Abstract
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Unfortunately, the authors do not report or control for the proportion of participants who developed AMS in the control groups of listed studies. This control event rate is an important variable as a lower baseline risk for developing AMS results in higher number needed to treat for the interventional drug (Low et al., 2012). Reviewed trials with acetazolamide 750 mg/day had a higher control event rate compared with lower dosages, which would wrongly imply greater efficacy if only unadjusted results are reported (Low et al., 2012). Furthermore, the acetazolamide 750 mg/day studies had an average slower ascent rate (1,600 m/day) than the 500 mg/day (2,985/day) and 250 mg/day (2,578 m/day) studies. As a slower ascent is well known to significantly lower the incidence of AMS (Hackett et al., 1976), any comparisons of efficacy without controlling for ascent rate is inherently flawed. When ascent rate is controlled, the efficacy for these dosages have negligible clinical differences (Kayser et al., 2012).
The studies chosen for inclusion are somewhat questionable. Two acetazolamide trials did not report rapid ascent (an inclusion criteria), and a treatment trial was arbitrarily included. A drug that is effective for treatment may not be effective for prophylaxis, as the body's physiological and biological responses may differ, leading to inappropriate conclusions. Not included was a trial of acetazolamide 250 mg/day compared with placebo that found a significant reduction of AMS by 19% in subgroup analysis (Gertsch et al., 2010). Although not a primary outcome, this cohort was >25% of the included studies; its inclusion would likely have altered the recommendations.
Finally, the authors erroneously described a trial of acetazolamide 250 mg/day the day of ascent versus the evening before ascent as 125 mg/day (Lipman et al., 2019). The correct acetazolamide 125 mg/day versus 250 mg/day found the reduced dose failed to demonstrate noninferiority, with increased risk of AMS and no demonstrable benefits. The authors concluded this reduced dose should not be recommended (Lipman et al., 2020).
In conclusion, we feel a more critical analysis of the literature is necessary for accurate recommendations on acetazolamide's efficacy for AMS prevention. And similar to well-sanctioned meta-analyses and systematic reviews have established (Kayser et al., 2012; Low et al., 2012; Ritchie et al., 2012), the recommended dose is acetazolamide 250 mg/day, with higher doses providing scant clinical improvement, with dose-dependent greater side effects (Dumont et al., 2000).