Sex-specific efficacy of acetazolamide for acute mountain sickness. A randomised clinical trial.
- 1University Hospital Zurich, Pulmonology Department, Zurich, Switzerland
Abstract
ImportanceAcute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated.
ObjectiveTo 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.
DesignRandomized, 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.
SettingBaseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic.
ParticipantsHealthy 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.
InterventionAcetazolamide 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 MeasuresPrimary 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.
ResultsOf 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 RelevancePreventive 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 RegistrationClinicalTrials.gov Identifier: NCT06499727
Key PointsO_ST_ABSQuestionC_ST_ABSDoes preventive acetazolamide reduce acute mountain sickness (AMS) more effectively in female than in male lowlanders ascending to 3600m?
FindingsIn 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.
MeaningPreventive acetazolamide reduces AMS in healthy lowlanders without demonstrating sex-specific efficacy, but its worse tolerability in females warrants investigation of sex-specific dosing.
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BibTeX
@misc{taalaibekova2026sexspecific,
title = {{Sex-specific efficacy of acetazolamide for acute mountain sickness. A randomised clinical trial.}},
author = {A. Taalaibekova and J. Roche and A. Haefliger and D. Hertig and M. Mademilov and K. Magdieva and A. Bolotbek and G. Mirzalieva and T. Li and K. von Gruenigen and A. Vella and S. Zahner-Ulrich and B. Champigneulle and J. Mueller and M. Lichtblau and S. Verges and K. E. Bloch and S. Ulrich and T. M. Sooronbaev and M. Furian},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.26362614},
url = {https://www.medrxiv.org/content/10.64898/2026.09.09.26362614v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sex-specific efficacy of acetazolamide for acute mountain sickness. A randomised clinical trial.
AU - A. Taalaibekova
AU - J. Roche
AU - A. Haefliger
AU - D. Hertig
AU - M. Mademilov
AU - K. Magdieva
AU - A. Bolotbek
AU - G. Mirzalieva
AU - T. Li
AU - K. von Gruenigen
AU - A. Vella
AU - S. Zahner-Ulrich
AU - B. Champigneulle
AU - J. Mueller
AU - M. Lichtblau
AU - S. Verges
AU - K. E. Bloch
AU - S. Ulrich
AU - T. M. Sooronbaev
AU - M. Furian
PY - 2026
DA - 2026/09/09
PB - medRxiv
DO - 10.64898/2026.09.09.26362614
UR - https://www.medrxiv.org/content/10.64898/2026.09.09.26362614v1
AB - ImportanceAcute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated. ObjectiveTo 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. DesignRandomized, 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. SettingBaseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic. ParticipantsHealthy 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. InterventionAcetazolamide 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 MeasuresPrimary 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. ResultsOf 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 RelevancePreventive 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 RegistrationClinicalTrials.gov Identifier: NCT06499727 Key PointsO_ST_ABSQuestionC_ST_ABSDoes preventive acetazolamide reduce acute mountain sickness (AMS) more effectively in female than in male lowlanders ascending to 3600m? FindingsIn 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. MeaningPreventive acetazolamide reduces AMS in healthy lowlanders without demonstrating sex-specific efficacy, but its worse tolerability in females warrants investigation of sex-specific dosing.
ER -