Health economics perspective of fesoterodine, tolterodine or solifenacin as first-time therapy for overactive bladder syndrome in the primary care setting in Spain

Overactive bladder (OAB) is a syndrome characterized by symptoms of urinary urgency, with or without urge incontinence, often accompanied by daytime frequency and nocturia. It is caused by an overactive detrusor muscle and may be accompanied by neurological dysfunction [1‐3]. The prevalence in adults ranges between 10% and 20% and increases with age [4‐6]. In Europe the prevalence in the general population >18 years of age is 11.8% and is similar for men and women [4, 7, 8]. In Spain the population-based EPICC study estimated the prevalence of OAB to be 21.5% in adults ≥40 years of age and 38.5% in institutionalized people ≥65 years of age [9, 10]. OAB has a negative effect on quality of life in affected individuals, which results from both the characteristic symptoms of OAB syndrome as well as the coping strategies frequently adopted to reduce symptom impact [11, 12]. People often take extreme measures to reduce urinary frequency and episodes of incontinence, which significantly impacts their physical health, vitality, social life, emotional state and functionality [13‐15]. Many individuals do not seek professional help for OAB symptoms and only a quarter receive treatment [5, 16, 17].

Pharmacological treatment of OAB aims to decrease involuntary contractions of the detrusor muscle of the bladder by blocking the bladder receptors with antimuscarinic drugs [18‐21]. Efficacy, safety, and tolerability [22‐26] as well as improved health-related quality of life [27] have been demonstrated in clinical studies for the antimuscarinics fesoterodine, tolterodine and solifenacin. However little is known about how these findings from clinical trials extrapolate to the heterogeneous populations seen in primary practice. Several studies indicate that real-world adherence is low and is typically attributed to a perceived lack of efficacy or tolerability issues [28, 29].

OAB is associated with high direct healthcare costs [30‐32]. Factors contributing to the cost of OAB include drug treatment, physician visits, hospitalizations and laboratory tests. Evidence comparing antimuscarinic drugs with respect to resource use and costs is limited, and totally lacking from a Spanish National Health System (NHS) perspective. To address this gap and the growing need for naturalistic multicenter studies, this study was conducted to compare healthcare resource utilization and related costs in patients initiating treatment with fesoterodine, tolterodine, or solifenacin for the treatment of OAB syndrome in the primary care setting in a representative sample of the Spanish NHS.

Of the 170,880 patients regularly seen at the study sites, 2778 patients initiated OAB treatment during the study period. Of these, 1971 met the study criteria and were enrolled (Figure 1). Of these, 952 (48.3%) were treated with solifenacin, 717 (36.4%) with tolterodine and 302 (15.3%) with fesoterodine. Patients treated with tolterodine were significantly older and included significantly more females compared with solifenacin and fesoterodine (Table 2). However disease burden, assessed by the number of comorbid diagnoses and the Charlson comorbidity index, was similar in the 3 groups. The mean time from diagnosis to initiation of antimuscarinic treatment and the MPR were significantly higher with solifenacin compared with tolterodine and fesoterodine. The mean duration of antimuscarinic treatment was numerically higher for fesoterodine, but no statistical differences were found among drugs. The most commonly prescribed doses were fesoterodine 8 mg, solifenacin 5 mg and tolterodine 4 mg. A higher percentage of patients treated with tolterodine, compared with fesoterodine or solifenacin, were prescribed a second antimuscarinic treatment during the study period (7.9% vs 4.3% and 3.6%, respectively; P = 0.001).

No statistically significant differences were found in pre-treatment costs among treatment groups. Costs for outpatient visits, analytical tests, radiology, laboratory tests, hospitalization days and absorbent products used were not significantly different by antimuscarinic group prior to the study.

Compared with patients treated with solifenacin and tolterodine, patients treated with fesoterodine used significantly fewer antidepressants (Table 3), including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Use of antibiotics/antiseptics was significantly lower in patients receiving fesoterodine or solifenacin compared with tolterodine (P < 0.001 for both). Fesoterodine was associated with decreased use of benzodiazepines/hypnotics and laxatives, although differences were not significant.

After adjusting for covariates, patients treated with fesoterodine had fewer outpatient medical visits of any type compared with solifenacin and tolterodine (13.2 vs. 15.1 and 16.4, respectively; P < 0.001), including primary care (11.6 vs. 12.9 and 14.2, P < 0.001), specialist (1.5 vs. 2.0 and 2.0, P < 0.001), and emergency room (0.1 vs. 0.2 and 0.3, P < 0.001) visits (Table 4). Differences in use of analytical and complementary tests, x-rays, and days of hospitalization were not significant. Patients treated with fesoterodine had significantly lower healthcare costs versus those receiving solifenacin and tolterodine: €1639 vs €1780 and €1893, respectively (P = 0.003; Table 5), despite significantly higher drug costs for fesoterodine (€740 vs €626 and €624; P < 0.001). Fesoterodine-treated patients incurred significantly lower costs for outpatient visits compared with solifenacin-treated and tolterodine-treated patients (€433 vs €533 and €563, respectively, P < 0.001), especially in primary care (€268 vs €300 and €329, P < 0.001); concomitant medication expenses were significantly lower with fesoterodine (€216 vs €305 and €335, p <0.001). Treatment differences in adjusted costs of radiology, analytic, and complementary tests and days of hospitalization were not significant. Adjusted total healthcare costs were significantly higher in patients receiving tolterodine compared with those treated with fesoterodine (P < 0.05; Table 5).

In a secondary analysis in which drug prices were assumed to be those currently set by the NHS (Figure 2), the trends observed in healthcare costs were similar to those described in the primary analysis. Total healthcare costs were similar for patients treated with fesoterodine and tolterodine, despite the 40% reduction in the price of tolterodine. Both fesoterodine and tolterodine were associated with significantly lower total healthcare costs than solifenacin.

There are few reports detailing healthcare resource utilization and corresponding costs in routine clinical practice with antimuscarinics. This study indicates that fesoterodine treatment for OAB was associated with lower healthcare resource use than solifenacin or tolterodine treatment, and therefore lower average costs per patient, in routine clinical practice in the Spanish NHS. The treatment groups were comparable at baseline, as indicated by burden of comorbidity and duration of antimuscarinic treatment. There were no significant differences in resource use and costs incurred during the year preceding the index date; baseline costs per patient were lower because no antimuscarinics were prescribed and patients were not actively followed for OAB. This study included a large sample of medical records from three different geographic regions of Spain. Our findings did not vary by location and thus are likely generalizable throughout Spain.

Antimuscarinic cost was higher in patients treated with fesoterodine because a greater proportion of patients received the higher dose and had a longer duration of use compared with patients treated with solifenacin and tolterodine. The additional pharmacy costs found in fesoterodine-treated patients were offset by overall lower healthcare use, mostly driven by reductions in medical visits (of all types) and OAB-related concomitant medications compared with solifenacin and tolterodine. After controlling for confounding variables, fesoterodine-treated patients had a significantly lower total annual healthcare cost per patient. This represents an annual per-patient savings of approximately €141 to the Spanish NHS when compared with solifenacin and approximately €254 versus tolterodine. From a healthcare decision-making perspective, these savings are substantial in view of the number of patients with OAB in the NHS. In a secondary analysis, the total annual per-patient costs for fesoterodine were similar to those of tolterodine when the price of tolterodine was reduced by 40% to reflect current prices subsequent to the loss of patent protection in Spain. Both fesoterodine and tolterodine showed significantly lower total healthcare costs than solifenacin.

The cost advantage of fesoterodine over tolterodine may be explained by its greater efficacy, which may result from pharmacokinetic differences. Fesoterodine has greater bioavailability and therefore a greater possibility of exerting therapeutic effects. The improved efficacy of the higher fesoterodine dose (8 mg) has been established in clinical trials [22, 25, 39] and primary medical practice [40]; this dose was used by 57% of patients taking fesoterodine in our study.

In contrast, titration of solifenacin to the higher dose (10 mg) has not been shown to be associated with increased efficacy [41, 42]; in our study, 13% of patients taking solifenacin used the 10-mg dose. A 4-mg dose of tolterodine ER is the only commercially available formulation; 12% of patients taking tolterodine received a 2-mg twice daily standard (i.e. not extended release) dose. Therefore it is possible that patients taking solifenacin and tolterodine may have received an ineffective dosage in our study. However our results under real-world conditions appear to be consistent with those observed in head-to-head comparative clinical trials. The Fesoterodine Assessment and Comparison Versus Tolterodine (FACT) trials showed that fesoterodine 8 mg is superior in efficacy to tolterodine ER 4 mg, with significantly greater reductions in episodes of urgency and urgency with incontinence and a significantly higher proportion of “dry” patients [24, 25, 39]. Likewise, comparative clinical trials of solifenacin versus tolterodine showed these two drugs to be similar in efficacy for the treatment of symptomatic OAB [43].

There are several limitations to this study. Some patients with OAB may have been excluded because of disease miscoding/misclassification, and some patients diagnosed as having OAB may not have the disease. The risk of disease misclassification was minimized in this study because physicians in participating locations were well trained in medical data recording and the computerized system includes regular quality control testing. Under-recording of healthcare resource use, whether an oversight by healthcare professionals or due to resource use outside of the geographical areas of interest, may have led to an underestimation of total costs. In all cases these potential biases are likely to have affected the three study drugs equally. Direct non-health costs (i.e. out-of-pocket costs paid by the patient that are not funded by the NHS) could not be assessed, because none of the three databases analyzed accounts for these costs. Out-of-pocket costs of OAB can be substantial, particularly for non-funded absorbent products. Because only 10% of the records analyzed were on occupationally active patients, an economic analysis that considers effects on productivity could not be performed. Furthermore it was not possible to assess OAB severity among patients for any of the antimuscarinic drugs prescribed; significant differences among groups could have influenced outcomes. However the fact that no significant differences in resource use and/or healthcare costs were found in the year prior to the index date suggests that symptom severity was similar among treatment groups.

This study demonstrated that in primary clinical practice in Spain, treatment of OAB with fesoterodine was a cost-saving therapy compared with solifenacin or tolterodine in the NHS system, and that the higher cost of fesoterodine therapy could be offset by lower overall healthcare resource use. Fesoterodine was associated with decreased healthcare resource utilization, including medical visits of all types as well as concomitant medications; this reduced utilization translated into significantly lower total annual healthcare costs per patient. Future studies in other healthcare settings are needed to confirm these findings.