Dose and aging effect on patients reported treatment benefit switching from the first overactive bladder therapy with tolterodine ER to fesoterodine: post-hoc analysis from an observational and retrospective study

Overactive bladder (OAB) is a lower urinary tract disorder characterized by urgency with or without urge incontinence, often with increased daytime frequency and nocturia[1–4]. The prevalence of OAB increased with age[5–8]. In Spain, the EPICC study showed that the prevalence of OAB, previously estimated in adults ≥40 years of age at 21.5%[9], was 5.9% for women aged 25–64, 4.6% for men aged 50–65 and 38.5% for institutionalized people over 65[10]. The symptoms associated with OAB can significantly affect the psychological, social, occupational, domestic, and sexual aspects of those who suffer from it[11]. As a result, OAB has a negative impact on the patient’s quality of life[12, 13]. Despite the significant impact of OAB on patients’ lives and the availability of treatment options, only a small percentage of elderly patients seek and receive treatment[9, 14].

Antimuscarinic agents are the pharmacological mainstay of OAB treatment[15]. Patients, however, often do not respond to them appropriately, largely because of non-compliance, but also due to lack of efficacy or intolerance[16]. In these cases, the symptoms of these patients may be improved by changing the drug[17–20] and behavioural therapy techniques. In this way, previous randomized studies have demonstrated the superior efficacy of fesoterodine over tolterodine[18, 19, 21].

Therapeutic benefit might be achieved with higher doses. The literature supports that the efficacy of anticholinergics is enhanced by dose escalation[22–24]. Moreover, flexible dosing reflects clinical practice better than fixed dosing[23]. Fesoterodine is a nonselective antimuscarinic agent that has showed a dose-dependent response[22]. This dose response has not been demonstrated with all of the other antimuscarinic agents that offer multiple doses[4].

Several studies have suggested that antimuscarinic agents are generally effective and well-tolerated in older subjects[25–29]. However, the use of drugs in clinical trials markedly differs from that of the routine clinical practice in several aspects, thus limiting the generalization of results[30]. In this sense, non-interventional studies, may provide complementary information on the effectiveness of specific treatments in real clinical practice settings[31]. Then, data from open-label or observational studies exploring the subjective patient perception of the effectiveness of fesoterodine, in symptomatic OAB subjects not satisfied with tolterodine, would also be relevant to clinical management in the daily practice[8, 32].

Here, we carried out a post-hoc analysis from the IMPACTA study[32] to evaluate whether aging and dose escalation to fesoterodine 8 mg compared to fesoterodine 4 mg, were associated with higher patient-reported treatment benefit and clinician perception of change, after switching from their first OAB tolterodine ER-based therapy, in daily clinical practice.

This was a post-hoc analysis, from a non-interventional study, involving patients who expressed dissatisfaction with their prior and first OAB treatment with tolterodine ER, principally because of lack of effectiveness or tolerability problems.

The present data, show that switching to flexible doses of fesoterodine 4 or 8 mg, in the usual clinical practice, provided improvements in the state of the urinary problems in a very high portion of patients, both in the physician’s and patient’s point of view. Furthermore, patients declared being satisfied with the new treatment, and more than 90% of them, reported preferring fesoterodine treatment instead of tolterodine ER. Our findings are in consonance with those reported in an open-label study[8] in which flexible-dose fesoterodine significantly improved OAB symptoms and rates of treatment satisfaction in subjects who were dissatisfied with prior tolterodine therapy.

One possible reason for such findings may lie in the pharmacological profile of fesoterodine. In contrast to tolterodine, which is metabolized in the liver via cytochrome P450 (CYP) 2D6 to produce the active metabolite 5-hydroxymethyl tolterodine (5-HMT), hepatic enzymes are not involved in the conversion of fesoterodine to 5-HMT[19, 22]. Fesoterodine is extensively and rapidly converted to 5-HMT, so no fraction of fesoterodine is detectable in plasma after administration, unlike tolterodine[19, 22]. Moreover, there is substantial interindividual variability in CYP2D6 metabolic activity, while, the esterases that convert fesoterodine to 5-HMT do not exhibit genotypic variations[8, 38, 39]. Thus, the pharmacokinetic variability among individuals treated with fesoterodine is lower[8].

Additional explanations for these findings, particularly the high figures of effectiveness as perceived by both clinicians and patients, could go in two ways. In one way, previous randomized studies have demonstrated the superior efficacy of fesoterodine over tolterodine[18, 19, 21]. Therefore, it should be no surprise to see replication of such results in routine medical practice. On the other hand, these findings should also be interpreted in the light of the fact that the cohort of patients included in this analysis needed a change in its previous tolterodine-based therapy of their OAB symptoms. Moderate improvements, as shown in the urinary questions (see Tables3 and4), could then be perceived as important benefits from the patient’s or clinician’s perspective, because such moderate improvements were observed in the urinary symptoms that best define the OAB condition. Finally, no possible ceiling effect in the CGI-I scale has been described yet. However, as the TBS is a one-item scale with four possible categories of response (greatly improved, improved, no changed and worsened during the treatment), a ceiling effect could not be completely ruled-out.

To date, few studies have addressed the efficacy and tolerability of fesoterodine in elderly patients[29, 40]. Here, the benefits of switching to fesoterodine do not seem to be age-related. Thus, the percentage of younger patients who reached treatment benefit (according to TBS and CGI-I scales) was similar to that in older subjects. No statistically significant difference was observed regarding the degree of worry, bother or interference with the daily-living activities due to usual urinary symptoms, between younger patients and those over 65 years. Our results were compatible with those from randomized studies with antimuscarinic agents for OAB, which showed a similar efficacy irrespective of age[27, 40]. Conversely, these results differ from those obtained in a post-hoc analysis of data from two randomized fesoterodine 4 mg and 8 mg studies. There, patients stratified according to age into three categories (<65, ≥65- < 75, ≥75), showed greater treatment response and improvements in the two younger groups, while, in the ≥75 years group, improvement was only observed with the 8 mg dose[29].

The results presented here show that compared with 4 mg, fesoterodine dose escalation to 8 mg provides significant additional improvements. In the patient’s opinion, worry, bother and interference–related OAB symptoms, improved or showed a trend to greater improvement with higher dosing. 8 mg of fesoterodine provides also higher improvement in term of both patient-reported-treatment benefit and clinical global impression of change.

In addition, compared with subjects receiving 4 mg, a significantly greater proportion of subjects receiving fesoterodine 8 mg, reported drug compliance preference and satisfaction with the new treatment. Our findings, stemming from the usual clinical practice, were in consonance with those reported in previous randomized studies, where the higher 8-mg dose provides additional benefit compared with the lower dose at most end points[22, 41]. Up to now, we are unaware of the existence of non-interventional studies that addressed the issue of efficacy of fesoterodine dose-escalation. The only open-label, single-arm study that addressed it, did not compare the efficacy between subjects treated with 4-mg dose throughout study and subjects who escalated to the 8-mg dose[8].

The availability of two doses of fesoterodine allows for individualization of patient care[8]. Dose escalation may allow for improved outcomes in those patients who reported good tolerability and desire greater symptom relief[8]. In the above-mentioned open-label study, half of the subjects opted to escalate their fesoterodine 4 mg dose to 8 mg[8]. In the present study nearly 70% of subjects received the higher fesoterodine 8 mg dose. Here, the reasons for dose escalation were not recorded either. However, this could be indicative of the fact that, the percentage of patients treated with 8 mg that switched due to lack of tolterodine effectiveness, was significantly higher than those in the 4 mg group. While, side effects were the cause for switching in 23.5% of those titrated to 4 mg vs. 16.1% of those escalating to 8 mg.

The present post-hoc analysis had limitations. We did not capture reasons why physicians/patients did or did not opt for dose escalation. This may be important, because the reasons underlying the decision whether or not to increase the dose, probably varied between individuals, but reflect optimization of the balance between efficacy and tolerability[8]. Additionally, there were limitations inherent in the observational design of the study. In this study, the groups of patients were not well-balanced. Most of the patient characteristics assessed were different between groups. One of them is the treatment length. This could be a confounding factor, but it is not, because the mean time of treatment length was more than two months in all our groups, and significant fesoterodine improvements had been reported as early as two weeks after initiation of treatment[22].

In spite of the limitations of the study, it showed the benefit that patients dissatisfied with tolterodine ER perceive upon changing to fesoterodine, which is greater at higher doses. Patient perception of OAB treatment outcomes may be a useful indicator of benefit and might help drive persistence on treatment, which is known to be poor in OAB[20].

Our analysis suggests that a change from tolterodine ER-based therapy to fesoterodine in symptomatic OAB patients was associated with increased patient treatment benefit. Improvement was not affected by age. Moreover, fesoterodine dose escalation to 8 mg provided significant additional improvement in terms of treatment response, treatment satisfaction, degree of worry-related urinary symptoms, and drug compliance.