The efficacy of alvimopan in the management of postoperative ileus was evaluated in 6 multicenter, randomized, double-blind, parallel-group, placebo-controlled studies: 5 U.S. studies (Studies 1 to 4 and 6) and 1 non-U.S. study (Study 5). Patients 18 years of age or older undergoing partial large or small bowel resection surgery with primary anastomosis for colorectal or small bowel disease, total abdominal hysterectomy, or radical cystectomy for bladder cancer (in this procedure, resected segments of bowel are used for reconstruction of the urinary tract) under general anesthesia were randomly assigned to receive oral doses of alvimopan 12 mg or matching placebo. The initial dose was administered at least 30 minutes and up to 5 hours prior to the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first postoperative day and continued until hospital discharge or a maximum of 7 days. There were no limitations on the type of general anesthesia used, but intrathecal or epidural opioids or anesthetics were prohibited.

All patients in the U.S. studies were scheduled to receive intravenous patient-controlled opioid analgesia. In the non-U.S. study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration (intravenous or intramuscular). In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia. A standardized accelerated postoperative care pathway was implemented: early nasogastric tube removal (before the first postoperative dose); early ambulation (day following surgery); early diet advancement (liquids offered the day following surgery for patients undergoing bowel resection and by the third day following surgery for patients undergoing radical cystectomy; solids by the second day following surgery for patients undergoing bowel resection and by the fourth day following surgery for patients undergoing radical cystectomy), as tolerated.

Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded.

The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. Although both 2-component (GI2: toleration of solid food and first bowel movement) and 3-component (GI3: toleration of solid food and either first flatus or bowel movement) endpoints were used in all studies, GI2 is presented as it represents the most objective and clinically relevant measure of treatment response in patients undergoing surgeries that include a bowel resection. The time from the end of surgery to when the discharge order was written represented the length of hospital stay. In the 6 studies, 1,058 patients who underwent a surgery that included a bowel resection received placebo (not including 157 for total abdominal hysterectomy) and 1,096 patients received alvimopan 12 mg (not including 143 for total abdominal hysterectomy).

The efficacy of alvimopan following total abdominal hysterectomy has not been established. Therefore, the following data are presented only for surgeries that included a bowel resection (i.e., bowel resection or radical cystectomy).

Bowel Resection or Radical Cystectomy: A total of 2,154 patients underwent a surgery that included a bowel resection. The average age was 62 years, 54% were males, and 89% were Caucasian. The most common indications for surgery were colon or rectal cancer/malignancy, bladder cancer, and diverticular disease. In the non-U.S. bowel resection study (Study 5), average daily postoperative opioid consumption was approximately 50% lower and the use of non-opioid analgesics substantially higher, as compared with the U.S. bowel resection studies (Studies 1 to 4) for both treatment groups. During the first 48 hours postoperatively, the use of non-opioid analgesics was 69% compared with 4% for the non-U.S. and U.S. bowel resection studies, respectively. In each of the 6 studies, alvimopan accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written as compared with placebo. Hazard ratios greater than 1 indicate a higher probability of achieving the event during the study period with treatment with alvimopan than with placebo. Table 1 provides the Hazard Ratios, Kaplan Meier means, medians, and mean and median treatment differences (hours) in gastrointestinal recovery between alvimopan and placebo.

The Kaplan Meier estimate probabilities of patients receiving alvimopan who achieved GI2 were numerically higher at all times throughout the study observation period compared with those of patients receiving placebo (see Figures 1 and 2).

Figure 1: Time to GI2 Based on Results from Studies 1 through 5

Figure 2: Time to GI2 Based on Results from Study 6

In Studies 1 to 4, the differences between alvimopan and placebo patient groups in median time to ‘discharge order written’ ranged from 6 to 22 hours, in favor of alvimopan patients. The group differences in mean time to ‘discharge order written’ ranged from 13 to 21 hours. In Study 6, the median time difference was 19 hours in favor of alvimopan patients (mean time difference 22 hours).

Alvimopan did not reverse opioid analgesia as measured by visual analog scale pain intensity scores and/or amount of postoperative opioids administered across all 6 studies.

There were no sex-, age-, or race-related differences in treatment effect.

The incidence of anastomotic leak was low and comparable in patients receiving either alvimopan or placebo (0.7% and 1.0%, respectively).