2008 BJU International. No claim to original US government works Mini-review Article ADHERENCE TO DRUG THERAPY IN PATIENTS WITH OAB BASRA et al. BJUI BJU INTERNATIONAL A review of adherence to drug therapy in patients with overactive bladder Ramandeep K. Basra, Adrian Wagg 1, Christopher Chapple 2, Linda Cardozo 3, David Castro-Diaz 4, Montserrat Espuna Pons 5, Mike Kirby 6, Ian Milsom 7, Mark Vierhout 8, Philip Van Kerrebroeck 9 and Con Kelleher Guys and St Thomas NHS Foundation Trust, and 1 University College London, 2 Royal Hallamshire Hospital, Sheffield, 3 Kings College Hospital, London, 6 Centre for Research in Primary and Community Care, University of Hertfordshire, Herts, UK, 4 Universitario de Canarias, Tenerife, 5 Universidad de Barcelona, Barcelona, Spain, 7 Sahlgrenska University Hospital, Goteborg, Sweden, 8 Radboud University Medical Center, Nijmegen, and 9 University Hospital Maastricht, Maastricht, the Netherlands Accepted for publication 22 February 2008 Drug therapy for overactive bladder (OAB) is associated with improvements in symptoms and quality of life, but the short- and long-term adherence and persistence is suboptimal. In this review we outline methods of measuring, and factors affecting, adherence to pharmacotherapy in patients with OAB. Clinical practice suggests that adherence rates reported in clinical trials are much greater than in real practice. Factors affecting adherence include psychological and social variables that might alter patients perception of the benefits of taking medication, and the effect of comorbidity and polypharmacy. Whilst there is some evidence that lack of efficacy and side-effects are contributory, these additional factors are also important. KEYWORDS adherence, overactive bladder, pharmacotherapy INTRODUCTION Overactive bladder (OAB) is a chronic symptom complex characterized by urinary urgency, frequency and nocturia with or without urge incontinence [1]. The prevalence of OAB in the general population is reported to be 14 16% [2]. OAB is known to adversely affect the quality of life (QoL) of patients and perhaps the greatest benefits of treatment experienced by patients are improvements in QoL [3]. Treatment for OAB consists of lifestyle and behavioural measures, and antimuscarinic drug therapy. Although OAB is not a lifethreatening condition, suboptimal adherence to medication has implications for patients QoL, and might be associated with loss of faith in the clinician and the treatment regimen prescribed. Failure to recognize poor adherence can lead to inappropriate dose escalation, changes in medication, invasive investigations and an increased cost of disease management [4]. The efficacy of drug therapy depends on a patient s ability to take the prescribed medication for an appropriate period. This is influenced by factors including symptom severity, the ability to obtain the medication, perceived efficacy and the presence of side-effects [5]. Poor adherence to medication represents a major challenge in the management of OAB. Continued adherence to antimuscarinic therapy is low but comparable with adherence to medication in other chronic disorders, at 40% [6]. Repeat prescription data from the UK suggest that the median duration of antimuscarinic drug use is 3 months after an initial prescription. Even with these data it is estimated that only half of people prescribed medication take enough drug to reach therapeutic levels [6]. The lack of understanding of the natural history of OAB makes it difficult to give a firm recommendation as to the optimum duration of therapy required, leading to further confusion on the part of patients. The aim of this review is to describe methods of measuring adherence to pharmacotherapy, present the available persistence data for antimuscarinic medication, and the reasons for poor adherence in patients with nonneurogenic OAB. MEASURING ADHERENCE Haynes et al. [6] define adherence as the extent to which the patients behaviour coincides with medical or health advice. There is no reference standard measure of adherence; several methods have been used for assessing medication use in the assessment of many clinical conditions (Table 1) [7 12]. Methods used for measuring adherence in clinical trials are seldom stated, but counting returned medication at scheduled visits is the usual method. Adherence to medication in clinical practice tends to be assessed indirectly by asking patients about symptom improvement and adverse events and/or by direct questioning about drug use. All of these methods of assessing adherence rely on accurate information from patients. Methods which increase the accuracy of measurements of adherence, e.g. the use of electronic medication monitors and biological assays, are costly and associated with specific feasibility and acceptability issues. There are no biological assays which can indicate the use of antimuscarinic medication, and further, 774 2008 BJU INTERNATIONAL 102, 774 779 doi:10.1111/j.1464-410x.2008.07769.x
ADHERENCE TO DRUG THERAPY IN PATIENTS WITH OAB TABLE 1 Methods for measuring adherence/persistence with drug therapy Method Description Advantages Disadvantages Self report Validated questionnaires/ interview Return unused medication Retrospective review of pharmacy/ medical notes MPR Electronic medication monitors Medication weight Biological assays Return blister packs at follow-up visit Review history of medication Days of medication supply dispensed/days between prescription refills Electronic chips in bottle tops record how often the bottle is opened Weight of medication containers are measured to evaluate medication use Record drug, metabolite or tracer compounds in blood or urine tests Self reporting of medication adherence includes direct questioning and use of validated questionnaires, e.g. the medication adherence report scale (MARS), used to measure adherence to medication in OAB [7,8] Cost-effective method of measuring adherence/ compliance, often used in clinical trials Review of medical notes is a useful method of evaluating prescribed/dispensed drug and symptom severity reporting. Pharmacy record review assumes that medication dispensed equals medication used Review of pharmacy records is useful as an economic method of tracking treatment costs and prescribing practice [10] Useful in long-term retrospective analysis of medication use Evaluate the pattern of medication use Method does not rely on patient self report. Useful method of assessing use of topical ointments/ creams, nebulized medication Assays such as HbA1C provide information about blood sugar control over a prolonged period Patients might claim to adhere to therapy to avoid disapproval from clinicians Third party estimates of adherence tend to overestimate patients adherence [9] Patients might dispose of medication before assessment. This method relies on patients remembering to bring in medication packaging Relies on accurate note keeping, documentation of drug switches, symptom severity and continued care in one institution Reviewing pharmacy records might overestimate adherence Assumption; medication dispensed equals medication used This method assumes that single and correct doses of medication are dispensed each time the container is opened, and that it is only opened to remove medication, and closed afterwards [11] In a study of nebulized asthma medication, a proportion of subjects fed through much of their medication in the 24 h before study visits [12] High costs limit the feasibility of these tests. Concomitant medication, food interactions, and the dosing schedules might affect test results [9] the acceptability of invasive methods might limit their acceptability in practice. Retrospective reviews of medication and pharmacy renewal scripts represent an economic method of measuring adherence in a large patient population, but tend to overestimate medication use. FACTORS AFFECTING ADHERENCE There are many factors which can alter patients perception of the benefits of taking medication and thus the likelihood of taking their medication. Social and cultural factors include (patient factors) socio-economic status, education, smoking, alcohol consumption and beliefs about illness and treatment [7]. The condition being treated must be sufficiently bothersome to the patient to merit intervention, and the benefit of treatment must be noticeable and advantageous. Treatment factors include the presentation and efficacy of medication, the cost (financial or personal), dosing frequency and expectations of treatment. The route of administration of medication is also a factor which influences adherence. DISEASE FACTORS Treatment efficacy and tolerability: If a treatment is ineffective, patients are unlikely to take it and physicians unlikely to prescribe it. Studies of antimuscarinic therapy for treating OAB have shown that treatment is effective over the short- and long-term for a significant proportion of users. It has also been shown that treatment results in a diminution of the considerable associated morbidity. The assessment of efficacy in clinical trials has usually focused on the effect at trial completion. The time to reach clinical effectiveness after commencing antimuscarinic therapy might also affect persistence with medication. If patients notice significant improvements early after starting treatment then compliance is likely to be increased [4]. Although poor adherence with pharmacotherapy in OAB is a recognized limitation of treatment success, there are few studies investigating the real world situation. Most trials are of short duration (8 12 weeks), with intensive follow-up and incentives which encourage adherence. Trial subjects might not be representative of the general population who are likely to receive treatment, and thus in clinical trials the rate of adherence is usually >80%. 2008 BJU INTERNATIONAL 775
BASRA ET AL. TABLE 2 Adherence results for extension studies of oxybutynin, darifenacin, tolterodine and solifenacin Study Study design Adherence Adverse events/discontinuation ER oxybutynin [8] 1-year extension study. 1067 participants started on 5 mg, followed by weekly 5 mg increments, until the patient was continent or until there was optimum balance between symptom control and tolerability. 63% of patients who continued therapy >3 months remained on medication at 1 year Dry mouth reported by 8.4% Discontinuation due to adverse events 24% Darifenacin [9] 24-month extension study. All patients received 7.5 mg for the first 2 weeks of the study, and then offered dose escalation to 15 mg; 719 participants. IR tolterodine [10] 1-year extension study of 2 mg, twice daily; 712 participants Solifenacin [11] Trospium [12] 1-year extension study. 1633 participants commenced on 5 mg, then offered dose escalation to 10 mg 9-month extension study. 407 participants commenced on trospium 20 mg twice daily. 475 (63%) completed the study >85% of the study participants achieved >80% compliance at 2-year follow-up 62% (441) completed the study 23% required dose reduction 1329 (81%) patients completed study 265 (65%) patients completed study Discontinuations due to: insufficient clinical response 9.5%, adverse events 8.9% Discontinuations due to adverse events 15%, of which 10% were due to dry mouth Discontinuations due to adverse events 4.7%, of which 0.4% were due to dry mouth Discontinuations due to adverse events 9% In open-label extension studies high levels of adherence have been shown over considerably longer treatment periods; however, the same caveats must apply when extrapolating these findings to the general patient population. There have been five longterm, open-label extensions of randomized controlled studies assessing adherence with oxybutynin, darifenacin tolterodine, solifenacin, and trospium [8 12]; the results are shown in Table 2. The primary outcome measure in most short studies focuses on treatment efficacy. Subject withdrawal and adverse-event reporting are used to indicate drug tolerability. Other factors affecting adherence are not routinely assessed but these clearly need consideration as a significant proportion of subjects stop treatment for other reasons. There are few community-based studies evaluating adherence with drug therapy in OAB. Kelleher et al. [13] conducted a retrospective study of patients with low bladder compliance and detrusor overactivity. Women were contacted 6 12 months after their initial investigations and asked to provide an account of the treatments received, treatment duration, efficacy, side-effects and residual urinary symptoms; 83% of women were treated with immediate release (IR) oxybutynin. Figure 1 shows the number of women continuing with anticholinergic medication up to 6 months after commencing treatment; 59.5% FIG. 1. The number and percentage of women continuing anticholinergic medication between 2 weeks and 6 months. Values above the bars represent the number of women, and the bars represent the percentage of the total of 231 women, Reproduced from [13] with permission. Percentage, % 100 222 90 80 70 159 60 50 40 88 30 20 42 10 0 2 weeks 1 month 3 months 6 months reported symptom cure or improvement; 40% discontinued medication due to sideeffects and 29% failed to renew their initial prescription [13]. In a further follow-up study, women with detrusor overactivity were prescribed IR oxybutynin twice daily, at a starting dose of 2.5 mg or 5 mg [14]. Patients were instructed to increase the dose of oxybutynin fortnightly to a maximum dose of 5 mg three times daily over 6 weeks, to a level where treatment efficacy was balanced by the tolerability of side-effects. At 2-year follow-up, 69% of FIG. 2. Duration of treatment and the maximum incremental dose achieved in patients commenced on 2.5 mg and 5 mg of twice-daily oxybutynin; (?, maximum dose of oxybutynin unknown), From [14]. 9 8 7 6 5 4 3 2 1 0 2.5 mg bd 5 mg nocte? 5 mg 10 mg 15 mg 20 mg women responded to postal questionnaires; 67% of respondents had abandoned drug therapy, of whom 24% stopped because of adverse events. Of the women who abandoned therapy, 63% did so within 2 months; 53% reported symptom improvement or cure. In many respects the results were similar to the first study, despite the additional advice and instruction. Figure 2 [14] shows the duration of treatment persistence with oxybutynin. Although the study was under-powered to detect differences between the groups, the results showed no significant advantage in terms of efficacy or adherence with oxybutynin when commencing therapy at two doses, with patient-controlled dose escalation. Most patients abandoned therapy within 4 6 months, and the authors suggested early follow-up in an attempt to reinforce adherence. 776 2008 BJU INTERNATIONAL
ADHERENCE TO DRUG THERAPY IN PATIENTS WITH OAB A retrospective analysis of a pharmacyclaims database evaluated adherence to IR oxybutynin and tolterodine over a 6-month period using the medication possession ratio (MPR, the ratio of days of medication supply dispensed to days between prescription refills); 32% of patients taking tolterodine vs 22% taking oxybutynin continued to use drug therapy for 6 months. The MPR for the tolterodine group (83%) was higher than for the oxybutynin group (64%). On average, patients using oxybutynin discontinued therapy on day 45 compared with day 59 for patients using tolterodine [15]. Adverse events associated with antimuscarinic therapy include dry mouth, constipation, dry eyes, blurred vision and cognitive impairment, amongst others, and are significant and well recognized factors in the discontinuation of drug therapy. TREATMENT FACTORS Reducing the frequency of medication doses might improve adherence with therapy. Evidence suggests that once-daily dosing of medication is more likely to be adhered to than twice, three or more times per day [16]. This is particularly important when patients have comorbidities or concomitant therapies, as can be the case for elderly patients with OAB. Dose flexibility allows patients to titrate symptom improvement against side-effects. Alternative modes of delivery, e.g. transdermal delivery systems (TDS), might improve adherence. The efficacy and tolerability of TDS oxybutynin has been investigated in several trials, and the rate of adverse events is comparable or lower than that of oral preparations. Side-effects specific to TDS preparations include skin irritation and problems with adhesion, particularly for patients residing in warmer climates [17]. The MATRIX trial evaluated the efficacy and safety of the oxybutynin TDS in patients with OAB. Adverse events were associated with discontinuation of medication in 10% of patients in the 12-week blind period, and 7% in the open-label period. Site pruritis was the most commonly reported adverse event, affecting 18% of subjects [18]. Inadequate symptom control, unmet or unrealistic expectations and inadequate follow-up after initiation of therapy are also important treatment factors affecting adherence to medication [19]. SOCIAL/CULTURAL FACTORS PATIENT FACTORS Whilst cost might not be such an immediate incentive in the UK where prescription medications are either free or associated with a small charge, in many countries patients pay a substantial proportion of prescription charges. Cost-conscious prescribers or those where drug availability is limited by reimbursement will often opt for cheaper medications, with potentially reduced efficacy or high side-effect profiles, or even discontinuation of the medication altogether. A study conducted in the USA investigated persistence with extended release (ER) tolterodine and oxybutynin, and IR oxybutynin in Medicaid patients [20]. Low-income patients or those with high healthcare costs relative to income are eligible for Medicaid. Adherence to medication was calculated from prescription claims over a 3-year period. Discontinuation rates with oxybutynin IR were significantly greater than for tolterodine ER after 30 days. Patients taking oxybutynin IR after 30 days were no less likely to abandon therapy than patients taking tolterodine ER. After 30 days, discontinuation of treatment in the oxybutynin ER group was greater than for tolterodine ER; 6% of patients switched medications. Men continuing treatment beyond 30 days were more likely to persist with therapy than women. Newly diagnosed patients were less likely to abandon therapy than patients diagnosed >6 months earlier. Patients aged <18 years were less likely to discontinue their original therapy than patients aged 18 39 years. Patients from ethnic minorities were more likely to abandon or switch therapies than Caucasians. Cultural beliefs about pharmacotherapy, access to healthcare for ethnic minorities, education and language barriers might be contributing factors to the low adherence in ethnic minorities. Young patients might be more compliant with treatment if a parent supervises medication dosing. Variation in drug metabolism [21], fewer comorbidities and prescribed medicines in young patients might contribute to fewer or better tolerance of side-effects, and better adherence to therapy. Factors affecting persistence with medication in OAB were investigated in a Medicaid population in California. Predictors of higher persistence with medication included white ethnicity, previous episodes of hospitalization and previous use of topical drugs or antipsychotics. Factors associated with reduced adherence included polypharmacy and a previous history of depression and UTI [22]. A recent study investigated the relationship between the use of healthcare resources in older (>65 years) patients with OAB [23]. All patients were enrolled in a Medicaremanaged care-plan in the USA; 275 participated in the study, all of whom had received at least one antimuscarinic prescription every 6 months (over a 1 3-year period). Prescription-refill patterns were used to calculate adherence to medication; the average MPR was 42% over 3 years. Healthcare costs were US$ 5691 6099 over the same period. A higher QoL was also associated with a higher MPR. After controlling for other variables such as gender and age the MPR remained the strongest predictor of decreased healthcare costs. Increased patient age and comorbidity had a negative influence on treatment adherence. The influence of individual antimuscarinic therapy on adherence and healthcare use was not examined. Poor adherence with antimuscarinic medication might be deliberate. Patients might choose to use medication when their symptoms are likely to cause bother, such as long journeys, or social events. BELIEFS ABOUT ILLNESS AND TREATMENT Counselling of patients at the start of treatment significantly affects adherence. The promise of unrealistic efficacy over too short an interval or failure to advise about the nature or severity of expected side-effects might have a negative effect. Women with OAB participated in a study investigating attitudes towards prescribed medicines and their influence on compliance [24], using validated questionnaires. Abandoning therapy was associated with increased concern about using an antimuscarinic drug, and low perceived benefit from treatment. Higher perceived necessity of antimuscarinic therapy was associated with better compliance. 2008 BJU INTERNATIONAL 777
BASRA ET AL. Patients with an internal locus of control (who link their behaviours and choices to a high likelihood of reward) are more likely to be proactive in decision-making with their clinician and more likely to adhere to medication than those with an external locus. These patients tend not to see such links and do not engage in such behaviours [25]. There are no published recommendations to physicians about treatment duration for OAB. In many cases the recommendation appears to be short-term, with the option of long-term therapy for those who have a return of symptoms after stopping treatment. Specifying a short duration of likely treatment alters the impression of treatment adherence at 6 months. The duration of initial prescription also alters treatment duration; not all patients seek a repeat prescription. DISCUSSION Adherence to antimuscarinic medication in clinical studies is better than that reported in clinical practice. The adherence rates reported for OAB are comparable with adherence to therapy in other chronic diseases. Whilst there is some evidence that lack of efficacy and side-effects are contributory, many additional factors are also important. There is no uniform guidance on the required duration of therapy and the need for long-term treatment for this condition. It is assumed in clinical trials that patients want to take medication and are motivated to do so, but this might not be so in clinical practice. Whilst cost should not be the major factor in clinical decision-making, the cost benefit of all treatments for conditions that are not life-threatening is likely to be important both for the individual and the healthcare provider. Experimental therapies like botulinum toxin eliminate factors such as patient motivation and adverse events associated with antimuscarinic medication, and might thus be associated with greater symptom control and treatment tolerability. Willingness to use experimental therapies such as botulinum toxin might be associated with symptoms that are refractory to conventional drug therapy. This might represent a niche population with severe symptoms and cannot be extrapolated to the entire population affected by OAB. CONFLICTS OF INTEREST Ramandeep Basra has no conflicts of interest. The following authors are members of the European Overactive Bladder Forum sponsored by Astellas; Adrian Wagg, Christopher Chapple, Linda Cardozo, David Castro-Diaz, Philip Van Kerrebroeck, Mike Kirby, Ian Milsom, Montserrat Espuna Pons, Mark Vierhout, Con Kelleher. This manuscript was prepared independently by the authors. REFERENCES 1 Abrams P, Cardozo L, Fall M et al., Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. 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