Subjective Measures of Efficacy: Quality of Life, Patient Satisfaction and Patient-Oriented Goals the Search for Value

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1 european urology supplements 6 (2007) available at journal homepage: Subjective Measures of Efficacy: Quality of Life, Patient Satisfaction and Patient-Oriented Goals the Search for Value Peter K. Sand * Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States Article info Keywords: Antimuscarinic therapy Overactive bladder Quality of life Therapeutic index Value Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Patients with overactive bladder syndrome are significantly affected by their symptoms of urinary urgency, frequency, nocturia, and urge urinary incontinence. The measurement of this impact on their lives is probably best appreciated by health-related quality-of-life instruments and global subjective assessments of patient satisfaction. Treatments for this syndrome should offer more than just efficacy in reducing urinary frequency and incontinence episodes, but should also offer value. A proposal for the calculation of value in treating overactive bladder syndrome and an assessment of the value of the six branded antimuscarinic agents available in the United States is proposed. The impact of overactive bladder syndrome on quality of life is presented for the Multicenter Assessment of TRansdermal therapy in overactive bladder with oxybutinin TDS (MATRIX) trial of over 2800 patients. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Evanston Continence Center, 1000 Central Street, Suite 730, Evanston, IL 60201, United States. Tel ; Fax: address: p-sand@northwestern.edu. 1. Introduction In patients with any chronic health condition, assessing treatment outcomes is difficult. In those with quality-of-life issues who have no defined progression, end-organ effect, or projected mortality, efficacy measures are even more challenging to assess. This is where the true utility of conditionspecific quality-of-life instruments is found. When it comes to the overactive bladder (OAB) syndrome [1], condition-specific quality-of-life instruments have been invaluable. Although OAB has a significant impact on general quality-of-life measures, such as the Ware SF-36 [2], this is a crude instrument to measure changes in quality of life compared with condition-specific measures, such as the Urogenital Distress Inventory (UDI) [3], Incontinence Impact Questionnaire (IIQ) [4], Overactive Bladder Questionnaire (OAB-Q) [5], andthe King s Health Questionnaire (KHQ) [6]. These instruments have proved to be useful, reproducible, and responsive to treatment effect in men and women with OAB. Such instruments and global subjective assessments of patient satisfaction may be more illustrative of success with treatment for OAB than evaluation of bladder diary recordings of leakage episodes and micturition frequency [7] /$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 european urology supplements 6 (2007) Efficacy assessment: reduction in incontinence episodes The reduction in incontinence episodes as a surrogate for efficacy for six branded medications for OAB is shown in Table 1. These data are taken from the US Food and Drug Administration approved package inserts for these medications [8 12]. Just looking at the efficacy in reducing incontinence episodes clearly does not help us appreciate the value for the individual. Package insert data for darifenacin complicates this comparison even further because there are no mean data to compare for this drug and all other medications have reported their reduction in incontinence episodes as mean or mean and median data. Median reductions in incontinence episodes tend to be about 20% higher for these medications in comparison to the mean data, but this may not be true for darifenacin. Staskin and Wein [13] have suggested that we need to subtract the reduction in incontinence episodes of the active compound from the placebo in these phase 3 trials to begin to appreciate the relative potency of the compounds. This can help us remove the difficulty in comparing mean and median data and helps the clinician evaluate the potency of the compounds on a more even playing field. The expectations of a positive outcome for medications given during a placebo-controlled trial may be different in different trials and thus may inflate the reduction in incontinence episodes in some trials. 3. Efficacy: safety ratio Diminution of the therapeutic index (efficacy/ adverse events) by the marked potential for anticholinergic side effects can totally invalidate the assumption that significant reduction in leakage episodes is a good way to measure successful treatment. In a survey of women over the age of 60 yr taking generic oxybutynin at our institution, we found that 50% of those women who said they had resolved their incontinence on treatment refused to continue therapy because of severe dry mouth [14]. This illustrates the importance of tolerability in pharmacologic treatment of OAB. If we assess the therapeutic index for the medications in Table 1 with a crude estimate using dry mouth and constipation as the primary adverse events and then divide the adjusted percent reduction in incontinence episodes (active compound placebo) by the combined adverse events rate (dry mouth + constipation), we can begin to appreciate the relative value of these agents. For example, the crude therapeutic index of transdermal oxybutynin 3.9 mg would be 2.86 (62% 42%/4% + 3%), whereas it would only be 0.79 (53% 30%/23% + 6%) for tolterodine ER 4 mg. 4. Treatment value Therapeutic index may be limited in its ability to measure patient-centered goals. We really need to assess the value of therapy to the individual. This would probably best be measured by a combination of a pretreatment assessment of the patient s own individual goals for therapy, an assessment of adverse events and efficacy in achieving these goals with treatment, and an evaluation of whether the cost and effort to participate in the treatment regime was worth it for the patient. Does the treatment have value? We could assess value by dividing the therapeutic index by the cost of the medication. The value for trospium would be (60% 44%/20% + 10%) divided by the cost of $119.99, which is equal to The value for darifenacin would be (55% 46%/ 20% + 15%) divided by the cost of $ or However, this pure economic assessment may miss the significance for the individual, depending on the individual s wealth and the impact of OAB on quality of life. Value could be assessed independently or as a comparison to other activities in the patient s life Table 1 Selected package insert data for the six branded medications for overactive bladder marketed in the United States Medication Monthly cost, $ * Incontinence reduction, placebo Incontinence reduction, active Incidence dry mouth Incidence constipation Tolterodine ER 4 mg % 30% 23% 6% Oxybutynin ER 10 mg % 36% 29% 7% Transdermal oxybutynin 3.9 mg % 42% 4% 3% Solifenacin 5 mg % 41% 11% 5% Darifenacin 7.5 mg % 46% 20% 15% Trospium 20 mg twice daily % 44% 20% 10% * Cost data from Walgreen s pharmacies, Chicago, IL (23 July 2006) [8 12].

3 440 european urology supplements 6 (2007) (eg, is the value of this treatment in your life equivalent to getting your driver s license?). A medication that reduces leakage episodes by 53%, costs $129/mo, and causes moderate dry mouth requiring the use of glycerin spray and special toothpaste may not have value for some patients. The improvement in incontinence may not be worth the cost and the hassle. Value is individual. The pensioner on a limited budget may be more, equally, or less affected by three incontinence episodes and 13 voids per day than the wealthy, 42-yr-old mother of three schoolaged children, but the value of the treatment is likely to be very different for both of them. A bladder diary cannot tell us about the value of the treatment, but global subjective responses and disease-specific quality-of-life instruments may better approximate it. In clinical practice we encounter the patient s assessment of the value of treatment in many different forms. The patient may tell us that she stopped the medicine because of dry mouth, constipation, or sedation or because it cost too much. Or she may not return for any further visits expressing what she views as our value to her. If the drug had cost less, had fewer side effects, or made her completely continent would that have been enough? We seek to find these answers because we recognize that persistence on therapy is poor with fewer than 20% of patients staying on therapy beyond 6 mo. 5. Quality of life In phase 3 and 4 trials, we seek out information on the efficacy and safety of a drug. Marketing teams delight in comparative results to highlight the advantage of their product or the weakness of another in these trials. But what is more important: to study antimuscarinics in phase 3 placebo-controlled trials and understand their efficacy and tolerability relative to placebo or to examine their impact on quality of life in unblinded, uncontrolled, phase 4 trials in real-life settings [15]? Clearly both have merit and allow us to appreciate different characteristics of these medications in different populations. Phase 4 trials offer the advantage of recruiting larger numbers of patients without strict recruitment guidelines. They can assess how these medications affect men and women who do not qualify or ordinarily might not participate in a randomized, controlled trial. Increased enrollment in phase 4 trials also allows us to look at subsets of populations to better understand how medications may affect them differently. The effects of antimuscarinic agents on healthrelated quality of life (HRQOL) of patients with OAB has recently been reported in a meta-analysis of placebo-controlled trials [16]. Of the 56 trials included, 25 reported HRQOL or patient-reported outcomes or both. No significant differences in HRQOL benefits between the different antimuscarinic agents were noted. However, there were limitations in the reported data due to the inconsistencies in the instruments used. In addition, few studies reported data on specific HRQOL domains. Despite this fact, significant differences between antimuscarinic agents and placebo were recorded for global and disease-specific domains. Several areas of HRQOL were improved by antimuscarinics, including physical activities, sleep and energy, emotions, and relationships. In a phase 3 trial of transdermal oxybutynin, 39% of patients on the active medication were completely dry on a 3-d diary [17]. Dry mouth and constipation were not significantly different than in those using a placebo. How did this affect their quality of life? During these trials, patients completed short forms of the UDI (UDI-6) and the IIQ (IIQ-7). A recent subanalysis of these data sought to analyze the importance of the percent reduction in urge urinary incontinence episodes from patients voiding diaries on quality of life as measured by the UDI-6 and the IIQ-7 instruments. Patients in the phase 3a study who had <50% reduction in incontinence episodes on the voiding diary had improvement in UDI-6 scores equal to placebo at 6 and 12 wk of treatment as seen in Table 2 [17]. As one might expect, this limited improvement in Table 2 Median change from baseline in the UDI-6 at week 6, week 12, and at LOCF in patients with varying reductions in incontinence episodes treated with transdermal oxybutynin 3.9 mg in the phase 3a US trial [17] Change in UDI-6 Week 6 50 (n = 74) 10 (n = 31) 66.7 (n = 47) 17.9 (n = 58) 66.7 (n = 13) 34.8 (n = 92) Week (n = 71) 6.8 (n = 26) 66.9 (n = 44) 16.7 (n = 53) 66.9 (n = 14) 42.4 (n = 83) LOCF 50 (n = 84) 8.1 (n = 31) 67.2 (n = 50) 19.2 (n = 65) 66.9 (n = 14) 39.4 (n = 101) UDI-6 = Urogenital Distress Inventory 6; LOCF = last observation carried forward.

4 european urology supplements 6 (2007) Table 3 Median change from baseline in the UDI-6 at week 6, week 12, and at LOCF in patients with varying reductions in incontinence episodes treated with transdermal oxybutynin 3.9 mg in the phase 3b US trial [17] Change in UDI-6 Week (n = 79) 16.9 (n = 26) 55.6 (n = 52) 29.9 (n = 53) 59.1 (n = 37) 34.8 (n = 92) Week (n = 70) 22.5 (n = 26) 68.2 (n = (n = 50) 52.5 (n = 14) 66.9 (n = 83) LOCF 55.6 (n = 83) 17.2 (n = 30) 65.5 (n = 56) 22.7 (n = 57) 35.9 (n = 14) 42.4 (n = 101) UDI-6 = Urogenital Distress Inventory-6; LOCF = last observation carried forward. leakage episodes did not have any impact on quality of life. Those whose reduction in urge urinary incontinence episodes was 50% had significant improvement in their UDI-6 scores. This improvement in quality-of-life scores did not improve further between week 6 and week 12, but did improve in the cohort of patients who had a 75% or 100% reduction in urge urinary incontinence episodes. But the improvement in UDI-6 scores was no different in the patients who had a 75% versus a 100% reduction in leakage episodes. Patients perception of improvement in quality of life reached a maximum when they had had a 75% reduction in leakage episodes. This is where the subject found optimal value for this treatment. In the phase 3b trial, a similar analysis of the data in Table 3 revealed that by week 6 of the trial achieving a 50% reduction in urge urinary incontinence episodes was associated with maximal improvement on the UDI-6 that remained unchanged even in the 37 patients who were completely continent after 6 weeks of treatment [17]. It is interesting to note that 80% of the patients in the phase 3a trial were naïve and may have been more responsive to change in the UDI-6 versus patients in the phase 3b trial who were all previously treated with antimuscarinic agents. The same analysis done with the IIQ-7 in Table 4 showed than in the phase 3a trial, by week 6, a 50% reduction in urge urinary incontinence was associated with far better IIQ-7 scores than in those who did not achieve this reduction in leakage episodes [17]. At study end, 75% and 100% reductions in leakage episodes were associated with even greater improvement in the IIQ-7. But again there was little difference between these two thresholds. Similar findings in thresholds for response of the IIQ-7 were also noted in the non-naïve patients in the phase 3b trial as seen in Table 5 [17]. Patients did not have to be perfectly dry to have large and significant improvement in their quality-of-life scores. Although these phase 3 data are informative, phase 4 trials may be better at examining quality of life, but both are limited in assessing value because Table 4 Median change from baseline in the IIQ-7 at week 6, week 12, and at LOCF in patients with varying reductions in incontinence episodes treated with transdermal oxybutynin 3.9 mg in the phase 3a US trial [17] Change in IIQ-7 Week Week LOCF IIQ-7 = Incontinence Impact Questionnaire 7; LOCF = last observation carried forward. Table 5 Median change from baseline in the IIQ-7 at week 6, week 12, and at LOCF in patients with varying reductions in incontinence episodes treated with transdermal oxybutynin 3.9 mg in the phase 3b US trial [17] Change in IIQ-7 Week (n = 80) 36.9 (n = 26) 50.6 (n = 53) 48.3 (n = 53) 64.9 (n = 38) 33.2 (n = 68) Week (n = 70) 9.9 (n = 26) 77.9 (n = (n = 50) 78.1 (n = 39) 36.5 (n = 57) LOCF 71.4 (n = 83) 9.0 (n = 30) 77.9 (n = 56) 31.1 (n = 57) 78.1 (n = 47) 37.6 (n = 66) IIQ-7 = Incontinence Impact Questionnaire 7; LOCF = last observation carried forward.

5 442 european urology supplements 6 (2007) the medication and care are provided without cost to the subject. Kelleher has shown quality-of-life scores do correlate with the global subjective response to treatment. Analysis of the KHQ showed that clinically meaningful changes were associated with a 5-point change from baseline in the individual domain scores. These changes are associated with meaningful changes in the effect size of 0.02 [18]. 6. MATRIX trial The Multicenter Assessment of TRansdermal therapy in overactive bladder with oxybutinin TDS (MATRIX) trial probably contains more data regarding the impact of OAB on quality of life and the effect of antimuscarinic therapy on this than any prior study [17]. Ambulatory men and women >18 yr old with one or more symptoms of OAB (urge urinary incontinence, urgency, or frequency) were eligible to enroll in this study. MATRIX was an open-label, randomized, community-based, prospective study in which all patients received OXY-TDS (3.9 mg/d) applied twice weekly for up to 6 mo. Patients at certain study sites received additional educational materials in conjunction with OXY-TDS; study sites were randomized 1:1 to determine which sites would provide these materials. Quality of life and depression were assessed during clinic visits at baseline, month 3, and month 6 using the KHQ and the Beck Depression Inventory II (BDI-II), respectively, in this trial of 2878 patients. Because of its size and relatively open entry criteria, this study will offer us the ability to study OAB impact and treatment effect in minorities, men, the advanced elderly, and working men and women. The study enrolled 285 African Americans, 137 Hispanics, 369 men, 699 patients 75 yr old, and 1112 working men and women. A total of 57% of the patients had previously used antimuscarinics to treat their OAB syndrome; 55% of these 1560 people had previously been treated with extended release tolterodine, and 22% had previously used the immediate-release product. Extended-release oxybutynin was used by 32% of patients and 23% had used prior immediaterelease oxybutynin. Prior therapy was said to have been stopped by patients because it was ineffective (53%) and or because of side effects (22%). A total of 17,494 concomitant medications were being taken by 2581 patients enrolled in the trial. These patients were significantly affected by their OAB symptoms. On a 6-point Lickert global subjective response scale, 78% of patients rated their OAB syndrome as a moderate to severe problem at baseline. Responses to the KHQ revealed that 57.4% of patients said their social life was affected, with 41.4% reporting that OAB interfered with their visiting with friends. Family life was affected in 37.8% and 37.3% said that OAB affected their sex lives. Even more impressive was that 52.1% of those responding to the BDI-II said that OAB syndrome had an impact on their interest in sex. These MATRIX data make it clear that men and women with OAB are significantly affected by these symptoms and would likely find value in an effective treatment at a reasonable price with few side effects. 7. Conclusions The symptoms of urinary urgency, frequency, nocturia, and urge urinary incontinence associated with the OAB syndrome have a significant impact on the patient. This is demonstrated through HRQOL instruments and global subjective assessment of patient satisfaction. When assessing a treatment for this condition we should consider not just its effectiveness in reducing urinary frequency and incontinence episodes but also the value it provides for the individual patient in terms of quality of life. Conflicts of interest Advisor to the following companies: Watson, Indevus, Esprit, Astellas, Ortho, Pfizer, Glaxo Smith Kline and Allergan. Grants received from: Watson, Astellas, Ortho, Indevus and Allergan. References [1] Abrams P, Cardozo L, Fall M, et al. The standardization of terminology of lower urinary tract function: report from the Standardization Sub-Committee of the International Continence Society. Neurourol Urodyn 2002;21: [2] Ware Jr JE, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczak A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care 1995;33(4 Suppl): AS [3] Van der Vaart CH, de Leeuw JR, Roovers JP, Heintz AP. Measuring health-related quality of life in women with urogenital dysfunction: the urogenital distress inventory and incontinence impact questionnaire revisited. Neurourol Urodyn 2003;22: [4] Coyne KS, Revicki DA, Hunt T, et al. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res 2002;11:

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