Novel therapies for postoperative nausea and vomiting: statistically significant versus clinically meaningful outcomes.

Postoperative nausea and vomiting (PONV) remains a common complication for both inpatients and outpatients undergoing surgical procedures. PONV is a complex physiologic phenomenon involving multiple neurophysiologic pathways and both central and peripheral receptor mechanisms. The frequently used antiemetics produce dopamine, acetylcholine, histamine, and serotonin receptor blocking properties. More recently, the neurokinin (NK)-1 receptor antagonists were also shown to have the potential for both preventing and treating PONV. In this issue of Anesthesia & Analgesia, Gan et al. report on rolapitant, a novel NK-1 receptor antagonist with a long elimination half-life value, for the prevention of PONV. This clinical trial was designed as a dose-ranging study involving both placebo and active comparator controls. The authors concluded that “rolapitant reduced the incidence of postoperative vomiting in a dose-dependent manner and was superior to placebo at all doses studied. ” They also noted that “there was no statistically significant difference between rolapitant (at any of the studied doses) and ondansetron in terms of the primary outcome variable. ” Although these statements are certainly true based on the data presented in this article, a more important question relates to how best to interpret these findings in the context of routine patient care. In other words, are the statistically significant differences reported clinically meaningful? The stated aim of the study by Gan et al. was to evaluate the efficacy and safety of a range of oral rolapitant monotherapy doses (versus a placebo) for preventing PONV from 0 to 24 hours after anesthesia. Unfortunately, the term “PONV” carries no formal agreed-upon definition in the research literature. In this study, the stated hypothesis was that “rolapitant is more effective than placebo in reducing the incidence of postoperative vomiting. ” Postoperative vomiting and/or retching is easier to quantify as an end point in an antiemetic drug study because no subjective evaluation of the severity of emetic symptoms is required, and the collection of data is straightforward and unambiguous. It is also well recognized that many antiemetic drugs are more effective at decreasing the incidence of vomiting/ retching than nausea. Given the recognized bias against publishing clinical trials that report “negative outcomes,” it is not surprising that these authors chose an end point that had an increased likelihood of demonstrating a positive outcome. There is, however, some peril in doing so. Whereas rolapitant does decrease the incidence of vomiting compared with placebo, it showed remarkably little effect on nausea. It is interesting to note that the active comparator in this trial, ondansetron, also had little effect on postoperative nausea. However, when the more stringent criterion of “no PONV” was examined, there were very few statistically significant differences with either ondansetron or rolapitant compared with the placebo group (Table 2 in Gan et al.). The statistically significant difference reported for rolapitant 70 mg (although not for rolapitant 200 mg) was attributed to the lower incidence of “no PONV” in the placebo group compared with the “no nausea” end point rather than an increased efficacy of the “active” drug groups. Although severity of nausea was assessed in this trial using an 11-point verbal response scale (VRS), only categorical descriptions of nausea data are presented in the article. The “no nausea” end point, presumably representing a VRS score 0, and the time to “significant nausea” are included in Table 2 of the article by Gan et al. For the purposes of this study, “significant nausea” was defined as a subject reporting a VRS nausea score 4. Given the discrete cutoff, “severe nausea” also becomes a categorical assessment. Nausea evaluated in this manner may fail to detect subtle differences in severity that might have been shown by a more robust presentation of actual VRS nausea scores over time. “No PONV” is widely studied and some experts would consider it to be a more stringent end point. The best evidence to date would suggest that 3 frequently used generic antiemetics (namely, ondansetron, droperidol, and dexamethasone) each result in a relative risk reduction of approximately 25% for the “no PONV” end point. In the From the *Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; †Department of Anesthesiology, Cedars Sinai Medical Center, Los Angeles, California; ‡Department of Anesthesiology, Policlinico Abano, Abano Terme, Italy; and §White Mountain Institute, Los Altos, California.