In Response to Ibuprofen vs Acetaminophen in AMS Prevention by Kanaan et al

To the Editor:

For over 40 years the Nepal Himalaya has been a site for pioneering clinical trials investigating the understanding, prevention, and treatment of high altitude illness.¹ The approach to Mount Everest base camp is an often-used route for these studies because it has a rapid ascent profile traditionally resulting in a high incidence of acute mountain sickness (AMS). Although unfortunate for trekkers, this area has proven fruitful for researchers who benefit from large numbers of enthusiastic participants in addition to robust effect sizes that allow for well-powered trials. We were interested to read the recent publication in Wilderness & Environmental Medicine by Kanaan et al that continued this research tradition, with a comparison of acetaminophen vs ibuprofen for the prevention of AMS.² However, their power analysis overestimated the expected incidence of AMS, resulting in an unforeseen limitation that was not discussed and likely affected their conclusions.

Recent studies in Nepal have found that the incidence of AMS has decreased dramatically. Although good news for trekkers, it is bad news for investigators attempting to adequately power a clinical trial. The Annapurna circuit has witnessed almost a 50% decline in AMS over the past 24 years, down to 22%³; at the Himalayan Rescue Association clinic in Manang, researchers recently observed approximately 1 case of AMS every other day.⁴ Likewise, at the common enrollment villages of Pheriche and Dingboche on the approach to Mount Everest base camp, a recent study found AMS incidence had decreased to 17%, half of the historical norm.⁵ There is likely a similar reduction in AMS incidence at the study end-point village of Lobuje. The most recent AMS incidence of 32% that Kanaan et al used for their power analysis was based on data gathered 6 years before their study,⁶ but the observed incidence of AMS at Lobuje ended up at 19%.²

Without a placebo arm, the authors do not know if these medications reduced the incidence of AMS at all. Although the authors did not state it, the predetermined effect size of their superiority trial was 20%, which would have required an absolute benefit of ibuprofen over acetaminophen in preventing AMS that was greater than the actual existence of disease in the population being studied.

For accurate conclusions, it is necessary to analyze the results in the context of the witnessed incidence of disease, rather than purely on a priori estimates. Reverse calculation of the necessary enrollment for a superiority trial with an effect size of 10% (which may not be clinically significant) would have required 368 participants. This enrollment burden may not be feasible in a single trekking season.^2,5 Furthermore, the observed 19% incidence of AMS is similar to that found previously by acetazolamide for prevention of AMS at Lobuje.⁷ Therefore, it stands to reason that any adequately powered trial that contemplates a novel chemoprophylactic at these sites would require the unlikely presumption that the hypothetical drug would be more efficacious than acetazolamide. The decreased incidence rate of AMS witnessed on the ascent to Mount Everest base camp is likely the result of continued outreach by the Himalayan Rescue Association and high-altitude researchers and educators around the world. This raises a question: Have we done our job too well and stymied future high-altitude studies at one of the world’s great field settings?

The ascent to Mount Everest base camp is metaphorically littered with the remains of the multitude of drugs that were shown to be ineffective for prevention of AMS or subsequently disproven. We think that this study does not adequately determine the relative effectiveness of ibuprofen and acetaminophen for prevention of AMS. Would a hypothetical 40% larger sample size confirm the observed trend of superiority of ibuprofen over acetaminophen for prevention of AMS,² thus proving statistical significance? It is impossible to say. Because there was no placebo arm in this study, an alternative explanation may be that both drugs improved a large, but unknown, incidence of AMS, which is unlikely given the recently reported regional AMS rates. What we do know is that the high likelihood of type II error limited the ability to reject the null hypothesis and confidently conclude that the two drugs are “equivalent.” This failure to observe sufficient evidence for null hypothesis rejection is not synonymous with a conclusion of equivalence. Current constraints of the approach to Mount Everest base camp may challenge single-season trials based on a testable effect size. As high-altitude research has matured, field studies deserve the same methodological rigor expected in the other houses of medicine. Considering the proven benefit of ibuprofen for the prevention of AMS,^6,8 it deserves further consideration and study before either being fully embraced or dismissed outright.

References

Hackett

P.H.

Rennie

Levine

H.D.

The incidence, importance, and prophylaxis of acute mountain sickness. Lancet. 1976; 2, 1149–1155.

Kanann

N.C.

Peterson

A.L.

Pun

et al. Prophylactic acetaminophen or ibuprofen result in equivalent acute mountain sickness incidence at high altitude: a prospective randomized trial. Wilderness Environ Med 2017; 28, 72–79.

McDevitt

McIntosh

S.E.

Rodway

Peelay

Adams

D.L.

Kayser

Risk determinants of acute mountain sickness in trekkers in the Nepali Himalaya: a 24-year follow-up. Wilderness Environ Med 2014; 25, 152–159.

Pitman

J.T.

Thapa

G.B.

Stuart

N.H.

Field ultrasound evaluation of central volume status and acute mountain sickness. Wilderness Environ Med 2015; 26, 319–326.

Lipman

G.S.

Kanaan

N.C.

Phillips

et al. Study looking at end expiratory pressure for altitude illness decrease (SLEEP-AID). High Alt Med Biol 2015; 16, 154–161.

Gertsch

J.H.

Corbett

Holck

P.S.

et al. Altitude sickness in climbers and efficacy of NSAIDs trial (ASCENT): randomized, controlled, trial of ibuprofen versus placebo for prevention of altitude illness. Wilderness Environ Med 2012; 23, 307–315.

Gertsch

J.H.

Lipman

G.S.

Holck

P.S.

et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the headache evaluation at altitude trial (HEAT). Wilderness Environ Med 2010; 2, 236–243.

Lipman

G.S.

Kanaan

N.C.

Holck

P.S.

Constance

B.B.

Gertsch

J.H.

PAINS Group

Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with non-steroidal anti-inflammatories. Ann Emerg Med 2012; 59, 484–490.