Economic Evaluation of Tegaserod vs. Placebo in the Treatment of Patients with Irritable Bowel Syndrome: An Analysis of the TENOR Study

Authors


Andrea Bracco, AMGEN (Europe) GmbH, Zug, Switzerland. E-mail: andrea.bracco@amgen.com

ABSTRACT

Objectives:  Tegaserod is effective, safe, and well-tolerated in the treatment of patients with irritable bowel syndrome (IBS) with constipation. The aim of this study was to assess, from a payer perspective, the cost-effectiveness of tegaserod in the treatment of IBS patients, based on the TEgaserod in NORdic region (TENOR) trial data.

Methods:  Female and male patients (Rome II criteria) were randomized to receive tegaserod 6 mg b.i.d. or placebo for 12 weeks. Patients (247 tegaserod; 238 placebo) completed the EuroQol EQ-5D questionnaire at baseline, Week 4, and Week 12. A 12-week economic study was undertaken to assess the incremental cost-effectiveness ratio (ICER) of tegaserod in terms of cost per quality-adjusted life-year (QALY) gained. Cost-effectiveness acceptability curves were calculated toestimate the probability of tegaserod being cost-effective at different benchmark values of cost per QALY gained.

Results:  By assuming a daily drug cost to payers of €2, €3, and €4, the ICER of tegaserod ranges between €19,000 and €38,000 per QALY gained, with the percentage of the bootstrap estimates below the willingness to pay level of €50,000 per QALY gained ranging between 90% and 69%.

Conclusions:  This study established directly from a randomized controlled clinical trial that tegaserod is cost-effective in the treatment of non-D-IBS patients.

Introduction

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) motility and sensory disorder characterized by abdominal pain/discomfort, bloating, and altered bowel habit, which determines the subtype classification: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), or IBS with alternating bowel symptom (IBS-A) [1–3]. IBS is a chronic condition and many sufferers experience symptoms for 10 years or more. The estimated symptom prevalence of IBS in Western countries is 10% to 15%, with each IBS subtype occurring at a similar frequency [1–5]. Considerable variation exists in the diagnosis rates of IBS. This is largely due to inconsistent use of diagnostic guidelines [6] and because more than one-third of sufferers fail to seek medical advice [4].

Although typically not life-threatening, IBS causes significant impairment to sufferers' quality of life (QoL), affecting their daily routines, relationships, social lives, and emotional well-being [4,5,7,8]. IBS sufferers have significantly more time off work than nonsufferers [4,9], and IBS-related absenteeism and reduced work productivity place a substantial economic burden on employers [10].

Patients with IBS symptoms also utilize a significant amount of health-care resources. Although many patients with IBS symptoms do not seek medical advice, epidemiological studies show that IBS accounts for approximately half of all visits to gastroenterologists in the United States and UK [11,12]. Also, because of the chronic and complex nature of IBS symptoms, many patients require a substantial amount of outpatient and inpatient care, laboratory and radiological tests [13].

Consequently, IBS is associated with a substantial burden of illness because of its prevalence, morbidity, and associated cost. Studies on the economic impact of IBS estimated that direct costs for treating IBS patients and indirect costs due to productivity loss/absenteeism amount to $25 billion per year in the United States [14–18]. It has been calculated that the yearly cost of a patient with severe IBS is $2348 [19] in the UK and €995 in Germany [20]. Overall, the economic impact of IBS is comparable to that of other chronic and episodic diseases, and its costs exceed those of asthma and migraine [21–23].

Traditional therapies for IBS, including antispasmodics, laxatives, and antidiarrhea agents do not provide adequate symptom relief for many patients as they target only one of the multiple symptoms, and may aggravate others [24–26]. Furthermore, their efficacy and safety have not been assessed by well-designed, randomized controlled clinical trials [25,26].

In contrast, tegaserod, a 5-HT4 receptor partial agonist and promotility agent, targets the multiple symptoms of IBS-C. Tegaserod has been shown to facilitate the peristaltic reflex, increase water movement into the bowel lumen, and inhibit the visceral afferent responses associated with abdominal pain [27–29]. The efficacy and safety of tegaserod have been investigated in four key Phase III randomized, double-blind, placebo-controlled trials involving almost 6000 IBS-C patients [30–33], including the Nordic region: TEgaserod in NORdic region (TENOR) study [34]. Although the effect of tegaserod on patients' QoL was not routinely investigated [35], treatment has been associated with improvements in patients' QoL and work productivity [33].

The objective of the current study was to assess whether tegaserod is cost-effective in the treatment of IBS patients. This analysis is based on the clinical results from the TENOR study [34], which is representative in its design and findings of other controlled trials of tegaserod [30–33,35]. In an environment where health-care resources are scarce, it is important to demonstrate not only that a new product is safe and efficacious, but also that it offers value for money to purchasers. Nevertheless, to date, only one published article has assessed the cost-effectiveness of an agent for IBS, specifically IBS-D (alosetron) [36]. To our knowledge, this study is the first analysis of the cost-effectiveness of an agent designed to treat IBS-C.

Methods

Study Design

The economic evaluation of tegaserod was performed with the data collected from the TENOR study, which was a multinational, multicentre, double-blind, randomized, placebo-controlled clinical trial conducted in Nordic countries. Clinical results and patient enrollment are described in detail elsewhere [34]. In brief, the study consisted of a 2-week baseline period without medication, a 12-week randomized double-blind treatment period, followed by a 4-week withdrawal period without medication. Patients were not allowed to take medications affecting GI motility and/or visceral perception, antiflatulence agents, opioids/narcotic analgesics, prokinetics, anticholinergics, antispasmodics, or antidepressants (except at stable doses taken for indications other than IBS for at least 3 months before commencement of the study). Laxatives were permitted only as rescue medication.

A total of 647 patients were randomized to receive either tegaserod 6 mg b.i.d. (327 patients) or placebo (320 patients). The number of days of treatment with tegaserod or placebo was recorded. Patients' QoL/utility was directly obtained in the study using the EuroQol EQ-5D instrument for measuring patients' health states at baseline [37,38], after 4 weeks, and after 12 weeks or at discontinuation. The three EQ-5D assessments were used subsequently for calculating the gains in quality-adjusted life-year (QALY) in the study. The QALY is an outcome measure that has the advantage of combining the time (year) spent in different health states with an estimate about the quality of this time.

As the EQ-5D was only introduced as a study amendment 6 months after the release of the trial protocol and after patient enrollment had started, only 75% of the patients were eligible to complete the questionnaire.

Utility Estimates

Patient utilities were obtained from the EQ-5D questionnaire [37,38], which consists of two parts. In the first part (the health state description), patients answer five questions on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (scored on a 3-point Likert scale). The first part provides a classification of the patient's health state, which can then be valued according to “tariff” values. Tariff values are derived from a sample of the general population in the community, the most relevant population for public policy analysis [39]. Well-established algorithms exist for the transformation of the descriptive part of EQ-5D to utility values [40]. The second part is a visual analog scale (VAS), which is similar to a thermometer marked from 0 (worst imaginable health state) to 100 (best imaginable health). As the VAS cannot be used to measure utility directly [41], utility measures for this economic evaluation were obtained from the first part of the EQ-5D questionnaire (the health state valuation). The EQ-5D is applicable to a wide range of health conditions and treatments and has been specifically validated for use in IBS patients [42].

Economic Analysis

The incremental cost and the incremental utility gain of tegaserod treatment vs. placebo over the 12-week treatment period of the TENOR trial were compared [34]. The perspective of the study was that of a third-party pharmacy payer, based only on the cost of tegaserod. Other costs, such as those associated with patient visits, were not included in this analysis. The cost per patient was calculated assuming that the cost of tegaserod per treatment day was either €2, the current public price of tegaserod in Switzerland, €3 or €4. As it was assumed that patients receiving placebo represent untreated patients, the cost of drugs in the placebo arm was set at zero. The time period of the analysis was set at 12 weeks, because treatment and follow-up data from TENOR are available for this period [31].

The number of QALYs gained was estimated by calculating the average gain in utility per patient from the baseline period and over the 12-week period of the study, based on EQ-5D health state scores derived from the Health States Tariff evaluation. As the average utilities for patients in the tegaserod and the placebo groups differed at baseline, an analysis of covariance (ANCOVA) regression controlling was performed. The difference in baseline utilities between the treatment and placebo groups may have been caused by differences in underlying covariates, such as small differences in age, sex, and country composition between the two groups. Nevertheless, baseline utilities and countries were the only covariates used for the ANCOVA model as they were the only significant factors. For some reason, patients from Norway and Finland reported significantly higher utilities than did patients from Denmark and Sweden. The utilities predicted by the regression model are those that would have occurred had the baseline utilities been equal. This method provides an unbiased estimation of differential QALYs and a more precise estimate of its variance [43–46]. There are some important reasons why it is particularly important to control for baseline utilities when estimating QALYs. The first is that baseline utilities usually enter directly into the QALY calculation and thus strongly influence the number of QALYs gained. The second is that the point estimate of the incremental cost-effectiveness ratio (ICER) may be sensitive to even a small imbalance in utilities between the arms of the trial [47]. Nevertheless, the number of QALYs gained per patient was also calculated with the unadjusted baseline utility scores and the results of this calculation will be described in the sensitivity analysis.

Missing data due to study withdrawals and noncompletion of the EQ-5D questionnaire were interpolated using the last-observation-carried-forward (LOCF) method. In the sensitivity analysis, we also tested what the results would be if patients with missing data were excluded.

The number of QALYs for each patient was calculated as the area under the utility curve (AUC) from baseline and over the 12-week period of the study. Since the utility was only measured at baseline, 4 weeks and 12 weeks, it was assumed that it changed linearly between measurements.

Bootstrap Analysis and Cost-Effectiveness Acceptability Curves

The ICER of Treatment 1 (tegaserod) compared with Treatment 0 (placebo) is defined as ICER = ΔC/ΔE, where ΔE = Ē1 − Ē0 is the difference in effect, ΔC = 1 − 0 is the difference in drug costs. A well-known problem with the cost-effectiveness ratio is its unfavorable statistical properties that make it difficult to calculate conventional confidence intervals. Thus, cost-effectiveness acceptability curves have been increasingly used to present the uncertainty of the cost-effectiveness estimate in a way that overcomes the problems associated with ICERs [48].

Nonparametric bootstrapping was used to estimate the uncertainty of the cost-effectiveness estimate, because the distribution of costs and QALY gains are non-normal and skewed. Nonparametric bootstrapping is a resampling technique useful for estimating various statistics without using traditional parametric formulas [49,50]. The basic principle of bootstrapping is to use the available data sample for resampling with replacement [50,51]. The resampling is performed many times, and the size of each bootstrap resample is the same as for the original sample.

In each round of resampling, cost and QALYs were resampled for patients in the treatment and placebo groups separately, and a bootstrap estimate of the average QALY gain (for tegaserod and placebo patients) and the average drug cost (for tegaserod patients) was calculated. Then for each bootstrap replication, an ICER can be calculated. In total, 2000 bootstrap replications of the average QALY gain, the average cost, and ICERs were calculated.

The cost-effectiveness acceptability curve is constructed by calculating the proportion of bootstrap replications of the ICER that is acceptable at different levels of willingness to pay per QALY, and determined by the slope of the line passing through the origin on the cost-effectiveness plane.

A sensitivity analysis was performed using the unadjusted baseline EQ-5D utility scores, and the ICERs and cost-effectiveness acceptability curves were also calculated [52].

Results

Population Enrolled in the Health-Economic Analysis

A total of 485 out of 644 patients (75% of patients randomized in the TENOR study) were eligible to answer the EQ-5D questionnaire; 247 (75.5%) in the tegaserod group and 238 (74.4%) in the placebo group. The demographic and disease background information presented in Table 1 shows that there were no clinically important differences between patients randomized in the double-blind treatment period and patients eligible to complete the EQ-5D questionnaire.

Table 1.  Demographic and disease background information comparison between patients who filled out the health economic questionnaire (n = 485) and the intent-to-treat population (n = 644)
 Total trial population
n = 644
Total HE population n = 485P-value*
  • *

    Chi-squared test performed for significance test.

  • t-test performed for significance test.

  • Only variable MEDTAK1C used to assess prior drug treatment for IBS symptoms.

  • HE, health economic; IBS, irritable bowel syndrome.

Sex: n (%)
 Male91 (14.1)70 (14.4) 
 Female553 (85.9)415 (85.6)0.8856*
Race: n (%)
 Caucasian641 (99.5)483 (99.6) 
 Asian2 (0.3)1 (0.2) 
 Other1 (0.2)1 (0.2)1.0000*
Age (years)
 Mean ± SD44.3 ± 12.144.4 ± 12.3 
 Range18–6519–650.8586
Weight (kg)
 Mean ± SD69.6 ± 13.569.6 ± 13.1 
 Range34–14334–1340.9971
Duration of IBS symptoms (months)
 Mean ± SD204.1 ± 161.4211.7 ± 165.1 
 Range12–72012–7200.4407
Prior drug treatment for IBS symptoms: n (%)
 No383 (80.6)377 (80.4) 
 Yes92 (19.4)92 (19.6)0.9234*

Treatment Cost

The mean number of treatment days was calculated for both the tegaserod and placebo groups. The patients received treatment for on average 73.1 days in the tegaserod group, and 77.0 days in the placebo group. The cost of tegaserod treatment was calculated by multiplying the treatment duration in days by the cost per day. As mentioned previously, the placebo arm was treated as a proxy for no treatment, with no costs incurred.

EQ-5D Scores

EQ-5D average baseline utilities were 0.713 in the tegaserod group and 0.740 in the placebo group before adjustment with the ANCOVA regression model. At Week 4, average utilities were 0.791 and 0.766, respectively, for the tegaserod and the placebo groups, and at Week 12, 0.787 in the tegaserod group and 0.753 in the placebo group. The adjusted average utility scores obtained using the regression model were 0.726 at baseline for both the tegaserod and the placebo groups. At Week 4, the adjusted utilities were 0.7954 for patients receiving tegaserod and 0.7587 for placebo-treated patients, and at Week 12 utilities were 0.7915 and 0.7468 for the tegaserod and the placebo groups, respectively. As highlighted in Table 2, the change from baseline to Week 4 was 0.0694 for the tegaserod group and 0.0327 for the placebo group (P = 0.036), and from baseline to Week 12 the change was 0.0655 and 0.0207 for the tegaserod and the placebo groups (P = 0.023), respectively.

Table 2.  EQ-5D utility score (LOCF) fitting an ANCOVA model (n = 485)
TimeTegaserodPlaceboP-value*
ActualChange from baselineActualChange from baseline
  • *

    ANCOVA controlling for baseline utility and country.

  • LOCF, last observation carried forward.

Baseline
 n247 238  
 Mean0.726 0.726  
 SD0.248 0.224  
Visit 3 (Week 4)
 n247 238  
 Mean0.79540.06940.75870.03270.036
 SD0.2000.2420.2070.203 
Visit 4 (Week 12)
 n247 238  
 Mean0.79150.06550.74680.02070.023
 SD0.2140.2470.2440.245 
Number of days in the treatment73.1 77.0  

Base-Case Analysis

The incremental average gain in QALYs can be calculated as the difference in AUC between placebo and tegaserod, which is represented by the shaded area in Figure 1. The incremental gain in QALYs with adjusted utilities for the tegaserod group over the placebo group was equal to 0.0077. [4/52 × (0.726 + 0.7954)/2 + 8/52 × (0.7954 +0.7915)/2 − 4/52 × (0.726 + 0.7587)/2 − 8/52 × (0.7587 + 0.7468)/2].

Figure 1.

Utility levels and gain in quality-adjusted life-years with tegaserod compared with placebo with adjusted baseline utility scores.

With a daily tegaserod cost of €2, the average cost in the treatment group was €73.14 × 2 = €146.3, and the ICER of tegaserod was €146.3/0.0077 = €19,000 per QALY gained. The ICERs calculated, as above, with a daily treatment cost of €3 and €4 were €28,500 and €38,000, respectively, per QALY gained. All these ICER values are below the €50,000 per QALY gained, which is the threshold commonly used to assess whether or not an intervention can be considered cost-effective [53].

Cost-Effectiveness Acceptability Curves

A cost-effectiveness acceptability curve provides an estimate of the sampling distribution of costs and effects that lie below the price that corresponds to the maximum willingness to pay for a gained effect unit, the price line in the graph [54–56]. Figure 2 illustrates the cost-effectiveness acceptability curves for tegaserod with daily treatment costs ranging from €2 to €4 per day. At a daily cost of €2, nearly 90% of the bootstrap cost-effectiveness estimates fall within a benchmark value for cost-effectiveness of €50,000. For the higher tegaserod prices of €3 and €4 per day, the percentage of estimates below the threshold of €50,000 per QALY gained were 81% and 69%, respectively.

Figure 2.

Base-case analysis: cost-effectiveness acceptability curves for tegaserod at a daily cost of 2€, 3€, and 4€.

Sensitivity Analysis

The results of the sensitivity analysis performed using the unadjusted utilities show that the incremental gain in QALYs for the tegaserod group over the placebo group was equal to 0.0108. [4/52 × (0.7125 + 0.7913)/2 + 8/52 × (0.7913 + 0.7872)/2 − 12 × 0.7125/52 − 4/52 × (0.7399 + 0.7657)/2 − 8/52 × (0.7657 + 0.7532)/2 + 12 × 0.7399/52]

With a daily tegaserod cost of €2, the average cost in the treatment group was €73.14 × 2 = €146.3, and the ICER of tegaserod was €146.3/0.0108 = €13,500 per QALY gained. The ICERs calculated with a daily treatment cost of €3 and €4 were €20,200 and €27,000, respectively, per QALY gained. These ICER values are below those that were based on adjusted utility values.

The cost-effectiveness acceptability curves of the sensitivity analysis using unadjusted utilities for a tegaserod daily treatment cost ranging from €2 to €4 per day are illustrated in Figure 3. At the daily treatment cost of €2 per day, 98% of the bootstrap cost-effectiveness estimates are below the threshold of €50,000 per QALY. At the higher tegaserod cost of €3 and €4 per day, the percentage of bootstrap estimates below the threshold was 95% and 90%, respectively. All these percentages are above those calculated in the base-case analysis.

Figure 3.

Sensitivity analysis: cost-effectiveness acceptability curves for tegaserod at a daily cost of 2€, 3€, and 4€. Unadjusted values.

If only women are included in the analysis, the ICERs fall in the range of €20,700 to €41,400, for a tegaserod price of €2, €3, and €4, respectively. If only men are included, the ICERs fall in the range of €12,800 to €25,600.

Some utilities were extrapolated based on the LOCF principle. If we repeat the calculation above with only the patients with complete utility measurements included, then the average QALY gain would be 0.013, and the cost-effectiveness ratios would be €11,300 for a daily tegaserod cost of €2, €16,900 for a daily tegaserod cost of €3, and €22,500 for a daily tegaserod cost of €4. This shows that the inclusion of LOCF utilities did not introduce any upward bias in favor of the treatment group.

Discussion

Irritable bowel syndrome is a chronic disease with high reported symptom prevalence in Western populations, but no new agent specific to IBS has been introduced in Europe in decades. In previous clinical trials, tegaserod has proved to be an effective and well-tolerated treatment for abdominal pain, bloating, and constipation, which are the most common symptoms of IBS [30–34,57,58]. Nevertheless, no published study has yet reported on the cost-effectiveness of tegaserod.

In this study, treatment costs and utility data from the EQ-5D questionnaire were collected prospectively in a randomized, placebo-controlled clinical trial and combined to assess the cost-effectiveness of tegaserod in the treatment of patients with non-IBS-D. An advantage of a generalized outcome measure like QALY is that it allows comparison of interventions within and across therapeutic areas in terms of cost per QALY gained [56].

The base-case economic analysis of this study established that the ICERs for tegaserod calculated at the daily treatment costs of €2, €3, and €4, fall in the range of €19,000 to €38,000 per QALY gained with a probability of being cost-effective at a threshold of €50,000 per QALY gained ranging between 90% and 69%.

The ICERs calculated in the sensitivity analysis, performed with unadjusted baseline utility scores and calculated with the same tegaserod treatment costs, range between €13,500 and €27,000 per QALY gained. These values are much lower than those calculated in the base-case analysis. The cost-effectiveness acceptability curves calculated in the sensitivity analysis show that the percentages of estimates below the threshold of €50,000 per QALY gained fall between 98% and 90%.

The current study, however, had some limitations. It only included the drug cost for tegaserod, but not associated IBS medical costs. Thus, potential medical cost-offsets with tegaserod, such as the cost reduction of extra medical and diagnostic visits, hospitalizations, and concomitant treatments often used by IBS patients to treat the multiple symptoms of the condition, were not taken into account. Furthermore, in this economic analysis, indirect costs were not included as these data were not collected in the TENOR trial. Nevertheless, the results of a recent multinational clinical trial in IBS-C patients showed that tegaserod reduced productivity loss compared with placebo [59]. Additionally, a retrospective assessment of GI-related resource use in a managed care setting in the United States showed that tegaserod was associated with consistent and significant decreases in most resource categories [60]. Therefore, inclusion of these factors would probably only reinforce the conclusion that tegaserod is cost-effective.

This study is an economic analysis using data collecting in a randomized placebo controlled trial. Although the cost-effectiveness of tegaserod vs. an alternative active treatment would be more relevant for health-care decision-makers, tegaserod is currently the only drug approved for IBS with constipation. A comparison of tegaserod with an active treatment is currently not possible or relevant.

Since this study is based on a randomized controlled trial, one limitation is the validity of these results in the real-world clinical practice. The follow-up time was quite short, for example. Our results regarding costs and QALY are only valid for the 12-week time frame used in the study. If the results would be similar for long-term evaluation of tegaserod is an issue for further research.

In the United States, however, where it has been on the market since 2002, tegaserod is indicated for the short-term treatment of women with IBS-C. Thus, there is reason to believe that the time frame of this analysis reflects the recommended use of the drug. In the TENOR trial, male patients, for whom the drug is not recommended, were enrolled in the study. Nevertheless, as presented in the sensitivity analysis, if the male population is excluded, the results are little worse but the difference compared with the base-case results is small.

It should be also mentioned that the threshold of €50,000 per QALY used in this study is primarily based on a rule of thumb. In practice, the willingness to pay per QALY could very well vary depending on the nature of the disease, and the duration of symptoms. Whether the €50,000 threshold is the most appropriate in our study is uncertain, but we used it in the absence of better information regarding the societal willingness to pay for treating patients with IBS.

Conclusions

An extensive clinical trial program has established that tegaserod is currently the only effective and well-tolerated treatment for abdominal pain, bloating, and constipation in IBS patients without diarrhea [30–34,57,58]. This analysis demonstrates that tegaserod is also a cost-effective treatment for patients with IBS.

The authors would like to thank Mattias Ekman for his helpful support in the statistical analysis of the data.

Source of financial support: This study was funded by Novartis Pharma AG, Basel, Switzerland.

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