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Keywords:

  • Alvimopan;
  • cystectomy;
  • ileus;
  • cost-effectiveness;
  • Markov-model

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

What's known on the subject? and What does the study add?

  • No cost-effectiveness studies exist in patients after radical cystectomy for the routine use of alvimopan for the prevention of postoperative ileus.
  • The present study provides a reasonable estimate of the cost-effectiveness of alvimopan for the prevention of postoperative ileus in the patient after radical cystectomy.

Objective

  • To determine if the cost of administering alvimopan, to help restore bowel function after abdominal surgery, to all patients undergoing radical cystectomy (RC) is cost prohibitive.

Patients and Methods

  • A cost-effective analysis was conducted from a healthcare payer perspective using a decision-tree model that incorporated direct healthcare costs and probabilities associated with the possible events and outcomes.
  • Sensitivity analyses were conducted on the influence of the cost and effectiveness of the drug, the probability of POI in RC patients, and the extended length of stay (LOS) as a result of POI.
  • Precision in estimates was determined using probabilistic sensitivity analyses with 5000 Monte-Carlo simulations.

Results

  • Under the base case assumption, the additional cost of a patient's LOS related to POI was $10 246 per person. Under the assumption that 15.6% of patients will have POI, the mean cost associated with POI in a cohort of patients not treated with alvimopan was $1597 (90% confidence interval [CI] $1335–1875) per patient.
  • Conversely, the routine use of alvimopan for all patients undergoing RC was associated with a mean POI-associated cost of $1495(90% CI $1312–1696) per person, which represents the cost of alvimopan ($700 per hospitalisation) and a 50% reduction in the rate of POI.
  • Sensitivity analyses revealed that there is a cost savings with the routine use of alvimopan under the following conditions: the POI results in extending LOS by ≥3.5 days, POI occurs in ≥14% of patients undergoing RC, or the drug results in a relative risk reduction of ≥44%.

Conclusions

  • Routine use of perioperative alvimopan may not be cost prohibitive because of its influence on POI rate and associated costs.
  • The cost-effectiveness of alvimopan is influenced by the POI incidence and the degree to which the drug can decrease the LOS.

Abbreviations
LOS

length of stay

POI

postoperative paralytic ileus

RC

radical cystectomy

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Radical cystectomy (RC) with pelvic nodal dissection is the standard surgical treatment for muscle-invasive urothelial carcinoma of the bladder. Patients undergoing this operation often have significant comorbid conditions due to the strong association of age and tobacco use with development of bladder cancer. As a result, patients undergoing RC with pelvic node dissection have a high rate of perioperative morbidity. Improvements in surgical technique and perioperative care have significantly reduced the perioperative morbidity and mortality but complication rates as high as 60% are reported in contemporary series from high-volume centres [1, 2]. One of most common complications is postoperative paralytic ileus (POI). Transient cessation of bowel activity is expected after major abdominal surgery with small bowel motility and gastric emptying returning quite quickly (within 24 and 48 h, respectively). However, large bowel recovery is typically more protracted, taking 3–5 days to resume activity [3, 4]. The definition for POI is highly variable but is generally defined as diminished intestinal motility after surgery beyond the expected transient cessation of bowel activity.

A POI occurs in 10–40% of patients undergoing RC and may contribute to 50–70% of all complications [1, 5-9]. Estimates of the added costs of POI indicate that a POI doubles the cost of the hospital stay [10]. Thus, POI continues to be a source of serious morbidity and adds substantial cost to hospitalisation for these patients.

Recently approved by the USA Food and Drug Administration for prevention of POI, alvimopan is a peripherally active μ-opioid receptor antagonist that selectively blocks gastrointestinal effects of opioids without blocking central opioid receptors [11]. One of the most common postoperative complications after a RC is POI, which may be exacerbated by narcotic use. By blocking intestinal opioid receptors with alvimopan, it is anticipated that recovery of postoperative gastrointestinal function may be accelerated. Alvimopan is given immediately before surgery and twice a day orally until patients have bowel activity. Three randomised double-blind placebo controlled trials of alvimopan have demonstrated efficacy in accelerating postoperative gastrointestinal recovery in patients who have undergone resection of small or large bowel [12-14]. However, the efficacy of alvimopan in a RC population has not been studied and is currently being evaluated in a randomised controlled trial [15].

If found to be effective in RC patients, introducing routine use of perioperative alvimopan may decrease length of stay (LOS) and decrease additional costs associated with POI. It is not clear if the benefits of alvimopan outweigh the added cost of treating all patients with this drug undergoing RC. The purpose of the present study was to evaluate the cost-effectiveness of alvimopan among patients undergoing RC for bladder cancer.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Cost-Effectiveness Analysis and Assumptions

A cost-effectiveness analysis model from a societal perspective was used to compare the additional cost of treating POI after RC vs the additional cost of alvimopan. The model was designed to compare the relative costs and outcomes of these two competing strategies. Similar to a randomised trial in RC patients comparing Alvimopan vs placebo, the base case is a patient undergoing RC who receives one dose of alvimopan before surgery and twice daily for 7 days or until hospital discharge, up to 15 doses. The algorithm was designed to sample from a probability distribution of variables shown in Table 1 [1, 2, 6, 8, 16, 18, 27]. Incidence rates for POI were gathered from contemporary published rates for large volume centres (Table 2) [1, 6, 8, 9, 16-18]. Model estimates were based on an extensive published literature review, local hospital cost data and/or Medicare reimbursement data when applicable (Table 1). Outputs were displayed as estimates with 90% CIs. The relative risk reduction on the rate of POI afforded by alvimopan was estimated based on results from randomised clinical trial results in patients who have undergone intestinal resection or hysterectomy [14].

Table 1. Model variables.
VariableMean (sd)
Cost of alvimopan for 15 doses, $700 (70)
Probability of POI, % [1, 2, 6, 8, 16, 18, 27]15.6 (5.00)
Daily cost of hospital stay, $1110 (111)
Additional LOS due to POI, days [1, 2, 6, 8, 16, 18, 27]4 (0.5)
plain abdominal radiograph of the kidneys, ureters and bladder, $150 (66.3)
Central venous catheter (CVC), $301 (36)
Total parenteral nutrition, $240 (37)
i.v. fluid, $24 (2.4)
Laboratory tests, $576 (58)
Inpatient consultation, $158 (16)
Nasogastric tube, $91 (13)
Medications300 (30)
CT, $1393 (139)
Probability of CT, %30 (3)
Probability of consultation, %30 (3)
Probability of CVC, %30 (3)
POI relative risk reduction, %50 (5)
Table 2. POI rates in RC populations.
StudyYearPatients, nPOI rate, %)
Chang et al. [16]200230417.8
Soulie et al. [18]20027312.3
Cookson et al. [6]200330422.7
Lee et al. [17]200426215.0
Hollenbeck et al. [8]2005253810.0
Shabsigh et al. [1]2009114216.0
Svatek et al. [9]201028315.2
Overall 490615.6

All costs were updated to 2011 USA dollars with the Gross Domestic Product Deflator Inflation Calculator [19]. Markov modelling was designed with TREEAGE PRO HEALTHCARE (Treeage Pro Healthcare. Inc. Williamstown, MA: Treeage Software; 2009).

Sensitivity Analysis

Initial generalised sensitivity analysis for all model estimates was depicted using a Tornado diagram constructed to compare the relative importance of each model assumption. In this plot, the sensitive variable is modelled as an uncertain value, while all other variables are held at baseline values. Specific sensitivity analyses were then performed to investigate the effect of adjusting several base case assumptions, including the cost of alvimopan, the POI rate, the extended LOS as a result of POI, and the estimated effect of alvimopan on POI rate. The probability distributions for model variables were derived from the literature when available (Table 1). For cost estimates, average and standard deviations (sd) determined from available cost estimates were used to define normal distributions. For all other cost estimates, where a range of estimates was not available, baseline values and sds (±10% of baseline values) were used to define normal distributions. In all, 5000 Monte Carlo simulations were conducted for probabilistic sensitivity analysis to simultaneously consider the uncertainties in our value estimates. Probabilistic sensitivity analysis uses a distribution of variables randomly selected iteratively to define a distribution of a parameter of interest.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Model assumptions with sds are shown in Table 1. The POI rate was 15.6% and the additional LOS due to POI for a patient undergoing RC was estimated to be 4 days (Tables 1, 2). Additional cost of a patient's hospital stay related to POI included the costs per additional hospital room and board, imaging tests, laboratory studies, parenteral nutrition, i.v. fluids, and medications for all patients (Table 1). Additional costs for CT, central venous access catheter placement, and nasogastric tube decompression were assumed for a proportion of patients (Table 1). The average cost of alvimopan was $700 per person [20].

A diagram of the decision tree used to evaluate the cost-utility of alvimopan for RC patients using model assumptions is shown in Fig. 1. Under the base case assumption, the additional cost of a patient's hospital stay related to POI was $10 246 per person. Under the assumption that 15.6% of patients will have POI, the mean cost associated with POI in a cohort of patients not treated with alvimopan was $1597 (90% CI, $1335–1875) per patient. On the other hand, the routine use of alvimopan for all patients undergoing RC was associated with a mean POI-associated cost of $1495(90% CI $1312–1696) per person after RC, which represents the cost of alvimopan ($700 per hospital stay) and a 50% reduction in the rate of POI. Thus routine use of alvimopan under these assumptions resulted in a cost saving compared with patients undergoing RC without alvimopan. Probabilistic sensitivity analyses showed that the likelihood that alvimopan results in a cost savings for patients undergoing RC under model assumptions is 74.2%.

figure

Figure 1. Decision tree for determining cost utility of alvimopan in a RC population.

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A Tornado diagram was constructed based on sensitivity analysis to explore the influence of model inputs on output estimates (Fig. 2). This analysis identified additional LOS, probability of POI, cost per hospital stay, cost of alvimopan, and the drug's relative risk reduction on the incidence of POI, as the variables having the most influence in the model estimates (Fig. 2). Subsequent sensitivity analyses were undertaken to explore the individual role of these variables.

figure

Figure 2. Tornado diagram. The sensitive variable is modelled as an uncertain value, while all other variables are held at baseline values. The numbers to the right of the variables indicate the range used for sensitivity analysis.

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For the base case, a POI was assumed to increase the LOS by 4 days. One-way sensitivity analysis was conducted to explore the associated costs with using alvimopan across a range of extended LOSs as a result of POI (2–8 days). A threshold value of 3.5 days was identified, such that if a POI resulted in an average extended LOS of ≥3.5 days, a cost benefit could be realised with routine use of alvimopan (Fig. 3).

figure

Figure 3. One-way sensitivity analysis examining the influence of additional LOS due to POI.

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One-way sensitivity analysis was used to evaluate the impact of likelihood of POI on cost-effectiveness of alvimopan (Fig. 4). An incidence of 14% is needed to achieve cost equivalence and an incidence of 30% results in a cost advantage of $837 per person ($3074 for placebo vs $2237 for alvimopan).

figure

Figure 4. One-way sensitivity analysis examining the influence of the probability of POI at baseline.

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The influence of the effectiveness of alvimopan on decreasing the POI rate is shown in Fig. 5. The base case value assumes a relative risk reduction of 50% decreasing the incidence from 15.6% to 7.8%. Alvimopan results in cost savings as long as there is at least a risk reduction of 44%. At a risk reduction of 22.5%, Alvimopan is slightly more costly at $1936.4 for average POI-related cost per patient compared with $1595 for average POI-related cost per patient not taking the drug but there is still a benefit in 3.4% of patients who avoid POI. A two-way sensitivity analysis was performed to evaluate the simultaneous influence of cost and risk reduction on the cost utility of routine alvimopan administration to RC patients. As long as the average cost of alvimopan is <$800, there was a cost benefit for this agent even with a POI rate of 10%.

figure

Figure 5. Two-way sensitivity analysis evaluating the influence of cost and risk reduction of alvimopan.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Alvimopan is a μ-receptor antagonist that has been shown to decrease rate of POI in patient populations undergoing bowel surgery. If alvimopan is effective in patients undergoing RC, this could considerably decrease the POI rate and limit postoperative morbidity and associated costs with RC. However, most patients undergoing RC do not have POI. In addition, at $700 per patient, the cost implications of routine use of this drug in RC patients must be considered. In this analysis we found that alvimopan offered a cost saving for patients undergoing RC using conservative assumptions. In addition, evidence that our estimate is robust was observed through probabilistic sensitivity analysis, which indicated that the probability of the present model resulting in a cost savings for patients treated with alvimopan was 74.2%.

Although the cost savings of $1600 for patients undergoing RC using alvimopan may seem like a modest benefit, most of our estimates were conservative and only included direct costs. Including indirect costs would magnify the impact. We assumed that the cost of alvimopan would be $700 per dose and that patients would take the drug for 7 days or until hospital discharge. However, it likely that the drug could be discontinued earlier than 7 days once there is return of bowel function. Furthermore, we assumed that the increased LOS afforded by a POI was 4 days. An improved cost-effectiveness rate was observed when the LOS was >3.5 days. In patients undergoing bowel surgery, Iyer et al. [21] retrospectively reviewed >17 000 patients and reported an increased LOS associated with POI of 4.9 days (13.8 vs 8.9 days). Therefore, it is possible that savings attributable to prevention of POI is >$1600 per patient.

A decision analysis approach was used to determine if routine use of alvimopan would be cost-effective for patients undergoing RC using a range of different assumptions. For the base case, we identified alvimopan to be cost-effective if the overall rate of POI was >14%. Additional sensitivity analyses showed that if alvimopan reduced the rate of POI by ≥44%, a costs savings would be achieved.

Multiple North American Phase III trials have studied the efficacy of alvimopan. Wolff et al. [12] randomised 510 patients to placebo, 6 mg or 12 mg alvimopan and concluded that alvimopan significantly accelerated postoperative gastrointestinal recovery by 15–22 h and time to hospital discharge for the 12-mg arm with a mean difference of 20 h. Delaney et al. [13] studied 451 randomised patients to placebo, 6 or 12 mg alvimopan and showed that the 6 mg dose significantly accelerated gastrointestinal recovery, but the 12 mg dose did not. Additionally, a discharge order was written with a mean difference of 14 h earlier for the 6-mg group. Viscusi et al. [14] studied 666 randomised patients to placebo, 6 or 12 mg alvimopan. The 12-mg group showed a significantly accelerated recovery of bowel function. After adjustment for duration of surgery and sex, both doses were seen to result in faster recovery of bowel function by a mean of 7.5 h. Ludwig et al. [22] randomised 654 patients to placebo, 6 or 12 mg alvimopan and also showed a significantly faster recovery of bowel function, with a mean difference of 20 h. In a European trail, Buchler et al. [23] also randomised 911 patients to placebo, 6 or 12 mg alvimopan and showed that the 6-mg group had a faster recovery of bowel function by a mean of 8.4 h.

In addition to improving time of bowel recovery, alvimopan has been shown to reduce morbidity from POI. Wolff et al. [24] performed a post hoc analysis of four trials to assess the morbidity associated with POI in 1409 patients who received either placebo or 12 mg alvimopan. An increased need for postoperative nasogastric tube was seen in the placebo group, 11.5% vs 6.6% in the treatment arm. Additionally, complications from POI resulted in a significantly longer LOS in 6.8% of the placebo group vs 2.1% of the treatment group. The present cost-effectiveness analysis did not investigate further downstream complications as a result of POI, e.g. cost associated with infection, poor wound healing, wound dehiscence, and need for additional surgical procedures. Inclusion of these cost estimates would further support use of alvimopan to reduce the rate of POI and hasten recovery of bowel function.

The use of alvimopan has also been shown to reduce LOS in patients undergoing bowel surgery. Bell et al. [25] studied the cost effectiveness of alvimopan in a post hoc analysis of four North American randomised trials. That study concluded that alvimopan resulted in a decreased LOS by a mean of 1 day. The cost of alvimopan in that study was $558.00 based on a mean use of 8.9 doses, with an upper limit of 15 doses, costing $937.50. A cost analysis revealed that the mean estimated hospital cost was $879–977 less for the alvimopan group. However, that group did not consider patients undergoing RC.

Concerns have been raised about the potential cardiovascular safety profile of alvimopan. For patients taking alvimopan for prevention of POI, a safety database analysis of 3975 patients identified a greater number of cardiovascular events (myocardial infarction, unstable angina, stroke, heart failure, serious arrhythmia, and cardiac arrest) in patients taking alvimopan [26]. An assessment of ‘blinded’ patient-level data of pre-specified cardiovascular events concluded that there is no evidence of increased cardiovascular events between patients assigned to treatment with alvimopan and placebo [26]. Nevertheless, concerns remain about the cardiovascular safety profile of this agent, especially in the RC population. As a result, a phase IV trial was initiated to address the cardiovascular safety profile among patients undergoing RC and to examine the effectiveness of alvimopan in this population [15].

The RC population could be significantly different from populations previously studied. Duration of surgery may be significantly longer in this patient population and may decrease the efficacy of alvimopan. Additionally, patients with bladder cancer may have a higher rate of cardiovascular disease and are older than the populations undergoing bowel resections unrelated to bladder cancer. From a safety standpoint, more studies are needed to address the cardiovascular safety profile of alvimopan in the RC population. We did not include negative cost consequences due to cardiovascular-related toxicity from alvimopan in the present analysis because there is no evidence to suggest that short-term alvimopan would increase risk of cardiovascular side-effects. However, we acknowledge that such effects could considerably influence the cost dynamics of such intervention.

We recognise additional limitations to the present analysis, with limitations regarding the accuracy of cost and estimates, given the variability of different practice patterns, local costs, and differences in outcomes after RC found in published series. We used an average estimate within a range of values drawn from the literature in probabilistic sensitivity analysis to try to account for variance and we show that over this range there is not significant variability in the model. The exact relative risk reduction of alvimopan in patients after RC is an important limitation of the present study. Alvimopan may show similar or significantly different efficacy in this population of RC patients who may be found to be older and have a longer duration of surgery. We choose to evaluate the influence of alvimopan on the POI rate to capture all the costs associated with POI and because POI is seen in a substantial percentage of patients undergoing RC. An alternative strategy of considering only the difference in LOS among treated and untreated RC patients, however, may provide a different estimate of the overall cost-effectiveness of this strategy. Despite these limitations, the present study provides important information for determining the cost utility of alvimopan in this population. In addition, the present analysis serves as a model upon which the cost-utility of any agent aimed at addressing complications may be interrogated.

In conclusion, our model indicates that routine use of perioperative alvimopan is unlikely to be cost prohibitive for patients undergoing RC. The decreased LOS afforded by the drug for patients undergoing RC most heavily influences the cost utility of alvimopan.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Dr. Robert Svatek is a study investigator in a clinical trial sponsored by Cubist Pharmaceuticals.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
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