The introduction of accelerated recovery programs (ARPs) has radically changed the management of patients undergoing abdominal surgery. “Fastrack surgery,” first described by Wilmore and Kehlet,1 involves optimization of preoperative, perioperative, and postoperative factors, including early feeding and mobilization.2 The reduction of length of hospital stay (LOS) after colorectal surgery within an ARP is widely reported.3,4 However, postoperative ileus (POI) remains a significant factor affecting LOS following colorectal surgery.5–7 POI is defined as a temporary impairment in GI function and is a common postoperative complication that may occur in those undergoing abdominal surgery.7 It is characterized by bowel distension and vomiting and delay to oral feeding and increased postoperative pain; it results in prolonged hospitalization and a subsequent significant increase in health care costs.7,8 The cause of POI is thought to be multifactorial with spinal and local sympathetic neural reflexes and inflammatory mediators playing some part. Open surgical procedures and increased bowel manipulation are thought to contribute to POI, although a recent multicenter study found no difference in POI-related morbidity between patients undergoing open or laparoscopic procedures.9 However, a Cochrane review published previously suggested that laparoscopic surgery reduced but did not completely prevent POI.10
Opiates, which are known to delay gastric emptying and inhibit the small bowel and colon, are also thought to exacerbate POI.11–13 Endogenous opioids are secreted into the GI tract as a result of surgical stress, whereas exogenous opiates are commonly used for analgesia in the perioperative period.14,15 Alvimopan is a novel µ-opioid receptor antagonist of µ-opioid receptors within the GI tract and is thought to block the GI effects of opioids, thereby reducing the likelihood of POI.16,17 A number of randomized controlled trials, a meta-analysis, and a Cochrane review have demonstrated the beneficial effect of alvimopan, which was approved for use in the United States in 2008.18–23 However, in the meta-analyses by Tan et al22 and Traut et al,23 studies with both traditional and accelerated recovery protocols were included, thus affecting the utility of a cumulative analysis. Although POI is reduced by ARP,24 it is not entirely eliminated.25,26
POI remains a significant and costly postoperative complication, despite the introduction of ARPs and laparoscopic surgery. No systematic review or meta-analysis to date has reported the effect of alvimopan exclusively within an ARP.
This meta-analysis considers whether the opioid receptor antagonist alvimopan reduces hospital LOS in comparison with placebo in patients enrolled in a standardized ARP after abdominal surgery.
The electronic databases Cochrane (1999–2010), Embase (1980 to week 7 2010), MEDLINE (1950 to week 3 February 2010), International Pharmaceutical abstracts (1970 to February 2010) using the search strategy (abdominal surgery OR colo?rectal surgery OR lower gastro?intestinal surgery OR bowel resection OR laparoscopic surgery OR (MeSH terms) abdominal surgery OR gastrointestinal surgery OR colorectal surgery OR intestine surgery OR intestine resection OR laparosc*) AND (Alvimopan OR Entereg OR Mu?opioid antagonist OR alvimopan) AND (length of stay OR inpatient stay OR patient discharge OR length of stay OR hospital discharge) were searched with the explosion and focusing facilities and English language restriction. In addition, an exploded search of the MeSH term “alvimopan” and the free-text terms “alvimopan,” “ADL 8 to 2698,” and “Entereg” were also performed. Finally, reference sections of included articles were examined to identify further relevant studies, and European and US clinical trials registers were searched for relevant completed trials.
All evidence level 1, randomized controlled trials (RCTs) that compared alvimopan 12 mg with a placebo given to adult patients undergoing abdominal surgery on a defined ARP, with an outcome of LOS, were included. Studies that did not include the licensed dosing regimen of alvimopan and studies in which the recovery protocol was not explicitly described or defined as “accelerated” were excluded.
One author (I.F.) reviewed the abstracts of all studies identified by the search strategy and excluded articles that clearly did not fulfill the selection criteria. Full articles of potentially relevant trials and studies were retrieved and reviewed (I.F. and P.V.S.), resulting in further exclusions following discussion. Data on study design, inclusion and exclusion criteria, outcomes, dosing schedule, and placebo use, statistical methodology, and results were collected from included articles (I.F. and P.V.S.).
Outcomes of Interest and Definitions
Length of Stay. LOS was defined by when the “hospital discharge order” (HDO) was written, which was measured from the calendar day after surgery to the calendar day of HDO.
Recovery of GI Tract Function. Recovery of GI tract function can be considered a composite assessment of upper GI tract recovery, ie, tolerance of solid food, defined by Ludwig et al19 as solid food ingestion without significant nausea or vomiting for 4 hours, and lower GI tract recovery, ie, first bowel movement or flatus. GI-3 recovery, defined below, considers these 3 events. Because the passing of flatus may be difficult to assess, a secondary end point, GI-2 recovery, which does not include passing of flatus in its criteria, is also commonly used.
GI-3 is defined by the later of the following 2 events: time that the patient first tolerates solid food and the time that the patient first passes either flatus or a bowel movement.
GI-2 is defined by the later of the following 2 events: time that the patient first tolerates solid food and the time that the patient first passes a bowel movement.
Assessment of Methodological Quality
All included studies were assessed and appraised for quality (I.F.) by the use of the CONSORT guidelines27 on reporting of RCTs that stipulate inclusion of details relating to enrollment, intervention allocation, follow-up, and data analysis.
Meta-analysis and Assessment of Risk of Bias and Heterogeneity
Data were inputted into a customized database, and a meta-analysis of the cumulative published data was conducted according to PRISMA guidelines28 with the use of Stata 11 (StataCorp LP, TX). The effect measures estimated were HRs for censored temporal data reported with 95% CIs. Meta-analysis of temporal data was undertaken by extracting published data from all trials and calculating the log HR and SE.29 A HR of >1 represented a benefit in recovery of GI function or a reduction in time to HDO favoring the alvimopan group, whereas a HR <1 represented benefit favoring the placebo group. A funnel plot was charted to assess for publication bias, whereas the x2 test and I2 statistic were used to test for statistical heterogeneity between the selected studies.
Results of Literature Search and Characteristics of Included Studies
The search strategy yielded 296 articles. Abstract review revealed only 14 articles that underwent full-text review and reference searching. Of these, 1 pooled analysis, 1 meta-analysis, and 4 articles not involving surgical intervention were excluded. After further exclusions (Fig. 1), 3 articles were selected for inclusion.14,19,20 Reference review of articles undergoing full review and a search of clinical trials registers did not identify any further relevant studies. All 3 studies were multicenter, randomized double-blind, placebo-controlled studies of patients undergoing open surgery. No randomized trials of alvimopan vs placebo following laparoscopic surgery were identified. Of the 1829 patients randomly assigned in the identified trials, 389 patients were randomly assigned to 6 mg of alvimopan. The pooled modified intention-to-treat population was 1388 patients, of whom 703 received 12 mg of alvimopan. No procedures in these studies were performed laparoscopically. The characteristics of the included studies are displayed in Tables 1 and 2.
Results of Assessment of Methodological Quality
Results of the quality appraisal for each study can be seen in Table 3. Viscusi et al14 and Ludwig et al19 followed the CONSORT guidelines more closely than Wolff et al20, who made no comment on consent of study participants or exclusion criteria. Furthermore neither Wolff et al20 nor Viscusi et al14 describe a process of power calculation or the process of randomization or blinding, yet Viscusi et al14 incorporated numerous exclusion criteria, including the presence of relevant comorbidities, thus affecting the generalizability of these results. The statistical methodology of all 3 studies was appropriate and similar, with all studies using a Kaplan-Meier analysis to analyze time-to-event data and reporting HR with 95% CI. Despite these limitations, it is felt that all 3 studies are of sufficient quality, and they fit the criteria described by Harbor and Miller34 of “1=, well conducted RCTs with low risk of bias.”
Results of Meta-analysis
Time to HDO. All 3 studies reported on time to HDO and demonstrated reduced time to HDO of between 15.2 and 24 hours with alvimopan (Table 4). The HR of Wolff et al20 was applied a statistical weighting of 19.90%; Viscusi et al,14 a statistical weighting 27.10%; and Ludwig et al,19 a statistical weighting of 53.00%. The pooled HR for reduction in time to HDO was 1.37 (1.23, 1.52), Z = 6.02 (p < 0.0001) with no statistically significant variability or heterogeneity between studies (χ2 = 0.63, df = 2, p = 0.73, I2 = 0%) (Table 5).
Time to GI-3 Recovery. All 3 studies reported on time to GI-3 recovery, and all reported reduced time to GI-3 recovery of between 9.9 and 22 hours with alvimopan (Table 4). The HR of Wolff et al20 was applied a statistical weighting of 24.26%; Viscusi et al,14 a statistical weighting of 31.79%; and Ludwig et al,19 a statistical weighting of 43.95%. The pooled HR for reduction in time to GI-3 recovery was 1.42 (1.25, 1.62), Z = 5.31 (p < 0.0001) with no statistically significant variability or heterogeneity between studies (χ2 = 2.55, df = 2, p = 0.28, I2 = 0%) (Table 5).
Time to GI-2 Recovery. All 3 studies reported on time to GI-2 recovery with all studies showing reduced time to GI-2 recovery of between 13.7 and 28 hours with alvimopan (Table 4). The HR of Wolff et al20 was applied a statistical weighting of 23.35%; Viscusi et al,14 a statistical weighting of 26.76%; and Ludwig et al,19 a statistical weighting of 49.89%. The pooled HR for reduction in time to GI-3 recovery was 1.49 (1.32, 1.68), Z = 6.42 (p < 0.0001) with no statistically significant variability or heterogeneity between studies (χ2 = 1.69, df = 2, p = 0.43, I2 = 0%) (Table 5).
Publication Bias. A funnel plot illustrating overall meta-analysis of time to HDO, GI-3, and GI-2 HRs was produced. All studies were found to lie within the 95% CI for all 3 outcomes, suggesting minimal publication bias (Fig. 2).
The literature search reported here demonstrates that few randomized trials to date have considered the role of alvimopan within a standardized ARP, whereas only 1 trial has reported alvimopan use following laparoscopic surgery. Our meta-analysis has shown that 12 mg of alvimopan given 2 hours before surgery, and twice a day until discharge, significantly accelerates GI recovery and reduces time to hospital discharge in patients undergoing open abdominal surgery enrolled in an ARP. However, the actual quantitative reduction in time until these 3 end points is low, in most cases, less than 24 hours.
This study has a number of limitations. First, the use of HDO date as a primary outcome may be unreliable, because it may be influenced by a number of factors, including admission to higher-level care, contraction of hospital-acquired infections, or nonmedical reasons for delayed discharge. The consideration of time to GI recovery in this meta-analysis was therefore used to further investigate the role of alvimopan. Second, we did not consider treatment emergent adverse events. The meta-analysis by Tan et al,22 however, found no significant difference in the incidence of either GI-related or non-GI-related (pruritus, hypo/hypertension, tachycardia, headache, insomnia, pyrexia) adverse events between both alvimopan groups and placebo. Importantly, a trial of alvimopan use in patients taking opioids for chronic pain demonstrated an increased proportion of patients experiencing myocardial infarctions. Following subsequent submission of a revised risk-management program, alvimopan was approved solely for the management of POI, but the concern regarding myocardial infarctions may yet threaten its widespread uptake.35
The results of this present study must be considered alongside a number of other meta-analyses. Both the meta-analysis by Tan et al22 and the Cochrane review by Traut et al23 report on time to discharge, GI-3 recovery, and GI-2 recovery. For these outcomes, Tan et al22 include 2 of the 3 studies also included in our meta-analysis and those of Herzog et al32 and Delaney et al.31 Meanwhile, Traut et al23 include the results of Taguchi et al,17 and the same 2 studies also included our meta-analysis. Neither meta-analysis included data from Ludwig et al,19 published after these studies, and neither reported sensitivity analyses performed to consider those studies with standardized ARPs. We excluded the work of Herzog et al32 and Taguchi et al17 because a conventional recovery pathway was used, whereas the recovery pathway used by Delaney et al31 was not specified. In comparison with our findings of HR for time to HDO, GI-3 recovery, and GI-2 recovery of 1.37, 1.42, and 1.49, Tan et al22 reported HR of 1.40, 1.50, and 1.58 and Traut et al23 reported HR of 1.31, 1.30, and 1.59. The lack of any considerable difference here suggests that alvimopan has a similar beneficial effect in all outcome fields, whether used within an ARP or not. Second, this meta-analysis considers reduction in time to the stated end points. This mirrors the reporting of results by the included trials. In contrast, a recent pooled-responder analysis of randomized trials within defined accelerated postoperative care pathway considered instead the proportion of patients reaching such end points on each postoperative day.36 These 2 different methods for reporting of such results enable the clinician to consider the effectiveness of alvimopan in different terms.
Postoperative ileus occurs commonly after abdominal surgery and results in delay to oral intake and prolonged hospital stay with subsequent increase in health care cost and hospital-related morbidity.7 ARPs that aim to optimize perioperative factors and encourage early feeding and mobilization may reduce POI, yet they do not eliminate it.25,26 Furthermore, laparoscopic surgery has been shown to reduce yet not completely prevent POI.10 POI therefore remains an important and costly postoperative complication. Given the effect of both endogenous and exogenous opioids on bowel motility, opioid receptor antagonists may reduce POI. Opioid antagonists currently approved for use in the United Kingdom, for example, naloxone, can cross the blood-brain barrier and therefore antagonize opioid analgesia. Alvimopan, a novel µ-opioid receptor antagonist, does not readily cross the blood-brain barrier and so is a selective antagonist of µ-opioid receptors within the GI tract.17 Our literature search demonstrates that level 1 evidence for the use of alvimopan in patients after open abdominal surgery within a defined ARP is limited. Our meta-analysis has shown that 12 mg of alvimopan reduces time to HDO, GI-3 recovery, and GI-2 recovery in such patients. Earlier discharge would result in direct cost savings while also reducing hospital-related morbidity, such as venous thromboembolism and hospital-acquired infections.37 With more than 36,000 colorectal resections and more than 30,000 abdominal hysterectomies performed in England each year, with mean hospital stays of 7 to 24.2 and 3.7 to 6.7 days,38 any intervention that reduces LOS or additional radiological studies would generate considerable cost savings. It is argued that such savings may be offset by drug cost (approximately $62 per capsule and $550 per course).39 However, Poston et al40 reported a large retrospective, matched cohort study of 1440 patients undergoing open or laparoscopic small- or large-bowel resection and demonstrated a reduction in total hospital costs by $1040, whereas Bell et al39 reported reduced costs of $879 to $977 in similar cohorts.
Laparoscopic surgery for colorectal resection is now widespread with proven advantages over conventional techniques including reduction of POI.10,41 However, to date, only limited evidence for the role of alvimopan after laparoscopic surgery is available.42–44 Barletta et al44 performed a single-center retrospective observational study and demonstrated no reduction in POI or LOS with alvimopan after laparoscopic colectomy. However, Obokhare et al43 have recently reported the first randomized trial of alvimopan following laparoscopic colorectal surgery and demonstrated a reduction in POI, yet no reduction in hospital stay with alvimopan. A further randomized trial studying the role of alvimopan after laparoscopic colorectal surgery is currently underway (clinical trials identifier NCT01258569) with results expected in 2012. Such work will help define the role of alvimopan after laparoscopic surgery.
This meta-analysis has shown that 12 mg of alvimopan given 2 hours before surgery and twice a day until discharge significantly accelerates GI recovery and subsequently reduces time to hospital discharge in patients undergoing open abdominal surgery enrolled in an ARP. Previous work has demonstrated that alvimopan is well tolerated with no increase in side effects or adverse events and no effect on the efficacy of opioid analgesia.22 However, a concern exists relating to adverse cardiovascular events with alvimopan that requires further investigation. The concept of a specific drug that will speed up recovery from abdominal surgery is obviously attractive. Accelerated GI recovery and improved patient comfort are important outcomes. However, perhaps a more an important consideration is that time to discharge was only reduced by between 15.2 and 24 hours in the 3 studies included in this article. Given the increasing move toward laparoscopic surgery, results of future randomized trials of alvimopan after laparoscopic surgery and cost-effectiveness analyses in such settings are required to define the role that such an intervention will play after abdominal surgery in modern practice.
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Alvimopan; Bowel resection; Postoperative ileus; Length of stay; Meta-analysis