Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis

A Randomized, Placebo-controlled Phase III Trial

Ashraf S. Habib, M.B., B.Ch.; Peter Kranke, M.D.; Sergio D. Bergese, M.D.; Frances Chung, M.D.; Sabry Ayad, M.D.; Naveed Siddiqui, M.D.; Johann Motsch, M.D.; David G. Leiman, M.D.; Timothy I. Melson, M.D.; Pierre Diemunsch, M.D., Ph.D.; Gabriel M. Fox, M.B.; B.Chir.; Keith A. Candiotti, M.D.

Disclosures

Anesthesiology. 2019;130(2):203-212. 

In This Article

Results

Disposition and Demographics

Between March 21, 2016, and January 11, 2017, 2,285 patients were enrolled, of whom 705 patients had a qualifying event of postoperative nausea or vomiting and were randomized; 702 received study drug (the modified intent-to-treat population; see figure 1). Two randomized patients withdrew consent and one refused medication just before dosing. The study arms were very similar in terms of baseline characteristics, including prophylactic antiemetics received (Table 1).

Figure 1.

Disposition of patients. *Day 7 follow up data not collected.

Clinical Effect

Primary and secondary efficacy endpoints are shown in Table 2. Complete response occurred in 67 of 235 patients in the placebo group (28.5%; 95% CI, 22.74 to 34.28%); 96 of 230 in the 10-mg amisulpride group (41.7%; 95% CI, 35.37 to 48.11%; P = 0.003; after Hommel's adjustment: P = 0.006); and 80 of 237 in the 5-mg amisulpride group (33.8%; 95% CI, 27.73 to 39.78%; P = 0.219). The difference between the success rate for 10 mg amisulpride and placebo was 13.2% (95% CI, 4.6 to 21.8), and the odds ratio was 1.80 (95% CI, 1.22 to 2.64). The adjusted odds ratio for occurrence of complete response for 10 mg amisulpride versus placebo using the Cochran-Mantel-Haenszel test was 1.81 (95% CI, 1.22 to 2.69), and using Logistic Regression analysis it was 1.85 (95% CI, 1.23 to 2.76).

During the first 30 min after study drug dosing, emesis occurred in 30 patients: 18, 8, and 4 in the placebo, 5-mg, and 10-mg amisulpride groups, respectively. All 30 patients received rescue medication, thus meeting the criteria for treatment failure. Accordingly, the 30-min window for excluding emesis events had no effect on the complete response rate in any arm. Complete response at each of the prespecified interim time points (2, 4, and 6 h) was around 20% higher with 10 mg amisulpride than placebo. The time to treatment failure was significantly longer for 10 mg amisulpride (median 443 min) than placebo (median 120 min), with a hazard ratio of 0.63 (95% CI, 0.50 to 0.80; P < 0.001; Figure 2).

Figure 2.

Kaplan–Meier curves of treatment success over time. HR, hazard ratio.

Emesis occurred in significantly fewer patients after either 5 mg or 10 mg amisulpride than placebo. Most other secondary endpoints were significantly improved by 10 mg amisulpride but not 5 mg, including rescue medication use, incidence of significant nausea, maximal nausea severity, and nausea evolution.

The mean length of stay in PACU after study drug dosing was 140.9 min with 10 mg amisulpride (SD, 174.2; median, 96.0 min; range, 0 to 1266) and 175.5 min with placebo (SD, 217.6; median, 116.0; range, 2 to 1353). Overall mean length of hospital stay after dosing was 50.3 h (SD, 79.7; median, 24.4 h; range, 0.7 to 716.3) with 10 mg amisulpride and 56.3 h (SD, 73.4; median, 29.2 h; range, 0.6 to 644.1) with placebo.

Safety

The number of treatment-emergent adverse events and the proportion of patients reporting at least one event were comparable between the placebo and amisulpride groups (Table 3). No deaths or withdrawals attributable to toxicity occurred. There were 17 serious adverse events in 14 patients, distributed evenly between the groups. Only nausea and vomiting occurring more than 24 h after dosing, flatulence, constipation, headache, infusion site pain, and pruritus were reported by 5% or more patients in any group. Unexpected or clinically relevant changes in hematology or clinical chemistry parameters were extremely infrequent in all groups.

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