A pair of Swiss trials investigating acetazolamide demonstrated positive results against placebo in preventing adverse altitude effects—both in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and in healthy lowlanders.
The trials showed that “preventive acetazolamide therapy reduced the incidence of [altitude-related adverse health effects (ARAHE)] in lowlanders with COPD and of [acute mountain sickness (AMS)] in healthy individuals 40 years of age or older during a 2-day sojourn at 3100 m; side effects were not limiting,” Konrad E. Bloch, MD, Department of Respiratory Medicine, University Hospital Zurich, Switzerland, and colleagues reported in NEJM Evidence.
“In this study, we found that approximately three of four patients with stable COPD who were normocapnic and not severely hypoxemic at low altitude experienced ARAHE when traveling to 3100 m while treated with placebo,” the study authors wrote. “Acetazolamide reduced the risk by nearly one half, had few side effects, and is thus more practical than oxygen therapy. Only one of three healthy individuals 40 years of age or older taking placebo experienced AMS at 3100 m; acetazolamide reduced the risk of AMS by about one third.”
As Bloch and colleagues report, easier access to high mountain areas means they are becoming popular tourist destinations among older and less fit individuals.
“Considering the globally high prevalence of chronic obstructive pulmonary disease (COPD) of 8 to 15%, many patients with COPD are expected among mountain travelers,” they wrote. They explained that ARAHE is a catch phrase composite that included AMS, severe hypoxemia, and other conditions requiring oxygen therapy and/or other medical interventions.
“ARAHE have been observed in 16 to 43% of lowlanders with COPD staying at 2048 to 3100 m,” Bloch and colleagues wrote. “In healthy, young individuals ascending rapidly to 3000 m, mild AMS is common (estimated at 11 to 31%) but rarely requires a medical intervention.” And, while acetazolamide or dexamethasone has been prescribed to prevent altitude illness in at-risk patients ascending higher altitudes (2500-3000 meters), “efficacy of drugs for preventing adverse altitude effects in patients with COPD or AMS among individuals older than 40 years of age is lacking, even though alterations in respiratory mechanics, pulmonary gas exchange, control of breathing, and comorbidities may render these individuals more susceptible to adverse consequences of hypobaric hypoxia compared with younger, healthy persons.”
Acetazolamide is a carbonic-anhydrase inhibitor that is used for healthy, young individuals to prevent AMS. But Bloch and colleagues noted that there is a dearth of data on the use of acetazolamide in individuals over age 40, “even though alterations in respiratory mechanics, pulmonary gas exchange, control of breathing, and comorbidities may render these individuals more susceptible to adverse consequences of hypobaric hypoxia compared with younger, healthy persons.”
Thus the two trials—trial 1 running from May 2017 to August 2018 and trial 2 running from May 2018 to August 2019, both conducted at the National Center for Cardiology and Internal Medicine in Bishkek (760 m) and the High-Altitude Clinic near Too-Ashu (3100 m), Kyrgyz Republic.
Trial 1 included participants (age 18-75) living at an altitude less than 800 m, who had COPD defined according to Global Initiative for Chronic Obstructive Lung Disease guidelines, “postbronchodilator forced expiratory volume in 1 second (FEV1) of 40 to 80% of predicted, FEV1/forced vital capacity below 0.7, pulse oximetry (SpO2) of 92% or greater, and arterial partial pressure of carbon dioxide (PaCO2) below 45 mm Hg, while breathing ambient air at an altitude of 760 m,” the study authors noted.
Trial 2 participants were 40-75 years old, without active disease, who were living at an altitude less than 800 m.
In both trials, participants had baseline characteristics assessed at 760 m and then were transported by minibus for a 3-5 hour bus ride to the high altitude clinic (3100 m), where they stayed for 2 days.
“During the altitude sojourn, participants maintained a structured program from 06:00 to 22:00 and night rest during the remaining time,” Bloch and colleagues wrote. “Apart from assessments, daytime activities included three meals, standardized physical exercises (stationary cycling to exhaustion on days 1 and 3), ad libitum walks around the building, and/or rest. Carbonated drinks or alcohol were not available at the study site.”
The trial participants were given acetazolamide—one 125 mg capsule in the morning and two 125 mg capsules at night or placebo 24 hours prior to their stay at the high-altitude clinic. This protocol was the same for both trials.
“The selected evening dose of acetazolamide was higher than the morning dose to achieve a strong effect on sleep related hypoventilation with excessive hypoxemia and sleep apnea,” the study authors explained.
“Primary outcomes of trial 1 was incidence of ARAHE at 3100 m defined as one or more of the following… AMS (LLS 1993 version 16 score of ≥3 points including headache and/or AMSc score of ≥0.7), severe hypoxemia (mean SpO2 of <80% for <30 minutes or <75% for >15 minutes), symptomatic cardiovascular disease requiring intervention or treatment, or study withdrawal upon request by the patient or the independent physician,” Bloch and colleagues wrote, and noted that the primary outcome for trial 2 was AMS defined as an “LLS of 3 or greater including headache at 3100 m.”
Trial 1
There were 90 participants in the intention-to-treat population randomized to placebo and 86 to acetazolamide; mean age was 57, and most were men. There were 12 who withdrew from the trial. The study authors noted that at baseline (760m), these participants had an “oxygen saturation of 92% or greater, arterial partial pressure of carbon dioxide less than 45 mm Hg, and mean forced expiratory volume in 1 second of 63–11% of predicted.”
Among the findings:
- 76% of the placebo group developed ARAHE versus 49% in the acetazolamide group (number needed to treat [NNT] 3.7 (95% CI, 2.5-8.0).
- Hypoxemia was the most common subtype of ARAHE, experienced by 44% of the placebo group and 16% of the treatment group.
- ARMS and other intercurrent illness and/or symptoms were similar between groups.
- 88% of ARAHE occurred within 20 hours after the ascent to 3100 m, with severe hypoxemia occurring during the first night.
- After treatment with oxygen and/or paracetamol (acetaminophen) symptoms completely or partially resolved within 1-3 hours.
Trial 2
There were 170 participants assigned to placebo and 175 to acetazolamide, with a mean age of 53, and in this trial most were women.
Among the findings:
- 32% of the placebo group and 22% of the treatment group experienced AMS—NNT to prevent one case of AMS was 10 (95% CI, 5 to 141).
- “The reduction in AMS incidence by acetazolamide was statistically significant in women (P=0.035) but not in men (P=0.770).
- Similar to trial 1, AMS occurred within 20 hours in 74% of the participants
- 31% of the placebo group and 7% of the treatment group developed hypoxemia.
Neither trial reported serious adverse side effects.
“In this study, we demonstrated the efficacy of acetazolamide in reducing the incidence of ARAHE in patients with COPD, mainly by preventing severe hypoxemia, “Bloch and colleagues wrote. “Although to date, no distinct threshold for dangerous hypoxemia has been established for patients with COPD, aiming to maintain SpO2 above 85 to 90% is a common clinical practice. For safety and ethical considerations, severe hypoxemia (SpO2 of <80% for >30 minutes or <75% for >15 minutes) was included in the ARAHE composite primary end point.”
Bloch and colleagues noted that the two trials “were not designed to allow conclusive comparisons between patients with COPD and healthy individuals, even though the setting and the intervention were identical and participants were similar age.”
The study author noted that a limitation of the study is that it is potential biased by “survivor effect,” given that ARAHE-related withdrawals among patients with COPD led to an incomplete assessment of secondary outcomes.
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Two trials of acetazolamide sdemonstrated positive results against placebo in preventing adverse altitude effects.
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Acetazolamide reduced the risk by nearly one half, had few side effects, and is thus more practical than oxygen therapy for individuals with COPD as well as healthy individuals over age 40.
Candace Hoffmann, Managing Editor, BreakingMED™
The study was funded by the Swiss National Science Foundation [Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung], Lunge Zurich, and the Swiss Lung Foundation.
Bloch disclosed no relevant relationships.
Cat ID: 154
Topic ID: 89,154,730,192,154,195,925
