What is the evidence regarding Entereg (alvimopan) use for cystectomy?

What is the evidence regarding Entereg (alvimopan) use for cystectomy?

Comment by InpharmD Researcher

Data suggests alvimopan can significantly accelerate gastrointestinal recovery and reduce the length of stay following radical cystectomy, which can correspond to a cost-benefit. However, there is a paucity of high-quality, randomized data aside from the phase 3 trial which led it its approval for cystectomy.

Background

Per 2020 guidelines from the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO), µ-opioid antagonist therapy (i.e., alvimopan) should be used to accelerate gastrointestinal recovery in patients undergoing radical cystectomy. Delayed return of bowel function is common following radical cystectomy, and this can lead to increased morbidity and prolonged hospital stay. Studies show alvimopan can significantly improve time to bowel function and shorten hospital stay following radical cystectomy. [1]

The first dose is given just prior to surgery and then continued until food is tolerated or for a maximum of 15 doses. Other postoperative complications are similar in patients receiving µ-opioid receptor antagonists, although these therapies are contraindicated in patients who have taken opioids for one week or greater prior to surgery. [1]

Alvimopan (Entereg®) is a peripheral-acting mu-opioid receptor antagonist that was approved for use following radical cystectomy in 2013 after evidence demonstrated a reduction in time to gastrointestinal recovery when compared to placebo (determined by tolerance of solid oral intake and first bowel movement). Further studies suggested an economic benefit with alvimopan use due to the reduced cost of hospitalization through the reduction in length of stay and decreased the use of health care services relating to the management of postoperative ileus. [1], [2], [3], [4]

A systematic review and meta-analysis included one randomized, controlled trial [Table 1] and four case-control studies to assess the use of alvimopan following radical cystectomy. The results of the analysis showed a reduced time to toleration of liquids (hazard ratio [HR] 1.34; 95% confidence interval [CI] 1.19 to 1.51; P <0.001) and solid foods (HR 1.22; 95% CI 1.11 to 1.34; P <0.001), first bowel movement (HR 1.27; 95% CI 1.12 to 1.43; P <0.001), and length of stay (HR 1.17; 95% CI 1.10 to 1.25; P <0.001) in patients who had received alvimopan. The analysis concluded that alvimopan significantly accelerates recovery of gastrointestinal function and reduces the length of stay in patients who underwent radical cystectomy; however, more data is needed to confirm these results because only one randomized trial was included. [4]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the evidence regarding Entereg (alvimopan) use for cystectomy?

Please see Tables 1-3 for your response.

Alvimopan Accelerates Gastrointestinal Recover After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial
Design	Multicenter, randomized, double-blind, placebo-controlled trial N=277
Objective	To extend the evaluation of alvimopan on GI recovery and other early postoperative outcomes in patients undergoing radical cystectomy
Study Groups	Alvimopan (n=143) Placebo (n=134)
Inclusion Criteria	Adults undergoing radical cystectomy who were scheduled for postoperative IV opioid-based analgesia and removal of the nasogastric tube by the morning of the first postoperative day
Exclusion Criteria	Patients undergoing partial cystectomy, have an ongoing history of short bowel syndrome, chronic constipation, or chronic diarrhea, and chemotherapy- or radiation-induced bowel dysfunction
Methods	Patients were randomized in a 1:1 ratio to receive either a single-dose oral alvimopan 12 mg or placebo 30 minutes and 5 hours before surgery start and then twice-daily oral doses were given postoperatively until either hospital discharge or a maximum of 7 days. Ambulation was encouraged on postoperative day 1. A liquid diet was offered on post-operative day 3 and solid food on postoperative day 4. Epidural anesthesia or analgesia was not permitted, and the routine use of non-opioid pain medications, like ketorolac or cyclooxygenase-2 inhibitors, was restricted to a two-dose maximum.
Duration	Follow-up: until hospital discharge or a maximum of 10 days
Outcome Measures	Primary: Time to upper (first toleration of solid food) and lower (first bowel movement) GI function recovery (GI-2) Secondary: Time to discharge order written, postoperative length of stay (LOS), postoperative ileus (POI) related morbidity, adverse events
Baseline Characteristics		Alvimopan (n=143)	Placebo (n=134)
	Age, years	66 ± 10.9	64 ± 9.8
	Males	113 (79%)	110 (83.3%)
	White	138 (95.5%)	131 (95.6%)
	BMI, kg/m²	28 ± 5.6	28 ± 5.5
	Smoking history	110 (76.9%)	109 (79.6%)
	Existing cardiovascular disease	27 (18.9%)	18 (13.1%)
	Blood transfusion given	55 (38.5%)	46 (33.6%)
	Surgery duration, hours (range)	5.8 ± 1.82 (2.9-10.7)	5.8 ± 1.95 (2.4-12.3)
Results		Alvimopan (n=143)	Placebo (n=134)	Hazard Ratio (95% CI)	P-value
	Time to upper and lower gastrointestinal recovery, days	5.5 ± 0.18	6.8 ± 0.23	1.773 (1.4 to 2.3)	<0.0001
	Time to discharge order written, days	6.9 ± 0.2	7.8 ± 0.2	1.668 (1.3 to 2.2)	<0.001
	Post-operative ileus-related morbidity	8.4%	29.1%	N/A	<0.001
	Post-operative length of stay, days	7.44 ± 3.05	10.07 ± 8.23	N/A	0.0051
Adverse Events	Common Adverse Events: Postoperative ileus (7.0% vs 26.3%); anemia (17.5% vs 19.7%); hypokalemia (16.8% vs 24.8%)
	Serious Adverse Events: serious post-operative ileus (4.9% vs 20.4%); dehydration (2.1% vs 5.1%); small intestinal obstruction (0.7% vs 5.1%); urinary tract infection (3.5% vs 1.5%); deep vein thrombosis and pulmonary embolism (0.7% vs 2.9%)
	Discontinuation due to Adverse Events: The most common treatment-emergent adverse event leading to drug discontinuation was post-operative ileus (3% vs 12%)
Study Author Conclusions	Adding alvimopan to a standardized care pathway provides further meaningful improvements in early in-hospital postoperative outcomes for patients undergoing RC. As such, alvimopan use represents an important advancement in surgical quality of care with the potential to reduce health care costs.
InpharmD Researcher Critique	Gastrointestinal recovery after radical cystectomy potentially depends on several factors, such as intraoperative fluid administration, bowel segment selection, use and extent of lymphadenectomy, and the surgical technique such as readaptation of the peritoneum. Because of the number of participating centers, variation in surgical and anesthetic practice, and differing patient characteristics, it was not feasible to stratify for these variables. More patients discontinuing due to adverse events in the placebo group (n=33, compared to 20 in the alvimopan group) may have biased the results toward the placebo since they were not included in this modified intention to treat analysis.

References:

Lee CT, Chang SS, Kamat AM, et al. Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol. 2014;66(2):265-272. doi:10.1016/j.eururo.2014.02.036

Alvimopan: A cost-effective tool to decrease cystectomy length of stay
Design	Retrospective, pre-post, cohort study N= 86
Objective	To evaluate the cost-effectiveness of the perioperative use of alvimopan in cystectomy and urinary diversion
Study Groups	Perioperative Alvimopan (n= 36) No Alvimopan (n= 50)
Inclusion Criteria	Patients that underwent cystectomy and urinary diversion for benign and oncologic indications between January 2008 and April 2012 at a single academic institution by seven surgeons
Exclusion Criteria	Patients that suffered Clavien 3b or greater complications (Death, Laparotomy for dehiscence/evisceration, Cardiogenic shock, Stroke requiring carotid endarterectomy, Ischemic leg requiring embolectomy, Laparotomy for small bowel obstruction, Laparotomy for delayed rectal injury, Status epilepticus, and Pulmonary hemorrhage)
Methods	In 2010, patients received alvimopan 12 mg preoperatively and then 12 mg q12h for up to 15 doses or until discharge. This study compared the outcomes and costs of patients two years before and after this alvimopan protocol was started. Pre-operative bowel preparation consisted of 4 L of polyethylene glycol and two days of a clear liquid diet. Radical or supratrigonal cystectomy was performed with an ileal conduit, Indiana pouch, transverse colon conduit, or Mainz neobladder. Patients received care in the surgical ICU or the acute care floor postoperatively.
Duration	No Alvimopan: 2008-2010 Alvimopan: 2010-2012
Outcome Measures	Length of Stay (discharge criteria was: tolerating solid food without nausea or vomiting, pain controlled on oral pain medications, ambulatory, and laboratory values and vital signs within normal limits); cost; readmission for ileus
Baseline Characteristics		Alvimopan (n=36)	No Alvimopan (n=50)
	Age, years (range)	62.2 ± 11.5 (41-82)	64.5 ± 12.5 (35-91)
	BMI, kg/m² (range)	28.8 ± 5.7 (14.8-40.2)	28 ± 5.1 (19.9-41.8)
	Male	27 (75%)	39 (78%)
	Current smokers	13 (36%)	11 (23%)
	Neo-adjuvant chemotherapy	8 (24%)	13 (27%)
	Surgery duration, minutes (range)	581.7 ± 153.6 (259-858)	637.8 ± 148 (279-977)
	Epidural analgesia	21 (60%)	36 (82%)
Results		Alvimopan (n=36)	No Alvimopan (n=50)	P-value
	Length of stay, days	8.6	10.5	0.005
	Readmission for ileus	0	2/45 (4.4%)	0.26
	Overall cost (adjusted to 2012 dollar values)	$32,443	$40,604	<0.001
Adverse Events	N/A
Study Author Conclusions	The use of alvimopan in the routine perioperative care of cystectomy and urinary diversion patients resulted in a decreased length of stay by 1.9 days. Additionally, the institution of routine perioperative alvimopan reduced costs by $7,062 (20% reduction). This demonstrates a real-world application of alvimopan at a moderate volume center.
InpharmD Researcher Critique	This retrospective study built upon the foundations of a multicenter RCT and helped to confirm the reduction in length of stay. In addition, it helped make the data more generalizable, as the RCT excluded patients with epidural analgesia, while this study included those patients. Limitations of this study include the retrospective nature. Biases can be introduced in the interpretation of the data due to the sequential nature of enrollment rather than having randomization. Additionally, the patient population was relatively small and were from a single medical center in Virginia.

References:

Manger JP, Nelson M, Blanchard S, Helo S, Conaway M, Krupski TL. Alvimopan: A cost-effective tool to decrease cystectomy length of stay. CEJU. 2014;67(4).

Alvimopan is associated with a reduction in length of stay and hospital costs for patients undergoing radical cystectomy
Design	Retrospective, database analysis N=1,087
Objective	To evaluate the impact of alvimopan in patient undergoing radical cystectomy (RC) for bladder cancer
Study Groups	Alvimopan (n=511) No alvimopan (n=576)
Inclusion Criteria	Diagnosis of bladder cancer; underwent an “elective” procedure on hospital day 0 or 1
Exclusion Criteria	Hospitals with no history alvimopan use; patients who underwent concurrent or secondary major abdominal procedures (e.g., gastrectomy, splenectomy) or urological procedures (e.g., nephrectomy)
Methods	This was a retrospective study using a large database (Premier Healthcare Database) that relied on ICD-9 codes. Patients who received alvimopan before surgery were compared to patients during the same timeframe who did not receive alvimopan.
Duration	2009 to 2015
Outcome Measures	Co-primary: length of stay; direct hospital costs Secondary: postoperative complications; readmission for ileus
Baseline Characteristics		Alvimopan (n=511)	No alvimopan (n=576)
	Age, years <55 55-64 65-74 ≥75	34 (6.7%) 109 (21.3%) 196 (38.4%) 172 (33.7%)	44 (7.6%) 129 (22.4%) 211 (36.6%) 192 (33.3%)	0.866
	Male	428 (83.8%)	476 (82.6%)	0.623
	Open surgery	355 (69.5%)	456 (79.2%)	<0.001
Results		Alvimopan (n=511)	No alvimopan (n=576)	P-value
	Length of stay, days	7	8	<0.001
	Alvimopan was associated with a reduction in overall hospital costs by -$2,709 (95% confidence interval [CI]-$4,507 to -$912; P=0.003), even though pharmacy costs were slightly higher (adjusted difference $390; 95% CI:$143 to $638; P=0.002). This cost difference was driven by the shorter duration of hospital stay. Alvimopan also showed a lower likelihood for readmission for ileus (odds ratio [OR] 0.63; 95% CI 0.40 to 0.98; P=0.041).
Adverse Events	N/A
Study Author Conclusions	This data shows that alvimopan is associated with a substantial cost-saving in patients undergoing RC, and suggest that routine use of alvimopan may be a potential cost-effective strategy to reduce the overall financial burden of bladder cancer
InpharmD Researcher Critique	This study is limited by its retrospective and database-driven design that relied on diagnostic codes. Since it was not a retrospective chart review, specific patient information could not be collected, and there may be a degree of unknown confounding. Additionally, the database did not publish information regarding accurate dosage of analgesics, tumor characteristics, clinical data, or performance status, which may all influence length of stay and costs.

References:

Huang JT-H, Cole AP, Mossanen M, et al. Alvimopan is associated with a reduction in length of stay and hospital costs for patients undergoing radical cystectomy. Urology. 2020;140:115-121. doi:10.1016/j.urology.2020.01.049