Purpose: We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial.Materials and Methods: Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach.Results: Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean +/- SD 8.44 +/- 3.05 vs 11.07 +/- 8.23 days, p = 0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p = 0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p = 0.04) but not total combined costs (p = 0.068) was significantly lower for alvimopan than for placebo.Conclusions: In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with post-operative ileus and decreasing the hospital stay.

BACKGROUND:Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE:To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS:We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION:Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS:Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS:Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY:This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT00708201.

You have accessJournal of UrologyBladder Cancer: Metastatic Disease + Staging1 Apr 20131870 ALVIMOPAN, A PERIPHERALLY ACTING MU-OPIOID RECEPTOR ANTAGONIST, ACCELERATES GASTROINTESTINAL RECOVERY AND DECREASES LENGTH OF HOSPITAL STAY AFTER RADICAL CYSTECTOMY Ashish M Kamat, Sam S Chang, Cheryl Lee, Gilad Amiel, Timothy Beard, Amr Fergany, R Jeffrey Karnes, Venu Menon, Wade Sexton, Joel Slaton, Robert Svatek, Shandra Wilson, Lee Techner, Richard Bihrle, Michael Koch, and Gary D Steinberg Ashish M KamatAshish M Kamat Houston, TX More articles by this author , Sam S ChangSam S Chang Nashville, TN More articles by this author , Cheryl LeeCheryl Lee Ann Arbor, MI More articles by this author , Gilad AmielGilad Amiel Houston, TX More articles by this author , Timothy BeardTimothy Beard Bend, OR More articles by this author , Amr FerganyAmr Fergany Cleveland, OH More articles by this author , R Jeffrey KarnesR Jeffrey Karnes Rochester, MN More articles by this author , Venu MenonVenu Menon Cleveland, OH More articles by this author , Wade SextonWade Sexton Tampa, FL More articles by this author , Joel SlatonJoel Slaton Oklahoma City, OK More articles by this author , Robert SvatekRobert Svatek San Antonio, TX More articles by this author , Shandra WilsonShandra Wilson Denver, CO More articles by this author , Lee TechnerLee Techner Lexington, MA More articles by this author , Richard BihrleRichard Bihrle Indianapolis, IN More articles by this author , Michael KochMichael Koch Indianapolis, IN More articles by this author , and Gary D SteinbergGary D Steinberg Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2289AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical cystectomy (RC) is a complex abdominopelvic procedure often associated with delayed gastrointestinal (GI) recovery that may prolong length of stay (LOS). Alvimopan (alv) is FDA-approved (2008) for acceleration of upper and lower GI recovery after bowel resection. A multicenter Ph 4 trial evaluated the potential benefit of alv in RC patients (pts). METHODS A randomized, double-blind, placebo (pla)-controlled trial was conducted in RC pts scheduled for opioid-based IV pt-controlled analgesia. Pts were randomized (1:1) to oral alv 12mg or pla; 1st dose preoperatively, then twice daily until hospital discharge or postop day 7 (max 15 in-hospital doses). Primary endpoint was time to recovery of upper (1st toleration of solid food) and lower (1st bowel movement) GI function (GI-2). Key secondary endpoints included time to discharge order written (DOW), postop LOS, and postoperative ileus (POI)-related morbidity, a composite endpoint including postop nasogastric tube insertion, POI that prolonged hospital stay, or readmission ≤7 days for POI. Opioid consumption and adverse events (AEs) were collected. Blinded cardiovascular (CV) AEs were independently-adjudicated. RESULTS 280 pts were randomized with 277 in the modified-intent-to-treat population. Pt and operative characteristics were comparable between groups. The mean age was 65 yrs, the majority (80%) were male, and 27% had T2 tumor stage. An open approach was used in 84% of cases; mean surgery duration was 5.8 hrs. All primary and key secondary endpoints achieved statistical significance (Table). Opiod consumption, incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs) were comparable across groups with the exception of POI which was lower in the alv group than pla (TEAE: 7% v. 26%; SAE: 3% v. 12%, respectively). AEs adjudicated as CV occurred in 8.4% (alv) and 15.3% (pla) of pts (relative risk=0.55; P=0.09). CONCLUSIONS In this randomized controlled trial, alv significantly accelerated GI recovery, shortened LOS, and improved early in-hospital postsurgical outcomes in pts undergoing RC for bladder cancer. The safety profile of alv, including independent adjudication of CV AEs, was similar to pla. Endpoint Placebo (N=134) Alvimopan 12mg (N=143) Difference P Value Time to GI-2 Recovery _HR — 1.8 — < 0.0001 _KM median, hours 149.6 117.0 −28.5 hours — _KM mean, hours 164.2 132.7 −31.5 hours — Time to DOW _HR — 1.7 — 0.0002 _KM median, hours 179.8 160.6 −19.1 hours — _KM mean, hours 188.4 166.0 −22.4 hours — Postoperative LOS, days _Median 8.0 7.0 −1.0 days — _Mean 10.07 7.44 −2.63 days 0.0051 POI-related morbidity, % 29.1 8.4 −20.7% < 0.001 DOW = Discharge order written; GI-2 = Time to upper (first toleration of solid food) and lower (first bowel movement) gastrointestinal recovery; HR = Hazard ratio; KM = Kaplan Meier; LOS = Length of stay; POI = Postoperative ileus; © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited ByKauf T, Svatek R, Amiel G, Beard T, Chang S, Fergany A, Karnes R, Koch M, O'Hara J, Lee C, Sexton W, Slaton J, Steinberg G, Wilson S, Techner L, Martin C, Moreno J and Kamat A (2018) Alvimopan, a Peripherally Acting μ-Opioid Receptor Antagonist, is Associated with Reduced Costs after Radical Cystectomy: Economic Analysis of a Phase 4 Randomized, Controlled TrialJournal of Urology, VOL. 191, NO. 6, (1721-1727), Online publication date: 1-Jun-2014.Daneshmand S, Ahmadi H, Schuckman A, Mitra A, Cai J, Miranda G and Djaladat H (2018) Enhanced Recovery Protocol after Radical Cystectomy for Bladder CancerJournal of Urology, VOL. 192, NO. 1, (50-56), Online publication date: 1-Jul-2014. Volume 189Issue 4SApril 2013Page: e767 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashish M Kamat Houston, TX More articles by this author Sam S Chang Nashville, TN More articles by this author Cheryl Lee Ann Arbor, MI More articles by this author Gilad Amiel Houston, TX More articles by this author Timothy Beard Bend, OR More articles by this author Amr Fergany Cleveland, OH More articles by this author R Jeffrey Karnes Rochester, MN More articles by this author Venu Menon Cleveland, OH More articles by this author Wade Sexton Tampa, FL More articles by this author Joel Slaton Oklahoma City, OK More articles by this author Robert Svatek San Antonio, TX More articles by this author Shandra Wilson Denver, CO More articles by this author Lee Techner Lexington, MA More articles by this author Richard Bihrle Indianapolis, IN More articles by this author Michael Koch Indianapolis, IN More articles by this author Gary D Steinberg Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Objective: To evaluate in-hospital clinical outcomes after open and laparoscopic bowel resection (BR) with or without alvimopan treatment.Background: Delayed return of gastrointestinal function after BR may be associated with greater postoperative morbidity and increased hospital length of stay (LOS). In clinical trials, alvimopan-a peripherally acting mu-opioid receptor antagonist-accelerated gastrointestinal recovery after open BR.Methods: A retrospective matched-cohort study (NCT01150760) was conducted using a national inpatient database. Each alvimopan patient was exact matched (surgical procedure, surgeon specialty) and propensity score matched (baseline characteristics) to a nonalvimopan BR patient. Outcomes included gastrointestinal and other morbidity (cardiovascular, pulmonary, infection, cerebrovascular, thromboembolic); mortality; readmission rate; and intensive care unit (ICU) stay (intent-to-treat [ITT] population). Postoperative LOS and estimated cost were also compared (modified ITT population).Results: Each cohort included 3525 ITT patients with similar baseline characteristics. Gastrointestinal (29.8% vs 35.7%) and other morbidity (cardiovascular [19.4% vs 24.0%], pulmonary [7.3% vs 10.5%], infectious [9.6% vs 11.8%], thromboembolic [1.2% vs 2.1%]), mortality (0.4% vs 1.0%), and mean ICU stay (0.3 vs 0.6 days) were lower in the alvimopan group (P <= 0.003 for each). Postoperative LOS and estimated direct cost were lower for all alvimopan patients and after laparoscopic and open BR (LOS: -1.1, -0.8, and -1.8 days respectively; cost: -$2345, -$1382, and -$3218, respectively; P <= 0.0008 for each).Conclusions: On average, alvimopan-treated patients had a lower incidence of mortality and most incidents of morbidities. Length of stay, ICU use, and estimated cost were also lower with comparable readmissions. These results in patients outside the clinical trial setting include laparoscopic colectomy and demonstrate a potential association between acceleration of gastrointestinal recovery and improved early postoperative outcomes.

Patients receiving alvimopan capsules had significantly lower total hospital costs compared with controls. Along with other initiatives to improve quality and reduce costs of surgical care, alvimopan might be a good choice for use in the perioperative management of patients who undergo segmental bowel resection with primary anastomosis.

A pooled post hoc responder analysis was performed to assess the clinical benefit of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, for the management of postoperative ileus after bowel resection.

I read with great interest the article in your Volume 22 issue by Carroll and Alavi regarding the pathogenesis and management of postoperative ileus (POI).[1] Alvimopan was reviewed by the authors and concluded to show “promise in reducing POI, but needs more rigorous investigation.”

Constipation disproportionately affects older adults, with a prevalences of 50% in community-dwelling elderly and 74% in nursing-home residents. Loss of mobility, medications, underlying diseases, impaired anorectal sensation, and ignoring calls to defecate are as important as dyssynergic defecation or irritable bowel syndrome in causing constipation. Detailed medical history on medications and co-morbid problems, and meticulous digital rectal examination may help identify causes of constipation. Likewise, blood tests and colonoscopy may identify organic causes such as colon cancer. Physiological tests such as colonic transit study with radio-opaque markers or wireless motility capsule, anorectal manometry, and balloon expulsion tests can identify disorders of colonic and anorectal function. However, in the elderly, there is usually more than one mechanism, requiring an individualized but multifactorial treatment approach. The management of constipation continues to evolve. Although osmotic laxatives such as polyethylene glycol remain mainstay, several new agents that target different mechanisms appear promising such as chloride-channel activator (lubiprostone), guanylate cyclase agonist (linaclotide), 5HT(4) agonist (prucalopride), and peripherally acting mu-opioid receptor antagonists (alvimopan and methylnaltrexone) for opioid-induced constipation. Biofeedback therapy is efficacious for treating dyssynergic defecation and fecal impaction with soiling. However, data on efficacy and safety of drugs in elderly are limited and urgently needed.

Although evidence suggests that laparoscopic colectomy (LC) results in faster gastrointestinal (GI) recovery than open bowel resection, previous studies were performed at single institutions or generally not controlled for diet introduction or perioperative care, making the results difficult to interpret. A prospective, observational, multicenter study was planned to investigate GI recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity after LC.

PURPOSE The economic effect of the use of alvimopan in four randomized, double-blind, placebo-controlled, Phase III, North American efficacy trials was analyzed. METHODS Patients were eligible for the study if they were 18 years or older, were undergoing laparotomy for partial small or large bowel resection with primary anastomosis, and were scheduled for postoperative pain management with opioid-based i.v. patient-controlled analgesia. Patients analyzed in the North American Phase III trials received placebo or alvimopan 12 mg orally before surgery. Doses were administered twice daily beginning the day after surgery until hospital discharge or for a maximum of 15 doses. RESULTS Compared with placebo, alvimopan was associated with a significantly shorter mean time to gastrointestinal (GI) recovery and a significantly shorter mean time to a written discharge order. Alvimopan was also associated with a mean hospital length of stay (LOS) of one full day less than placebo. The mean cost of alvimopan based on a mean of 8.9 12-mg doses was $558.00; the alvimopan cost at the upper limit of allowed dosing was $937.50. Combining the alvimopan and hospital costs for each patient, total costs for the alvimopan group were estimated to be lower than for the placebo group. CONCLUSION In a post hoc analysis, alvimopan was associated with significantly faster upper and lower GI recovery after bowel resection and a mean LOS reduction of one day compared with placebo. The mean estimated hospital cost was $879-$977 less for patients who received alvimopan compared with placebo. The base-case and sensitivity analyses suggest that, on average, the use of alvimopan compared with placebo may have a cost-saving effect in the hospital setting.

OBJECTIVE:To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection.DESIGN, SETTING, AND PATIENTS:This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients.MAIN OUTCOME MEASURES:The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded.RESULTS:Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo.CONCLUSIONS:Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

The localization of opioid receptors and their endogenous peptide ligands within the gastrointestinal (GI) tract and their role in the coordination of propulsion and secretion underscores the importance of opioid receptors in the maintenance of GI homeostasis. The peripherally acting μ-opioid receptor antagonists alvimopan and methylnaltrexone (MNTX) are currently under investigation as therapeutic agents to treat the deleterious GI side effects associated with opioid administration. These compounds have demonstrated efficacy in numerous animal models of GI function, and clinical studies have revealed their efficacy in the treatment of postoperative ileus (POI) and opioid-induced bowel dysfunction. Preservation of opioid-mediated analgesia has been demonstrated for these compounds in both the preclinical and clinical settings. Future studies exploring the benefits of selective antagonism of the peripheral μ-opioid receptor in the treatment of other GI conditions may open new therapeutic opportunities for alvimopan and MNTX.

BACKGROUND:Postoperative ileus (POI), a transient cessation of coordinated bowel motility, occurs to some extent after all major abdominal operations. This analysis examines gastrointestinal (GI) recovery and hospital discharge history in patients undergoing partial bowel resection (BR) or total abdominal hysterectomy (TAH) by laparotomy in the placebo arms of recent phase III alvimopan trials. STUDY DESIGN:This was a pooled post hoc analysis of placebo groups from randomized, double-blind, parallel-group, multicenter trials. All patients were uniformly managed with a standardized accelerated postoperative care pathway to facilitate GI recovery. RESULTS:Of the 727 BR patients and 140 TAH patients included in this analysis, POI as an adverse event was reported in approximately 14.7% of BR patients and 2.9% of TAH patients, and postoperative nasogastric tube insertion was required in 11.5% of BR patients and 0.8% of TAH patients. Time to first toleration of solid food was almost 2 days longer for BR patients than for TAH patients (BR, 4.1 days; TAH, 2.5 days). Approximately 34.4% of BR patients and 4.2% of TAH patients had discharge orders written 7 days or more after operation. Nearly half (40%) of patients undergoing TAH were discharged from the hospital before GI recovery was complete. Mean postoperative lengths of hospital stay after BR and TAH were 6.6 days and 3.4 days, respectively. CONCLUSIONS:Despite the relatively fast recovery observed with standardized accelerated postoperative care pathway use, POI as an adverse event was still reported in approximately 15% of BR patients and 3% of TAH patients. This analysis provides important clinical insight into the differences in GI recovery patterns and the incidence and impact of POI after BR and TAH.

Objective:To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients. Summary Background Data:Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials. Methods:A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) ≥2 hours before surgery and twice daily until hospital discharge for ≤7 days. The primary endpoint of each trial was time to recovery of GI function. Hospital discharge order (DCO) written, readmission, and morbidities were also assessed. Cox proportional hazard models were used to analyze treatment effects on time-to-event endpoints. Results:Alvimopan (6 or 12 mg) significantly accelerated GI recovery (GI-3; hazard ratio = 1.28 and 1.38, respectively; P ≤ 0.001 for both). Alvimopan significantly accelerated time to DCO written by 16 hours for 6 mg and 18 hours for 12 mg (P < 0.001 for both) from a mean of 147 hours for placebo. Alvimopan-treated patients had reduced postoperative morbidity compared with placebo, and incidence of prolonged hospital stay or readmission was significantly reduced (P < 0.001). Tolerability profiles were similar among groups. Conclusions:Alvimopan significantly accelerated GI recovery in BR patients. A 12-mg dose provided more consistent benefits across both sexes and all ages. Postoperative morbidity rates, prolonged hospital stay, and rates of hospital readmission were significantly reduced. Alvimopan reduces the consequences of POI after BR.

BACKGROUND:Postoperative ileus (POI), an interruption of coordinated bowel motility after operation, is exacerbated by opioids used to manage pain. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated gastrointestinal (GI) recovery after bowel resection in randomized, double-blind, placebo-controlled, multicenter phase III POI trials. The effect of alvimopan on POI-related morbidity for patients who underwent bowel resection was evaluated in a post-hoc analysis. STUDY DESIGN:Incidence of POI-related postoperative morbidity (postoperative nasogastric tube insertion or POI-related prolonged hospital stay or readmission) was analyzed in four North American trials for placebo or alvimopan 12 mg administered 30 minutes or more preoperatively and twice daily postoperatively until hospital discharge (7 or fewer postoperative days). GI-related adverse events and opioid consumption were summarized for each treatment. Estimations of odds ratios of alvimopan to placebo and number needed to treat (NNT) to prevent one patient from experiencing an event of POI-related morbidity were derived from the analysis. RESULTS:Patients receiving alvimopan 12 mg were less likely to experience POI-related morbidity than patients receiving placebo (odds ratio = 0.44, p < 0.001). Fewer patients receiving alvimopan (alvimopan, 7.6%; placebo, 15.8%; NNT = 12) experienced POI-related morbidity. There was a lower incidence of postoperative nasogastric tube insertion, and other GI-related adverse events on postoperative days 3 to 6 in the alvimopan group than the placebo group. Opioid consumption was comparable between groups. CONCLUSIONS:Alvimopan 12 mg was associated with reduced POI-related morbidity compared with placebo, without compromising opioid-based analgesia in patients undergoing bowel resection. Relatively low NNTs are clinically meaningful and reinforce the potential benefits of alvimopan for the patient and health care system.