Alvimopan, for Postoperative Ileus Following Bowel Resection

In the United States, nearly 350,000 patients undergo colorectal or small bowel resection (BR) annually.¹ These patients spend an average of 11 days in the hospital and account for >$15 billion in annual national healthcare costs.¹ All of these patients experience postoperative ileus (POI), a temporary impairment of gastrointestinal (GI) function.^2–4 Moreover, associated GI complications are common.⁵ For patients who undergo BR, length of hospital stay (LOS) is dictated mostly by timing of GI recovery. To facilitate GI recovery, some specialized centers have used accelerated care pathways, although readmission rates have been increased in some cases.^6–10 Reducing surgical complications and further accelerating GI recovery after BR could increase patient comfort, decrease the average LOS, and reduce costs, readmission rates, and other demands on healthcare resources.¹¹

The etiology of POI is complex, and major intrinsic contributing factors include surgical stress (ie, from physical manipulation of the bowel), secretion of inflammatory mediators and endogenous opioids in the GI tract, and changes in hormone levels and electrolyte and fluid balance.^12–15 Opioids are the most widely prescribed analgesics used to treat postoperative pain.¹⁶ However, opioids bind to mu-opioid receptors within the gut, exacerbating POI.^12,14 No specific treatment currently exists for the treatment or prevention of POI.

Alvimopan is a novel, oral, peripherally acting, mu-opioid receptor (PAM-OR) antagonist that has been studied in patients undergoing abdominal and pelvic surgery.^17–19 In 3 phase III multicenter trials, alvimopan accelerated GI recovery after BR or total abdominal hysterectomy (TAH).^17–19 Although the results favored alvimopan across studies, statistical significance and magnitude of treatment effect were not consistent with regard to the primary endpoint, a composite assessment that included toleration of solid food and first passage of flatus or stool (GI-3). Further, the individual studies were not powered sufficiently to investigate infrequent but clinically important postoperative morbidities or investigate potential differences between the 6- and 12-mg doses. Hence, a pooled analysis was performed to examine the safety and efficacy of alvimopan within the subgroup of patients who underwent BR.

METHODS

RESULTS

DISCUSSION

The current pooled analysis demonstrated that alvimopan 6 and 12 mg significantly reduced postoperative GI morbidity and significantly accelerated GI-3 recovery in patients undergoing BR in a cross section of surgical centers. Benefits were significant for both doses, but treatment benefits appeared greater and more consistent for alvimopan 12 mg, which demonstrated benefits in subset analyses in women and elderly patients. Both alvimopan 6 and 12 mg also significantly accelerated GI-2 recovery, an important secondary endpoint based on parameters that can be accurately documented and are important for hospital discharge decisions.²⁰ Moreover, both alvimopan doses produced a significant decrease in the incidence of POI as an SAE and a significant reduction in the proportion of patients who had prolonged hospital stay or readmission. Furthermore, alvimopan 12 mg significantly reduced, by almost 50%, the proportion of patients with prolonged hospital stay, manifested by a DCO written ≥7 days after surgery. The majority of AEs that resulted in DCO written ≥7 days after BR surgery were GI-related in the placebo group and non–GI-related in alvimopan groups, underscoring the potential benefit derived from alvimopan treatment with regard to GI-related adverse events influencing prolonged hospital stay. Alvimopan was generally well tolerated, and pain scores and opioid consumption were similar across all treatment groups. Adverse events were mainly GI-related and expected for patients undergoing BR and receiving postoperative opioid-based analgesia. Most patients in this study received opioid-based anesthetics and analgesia, which contributed to the observed incidence of postoperative nausea and other GI-related adverse events in this study. However, nausea and other adverse events were not more common in either alvimopan group compared with the placebo group. Therefore, alvimopan did not increase the rate of postoperative GI-related adverse events above that of placebo. Overall, the TEAE profile of alvimopan was comparable with that of placebo, and patients treated with alvimopan had a lower incidence of GI-related TEAEs.

The 3 clinical trials included in this analysis strictly implemented a postoperative management protocol for the acceleration of GI recovery. Multimodal management protocols that integrate the use of minimally invasive surgical techniques (eg, laparoscopy instead of laparotomy), opioid-sparing analgesia, early oral nutrition, and physical rehabilitation have been reported to significantly accelerate postoperative GI recovery and reduce LOS.²¹ However, such practices may result in an increased rate of hospital readmission,²² and opioids provide better pain control compared with other analgesics such as nonsteroidal anti-inflammatory drugs.²³ Moreover, in Cochrane Database analyses, although epidural administration of local anesthetics was found to accelerate GI recovery and reduce nausea after abdominal surgery compared with epidural or systemic opioids, it did not reduce LOS compared with patient-controlled opioid analgesia.^24,25 However, encouraging early oral nutrition and ambulation in patients undergoing BR or complex abdominal or pelvic colorectal surgery not only accelerated GI recovery but resulted in shorter LOS compared with traditional care and no increase in rehospitalization rates in 2 single-center studies.^6,26 Indeed, early oral nutrition and ambulation were encouraged in the alvimopan phase III trials, and the resulting median time to DCO written (6 days) after BR compares favorably with the 7-day mean LOS after colonic surgery that was reported in a recent survey of U.S. clinical practice.²⁷ Therefore, the benefits of alvimopan were in addition to those provided by improved postoperative care pathways.

This pooled analysis of all BR patients in the alvimopan phase III efficacy trial database provides an assessment of GI recovery patterns in patients undergoing BR managed by an accelerated postoperative care pathway. In contrast with the 3 individual trials, which enrolled heterogeneous surgery populations with varying patterns of GI recovery,^17–19 the current analysis pooled BR patients from all 3 trials, providing a homogeneous surgery population. In the individual trials, statistical significance and magnitude of effect were inconsistent with respect to GI recovery endpoints in the overall MITT population (BR and TAH). The analysis of pooled BR data revealed that alvimopan provided significant benefit at both doses, as assessed by the time to GI-3 and GI-2 recovery, readiness for HD, and hospital DCO-written endpoints. These results confirm and extend those already reported for the individual trials. Moreover, pooling data allowed further investigation of the potential differences between alvimopan doses. Indeed, alvimopan 12 mg consistently demonstrated greater benefit compared with alvimopan 6 mg for GI recovery, readiness for HD, and hospital DCO written. Alvimopan 12 mg also demonstrated greater benefit in female patients and older patients (age >65 years).

Pooling data allowed further insight into less frequent but clinically important postoperative morbidities and hospital readmission rates. Importantly, the rate of anastomotic leak was low and comparable for all groups, supporting the current view that accelerating GI recovery does not compromise healing of the anastomosis.¹⁵ Alvimopan reduced the incidence of clinically important events that are known to increase patient morbidity. Although the severity of GI-associated discomfort is difficult to assess objectively, postoperative NGT insertion is an indication that the patient is experiencing symptoms severe enough to warrant intervention. Both doses of alvimopan significantly reduced the proportion of patients who had postoperative NGT insertion compared with placebo. Moreover, fewer alvimopan-treated patients had POI as an SAE and POI or EPSBO as an SAE. Another indication of postoperative morbidity is prolongation of planned hospital stay or readmission, both of which were reduced with alvimopan treatment. Furthermore, both alvimopan groups had significant reductions of mean time to DCO written compared with the placebo group. These significant reductions were calculated based on the difference between the time of surgical procedure and discharge order written. Reduction in length of hospital stay based on day of hospital admission to day of hospital discharge was approximately 1 day (alvimopan 6 mg, 1 day; alvimopan 12 mg, 0.9 days). In addition to reduced cost associated with occupancy of hospital beds, earlier departure may mean a reduction in monitoring requirements and nursing support. Moreover, earlier departure from the hospital could be meaningful to patients. These reductions and the reduction in hospital readmissions suggest that alvimopan also reduces the average overall hospitalization time associated with BR surgery.

In theory, pooled analyses may be confounded by differences in randomization criteria between component trials, and individual study effects may be obscured. However, the phase III trials used for this analysis were all of similar design and used BR as a randomization criterion. Furthermore, a key strength of this study was that all patients were treated with an accelerated care pathway practiced at some specialized centers to facilitate GI recovery.^7,8 Indeed, the length of hospital stay for the placebo group in this analysis was 5 days less than the national average.¹ Thus, alvimopan provided benefits beyond those achieved by the accelerated care pathway alone.

CONCLUSION

In the pooled analysis of the phase III efficacy studies, alvimopan accelerated GI recovery and reduced postoperative morbidity and readmission after BR surgery.

ACKNOWLEDGMENTS

We would like to thank Amy Rachfal, PhD; ProEd Communications, Inc.; for her medical editorial assistance with this manuscript.

The following investigators and institutions participated in the Alvimopan Postoperative Ileus Study Group for studies 14CL302, 14CL308, and 14CL313: Herand Abcarian, MD, University of Illinois at Chicago, Chicago, IL; Shireen Ahmad, MD, Northwestern University Medical School, Chicago, IL; H. Randolph Bailey, MD, Baylor College of Medicine, Houston, TX; Paul Baron, MD, Discovery Alliance, Inc., Mt. Pleasant, SC; James Barone, MD, The Stamford Hospital, Stamford, CT; Joel Bauer, MD, Mount Sinai School of Medicine, New York, NY; P. Sue Beckwith, MD, The Iowa Clinic, Des Moines, IA; Maria Bell, MD, South Dakota Health Research Foundation, Sioux Falls, SD; Eric Bieber, MD, Geisinger Medical Center, Danville, PA; Sander R. Binderow, MD, Atlanta Colon and Rectal Surgeons, Atlanta, GA; Casey Blitt, MD, Tucson Medican Center, Tucson, AZ; Christine Brody, MD, The Damluji Research Center Medical Center, Oceanside, CA; Lance Bruck, MD, Jacobi Medical Center, Bronx, NY; W. Donald Buie, MD, University of Calgary, Calgary, AB; Thomas Cataldo, MD, Cooper Health System/University Medical Center, Camden, NJ; Michael A. Choti, MD, Johns Hopkins Hospital, Baltimore, MD; Colm Cole, MD, St. Paul's Hospital, Vancouver, BC; Robert L. Coleman, MD, Parkland Health and Hospital System, Dallas, TX; Gene Coppa, MD, Staten Island University Hospital, Staten Island, NY; Daniel Dempsey, MD, Temple University Hospital, Philadelphia, PA; Daniel Dent, MD, University of Texas Health Science Center at San Antonio, San Antonio, TX; Robert Donoway, MD, Horizon Institute for Clinical Research, Hollywood, FL; Richard C. Earnhardt, MD, Surgical Associates of Fredericksburg, Fredericksburg, VA; Warren E. Enker, MD, Beth Israel Medical Center, New York, NY; Edward J. Eyring, II, MD, Wasatch Clinical Research, Salt Lake City, UT; Samir Fakhry, MD, INOVA Fairfax Hospital, Falls Church, VA; Linda Farkas, MD, UPMC Cancer Pavilion, Pittsburgh, PA; Michael Ferrante, MD, UCLA Medical Center, Los Angeles, CA; Stephanie Fine, MD, West Jordan, UT; James W. Fleshman, MD, Washington University School of Medicine, St. Louis, MO; Philip Fleshner, MD, Cedars-Sinai Medical Center, Los Angeles, CA; Robert D. Fry, MD, Hospital of the University of Pennsylvania, Philadelphia, PA; Gerard J. Fulda, MD, Christiana Care Health System, Newark, DE; Susan Galandiuk, MD, University of Louisville Hospital, Louisville, KY; Gary Gecelter, MD, North Shore – Long Island Jewish Health System, New Hyde Park, NY; Todd M. Gerkin, MD, Central Carolina Surgery, PA, Greensboro, NC; Bimal Ghosh, MD, New York Harbor Healthcare System – Brooklyn Campus, Brooklyn, NY; Stephen Gordon, MD, Comprehensive NeuroScience, Inc., Atlanta, GA; Richard H. Greenberg, MD, Albert Einstein Medical Center, Philadelphia, PA; Roy Greengrass, MD, Mayo Clinic Jacksonville, Jacksonville, FL; Francis J. Harford, MD, Loyola University Medical Center, Maywood, IL; William E. Haun, MD, Exempla Saint Joseph Hospital, Denver, CO; Michael D. Holzman, MD, Vanderbilt University Hospital, Nashville, TN; Neil H. Hyman, MD, Fletcher Allen Health Care, Burlington, VT; Matthew Indeck, MD, Geisinger Medical Center, Danville, PA; Gaby A. P. Iskander, MD, Marshfield Clinic, Saint Joseph Hospital, Marshfield, WI; Ivan Kangrga, MD, Washington University Medical Center, St. Louis, MO; Donald G. Kim, MD, Michigan Medical PC/Ferguson Clinic, Grand Rapids, MI; Andrea Kurz, MD, Washington University Medical Center, St. Louis, MO; Edward Lee, MD, Albany Medical College, Albany, NY; Warren Lichliter, MD, Sammons Cancer Center, Dallas, TX; Daniel G. Lorch, Jr., MD, PAB Clinical Research, Brandon, FL; Kirk Ludwig, MD, Duke University Medical Center, Durham, NC; Robert D. Madoff, MD, Abbott Northwestern Hospital, Minneapolis, MN; Robert Martindale, MD, Medical College of Georgia, Augusta, GA; Martin McCarter, MD, Denver, CO; Ronald Medak, MD, The Damluji Research Center Medical Center, Oceanside, CA; Andrew Menzin, MD, North Shore University Hospital, Manhasset, NY; Fabrizio Michelassi, MD, University of Chicago Medical Center, Chicago, IL; Edward Michna, MD, Brigham & Women's Hospital, Boston, MA; Brent Miedema, MD, Columbia, MO; Benjie B. Mills, MD, Center for Women's Medicine, Greenville, SC; Deborah Nagle, MD, Graduate Hospital, Philadelphia, PA; Wade Naziri, MD, Carolina Research Center, Greenville, NC; Lars Newsome, MD, Scripps Memorial Hospital, La Jolla, CA; Bruce Orkin, MD, George Washington University Hospital, Washington, DC; Craig A. Paterson, MD, UMASS Medical Center, Worcester, MA; C. Richard Patterson, MD, Baptist Memorial Hospital, Memphis, TN; Michael Pearl, MD, State University of New York at Stony Brook, Stony Brook, NY; Mark Pello, MD, Cooper Health System, Camden, NJ; William B. Perry, MD, Wilford Hall Medical Center, Lackland AFB, TX; Alexander Pue, MD, Sharp Mary Birch Hospital for Women, San Diego, CA; Janice Rafferty, MD, University of Cincinnati College of Medicine, Cincinnati, OH; Mikhail I. Rakhmanine, MD, Lehigh Valley Hospital, Allentown, PA; Jebadurai Ratnaraj, MD, Washington University Medical Center, St. Louis, MO; Thanjuvar Ravikumar, MD, Montefiore Medical Center, Bronx, NY; Harry Reynolds, MD, University Hospitals of Cleveland, Cleveland, OH; Miguel A. Rodriguez-Bigas, MD, MD Anderson Cancer Center, Houston, TX; Rabih Salloum, MD, University of Rochester Medical Center, Rochester, NY; Armando Sardi, MD, St. Agnes HealthCare, Baltimore, MD; Steven Schechter, MD, Rhode Island Colorectal Clinic, Providence, RI; Paul W. Schroeder, MD, Medford Women's Clinic, LLP, Medford, OR; James V. Sitzmann, MD, University of Rochester Medical Center, Rochester, NY; Ronald P. Spencer, MD, Renstar Medical Research, Ocala, FL; Thomas Stahl, MD, Washington Hospital Center, Washington, DC; Raymond J. Staniunas, MD, Scott & White Memorial Hospital & Clinic, Temple, TX; John Daniel Stanley, MD, University of TN College of Medicine, Chattanooga, TN; Richard A. Steinbrook, MD, Beth Israel Deaconess Medical Center, Boston, MA; Kurt Stockamp, MD, Pensacola, FL; Theresa M. Terem, MD, Mt. Ranier Surgical Associates, Tacoma, WA; Michael L. Twede, MD, Salt Lake Women's Center, Salt Lake City, UT; Stephen Unger, MD, Mt. Sinai Medical Center, Miami Beach, FL; Anthony Vernava, MD, Colon/Rectal Surgery, Cleveland Clinic, Naples, FL; Eugene Viscusi, MD, Thomas Jefferson University Hospitals, Philadelphia, PA; Brian Warriner, MD, Vancouver Hospital, Vancouver, BC; Harry Joseph Wasvary, MD, Oakland Colon and Rectal Associates, Royal Oak, MI; James L. Weese, MD, UMDNJ-School of Osteopathic Medicine, Stratford, NJ; Carl J. Wescott, MD, Wake Forest University School of Medicine, Winston-Salem, NC; Steven Wexner, MD, Cleveland Clinic, Weston, FL; Barth L. Wilsey, MD, University of California Davis Medical Center, Davis, CA; Bruce G. Wolff, MD, Mayo Clinic, Rochester Methodist Hospital, Rochester, MN; Sherry Wren, MD, Palo Alto Veterans Health Care System, Palo Alto, CA; Richard T. Zera, MD, PhD, Hennepin County Medical Center, Minneapolis, MN.