placebo (n=155) was 34% (females 42% vs males 23%; P =.02) and under acetazolamide (n=148) was 24% (females 30% vs males 14%; P =.02). Overall RRR was 31% (95% CI, 0% to 52%) and ARR was 10% (95% CI, 0% to 22%). Sex-stratified RRR was 27% (95% CI, -9% to 52%) in females and 42% (95% CI, -28% to 74%) in males; between-sex RRR difference, -15% (95% CI, -65% to 57%). Females had a 4.8-fold higher risk of moderate-to-severe drug-related side effects than males.

Conclusions and Relevance

Preventive acetazolamide reduced overall AMS incidence at 3600 m, but the pre-specified 20% greater RRR in females (trial powered at 90%) was not observed. The nearly 5-fold higher risk of moderate-to-severe side effects in females warrants further investigation of sex-specific dosing.

Trial Registration

ClinicalTrials.gov Identifier: NCT06499727

Key Points

Findings

In this randomized, double-blind, placebo-controlled trial of 303 healthy lowlanders, preventive acetazolamide did not achieve a greater relative risk reduction of AMS in females than in males; the pre-specified 20% between-sex difference, for which the trial was 90% powered, was not observed. However, females experienced a 5-fold higher risk of moderate-to- severe drug-related side effects than males.

Meaning

Preventive acetazolamide reduces AMS in healthy lowlanders without demonstrating sex-specific efficacy, but its worse tolerability in females warrants investigation of sex-specific dosing.