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Overactive bladder (OAB) is a clinical diagnosis characterized by the presence of lower urinary tract storage symptoms, particularly urinary urgency – a sudden compelling desire to pass urine that is difficult to defer . The ICS defines OAB as ‘urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia’.
OAB is common in men and women, and is a chronic condition requiring long-term medical management and lifestyle changes . In one population-based survey of men and women aged ≥18 years in the USA, OAB was estimated to affect 16–17% of the adult population . Similarly, the results of a survey of men and women aged ≥40 years in Europe estimated the overall prevalence of OAB in this population at 16.6%, with a 19% prevalence in the UK alone . The European Association of Urology estimates the prevalence of OAB as varying from 10% to 26% in men, and from 8% to 42% in women, with a clear trend of increasing prevalence with advancing age. OAB often occurs simultaneously with other LUTS  and most older individuals have at least one such symptom, but OAB constitutes a specific sub-set of storage-phase symptoms .
The potential negative impact of OAB on quality of life, through its effects on day-to-day activities, is well established . Patients with OAB tend to curtail their participation in social activities and to isolate themselves. Nocturia is associated with sleep disruption, which decreases quality of life for patients and their partners . OAB is also associated with other co-morbidities, including fractures related to falls, urinary tract infections and skin infections [3,8]. These are distressing to patients and can be costly to treat; it is therefore not surprising that successful OAB therapy can be cost-effective [3,9].
The drugs most commonly prescribed for the treatment of OAB are antimuscarinics . These drugs decrease OAB symptom severity, but some patients experience adverse effects, most commonly dry mouth [11,12]. Furthermore, it may take several weeks for antimuscarinics to show their full benefit and maximum clinical efficacy [13,14]. Many find the balance of adverse effects against efficacy benefits to be unsatisfactory, and discontinue therapy [3,10]. However, the tolerability of adverse effects increases with prolonged usage of antimuscarinic drugs for OAB, by which time the efficacy of the therapy can also be perceived [13,15].
For pharmacotherapy to be beneficial in chronic conditions such as OAB, adherence and persistence are essential . Adherence (or compliance), defined as the extent to which a patient takes their prescribed medication at the correct interval and dose is the extent to which a patient continues treatment for the prescribed duration, measured either as the mean number of days between treatment initiation and discontinuation, or as the percentage of patients who persist with therapy for a minimum fixed number of days [17,18]. Patients with poor medication adherence have increased rates of morbidity and mortality, and poor adherence is itself associated with increased healthcare costs [19,20].
Persistence with long-term medication in chronic diseases is typically low (about 50%) . In 2003, the World Health Organization identified medication non-adherence (or non-persistence) as a leading cause of preventable morbidity, mortality and healthcare costs , and a more recent report by the New England Healthcare Institute estimated the avoidable burden to the US healthcare system of non-persistence, along with sub-optimal diagnosis, prescribing and medication administration, to be $290 billion per year, or 13% of total healthcare expenditures .
Sub-optimal persistence is therefore a major challenge for the successful management of OAB . The chronic nature of the condition means that effective treatment must be long term and continuous, and must be taken as prescribed. Persistence requires an acceptable balance between tolerability and efficacy, and unsurprisingly, is one of the critical predictors of outcomes in chronic conditions [15,25–27]. Persistence with therapy is important for sustained symptom control in OAB and consequent quality of life, and prompt initiation of optimal OAB treatment may delay or even prevent progression of the disease process [3,28].
Persistence at 12 months is much lower in routine practice than in the clinical trial setting, where the rate of persistence is usually >80% [15,24]. This is probably because the intensive follow-up and care involved in a clinical trial encourage adherence; trial subjects also may not be representative of the patients seen in clinical practice . Additionally, randomized trials generally underestimate adverse effects and problems with poor compliance/persistence compared with real-life settings . In contrast, in studies of clinical practice, many patients quickly discontinue OAB medication, part because of adverse effects [27,30,31]. Another study of US Medicaid patients found that only 32–44% of those prescribed OAB medications continued treatment beyond 30 days, eventually declining to a 5–9% persistence rate at 1 year . Similarly, a more recent study examining OAB medication compliance in a healthcare system in which patients do not pay for medication reported that 35% of patients did not refill a prescription for OAB medication over the 4 years evaluated .
Consistent with these previous reports, in a recent systematic review of studies published since 1998 on the treatment of OAB syndrome with anticholinergic therapy, rates of discontinuation from medical claims studies ranged from 43% to 83% of patients discontinuing medication within the first 30 days, with rates continuing to rise over time . Consistently, two similar independent retrospective analyses of prescription data conducted in Denmark and Sweden – the first over a 7-year period and the second over a 1.5-year period – reported similar continuation rates of <50% at 6 and 4 months, respectively, and <25% at 1 year [33,34]. Hence, in real-life settings versus in clinical trials, persistence with OAB medication appears to be sub-optimal.
Studies evaluating persistence are not limited to the treatment of OAB. The effectiveness of bisphosphonates in osteoporosis is compromised by poor adherence to treatment, because a significant proportion of patients abandon their treatment within 7 months of initiation and more than half stop the treatment within the first year. This is mostly the result of adverse effects, difficulty with drug administration and formulation [35–37]. Numerous studies have also been conducted evaluating the hindrances with antihypertensive drug adherence and persistence in controlling high blood pressure. Typically, only about 50% of patients for whom antihypertensive drug treatment is initiated persist on treatment 1 year later [18,38]. Overall, drug dose and formulation are important determinants of persistence, but patient awareness and education/support could also have an impact on patients' understanding of the importance of taking their medication continuously to control their symptoms.
One study compared adherence and persistence in six commonly used chronic diseases and associated medication classes: glaucoma (prostaglandin analogues), hyperlipidaemia (statins), osteoporosis (bisphosphonates), type 2 diabetes (oral antidiabetic drugs), hypertension (angiotensin II receptor blockers) and OAB (antimuscarinics). Six-month persistence rates and mean 12-month adherence rates were lowest for OAB medications (28% and 35%, respectively) . In comparison, about 57% of hypertensive patients continued past the first year after receiving their initial prescription [20,40].
The reasons underlying these low rates of persistence for OAB therapy in clinical practice are not clear. Few studies have reported either the predictors or the patient-reported reasons for OAB medication discontinuation [20,41]. In several retrospective database studies, rates of adherence or persistence were higher in patients taking extended-release formulations of tolterodine or oxybutynin than in those taking immediate-release formulations [16,21,25], although in one study this effect appeared to be the result of better adherence and persistence in older than in younger patients . Consistent with the latter finding, a retrospective study of claims data identified some predictors of OAB medication discontinuation, such as younger age (<65 years) and taking multiple daily doses, or taking an immediate-release formulation . Finally, another study found that rates of adherence and persistence were lower among Black than White patients .
The objective of this study was to estimate persistence rates for OAB patients taking antimuscarinic agentss based on UK NHS prescription data, where 88% of all prescriptions are free to the patient, and to investigate patterns of persistence with oral antimuscarinic drugs prescribed for OAB across different age groups over a 12-month period. Normally, prescriptions in UK practice are given on a monthly basis.
MATERIALS AND METHODS
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- MATERIALS AND METHODS
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UK prescription data from a longitudinal patient database were analysed retrospectively to assess persistence with darifenacin, flavoxate, oxybutynin (extended release [ER] and immediate release [IR]), propiverine, solifenacin, tolterodine (ER/IR) and trospium. Flexible dosing regimens existed for solifenacin (5/10 mg), darifenacin (7.5/15 mg) and oxybutynin ER and IR (5/10 mg and 2.5/3/5 mg, respectively).
Patients started treatment between January 2007 and December 2007, and data were collected up to December 2008, to allow each patient a full 12-month potential treatment period. Prescription data were provided by CSD Ltd (Chertsey, UK). Data were sourced from the medical records of >1 200 000 currently registered patients via general practice software, and anonymized prescription data were collated for all eligible patients with OAB (n= 4833), eliminating any risk of sampling bias.
Only patients new to a course of treatment (i.e. who had not been prescribed a particular treatment or dosage for at least 6 months before the study period) were included in this analysis. Therefore, patients were included only if they had been receiving a different antimuscarinic or the same antimuscarinic but a different dosage during the previous 6 months. Patients were excluded if they had already been prescribed the specific antimuscarinic or dosage referred to in the analysis at some point in the last 6 months before the evaluation period.
Persistence was defined as the mean number of days that a patient remained on therapy [17,18]. Each patient was tracked until they ceased to be continuously treated, with a break in therapy defined as an interval >1.5 times the expected number of days of therapy of the previous prescription, from the start of the script. Patients who ceased to be continuous but who restarted at a later date within the reference period were allowed back into the analysis at the point which they restarted. No formal statistical analyses were performed.
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Over the 12 months of the study, 4833 patients were prescribed the included antimuscarinic agents. The most prescribed drug during the 12-month period was tolterodine ER (1758 patients), followed by solifenacin (1381 patients) and oxybutynin IR (1371 patients) (Table 1). This is largely reflective of the UK market at the time . The mean number of prescriptions per patient was highest for solifenacin (10 mg; 6.6 prescriptions per patient), followed by propiverine (5.9), oxybutynin ER (4.9), solifenacin (5 mg) and tolterodine IR (both 4.7). Solifenacin 10 mg also had the highest mean duration of therapy per patient (216 days), followed by solifenacin 5 mg (158.7), tolterodine ER (156.7), tolterodine IR (151.7), oxybutynin ER (146.7), propiverine (141.1), trospium (138.5), darifenacin (135.9), oxybutynin IR (119.3) and flavoxate (77.4).
Table 1. Number of prescriptions per patient and duration of therapy (all patients)
|Treatment||Prescriptions per patient (n)||Duration of therapy (days)|
|Darifenacin (n= 23)||3.6||135.9|
|Flavoxate (n= 89)||2.6||77.4|
|Oxybutynin ER (n= 590)||4.9||146.7|
|Oxybutynin IR (n= 1371)||4.1||119.3|
|Propiverine (n= 97)||5.9||141.1|
|Solifenacin 5 mg (n= 1258)||4.7||158.7|
|Solifenacin 10 mg (n= 332)||6.6||216.0|
|Tolterodine ER (n= 1758)||4.5||156.7|
|Tolterodine IR (n= 482)||4.7||151.7|
|Trospium (n= 352)||4.5||138.5|
Consistent with previous reports, persistence with all antimuscarinic agents prescribed was generally low over the evaluation period. The longest persistence (defined as the mean number of days a patient remained on a particular therapy) was associated with solifenacin 5/10 mg (187 days; Fig. 1). At 3 months, 58% of patients who started on solifenacin (5/10 mg) were still on treatment (Fig. 2) compared with darifenacin (52%), tolterodine ER and propiverine (both 47%), tolterodine IR (46%), oxybutynin ER (44%), trospium (42%), oxybutynin IR (40%) and flavoxate (28%). At 6 months, the persistence with solifenacin treatment was 46%, compared with tolterodine ER and propiverine (both 36%), oxybutynin ER (35%), tolterodine IR and trospium (both 33%), darifenacin (30%), oxybutynin IR (29%) and flavoxate (16%). At 12 months, 35% of patients were still receiving solifenacin (Fig. 2), compared with tolterodine ER (28.2%), propiverine (26.8%), oxybutynin ER (26.1%), trospium (25.9%), tolterodine IR (24.1%), oxybutynin IR (21.7%), darifenacin (17.4%) and flavoxate (13.5%).
Figure 1. Mean time that patients remained on therapy with each antimuscarinic. Data are for combined doses for each antimuscarinic. Numbers are for patients starting treatment.
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Figure 2. Percentage of patients remaining on each antimuscarinic over 12 months. Data are for combined doses for each antimuscarinic. Numbers are for patients starting treatment.
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Sub-analyses of the 4833 patient prescription records by age and drug dosage were also performed. Patient numbers tended to increase with age and peak in the 60–79-year age groups (Table 2). In most cases, patients aged ≥60 years were more likely to persist with prescribed therapy over the 12-month period than younger patients (Fig. 3), for example patients aged ≥60 years on oxybutynin IR, propiverine, solifenacin (5/10 mg), tolterodine ER and trospium. However, this was not the case for oxybutynin ER, where persistence dropped consistently from age groups 50–59 through to 70–79 years, despite the number of patients on this treatment increasing through these age groups. With oxybutynin IR, propiverine and trospium, persistence peaked at 60–69 years and dropped in the age group 70–79 years. At 12 months, patients receiving solifenacin 10 mg were most likely to persist with therapy (up to 56.6% of 76 patients aged 70–79 years).
Table 2. Twelve-month persistence rates with prescribed antimuscarinic medication according to patient age
|Treatment||Age group (years)|
|Darifenacin (n= 23)|| || || || || |
| Total patients treated||1||5||7||3||4|
| Percentage on therapy at 12 months||N/A||20.0||14.3||66.7||N/A|
|Flavoxate (n= 89)|| || || || || |
| Total patients treated||11||10||18||20||20|
| Percentage on therapy at 12 months||18.2||N/A||11.1||15||25|
|Oxybutynin ER (n= 590)|| || || || || |
| Total patients treated||65||72||132||113||114|
| Percentage on therapy at 12 months||24.6||26.4||25.8||23.9||27.2|
|Oxybutynin IR (n= 1371)|| || || || || |
| Total patients treated||124||171||210||287||302|
| Percentage on therapy at 12 months||16.1||21.6||27.1||22.3||24.2|
|Propiverine (n= 97)|| || || || || |
| Total patients treated||7||16||19||25||23|
| Percentage on therapy at 12 months||28.6||18.8||36.8||32||21.7|
|Solifenacin 5 mg (n= 1258)|| || || || || |
| Total patients treated||143||199||259||313||225|
| Percentage on therapy at 12 months||21.7||25.1||32.0||31.3||25.3|
|Solifenacin 10 mg (n= 332)|| || || || || |
| Total patients treated||46||59||74||76||51|
| Percentage on therapy at 12 months||32.6||37.3||45.9||56.6||43.1|
|Tolterodine ER (n= 1758)|| || || || || |
| Total patients treated||211||271||375||400||346|
| Percentage on therapy at 12 months||19.0||26.2||28.5||34.8||32.1|
|Tolterodine IR (n= 482)|| || || || || |
| Total patients treated||52||65||77||113||123|
| Percentage on therapy at 12 months||13.5||24.6||15.6||36.3||27.6|
|Trospium (n= 352)|| || || || || |
| Total patients treated||26||63||63||97||74|
| Percentage on therapy at 12 months||15.4||27.0||31.7||23.7||29.7|
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- MATERIALS AND METHODS
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OAB requires long-term management to control symptoms and improve patient quality of life. Although antimuscarinics are the cornerstone of pharmacotherapy for OAB syndrome in men and women, persistence with prescribed therapy in Europe, including in the UK, remains low [33,34]. Furthermore, persistence rates vary between antimuscarinics: although this may be partly linked to efficacy and tolerability differences, persistence is generally better with extended-release and once-daily formulations [16,25].
The objective of the present study was to use real prescription data to extrapolate persistence patterns for antimuscarinics among patients in the UK across different age groups, over a 12-month period. As in previous studies, persistence was generally low for all the medications analysed, and patients aged 60 years and above were more likely to persist with prescribed oral antimuscarinic drugs than younger patients (40–59 years). Although more patients were prescribed tolterodine ER overall, solifenacin 10 mg was associated with the greatest mean number of repeat prescriptions per patient.
In the age group sub-analysis, patients taking solifenacin 10 mg had the highest persistence with therapy, particularly those aged >60 years. These findings are consistent with a long-term open-label extension study evaluating the efficacy and tolerability of solifenacin 5 mg and 10 mg, in which 81% of patients completed 40 weeks of treatment, with only 4.7% discontinuing treatment owing to adverse events. In the present study at 3 months, solifenacin was associated with the highest rate of persistence, whereas oxybutynin IR was associated with the lowest. At 12 months, solifenacin continued to be associated with the highest level of persistence, whereas darifenacin was associated with the lowest persistence. Although solifenacin was consistently associated with the highest rate of persistence compared with the other antimuscarinics included in the study, persistence was generally low for all the antimuscarinics during the 12-month evaluation period. These results are consistent with a recent retrospective study conducted in the Netherlands, investigating persistence with treatment with four commonly prescribed antimuscarinics (flavoxate, oxybutynin IR, tolterodine IR and solifenacin) by analysing prescription data over a 9-month period. The study found that, although persistence with treatment declined rapidly during the first 4 weeks, patients who started on solifenacin had consistently higher levels of persistence throughout the study period (47% of patients who started on solifenacin were still on treatment at 3 months, versus 24–38% for the other antimuscarinics evaluated) .
Patients who were initially prescribed solifenacin 5 mg and were later prescribed a dose increase to solifenacin 10 mg were considered non-persistent for solifenacin 5 mg at that time point, and treated as a new patient for the solifenacin 10 mg group. This limitation of the study applies to all antimuscarinics with more than one dose or strength. We did not report results for different strengths of antimuscarinics other than solifenacin in this study. Prescription numbers for darifenacin were too small to be split by strength and the availability of multiple strengths for oxybutynin ER/IR complicated interpretation of the data, so the results were combined. Similarly, data for short-acting antimuscarinics requiring multiple dosing were also combined to facilitate data analysis. No results are available for fesoterodine because the drug was not available in the UK at the time of this analysis.
Although these results are important, the study has some limitations. It was originally conceived as a post-marketing analysis of persistence, so it did not address a prospectively defined hypothesis, hence the descriptive nature of the analysis and the absence of comparative statistics. We were unable to ascertain treatment naivety using this method, which would have required a detailed search of any medication prescription ever given to an individual. There is also a paucity of information on patients' previous therapies, their symptom severity at enrolment, whether bladder training was used alongside antimuscarinic therapy and whether successful conservative and behavioural therapies resulted in cessation of treatment. We may also have assumed dose escalation for some therapies, so non-persistence at the lower dose of medication in these circumstances may have been underestimated. However, this limitation applied to all antimuscarinics studied where more than one dose is licensed. The small number of people in some prescription categories by age should also lead to caution in interpretation of the results for drugs in those categories.
Other aspects that limit our interpretation of these data are intermittent versus continuous therapy, and drug holidays (structured treatment interruptions to re-establish efficacy or avoid adverse effects for a short period, which are common practice in diseases such as HIV infection). Although continuous treatment with antimuscarinics is recommended to obtain maximum efficacy, in real-life situations, some patients may take drug holidays at their own discretion. Intermittent therapy refers to patients who only return for repeat prescriptions once their symptoms have returned or worsened (i.e. deliberate poor compliance). Patients might use medication only when their symptoms are likely to cause bother, such as on long journeys, or at social events . Similarly, drug holidays could have adversely affected our results. Finally, in the present study, reasons for discontinuing treatment were not recorded, which limits our interpretation of persistence failure and any further analysis.
We also cannot answer the question as to why older patients have higher persistence compared with younger ones. Previous retrospective studies have also found that age correlates positively with persistence [16,25], consistent with our findings. The reasons for this have not been fully elucidated, but several hypotheses seem plausible. Older patients may have fewer time pressures, or be used to taking other medications, or their more severe experience of OAB may mean that they derive more benefit from treatment. In contrast, one previous longitudinal cohort study of older (>65 years) patients with OAB found that patient age and co-morbidities had a negative influence on treatment adherence, although the influence of individual antimuscarinic therapy on adherence and healthcare use was not examined . A more recent publication assessed the effect of age on the efficacy and tolerability of fesoterodine (4 and 8 mg), and showed that efficacy was lower and the incidence of adverse effects was higher in patients aged >65 years. This may suggest that older people require more medication, rather than less, to control their symptoms, even if their symptoms are of a similar magnitude to those of their younger counterparts . Older people may, of course, simply be more likely to do as their clinician instructs. The apparent decrease in persistence for those >80 years of age, although still higher seen across all of the antimuscarinics, is likely to be multifactorial. This may reflect active decisions to stop medication on behalf of prescribers because of the pervasive, although sometimes misplaced, belief that older people do not do well on these medications; a diminution of the importance of this condition, compared with other co-morbid conditions seen as ‘more serious’ or an effect of the higher rate of adverse effects reported by this age group. None of these speculated reasons can be answered by our study, but each is worthy of further investigation.
In surveys evaluating patient-reported reasons for discontinuing antimuscarinic prescription medications for OAB, expectations about treatment efficacy and adverse effects were the most important factors, with 45.4% of patients reporting unmet treatment expectations as the reason for discontinuation [20,41]. Consistent with these surveys, a recently published 12-week observational study investigating factors that motivate physicians and patients to change their OAB treatment found that reasons for last treatment change included lack of efficacy (60%) and adverse events (24%) . Interventions promoting realistic expectations about treatment efficacy and adverse effects might therefore enhance adherence and persistence .
It is important for physicians to identify the most appropriate therapy to meet their patients' needs, to educate patients about the nature of their disease, and to provide regular support during the course of their treatment, thereby encouraging and improving persistence with therapy. Patient support may be achieved through external programmes that complement patient–physician interactions . For example, a 12-week Patient Support Programme in the UK, available to patients with OAB who are prescribed solifenacin, has helped to improve and maintain persistence with solifenacin therapy (≥76% of patients were still taking solifenacin at 3–12 months after enrolment on the patient support programme) . There are no other published data on the effectiveness of patient support programmes for OAB in the UK and at the time of this study, none was in operation. Subsequently, a support programme for fesoterodine has been introduced by Pfizer. Patient support programmes have also been successful at improving persistence in other therapeutic domains, for example in the context of osteoporosis medication in postmenopausal women. The PERSIST study showed that once-monthly dosing with ibandronate, coupled with the ibandronate patient support programme, improved persistence compared with once-weekly alendronate . Adherence/persistence may also be enhanced by simultaneously supporting the use of non-pharmaceutical lifestyle modifications and behavioural interventions .
These findings highlight the need for a better understanding of non-persistent patients and for the development of initiatives to improve the quality of drug therapy management [25,39]. Persistence rates vary among antimuscarinics but remain generally low in the UK and elsewhere. Further studies are required to investigate the reasons underlying this trend, such as lack of efficacy, poor tolerability or inconvenient dosing, why patients are lost to follow-up, whether symptoms resolve at some point during the prescribed treatment, and whether lack of patient understanding about the need for long-term management is a factor.