Alvimopan and Enhanced Recovery Pathways in Colorectal Surgery
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Review: Clinical Trial Outcomes Alvimopan and enhanced recovery pathways in colorectal surgery Clin. Invest. (2014) 4(2), 177–183 Postoperative ileus negatively impacts patient outcomes and healthcare Benjamin Crawshaw, Deborah S Keller utilization, increasing both postoperative length of stay and health & Conor P Delaney* care costs. In efforts to optimize perioperative care, efforts have been Department of Surgery, University Hospitals placed into developing tools to minimize postoperative ileus. Alvimopan Case Medical Center, Case Western Reserve (Entereg®) was developed to meet this need. Alvimopan has permitted University, 11100 Euclid Ave, Cleveland, OH, accelerated return of bowel function after abdominal surgery in select 44106 –5047, USA *Author for correspondence: patients. Alvimopan has the potential to significantly improve clinical and Tel.: +1 216 844 8087 financial results, and research is ongoing to determine effective further Fax: +1 216 983 7230 applications of this medication. E-mail: [email protected] Keywords: alvimopan • enhanced recovery pathways • entereg • postoperative ileus Postoperative ileus (POI) is defined as the transient cessation of coordinated bowel motility after surgical intervention, which prevents effective transit of intestinal con- tents and/or tolerance of oral intake [101] . Organ recovery following major abdominal surgery generally occurs in less than 24 h for small bowel, 24–48 h for the stomach and 48–120 h for the colon [1,2] . Thus, return of normal bowel function is expected within three to five days for laparoscopic and open surgery, respectively. When this fails to occur within this expected time frame, POI is clinically diagnosed. Out of the 22 million inpatient surgeries performed annually in the USA, an estimated 2.7 mil- lion are complicated by a delay in return of bowel function [3]. POI is especially common following colorectal surgery, occurring in up to 25% of patients [4]. The pathophysiology of POI remains poorly understood, but involves a complex interaction of neurologic, hormonal, inflammatory and mechanical factors regulat- ing the GI tract [1,5,6] . Direct bowel manipulation, edema from surgery, and inhaled anesthetics have all been shown to impact postoperative bowel function [2,7,8]. In addition, narcotic analgesics, common in the perioperative period, peripherally bind to receptors within the GI tract and slow motility [9,10]. These effects are most pronounced in the colon, as there is less intrinsic enteric stimulation than in other parts of the GI tract [11] . There are proven clinical and financial implications of POI[12] . For patients, nausea, vomiting and abdominal discomfort are the most common complaints; these symptoms contribute to patient morbidity, frustration and reduced quality of life. POI is a major driver of delayed hospital discharge, increased length of stay (LOS), and the resulting healthcare utilization [13,14]. The effects on healthcare costs have also been documented. POI has been estimated to account for 6.25% of total hospital costs in the USA, and review of the Health Care Financing Administration’s 1999–2000 database estimated POI contributes US $1.14 billion annually [101,102]. This review discusses current evidence for the use of alvimopan (Entereg®, Ado- lor and GlaxoSmithKline, PA, USA) as a pharmacologic adjunct to reduce POI in patients undergoing bowel resections. A systemic PubMed search was performed with the keywords “alvimopan” combined with “postoperative ileus”, “bowel resection”, 10.4155/CLI.13.135 © 2014 Future Science Ltd ISSN 2041-6792 177 Review: Clinical Trial Outcomes Crawshaw, Keller & Delaney ‘laparoscopy’ and ‘recovery pathway’. Additional relevant selective opioid antagonism within the GI tract without publications were identified from the references of selected affecting the efficacy of centrally acting analgesia [34]. studies, and from the authors’ personal databases. Inclu- The drug was approved by the US FDA in May 2008 sion of papers was decided by consensus of the authors for patients scheduled to undergo small or large bowel with a focus on large scale and sound Phase II and III resection via laparotomy [35]. Contraindications include studies in open and laparoscopic bowel resections. chronic opioid use, bowel obstruction and severe renal or hepatic failure. Recommended dosing is 12 mg by mouth Enhanced recovery pathways & laparoscopic within 2 h of surgery, then twice daily until discharge for surgery a maximum of 7 days (15 doses). Alvimopan has been Effective methods to reduce POI and LOS have been proven safe and generally well tolerated; the most common developed. To date, the most effective method in reduc- side effects are dyspepsia, hypokalemia, back pain and ing POI and its associated LOS is laparoscopic colorectal urinary retention [36–38,104]. In early studies with long- surgery. Several randomized-controlled trials, systematic term, low-dose use, there was an observed, but insignifi- reviews, and large-scale trials have proven the benefits of cant increase in cardiovascular events [36,37]. However, no laparoscopic colorectal surgery in accelerating gastrointes- causative link has ever been established and the effect has tinal recovery and shorter average LOS by 2–3 days [15–21] . not been reproduced in any other study, or noted in any While laparoscopic surgery may decrease the incidence of short-term use study. To ensure the safety of the drug, POI through decreased bowel manipulation and sympa- alvimopan carried a black box warning and is approved thetic stimulation, it does not eliminate the problem [16,22] . under a Risk Evaluation and Mitigation Strategy, which Standardized fast track or enhanced recovery pathways limits use to short term (less than 15 doses) and inpatients (ERP) have also successfully reduced LOS. Protocols exist in hospitals enrolled in the Entereg Access Support & for multiple fields of surgery, and incorporate elements Education program [105] . Because of this limited avail- including reduction in perioperative fluids, early oral ability, it has not been universally implemented into many refeeding, early mobilization, minimization of narcot- standard ERPs, but rather is used as an adjunct to them, ics, and pharmacologic treatment of ileus to reduce time when available for appropriate patients. Contraindications to return of bowel function [23,24,103]. ERP have demon- include chronic opioid use, bowel obstruction, and severe strated consistent reductions in POI and hospital LOS renal or hepatic failure. [22,23,25]. Several studies have shown that the implementa- tion of an ERP reduced LOS from 7–10 days to approxi- ■ Cost–effectiveness mately 4 days following colorectal surgery [16,17,19,26–28]. The cost benefits of alvimopan have been evaluated when The combination of laparoscopy with an ERP further hospital LOS was reduced about 1 day. A cost ana lysis optimizes short-term outcomes and healthcare utilization. study of the US studies estimated the average cost of the Both randomized controlled and single-institution studies addition of alvimopan to be $558, with a mean reduc- demonstrated additional significant reductions in mean tion in hospitalization by 1.2 days, and a mean savings LOS using laparoscopy with a standardized ERP [16–21] . of $879–977 per patient [26]. Analysis using a national database showed a significant reduction in total hospital Alvimopan costs of $2345 per patient with the addition of alvimo- ■ Background & pharmokinetics pan (p < 0.0001) [38]. The cost reduction remained sig- Pharmacologic adjuncts have been attempted to further nificant when open and laparoscopic cases are analyzed reduce or eliminate POI [29,30]. Beta blockers, neostigmine separately, with savings of $3218 (p < 0.0001) and $1382 and cisapride were all trialed to speed return of bowel (p = 0.0008) respectively. When analyzing prospective function; results were mixed and significant side effects, and historical data, Absher et al. confirmed cost savings notably cardiovascular events and abdominal cramping, of both open ($997 per case) laparoscopic cases ($531 limited their efficacy and use [31,32]. While successful in per case) [39]. managing postoperative nausea and emesis, metoclo- pramide was not effective in reducing POI [33]. Newer ■ Alvimopan & open colorectal surgery medications have aimed to counteract the gastrointestinal Multiple randomized-controlled trials support the use of slowing caused by endogenous and exogenous narcotics. alvimopan for patients undergoing open colorectal surgery The most promising and clinically proven medication to to reduce time to gastrointestinal recovery. Major Phase II date is alvimopan. and III studies are summarized in Table 1. Taguchi et al. Alvimopan is a systemically absorbed, peripherally published the results of the first double-blind prospective acting µ-opioid antagonist with high affinity for human trial of use of alvimopan in 78 postoperative patients in µ-opioid receptors. Due to its size and structure, this drug 2001 [40]. In this Phase II single-institution study, patients does not cross the blood-brain barrier and thus provides undergoing elective total abdominal hysterectomy or open 178 www.future-science.com future science group Alvimopan & enhanced recovery pathways in colorectal surgery Review: Clinical Trial Outcomes Table 1. Summary of major Phase II/III alvimopan studies in open surgery. Trial (year) Phase Enrolled Alvimopan dosages Gastrointestinal Discharge Ref. (n) versus placebo (mg) recovery (hazard ratio) (hazard ratio) Taguchi et al. (2001) II 78 1 1.2 (p = 0.59) 1.2 (p = 0.48) [40] 6 2.9 (p = 0.01) 2.0 (p = 0.008) Delaney et al. (2005) III 451 6 1.45 (p = 0.003) 1.50 (p < 0.001) [41] 12 1.28 (p= 0.059) 1.18 (p = 0.17) Wolff et al. (2004) III 469 6 1.28 (p < 0.05) 1.25 (p = 0.070) [27] 12 1.54 (p < 0.001) 1.42 (p = 0.003) Viscusi et al. (2006) III 665 6 1.24 (p = 0.037 1.36 (p = 0.002) [42] 12 1.26 (p = 0.028) 1.30 (p = 0.010) Buchler et al. (2008) III 911 6 1.22 (p = 0.042) 1.08 (p = 0.47) [44] 12 1.13 (p = 0.20) 1.07 (p = 0.49) colectomy were randomized to receive 1-mg alvimopan, alvimopan group (p = 0.003).