Linda N. Meurer, MD, MPH

BACKGROUND: In 1995, 3 independent studies found that OCs containing the progestogens desogestrel or gestodene (third-generation OCs) doubled the risk of VTE over OCs containing levonorgestrel. A subsequent warning issued by the Committee on Safety of Medicines of England altered prescribing and use patterns accordingly, but no reduction of VTE incidence occurred, suggesting that the original research was flawed.

POPULATION STUDIED: Subjects were selected from more than 3 million patient records contained in the United Kingdom General Practice Research Database, which includes personal characteristics, drugs prescribed, and clinical diagnoses. The investigators identified women aged 15 to 39 years who were users of either third-generation OCs (n=361,724) or OCs containing levonorgestrel (n=979,052) and whose records had been contained within the database for at least 1 year. A total of 106 cases of idiopathic VTE occurred within this cohort. These cases were matched with 569 controls for the case-control analysis. Patients were excluded if their VTE was due to an apparent proximate cause, such as pregnancy, recent surgery or lower limb injury, cancer, or recent severe trauma.

STUDY DESIGN AND VALIDITY: Two study designs were employed, a cohort design and a nested case-control design. Data for both were analyzed separately for 2 time periods from January 1993 to October 1995 (before the safety warning) and from January 1996 to December 1999 (following the warning). For the cohort study, person-time at risk was estimated from the date of first prescription of oral contraceptive until either the OC was stopped; a different study OC was prescribed; the woman died, left the practice, or became a case; or the study period ended. Summary incidence rates for the 2 periods were adjusted for age and compared between the 2 types of OC users. Each patient with idiopathic VTE (case group) was then matched with up to 6 patients without VTE (control group) by age, practice, and index date (both using OCs on the date of the diagnosis of the case). Odds ratios were calculated for both study periods individually and combined, with adjustments for body mass index, smoking history, duration of use of OCs, and whether a change in OC had occurred. The authors describe significant measures to assure the quality of the General Practice Database and made blinded assessments of outcome. By excluding women with predisposing risk factors for VTE they appropriately limited the study results to average risk individuals. Since 1,340,776 women contributed only 361,300 person-years of observation over 7 years of observation, significant variation in length of OC use must have occurred. In fact, though more women took third-generation OCs, these contributed fewer person-years to the analysis. Several known confounders (smoking, obesity, duration of OC use) were controlled for in the case-control analysis.

OUTCOMES MEASURED: The first case of idiopathic VTE as measured by careful chart review was the outcome of interest. The chart review was conducted by blinded investigators.

RESULTS: Both the cohort and matched case-control analyses of these data demonstrated an approximately two-fold increase in risk of VTE among users of third-generation OCs compared with OCs containing levonorgestrel (age-adjusted relative risk [RR]=1.9; 95% confidence interval [CI], 1.3-2.8 and odds ratio [OR] =2.3, 95% CI, 1.3-3.9). No difference in the age-adjusted incidence of VTE was apparent between the 2 study periods, though the proportion of users of third-generation OCs dropped significantly after the warning notice was issued. VTE was also independently associated with higher body mass index and smoking.

BACKGROUND: In 1995, 3 independent studies found that OCs containing the progestogens desogestrel or gestodene (third-generation OCs) doubled the risk of VTE over OCs containing levonorgestrel. A subsequent warning issued by the Committee on Safety of Medicines of England altered prescribing and use patterns accordingly, but no reduction of VTE incidence occurred, suggesting that the original research was flawed.

POPULATION STUDIED: Subjects were selected from more than 3 million patient records contained in the United Kingdom General Practice Research Database, which includes personal characteristics, drugs prescribed, and clinical diagnoses. The investigators identified women aged 15 to 39 years who were users of either third-generation OCs (n=361,724) or OCs containing levonorgestrel (n=979,052) and whose records had been contained within the database for at least 1 year. A total of 106 cases of idiopathic VTE occurred within this cohort. These cases were matched with 569 controls for the case-control analysis. Patients were excluded if their VTE was due to an apparent proximate cause, such as pregnancy, recent surgery or lower limb injury, cancer, or recent severe trauma.

STUDY DESIGN AND VALIDITY: Two study designs were employed, a cohort design and a nested case-control design. Data for both were analyzed separately for 2 time periods from January 1993 to October 1995 (before the safety warning) and from January 1996 to December 1999 (following the warning). For the cohort study, person-time at risk was estimated from the date of first prescription of oral contraceptive until either the OC was stopped; a different study OC was prescribed; the woman died, left the practice, or became a case; or the study period ended. Summary incidence rates for the 2 periods were adjusted for age and compared between the 2 types of OC users. Each patient with idiopathic VTE (case group) was then matched with up to 6 patients without VTE (control group) by age, practice, and index date (both using OCs on the date of the diagnosis of the case). Odds ratios were calculated for both study periods individually and combined, with adjustments for body mass index, smoking history, duration of use of OCs, and whether a change in OC had occurred. The authors describe significant measures to assure the quality of the General Practice Database and made blinded assessments of outcome. By excluding women with predisposing risk factors for VTE they appropriately limited the study results to average risk individuals. Since 1,340,776 women contributed only 361,300 person-years of observation over 7 years of observation, significant variation in length of OC use must have occurred. In fact, though more women took third-generation OCs, these contributed fewer person-years to the analysis. Several known confounders (smoking, obesity, duration of OC use) were controlled for in the case-control analysis.

OUTCOMES MEASURED: The first case of idiopathic VTE as measured by careful chart review was the outcome of interest. The chart review was conducted by blinded investigators.

RESULTS: Both the cohort and matched case-control analyses of these data demonstrated an approximately two-fold increase in risk of VTE among users of third-generation OCs compared with OCs containing levonorgestrel (age-adjusted relative risk [RR]=1.9; 95% confidence interval [CI], 1.3-2.8 and odds ratio [OR] =2.3, 95% CI, 1.3-3.9). No difference in the age-adjusted incidence of VTE was apparent between the 2 study periods, though the proportion of users of third-generation OCs dropped significantly after the warning notice was issued. VTE was also independently associated with higher body mass index and smoking.

BACKGROUND: In 1995, 3 independent studies found that OCs containing the progestogens desogestrel or gestodene (third-generation OCs) doubled the risk of VTE over OCs containing levonorgestrel. A subsequent warning issued by the Committee on Safety of Medicines of England altered prescribing and use patterns accordingly, but no reduction of VTE incidence occurred, suggesting that the original research was flawed.

POPULATION STUDIED: Subjects were selected from more than 3 million patient records contained in the United Kingdom General Practice Research Database, which includes personal characteristics, drugs prescribed, and clinical diagnoses. The investigators identified women aged 15 to 39 years who were users of either third-generation OCs (n=361,724) or OCs containing levonorgestrel (n=979,052) and whose records had been contained within the database for at least 1 year. A total of 106 cases of idiopathic VTE occurred within this cohort. These cases were matched with 569 controls for the case-control analysis. Patients were excluded if their VTE was due to an apparent proximate cause, such as pregnancy, recent surgery or lower limb injury, cancer, or recent severe trauma.

STUDY DESIGN AND VALIDITY: Two study designs were employed, a cohort design and a nested case-control design. Data for both were analyzed separately for 2 time periods from January 1993 to October 1995 (before the safety warning) and from January 1996 to December 1999 (following the warning). For the cohort study, person-time at risk was estimated from the date of first prescription of oral contraceptive until either the OC was stopped; a different study OC was prescribed; the woman died, left the practice, or became a case; or the study period ended. Summary incidence rates for the 2 periods were adjusted for age and compared between the 2 types of OC users. Each patient with idiopathic VTE (case group) was then matched with up to 6 patients without VTE (control group) by age, practice, and index date (both using OCs on the date of the diagnosis of the case). Odds ratios were calculated for both study periods individually and combined, with adjustments for body mass index, smoking history, duration of use of OCs, and whether a change in OC had occurred. The authors describe significant measures to assure the quality of the General Practice Database and made blinded assessments of outcome. By excluding women with predisposing risk factors for VTE they appropriately limited the study results to average risk individuals. Since 1,340,776 women contributed only 361,300 person-years of observation over 7 years of observation, significant variation in length of OC use must have occurred. In fact, though more women took third-generation OCs, these contributed fewer person-years to the analysis. Several known confounders (smoking, obesity, duration of OC use) were controlled for in the case-control analysis.

OUTCOMES MEASURED: The first case of idiopathic VTE as measured by careful chart review was the outcome of interest. The chart review was conducted by blinded investigators.

RESULTS: Both the cohort and matched case-control analyses of these data demonstrated an approximately two-fold increase in risk of VTE among users of third-generation OCs compared with OCs containing levonorgestrel (age-adjusted relative risk [RR]=1.9; 95% confidence interval [CI], 1.3-2.8 and odds ratio [OR] =2.3, 95% CI, 1.3-3.9). No difference in the age-adjusted incidence of VTE was apparent between the 2 study periods, though the proportion of users of third-generation OCs dropped significantly after the warning notice was issued. VTE was also independently associated with higher body mass index and smoking.

BACKGROUND: Common symptoms of fibromyalgia include chronic musculoskeletal pain and stiffness, fatigue, disrupted sleep, and tenderness over specific trigger points. Although commonly used for other chronic pain conditions, the efficacy of antidepressants for fibromyalgia is not well established. Also unclear is whether any benefit is independent of their effect on depression.

DATASOURCES: Forty-one articles comparing antidepressants with placebo for treating fibromyalgia were identified through a search of MEDLINE, PSYCLIT, EMBASE, FEDRIP, The Cochrane Library, and the reference list of retrieved articles. Sixteen of these were randomized placebo-controlled clinical trials reporting measurable outcomes. Two additional trials were excluded because the data were not extractable and another because it was a report of N-of-1 trials.

STUDY DESIGN AND VALIDITY: All of the potential articles were reviewed for inclusion in duplicate with strong inter-rater agreement. Each of the final 13 articles was assessed for quality by more than one person using an instrument developed by Jadad. The mean quality score was high at 5.6 (range=0-8). The authors listed the validity concerns of each article but did not exclude any of them. Since the studies were similar in terms of design, demographics, inclusion criteria, and outcomes assessment, the authors concluded quantitative pooling of the effects of antidepressants was appropriate. No effect of year of publication, study design, quality score, or drug class was found using meta-regression.

OUTCOMES MEASURED: The primary outcome was whether a patient was “improved” with therapy. Other outcomes included pain, fatigue, sleep disturbance, sense of well-being, and quantity and severity of trigger points. Additionally, the authors looked for any assessment of outcomes independent of the effect of therapy on depression.

RESULTS: From 10 trials with extractable data, the odds ratio for improvement with therapy was 4.2 (95% confidence interval [CI], 2.6-6.8). The number needed to treat (NNT) was 4 (95% CI, 2.9-6.3). The individual symptoms of pain, fatigue, sleep disturbance, and well-being showed significant improvements of moderate size, but quantity and severity of trigger points were not statistically different. The sample size was insufficient to draw meaningful conclusions regarding the relative benefit of different classes of antidepressants.

BACKGROUND: Common symptoms of fibromyalgia include chronic musculoskeletal pain and stiffness, fatigue, disrupted sleep, and tenderness over specific trigger points. Although commonly used for other chronic pain conditions, the efficacy of antidepressants for fibromyalgia is not well established. Also unclear is whether any benefit is independent of their effect on depression.

DATASOURCES: Forty-one articles comparing antidepressants with placebo for treating fibromyalgia were identified through a search of MEDLINE, PSYCLIT, EMBASE, FEDRIP, The Cochrane Library, and the reference list of retrieved articles. Sixteen of these were randomized placebo-controlled clinical trials reporting measurable outcomes. Two additional trials were excluded because the data were not extractable and another because it was a report of N-of-1 trials.

STUDY DESIGN AND VALIDITY: All of the potential articles were reviewed for inclusion in duplicate with strong inter-rater agreement. Each of the final 13 articles was assessed for quality by more than one person using an instrument developed by Jadad. The mean quality score was high at 5.6 (range=0-8). The authors listed the validity concerns of each article but did not exclude any of them. Since the studies were similar in terms of design, demographics, inclusion criteria, and outcomes assessment, the authors concluded quantitative pooling of the effects of antidepressants was appropriate. No effect of year of publication, study design, quality score, or drug class was found using meta-regression.

OUTCOMES MEASURED: The primary outcome was whether a patient was “improved” with therapy. Other outcomes included pain, fatigue, sleep disturbance, sense of well-being, and quantity and severity of trigger points. Additionally, the authors looked for any assessment of outcomes independent of the effect of therapy on depression.

RESULTS: From 10 trials with extractable data, the odds ratio for improvement with therapy was 4.2 (95% confidence interval [CI], 2.6-6.8). The number needed to treat (NNT) was 4 (95% CI, 2.9-6.3). The individual symptoms of pain, fatigue, sleep disturbance, and well-being showed significant improvements of moderate size, but quantity and severity of trigger points were not statistically different. The sample size was insufficient to draw meaningful conclusions regarding the relative benefit of different classes of antidepressants.

BACKGROUND: Common symptoms of fibromyalgia include chronic musculoskeletal pain and stiffness, fatigue, disrupted sleep, and tenderness over specific trigger points. Although commonly used for other chronic pain conditions, the efficacy of antidepressants for fibromyalgia is not well established. Also unclear is whether any benefit is independent of their effect on depression.

DATASOURCES: Forty-one articles comparing antidepressants with placebo for treating fibromyalgia were identified through a search of MEDLINE, PSYCLIT, EMBASE, FEDRIP, The Cochrane Library, and the reference list of retrieved articles. Sixteen of these were randomized placebo-controlled clinical trials reporting measurable outcomes. Two additional trials were excluded because the data were not extractable and another because it was a report of N-of-1 trials.

STUDY DESIGN AND VALIDITY: All of the potential articles were reviewed for inclusion in duplicate with strong inter-rater agreement. Each of the final 13 articles was assessed for quality by more than one person using an instrument developed by Jadad. The mean quality score was high at 5.6 (range=0-8). The authors listed the validity concerns of each article but did not exclude any of them. Since the studies were similar in terms of design, demographics, inclusion criteria, and outcomes assessment, the authors concluded quantitative pooling of the effects of antidepressants was appropriate. No effect of year of publication, study design, quality score, or drug class was found using meta-regression.

OUTCOMES MEASURED: The primary outcome was whether a patient was “improved” with therapy. Other outcomes included pain, fatigue, sleep disturbance, sense of well-being, and quantity and severity of trigger points. Additionally, the authors looked for any assessment of outcomes independent of the effect of therapy on depression.

RESULTS: From 10 trials with extractable data, the odds ratio for improvement with therapy was 4.2 (95% confidence interval [CI], 2.6-6.8). The number needed to treat (NNT) was 4 (95% CI, 2.9-6.3). The individual symptoms of pain, fatigue, sleep disturbance, and well-being showed significant improvements of moderate size, but quantity and severity of trigger points were not statistically different. The sample size was insufficient to draw meaningful conclusions regarding the relative benefit of different classes of antidepressants.

BACKGROUND: Acute mountain sickness results in symptoms such as headache, loss of appetite, nausea, fatigue, insomnia, and increased mortality in the first few days of exertion at high altitudes. Acetazolamide and dexamethasone have been recommended as treatments to prevent acute mountain sickness, although their efficacy and tolerability have not been well established.

DATA SOURCE: Thirty-three clinical trials comparing any pharmacologic treatment with placebo for the prevention of acute mountain sickness were identified through a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, a high altitude bibliography Web site, and the bibliographies of retrieved reports and review articles. Of these trials, 18 reported complete prevention of acute mountain sickness as an outcome and as related to ascents to 4050 to 5890 meters (13300 to 19300 feet). These were included in a qualitative analysis of efficacy for any pharmacologic treatment (all 18 trials) and statistical meta-analyses for dexamethasone (8 trials representing 161 subjects) and acetazolamide (9 trials representing 295 subjects).

STUDY DESIGN AND VALIDITY: Only one author determined whether studies met inclusion criteria. All 3 authors read the included articles for validity, applying the 3-item 5-point Oxford score. The mean quality score was 3 (range=2-5). A total of 17 of the 33 trials used an adequate method of blinding. Validity was not a criteria for inclusion in the review. Following the qualitative analysis of efficacy, relative benefit (relative risk [RR] of prevention of mountain sickness) and numbers needed to treat (NNTs) were calculated for 2 interventions, dexamethasone and acetazolamide. Although the studies were rated for validity using previously tested criteria, no information on study limitations is given with which to judge the direction of effect. Using more than one author to determine eligibility would have minimized investigator bias. Although included studies varied in their definitions of acute mountain sickness, the results were homogenous. The investigators limited the outcome to complete prevention of symptoms. This conservative approach would underestimate the efficacy of the treatments making any significant benefit more likely to be real. Unfortunately, no information is provided on the subjects in the trials, including information such as age, sex, training, smoking status, and other risk factors for acute mountain sickness. This information would have helped generalize the study results.

OUTCOMES MEASURED: The primary outcome measured was complete prevention of acute mountain sickness according to the definition used in each of the original studies. Although reported for some of the studies, the reduction in symptom severity was not considered a criterion for efficacy in this study. Secondary outcomes included prevention of headache, nausea, insomnia, and dizziness, and the development of adverse drug reactions.

RESULTS: In 8 trials of dexamethasone (n=161) and 9 of acetazolamide (n=295), all with exposure above 4000 meters, single daily doses of dexamethasone 8 mg, 12 mg, and 16 mg or acetazolamide 750 mg were all more efficacious than placebo (NNT=3 for both). Smaller doses (dexamethasone 0.5 and 2 mg in one trial, acetazolamide 500 mg in 3 trials) did not prevent mountain sickness over placebo. Five trials of acetazolamide reported symptom end points including insomnia, headache, nausea, and dizziness; all results favored acetazolamide (NNT=3-6). Both dexamethasone and acetazolamide demonstrated a trend toward greater efficacy (lower NNT) with faster ascent rates. There was no relative benefit (RR for prophylaxis=1) for trials with ascent rates below approximately 500 meters per day; but there was a five- to six-fold relative benefit for prophylaxis at the highest ascent rates. Regarding adverse effects, subjects in 2 of 5 studies were more likely to experience depression on weaning of dexamethasone (overall RR=4.5). Acetazolamide was associated with polyuria (RR=4.2) and paraesthesia (RR=4.0).

BACKGROUND: Acute mountain sickness results in symptoms such as headache, loss of appetite, nausea, fatigue, insomnia, and increased mortality in the first few days of exertion at high altitudes. Acetazolamide and dexamethasone have been recommended as treatments to prevent acute mountain sickness, although their efficacy and tolerability have not been well established.

DATA SOURCE: Thirty-three clinical trials comparing any pharmacologic treatment with placebo for the prevention of acute mountain sickness were identified through a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, a high altitude bibliography Web site, and the bibliographies of retrieved reports and review articles. Of these trials, 18 reported complete prevention of acute mountain sickness as an outcome and as related to ascents to 4050 to 5890 meters (13300 to 19300 feet). These were included in a qualitative analysis of efficacy for any pharmacologic treatment (all 18 trials) and statistical meta-analyses for dexamethasone (8 trials representing 161 subjects) and acetazolamide (9 trials representing 295 subjects).

STUDY DESIGN AND VALIDITY: Only one author determined whether studies met inclusion criteria. All 3 authors read the included articles for validity, applying the 3-item 5-point Oxford score. The mean quality score was 3 (range=2-5). A total of 17 of the 33 trials used an adequate method of blinding. Validity was not a criteria for inclusion in the review. Following the qualitative analysis of efficacy, relative benefit (relative risk [RR] of prevention of mountain sickness) and numbers needed to treat (NNTs) were calculated for 2 interventions, dexamethasone and acetazolamide. Although the studies were rated for validity using previously tested criteria, no information on study limitations is given with which to judge the direction of effect. Using more than one author to determine eligibility would have minimized investigator bias. Although included studies varied in their definitions of acute mountain sickness, the results were homogenous. The investigators limited the outcome to complete prevention of symptoms. This conservative approach would underestimate the efficacy of the treatments making any significant benefit more likely to be real. Unfortunately, no information is provided on the subjects in the trials, including information such as age, sex, training, smoking status, and other risk factors for acute mountain sickness. This information would have helped generalize the study results.

OUTCOMES MEASURED: The primary outcome measured was complete prevention of acute mountain sickness according to the definition used in each of the original studies. Although reported for some of the studies, the reduction in symptom severity was not considered a criterion for efficacy in this study. Secondary outcomes included prevention of headache, nausea, insomnia, and dizziness, and the development of adverse drug reactions.

RESULTS: In 8 trials of dexamethasone (n=161) and 9 of acetazolamide (n=295), all with exposure above 4000 meters, single daily doses of dexamethasone 8 mg, 12 mg, and 16 mg or acetazolamide 750 mg were all more efficacious than placebo (NNT=3 for both). Smaller doses (dexamethasone 0.5 and 2 mg in one trial, acetazolamide 500 mg in 3 trials) did not prevent mountain sickness over placebo. Five trials of acetazolamide reported symptom end points including insomnia, headache, nausea, and dizziness; all results favored acetazolamide (NNT=3-6). Both dexamethasone and acetazolamide demonstrated a trend toward greater efficacy (lower NNT) with faster ascent rates. There was no relative benefit (RR for prophylaxis=1) for trials with ascent rates below approximately 500 meters per day; but there was a five- to six-fold relative benefit for prophylaxis at the highest ascent rates. Regarding adverse effects, subjects in 2 of 5 studies were more likely to experience depression on weaning of dexamethasone (overall RR=4.5). Acetazolamide was associated with polyuria (RR=4.2) and paraesthesia (RR=4.0).

BACKGROUND: Acute mountain sickness results in symptoms such as headache, loss of appetite, nausea, fatigue, insomnia, and increased mortality in the first few days of exertion at high altitudes. Acetazolamide and dexamethasone have been recommended as treatments to prevent acute mountain sickness, although their efficacy and tolerability have not been well established.

DATA SOURCE: Thirty-three clinical trials comparing any pharmacologic treatment with placebo for the prevention of acute mountain sickness were identified through a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, a high altitude bibliography Web site, and the bibliographies of retrieved reports and review articles. Of these trials, 18 reported complete prevention of acute mountain sickness as an outcome and as related to ascents to 4050 to 5890 meters (13300 to 19300 feet). These were included in a qualitative analysis of efficacy for any pharmacologic treatment (all 18 trials) and statistical meta-analyses for dexamethasone (8 trials representing 161 subjects) and acetazolamide (9 trials representing 295 subjects).

STUDY DESIGN AND VALIDITY: Only one author determined whether studies met inclusion criteria. All 3 authors read the included articles for validity, applying the 3-item 5-point Oxford score. The mean quality score was 3 (range=2-5). A total of 17 of the 33 trials used an adequate method of blinding. Validity was not a criteria for inclusion in the review. Following the qualitative analysis of efficacy, relative benefit (relative risk [RR] of prevention of mountain sickness) and numbers needed to treat (NNTs) were calculated for 2 interventions, dexamethasone and acetazolamide. Although the studies were rated for validity using previously tested criteria, no information on study limitations is given with which to judge the direction of effect. Using more than one author to determine eligibility would have minimized investigator bias. Although included studies varied in their definitions of acute mountain sickness, the results were homogenous. The investigators limited the outcome to complete prevention of symptoms. This conservative approach would underestimate the efficacy of the treatments making any significant benefit more likely to be real. Unfortunately, no information is provided on the subjects in the trials, including information such as age, sex, training, smoking status, and other risk factors for acute mountain sickness. This information would have helped generalize the study results.

OUTCOMES MEASURED: The primary outcome measured was complete prevention of acute mountain sickness according to the definition used in each of the original studies. Although reported for some of the studies, the reduction in symptom severity was not considered a criterion for efficacy in this study. Secondary outcomes included prevention of headache, nausea, insomnia, and dizziness, and the development of adverse drug reactions.

RESULTS: In 8 trials of dexamethasone (n=161) and 9 of acetazolamide (n=295), all with exposure above 4000 meters, single daily doses of dexamethasone 8 mg, 12 mg, and 16 mg or acetazolamide 750 mg were all more efficacious than placebo (NNT=3 for both). Smaller doses (dexamethasone 0.5 and 2 mg in one trial, acetazolamide 500 mg in 3 trials) did not prevent mountain sickness over placebo. Five trials of acetazolamide reported symptom end points including insomnia, headache, nausea, and dizziness; all results favored acetazolamide (NNT=3-6). Both dexamethasone and acetazolamide demonstrated a trend toward greater efficacy (lower NNT) with faster ascent rates. There was no relative benefit (RR for prophylaxis=1) for trials with ascent rates below approximately 500 meters per day; but there was a five- to six-fold relative benefit for prophylaxis at the highest ascent rates. Regarding adverse effects, subjects in 2 of 5 studies were more likely to experience depression on weaning of dexamethasone (overall RR=4.5). Acetazolamide was associated with polyuria (RR=4.2) and paraesthesia (RR=4.0).