Persistence With Overactive Bladder Pharmacotherapy in a Medicaid Population

Statement of Problem and Rationale: The managementof chronic conditions, such as overactivebladder (OAB), is often limited by lack of patientadherence to medication. This article compares persistencerates among Medicaid patients who wereprescribed 1 of 3 drugs for treatment of OAB: 2 long-actingagents with once-daily dosing, tolterodine tartrateextended-release capsules (tolterodine ER) andoxybutynin chloride extended release (oxybutyninER), and oxybutynin immediate release (oxybutyninIR), requiring 3 tablets daily.

Methodology: The study population was comprisedof continuously enrolled Medicaid managedcare patients filling prescriptions for tolterodine ER,oxybutynin ER, or oxybutynin IR between January 1,2000, and December 31, 2003. Patients taking anyOAB drug in the first 6 months of their observed periodof enrollment were excluded to capture new usersonly. Using survival analyses adjusted for age, sex,and race, the rates of persistence by drug were analyzed.Possession time, the degree to which patientskeep medication available even though they may notbe taking it daily as prescribed, was also measured.

Results: Of 1637 patients (75% women, 45%African American, 26% younger than 18 years ofage), 182 were started on tolterodine ER, 215 on oxybutyninER, and 1240 on oxybutynin IR. Only 32%of those taking oxybutynin IR and 44% of those takingeither long-acting agent remained adherent past30 days. Of those remaining after 30 days, the riskof nonadherence was higher for oxybutynin ERthan for tolterodine ER (hazard ratio = 1.47; 95%confidence interval, 1.01-2.14).

Conclusion: Persistence rates are better forpatients taking drugs with once-daily dosing, butthere is a need for a better understanding of non-persistentpatients.

(Am J Manag Care. 2005;11:S121-S129)

Overactive bladder (OAB) has beendescribed as a "syndrome of symptoms,"and defined by the InternationalContinence Society as urgency,with or without urge incontinence, usuallywith frequency and nocturia.¹ OAB affectsnearly 33 million people in the UnitedStates,² making it more prevalent than asthma(15 million), osteoporosis (10 million),diabetes mellitus (7 million), or Alzheimer'sdisease (4 million).³ The estimated total economiccost of OAB was $12.02 billion in2000, with $9.17 billion and $2.85 billionincurred in the community and institutions,respectively.⁴ This estimate is relatively conservative,because it did not include thecosts of care for dry institutional residentswith OAB.⁴

Medications used to treat OAB have anticholinergicproperties. These agents blockmuscarinic effects inhibiting involuntarybladder contractions. Extended-release formulationsof antimuscarinic agents offer theconvenience of once-a-day dosing. Studiescomparing extended-and immediate-releaseformulations of oxybutynin and tolterodinehave reported a better therapeutic windowwith extended-release formulations and betterside effect profiles.⁵ With good complianceand adherence to these medications, patients'quality of life can be improved and healthservices utilization costs can be reduced.⁶

Because of the chronic nature of OAB, itis essential that medication be taken as prescribed.Persistence has been shown to beone of the critical predictors of outcomes inchronic conditions.⁷ Despite improvementsin recent years in the tolerability and efficacyof OAB medications, many patients donot comply with the instructions.^8-10 Withlong-term treatment, persistence is evenmore difficult for these patients.

Medication persistence rates in patientswith OAB have been found to be low regardlessof setting.^8,9,11,12 For example, Yu andcolleagues¹⁰ investigated 1-year persistencepatterns for OAB/urinary incontinence (UI)medication treatment in the CaliforniaMedicaid program. They enrolled adultpatients diagnosed with OAB/UI who hadreceived at least 1 OAB/UI medication fromJuly 1999 to April 2001. Persistence patternsof patients were measured as time todiscontinuation; adherence was measuredas medication possession ratio (MPR), whichcompares the cumulative days of drug supplywith the elapsed time since the date ofthe first prescription of the drug being measured.They found that of 6518 eligiblepatients, 5751 patients (88.2%) discontinuewithin the following year, and only 14.6%patients have an MPR ³ 0.80. Significantpredictors of higher persistence includeCaucasian, 75 years of age or older, pastmedication use, and initiating the extended-releaseform of the drug.¹⁰

OAB is of special significance to stateMedicaid plans because of its higher severityin women,² the high population of women inMedicaid, and higher per capita expendituresfor adults with Medicaid.¹³ Poor compliancecan be attributed to a variety offactors, including low level of education, culturaland social support factors, and sideeffects.^14-16 These factors, such as low educationlevel, may be more prevalent amongunderserved populations, such as Medicaidbeneficiaries. It would be likely that a higherprevalence of OAB and lower persistencerates exist simultaneously in the Medicaidpopulation.

To date, there is a paucity of literatureon medication adherence patterns amongMedicaid-eligible patients with OAB. Theobjective of this study was to compare persistenceand adherence patterns amongMedicaid managed care patients prescribed1 of 3 drugs for treatment of OAB: tolterodinetartrate extended-release capsules(tolterodine ER), oxybutynin chlorideextended release (oxybutynin ER), andoxybutynin immediate release (oxybutyninIR).

Methods

Sample.

The total population consisted ofmore than 400 000 Medicaid recipients froma mid-Atlantic state who were not in institutionsor eligible for Medicare. Recipients hadto be enrolled in 1 of 8, prepaid, state-contractedmanaged care organizations (MCOs).Enrollees include both those who qualifiedbecause of low income or by having highmedical expenses relative to their income.All prescription claims were retrieved for theMedicaid MCO enrollees receiving at least 1prescription between January 2000 andDecember 2003 for tolterodine ER, oxybutyninER, or oxybutynin IR. For each patient,the longest period of continuous enrollmentwas identified. Successive enrollment periodsthat were less than 45 days apart werecombined into a single continuous enrollmentperiod. The sample was limited to newusers by excluding those who had usedtolterodine ER or oxybutynin (ER or IR) inthe first 6 months of the selected enrollmentperiod, or had any use in a prior enrollmentperiod. Statistical significance is determinedat the a = .05 level.

Medication-

taking Status.

any

OAB medication-taking status was categorized intoswitching, discontinuation, or persistence.The index date of a study drug (index drug)was captured for each patient. If that patientfilled a prescription for a different OAB drugwithin 15 days of when their preceding prescriptionwas scheduled to run out, thepatient was classified as a "switch." If apatient did not fill OAB prescriptionwithin the same time period, this patientwas classified as "discontinued." If a patientdid not switch or discontinue after the firstprescription, they were considered persistent,and each subsequent prescription forthe same drug was confirmed until a switchor discontinuation was identified or until thepatient had no claims in the enrollment period.As a sensitivity analysis, results werecomputed with refill windows varying from15 days to 30 days. If a patient had switcheddrugs, the dispensing date of the new drugwas recorded as the switch date; if a patienthad discontinued, the original dispensingdate plus the day's supply were used to calculatethe discontinuation date.

Medication Possession Time.

Althoughit is recommended that patients take theirmedication on a daily basis, many patientswith OAB do not follow this practice. Forexample, they may take the drug only whenthey are going to leave their house. Thus,also tracked was the length of time patientsmaintained possession of the drug. That is,the time patients kept a certain minimumlevel of medication on hand through refillswas measured, although they may not havebeen persistent with the prescribed regimen.

Possession time was measured as the timepatients maintained an MPR of at least 30%.The MPR typically compares the cumulativedays of drug supply with the elapsed time.Here, the possession time was defined to bethe period during which the patient maintaineda given possession ratio. The patientmay have continued to refill the prescription,but not often enough to be compliant withtherapy every day. The calculation used was:

n

_n

n

Because the denominator did not includesurplus days, the surplus days after the thprescription were not counted in the numeratoreither. The MPRwas an estimation ofmedication persistence during the periodbetween the date of first prescription andthe date of th prescription.

Analysis.

Patient demographic characteristicswere examined by drug group. Percentby age category, sex, and race were calculated.A product-limit life table analysis wasused to construct survival curves of patientpersistence and possession time by indexdrug. Patients still persistent at the end oftheir enrollment period were censored atthat point. To determine whether differencesin persistence and possession time bydrug are statistically significant after adjustingfor age, sex, and race, a time-dependent,Cox proportional hazard model was used.The time-dependent model allows differenthazard ratios (HRs) in different time periods,and it can be used to account for differencesin behavior between patients whodrop after the first prescription and thosewho refill at least once. Persistence wascomputed using the 15-day refill buffer. Amodel was also tested in which the maximumfollow-up allowed was 360 days, incase extreme observations had a disproportionateeffect on results. Finally, modelswere also run in which a variable was added(individually) to indicate whether a patienthad a qualified diagnosis for OAB or a contraindicationin the 6 months before initiatingmedication. The codes used for thesediagnoses and contraindications are listed inthe Appendix.

Results

Sample.

The search of prescriptionrecords of more than 400 000 enrollees inMedicaid MCOs for tolterodine ER, oxybutyninIR, or oxybutynin ER filled betweenJanuary 1, 2000, and December 31, 2003,yielded 20 667 prescriptions of 3054 uniquepatients. After exclusions, the sample byindex drug included 1240 oxybutynin IRpatients, 215 oxybutynin ER patients, and182 tolterodine ER patients (Table 1).Another 48 patients had started on nonstudyOAB drugs. Of these 1637 patients,75% were women, 26% were younger than 18years old, and 45% were African American.The most significant difference between theindex drug cohorts was that 30% of the oxybutyninIR users were younger than 18 yearsof age; only 3% of the tolterodine ER usersand 17% of the oxybutynin ER users wereyounger than 18 years of age. The efficacy oftolterodine ER has not been demonstratedin pediatric populations.

Persistence.

P

P

P

P

The unadjusted survivalcurves of patient persistence by index drugare shown in Figure 1. Only 32% of thosestarting on oxybutynin IR and 44% of thosestarting on either tolterodine ER or oxybutyninER remained persistent after 30 days(<.001). That is, they did not refill theirinitial prescription. The 1-year persistencerates were 9%, 6%, and 5% for tolterodine ER,oxybutynin ER, and oxybutynin IR, respectively (= .086). Results are only slightlybetter if the more generous refill buffer of 30days is allowed. By this criterion, 30-daypersistence rates are 49%, 48%, and 39% fortolterodine ER, oxybutynin ER, and oxybutyninIR, respectively (= .004). The corresponding1-year rates are 12%, 5%, and 8% (= .038).

To determine whether differences in persistenceby drug are statistically significantafter adjusting for age, sex, and race, a time-dependentCox model was constructed thatallowed different HRs before and after thecritical 30-day mark. Using the Cox modelwithout controlling for covariates, and onlythe time variable, results showed that oxybutyninIR had a significantly higher rate ofdiscontinuation than tolterodine ER withinthe first 30 days (HR = 1.25; 95% confidenceinterval [CI], 1.01-1.53). After this initiallypoorer start, oxybutynin IR users discontinueat statistically the same rate as tolterodineER users. This corresponds to theunadjusted survival curve.

In a Cox model adjusting for age (<18years, 18-40 years, >40 years), sex, and race(Caucasian, African American, other), oxybutyninIR is not significantly differentfrom tolterodine ER (HR = 1.09; 95% CI,0.88-1.35) in the initial 30-day period(Table 2). Table 2 shows the HRs of non-persistence of oxybutynin IR and oxybutyninER compared with tolterodine ER.Because of the large drop in persistence forany of the 3 drugs in the first 30 days, theanalysis is stratified by time period, differentiatingbetween trends in the first 30 daysand trends in the period after 30 days. Theeffects are also shown on nonpersistence ofage, sex, and race. In the first 30 days, theoxybutynin ER and tolterodine ER do notdiffer statistically, in both adjusted (HR =0.96; 95% CI, 0.60-1.53) and unadjustedmodels (HR = 1.04; 95% CI, 0.80-1.35).However, of the users who continue past 30days, oxybutynin ER has a higher risk of discontinuationin both the adjusted (HR =1.47; 95% CI, 1.01-2.14) and unadjustedmodels (HR = 1.50; 95% CI, 1.03-2.18).

Possession Time.

The survival curves forpatient possession time with an MPR >30%are shown by index drug in Figure 2. About45% of those starting on oxybutynin IR and55% of those starting on either tolterodineER or oxybutynin ER maintain possessionafter 30 days. At 1 year, 16%, 22%, and 15%are maintaining possession of oxybutyninIR, tolterodine ER, and oxybutynin ER,respectively. The shape of the possessiontimesurvival curve points to a time-dependentmodel that can handle different HRsbefore and after 30 days of possession time.

No drug shows significantly different hazardrisk than another in either time period,in both unadjusted and adjusted Cox models.Detailed HR results are included inTable 2.

In a comparison of the distributions forpersistence and possession time, it wasfound that possession time is just 30 dayslonger than persistence for 80% of patients.On average, tolterodine ER and oxybutyninER users possess medication approximately40 days longer than they persist. The meandifference is greater for oxybutynin IR users,which is approximately 60 days.

Switching.

About 6% of the cohortswitched drugs before they were determinedto be otherwise nonpersistent or reached theend of the enrollment period, with little differenceby index drug. Of those who didswitch, 44%, 56%, and 20% (tolterodine ER,oxybutynin ER, and oxybutynin IR, respectively)switched in the first 30 days. The correspondingrates by 120 days were 50%, 80%,and 60%.

Demographic and Clinical Predictors.

Table 2 includes HRs from the Cox multivariatemodel, indicating how age, race, andsex affect persistence and possession time.Younger patients are half as likely to discontinuetheir original therapy compared withyoung adults aged 18 to 39 years (HR = 1.56;95% CI, 1.33-1.82). Patients aged 40 to 64years are significantly less likely to discontinuetherapy than the younger adults (HR =0.85; 95% CI, 0.74-0.97). Age has a similareffect on possession time.

African Americans and other minoritieswere more likely than Caucasians to discontinueor switch (HR = 1.22; 95% CI, 1.09-1.36). At 90 days, only 15% of AfricanAmericans remain persistent compared with27% of Caucasians. Similar racial effectsheld for possession time. Sex did not affectlong-term persistence; however, an interestingdifference shows up in the first 30 days.If men were going to discontinue, they weremore likely than women to stop therapy inthe first 30 days (HR = 1.16; 95% CI, 1.01-1.34). Men who continue past 30 days areless likely than women to stop (HR = 0.74;95% CI, 0.56-0.94).

As might be expected, patients who had aqualified diagnosis for OAB in the 6 monthsbefore initiating medication were less likelyto discontinue than others (HR = 0.80; 95%CI, 0.72-0.89; n = 715).

Discussion

Because patients eligible for Medicarewere excluded and there is a high prevalenceof children in most Medicaid plans, thecohort of OAB patients identified here wasyounger than what might be expected interms of more typical OAB patients. Amongthe 3 products of interest, oxybutynin IR useis predominant at 76% of users. This is likelya result of the preferred use of genericdrugs as a cost-containment measure inmany Medicaid plans.

Rates of persistence with OAB drugs werefound to be low among these Medicaid MCOpatients, with only 32% of the oxybutynin IRusers and 44% of users of either once-dailyagent refilling their first prescription at 30days. The difference is associated with thegreater number of young adults in the oxybutyninIR cohort, whose persistence is significantlyless than older adults. Of thosepatients who did fill a second prescription,persistence was significantly better forpatients receiving tolterodine ER comparedwith oxybutynin ER; the significant differencepersists after adjusting for demographicvariables (HR = 1.47; 95% CI, 1.01-2.14).In 2 clinical trials comparing the 2 longeractingagents over a 12-week period, resultson relative efficacy were mixed, whereasfewer tolterodine ER users experienced drymouth than did oxybutynin ER users.^17,18Thus, this difference may be a result of fewerpatients experiencing adverse effects, suchas dry mouth; however, a specific study thattests this hypothesis would be needed forconfirmation.

P

After the initially poorer persistence foroxybutynin IR users, those who do continueafter 30 days adhere at about the same rateas tolterodine ER users. It is possible thatthese patients experience more side effectsat the initiation of therapy. However, thosewho do not experience these side effects areable to persist without problems later. Therewas less difference between index drugs, andpossession time lasted 1 to 2 months longerthan persistence on a mean basis. Like persistence,possession time was lower amongyounger or minority individuals.Little data on persistence with OAB medicationhas been published in peer-reviewedjournals, but research abstracts of otherclaims studies also report low rates of persistence.For immediate-release formulations,Juzba and colleagues¹⁹ found that nearly half(48.2%) of the patients in their 1999 claimsstudy failed to refill their first prescription,and that continuation was more likely forpatients taking tolterodine ER than oxybutyninIR (n = 436). Boccuzzi et al found 12-month persistence rates of 24% fortolterodine ER patients, and 17% for oxybutyninIR patients (n = 36 142).¹² Chui et al⁹and Yu et al¹⁰ reported similar 12-monthresults also from studies of claims data. Zhouet al reported an adjusted odds ratio of discontinuationfor tolterodine ER versus oxybutyninIR users as 0.66 (<.001; n =11 893).⁸

Poor compliance can be attributed to avariety of factors, including low levels of formaleducation, cultural factors, side effects,and financial barriers.^15,16,20 Clinical studiesand patient surveys are necessary to betterunderstand reasons for nonpersistence withOAB medications and to develop interventionsto improve persistence. Clinical trialsof transdermal patches for administration ofoxybutynin ER have indicated reduced incidenceof side effects, and studies of thesenew therapies in routine clinical practice areneeded to replicate these findings in the realworld.^21,22

A good patient education program favorablyimpacts patient behavior, including compliancewith short-term therapies, long-termmanagement of chronic conditions, and preventivelifestyle recommendations.²³ It canalso build trust between healthcare providersand reduce anxiety, thus favorably impactinghealth outcome and patient satisfaction.²⁴Patient education programs have been carriedout in various settings and proved to be successfulin improving patient compliance.^25-27Because of its chronic nature, unpleasant sideeffects, and chronic treatment, a behavior-modifyingeducation program would be ofessential value to patients with OAB, particularlyamong those with lower educational status.Further efforts are called for to design aneffective educational program specifically targetedto this population.

There are limitations to assessing persistencepatterns from claims data, as done inthis study. Different methods are used tomeasure persistency in patient populations.The most commonly used method involvesobtaining information on pharmacy refillrecords, often from third-party institutions.These records are beneficial as an economicalmethod for tracking compliance onlarge numbers of patients. However, theymay overestimate compliance in that theyrepresent prescriptions filled or refilled andnot medications actually taken.

Conclusion

It can be concluded that persistence withOAB therapy in a Medicaid MCO populationis low. Research is needed to understand thereasons for low persistence, so that interventionscan be developed to improve persistenceand compliance. Medicaid managedcare plans will continue to face demands forreduced budgets and will continue toexplore different approaches to optimizecare and reduce risk. If low persistence withOAB therapies increases total cost of carefor patients with OAB, it is critical that managedMedicaid plans understand and addressthis problem. Further studies are needed tounderstand OAB drug treatment compliancepatterns in these populations as well as thefactors influencing these patterns.

Urology.

1. Wein AJ, Rovner ES. Definition and epidemiology ofoveractive bladder. 2002;60:7-12.

World J Urol.

2. Stewart WF, Van Rooyen JB, Cundiff GW, et al.Prevalence and burden of overactive bladder in theUnited States. 2003;20:327-336.

Mayo

Clin Proc.

3. Appell RA, Sand P, Dmochowski R, et al. Prospectiverandomized controlled trial of extended-release oxybutyninchloride and tolterodine tartrate in the treatment ofoveractive bladder: results of the OBJECT Study. 2001;76:358-363.

Urology.

4. Hu TW, Wagner TH, Bentkover JD, et al. Estimatedeconomic costs of overactive bladder in the UnitedStates. 2003;61:1123-1128.

J Urol.

5. Anderson RU, Mobley D, Blank B, et al. Once dailycontrolled versus immediate release oxybutynin chloridefor urge urinary incontinence. OROS Oxybutynin StudyGroup. 1999;161:1809-1812.

6. Kelleher CJ, Pleil AM, Reese PR. Health related qualityof life of patients with overactive bladder receivingtolterodine once-daily. Presented at: 31st AnnualMeeting of the International Continence Society; 2000;Tampere, Finland.

Manag Care Interface.

7. Noe LL, Sneeringer BP, Williamson T. The implicationsof poor medication persistence with treatment foroveractive bladder. 2004;17:54-60.

Value Health.

8. Zhou Z, Barr C, Torigie Y, Williamson TE, Shah J.Persistence of therapy with drugs for overactive bladder.2001;4:161.

Value Health.

9. Chui MA, Williamson T, Arciniega J, Thompson C,Beneke H. Patient persistency with medications for overactivebladder. 2004;7:366.

Value Health.

10. Yu YF, Yu AP, Ahn J, Nichol MB. Medication treatmentpersistence of overactive bladder/urinary incontinencepatients in a California Medicaid program and thebenefit of their refill adherence on urinary tract infection.2003;6:191.

BJU Int.

11. Homma Y, Paick JS, Lee JG, Kawabe K. Clinical efficacyand tolerability of extended-release tolterodine andimmediate-release oxybutynin in Japanese and Koreanpatients with an overactive bladder: a randomized,placebo-controlled trial. 2003;92:741-747.

Value Health.

12. Boccuzzi SJ, Le TK, Wogen J, Williamson T.Utilization patterns associated with tolterodine immediaterelease versus oxybutynin in the management of urinaryincontinence. 2002;5:274.

13. Kaiser Commission on Medicaid and the Uninsured.Medicaid: a lower-cost approach to serving ahigh-cost population. Available at: http://www.medicalredesign.org/pdf. Accessed January 2, 2005.

Am J Public Health.

14. Shea S, Misra D, Ehrlich MH, Field L, Francis CK.Correlates of nonadherence to hypertension treatment inan inner-city minority population. 1992;82:1607-1612.

J Natl Med Assoc.

15. Fong RL. Violence as a barrier to compliance for thehypertensive urban African American. 1995;87:203-207.

J Am Pharm Assoc.

16. Krueger KP, Felkey BG, Berger BA. Improving adherenceand persistence: a review and assessment of interventionsand description of steps toward a nationaladherence initiative. 2003;43:668-678.

Mayo Clin Proc.

17. Diokno AC, Appell RA, Sand PK, et al. Prospective,randomized, double-blind study of the efficacy and tolerabilityof the extended-release formulations of oxybutyninand tolterodine for overactive bladder: results ofthe OPERA trial. 2003;78:687-695.

Curr Med Res Opin.

18. Sussman D, Garely A. Treatment of overactive bladderwith once-daily extended-release tolterodine or oxybutynin:the Antimuscarinic Clinical Effectiveness Trial(ACET). 2002;18:177-184.

J Manag Care Pharmacy.

19. Juzba M, White TJ, Chang EY. Prevalence and costanalysis of overactive bladder in a managed care organization.2001;7:365.

N Engl J Med.

20. Iglehart JK. The American health care system—Medicaid. 1999;340:403-408.

Drugs Aging.

21. Bang L, Easthope S, Perry C. Transdermal oxybutynin:for overactive bladder. 2003;20:857-864.

Urology.

22. Dmochowski RR, Sand PK, Zinner NR, et al.Comparative efficacy and safety of transdermal oxybutyninand oral tolterodine versus placebo in previouslytreated patients with urge and mixed urinary incontinence.2003;62:237-242.

Med Econ.

23. Walker LM. Patient education: do it right, and everyonewins. 1992;69:155-158,160-163.

Med Econ.

24. Mangels LS. Tips from doctors who've never beensued. 1991;68:56-63.

Psychiatr Q.

25. Gray MJ, Elhai JD, Frueh BC. Enhancing patient satisfactionand increasing treatment compliance: patienteducation as a fundamental component of PTSD treatment.2004;75:321-332.

J Wound Care.

26. Brooks J, Ersser SJ, Lloyd A, Ryan TJ. Nurse-lededucation sets out to improve patient concordance andprevent recurrence of leg ulcers. 2004;13:111-116.

Clin Nurs Res.

27. Schaffer SD, Tian L. Promoting adherence: effects oftheory based asthma education. 2004;13:69-89.

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