Brian P. Murray, MD

: To compare the estimated direct costs of onabotulinumtoxinA with other overactive bladder syndrome (OAB) interventions for patients inadequately managed by an anticholinergic.

Study Design: A cost analysis compared the direct annual costs of 12 common pharmaceutical treatments, including branded and generic anticholinergics, and mirabegron; 1 injection procedure (intravesical injection of onabotulinumtoxinA); and 2 devices (sacral nerve stimulation [SNS] device implantation and percutaneous tibial nerve stimulation [PTNS]).

: Direct medical treatment costs were assessed from a United States payer perspective and included costs of drugs and/or procedures, administration (if applicable), and routine follow-up care. Drug acquisition costs were based on average wholesale price minus 15% and maximum allowable cost.

: During year 1, costs of pharmaceutical treatment ranged from $500 (oxybutynin) to $3472 (Detrol LA [long acting]); the cost for an injection procedure was $1892 (onabotulinumtoxinA); and costs for devices were $3395 (PTNS) and $19,443 (SNS). At years 5 and 10, respectively, costs were $2500 to $17,360 (oxybutynin) and $5000 to $34,720 (Detrol

LA) for pharmaceutical treatments; $9458 to $18,916 for onabotulinumtoxinA; $11,849 to $21,316 for PTNS; and $21,316 to $33,801 for SNS.

: This analysis suggests that short- and long-term costs of OAB treatment vary considerably. Pharmaceutical therapies were not necessarily less costly than injection procedures or devices. Among the injection procedure and device treatments, onabotulinumtoxinA was the least costly option at all time points. Although cost is an important component when comparing these treatments, aspects such as efficacy and safety must be considered when deciding on an appropriate treatment for OAB.

The International Urogynecological Association and the International Continence Society define overactive bladder syndrome (OAB) as a constellation of urinary symptoms, characterized by urinary urgency, and usually accompanied by frequency and nocturia, in the absence of urinary tract infection (UTI) or other obvious pathology.

OAB may occur with or without urinary incontinence (UI). OAB is among the most common disorders among older adults, affecting approximately 16.0% of men and 16.9% of women in the United States.

 The prevalence of OAB peaks around age 60 for both men and women; however, increasing age is associated with higher prevalence of OAB among men but not women.

Owing to its high prevalence, OAB places a substantial cost burden on society and payers, in particular. The total societal cost of OAB with UI in the United States was projected to be $76.2 billion in 2015, and is expected to increase as the population ages.

 The majority of the total cost of OAB (75%) is attributable to direct medical costs of treatment, such as pharmacotherapy or surgical procedures.

Much of the treatment cost is due to the need to try multiple agents or procedures. Although behavioral therapy, such as fluid restriction, or bladder or pelvic floor muscle training, are recommended as first-line therapy in OAB by the American Urological Association, most patients will require pharmacological treatment and are usually initiated on generic anticholinergic agents.

 However, a retrospective claims analysis of 103,250 patients diagnosed with OAB who were prescribed an anticholinergic found that 92% of patients failed their anticholinergic treatment.

 Published OAB patient surveys have described poor treatment efficacy and intolerable adverse effects (AEs) as the main reasons for anticholinergic discontinuation.

 Patients who fail initially prescribed anticholinergic therapy still have a variety of treatment options. These include long-acting branded anticholinergics; topical anticholinergic formulations; beta-3 adrenergics, such as mirabegron; bladder chemodenervation with onabotulinumtoxinA injection; and implantable devices, such as sacral neuromodulation (ie, sacral nerve stimulation [SNS]) or peripheral tibial nerve stimulation [PTNS]).

 As healthcare costs rise in the United States, combined with the anticipated increase in the prevalence of OAB with the aging population, the cost of new therapies is a key driver of payers’ reimbursement and access decisions. The main objective of this study is to compare, from a payer perspective, the cost of onabotulinumtoxinA injection with the costs of other OAB treatment in patients who are inadequately managed on an anticholinergic.

An Excel-based cost model was developed to compare the annual costs of onabotulinumtoxinA 100 units (U) injection with 12 commonly used pharmaceutical treatments and 2 medical devices for OAB. Pharmaceutical treatments included Enablex (darifenacin) 7.5 mg daily; Toviaz (fesoterodine fumarate) 4 mg or 8 mg once daily; Myrbetriq (mirabegron) 50 mg once daily; oxybutynin chloride IR (immediate release) 5 mg twice daily; Ditropan XL (oxybutynin chloride extended release) 10 mg once daily; Gelnique (oxybutynin chloride) 10% gel once daily; Vesicare (solifenacin) 5 mg or 10 mg daily; tolterodine IR (immediate release) 2 mg twice daily; tolterodine LA (long acting) 4 mg once daily; Detrol LA (tolterodine long-acting) 4 mg once daily; trospium chloride IR 20 mg twice daily; and Sanctura XR (trospium chloride extended release) 60 mg once daily. Additional treatments for OAB included 2 medical devices, SNS device implantation and PTNS. These treatments were selected to reflect all of the FDA approved treatments (branded and generic) available to patients with OAB.

The analysis took the perspective of a commercial US payer and estimated the direct healthcare costs of each intervention. Direct healthcare costs included costs of the drug, procedural costs (where applicable), follow-up care, and AE costs (Table 1). Although each intervention is associated with a specific set of AEs, for the base case, only AE costs attributable to onabotulinumtoxinA were included. Drug acquisition cost for generic pharmaceutical medications were estimated using maximum allowable cost, a payer-specific negotiated rate. The maximum allowable cost rates were obtained from a survey of multiple insurers to provide an estimated national average (unpublished data). Cost for branded pharmaceutical medications was estimated to be 85% of the 2015 average wholesale price. The total cost of using pharmaceutical medications included drug costs and 2 annual physician visits for follow-up. Additionally, for mirabegron, it was assumed that 13% of patients would be prescribed metoprolol based on an analysis of MarketScan claims data, and these patients would require 1 additional physician visit to assess interactions with metoprolol (unpublished data on file). Medicare reimbursement rates were used to estimate costs associated with procedures, follow-up office visits, and office visits for management of AEs. Commercial costs were based on the estimation that private payer rates would be 122% of Medicare rates, based on a Medicare Payment Advisory Commission report in which Medicare rates averaged 82% of private payer rates in 2011.

 Costs were evaluated over a 1-, 5-, and 10-year time horizon. For onabotulinumtoxinA compared with SNS and PTNS, the 5- and 10-year time horizon was of particular interest to ensure appropriate characterization of the introductory and maintenance phase costs of SNS and PTNS.

 The cost of onabotulinumtoxinA included drug cost (100U) administered 1.72 times per year, based on the mean number of annual injections administered in a long-term extension study

; administration costs at the physician’s office ($310.58 per injection procedure, based on 2015 Current Procedural Terminology [CPT] code 52287); 1 bladder scan (CPT 51798; $18.99); 1 follow-up physician visit (CPT 99213; $73.08) after each treatment cycle; and costs associated with UTI (12% per cycle) and urinary retention (6% per cycle), based on the reported AE rates compared with placebo in a phase 3 clinical trial.

 The costs of a UTI were assumed to include the cost of 1 physician visit ($73.08) and 1 cycle of ciprofloxacin (500 mg, 10 tablets) at $3.00 per cycle.

 The cost of urinary retention included 1 physician visit and 63 days of intermittent catheterization,

 assuming the use of 4 catheters per day, at $1.85 per catheter.

 All administration is assumed to occur in a physician outpatient office setting for the base-case analysis; however, previous research has indicated that in Europe, the cost of onabotulinumtoxinA may be largely attributable to treatment setting.

 Thus, administration in an ambulatory surgical center (ASC) ($801 per injection procedure) or hospital outpatient setting ($1297 per injection procedure) was explored in a sensitivity analysis. In this analysis, it was assumed that 60% of procedures took place in a physician’s office, 25% in an ASC setting ($838.82), and 15% in a hospital outpatient setting ($1377.47). The cost of SNS included cost of the device, device eligibility testing by peripheral nerve evaluation (PNE) and/or staged implantation, cost of permanent implantation, device maintenance (assuming patients receive 2 reprogramming visits per year),

 and cost of battery replacement at Year 7 (Table 2).

For the base case, it was assumed that SNS device implantation was conducted at an ASC with a bundled payment for procedure and device. Only a proportion of patients (51%) evaluated for SNS ultimately received a permanent implant. This proportion was calculated as the sum of patients with successful PNE who move directly to surgical lead and battery placement, patients who fail PNE but respond to a staged trial and proceed to implantation, and patients who directly enter a 2-stage procedure (Figure 1).

 Device replacement was assumed to occur at a rate of 3% per year.

The cost of PTNS includes the cost of physician-office—based neurostimulation at a rate of $120.72 per visit (CPT 64566). Patients are assumed to receive weekly treatments for the first 12 weeks, with maintenance visits every 3.64 weeks thereafter, based on a median of 1.1 treatments per month reported among patients enrolled in the Sustained Therapeutic Effects of Percutaneous Tibial Nerve Stimulation study.

 All patients were assumed to have complete adherence to prescribed therapy. For the base-case analysis, patient cost-sharing was not considered.

In the analysis of onabotulinumtoxinA compared with pharmaceutical therapies, total cost of anticholinergics over 1 year ranged from $500 (oxybutynin chloride IR to $3472 (Detrol

LA), and the cost of mirabegron was $3266. At years 5 and 10, respectively, the costs of anticholinergic treatment ranged from $2500 and $5000 (oxybutynin chloride IR), to $17,360 and $34,720 (Detrol LA), and the costs of mirabegron were $16,330 and $32,660. OnabotulinumtoxinA was associated with a total annual cost of $1892—a lower annual cost than all branded medications included in the analysis, but more costly than 3 of the 4 generic anticholinergics (tolterodine tartrate IR, trospium chloride IR, and oxybutynin chloride IR) included in the analysis. In the sensitivity analysis exploring the impact of onabotulinumtoxinA administration split between the physician office (60%), ASC (25%), and hospital outpatient (15%) settings, the total annual cost for onabotulinumtoxinA treatment was $2505, which was still less expensive than all branded medications except for Sanctura XR and Ditropan XL, and more costly than the 4 generic anticholinergics (Figure 2).

In the analysis that compared onabotulinumtoxinA 100U injection procedure with device treatments, year 1 costs were $1892 (onabotulinumtoxinA), $3395 (PTNS), and $19,443 (SNS). At years 5 and 10, respectively, the costs were as follows: $9458 and $18,916 (onabotulinumtoxinA); $11,849 and $21,316 (PTNS); and $21,316 and $33,801 (SNS) (Figure 3). The first-year cost of SNS was approximately 10 times higher than that of onabotulinumtoxinA due to the high initial cost of testing and device implantation. While costs for SNS were reduced in subsequent years, the total 5- and 10-year costs for SNS remained the highest of all the treatments evaluated.

Results from this study suggest that the total annual cost of onabotulinumtoxinA treatment for OAB patients who are inadequately managed on an anticholinergic is lower than the annual costs of the most commonly used branded pharmaceutical agents, and of the costs of SNS and PTNS, both in the short and long term. As expected, costs for onabotulinumtoxinA were higher than the costs of generic anticholinergics included in the analysis.

The cost of pharmaceutical medications included drug costs and 2 annual physician visits for follow-up. Additionally, for mirabegron, it was assumed that 13% of patients would be prescribed metoprolol, and would require 1 additional physician visit to assess interactions. The marginal increased cost of $11.59 associated with the extra office visit was negligible, and accounts for less than 0.4% of the total annual cost of mirabegron therapy ($3266.19). The model did not include costs due to AEs for pharmaceutical treatments. The inclusion of AEs for onabotulinumtoxinA, but not for pharmaceutical comparators, resulted in an overestimate for cost of onabotulinumtoxinA in comparison with the costs of pharmaceutical treatments. The assumption of battery replacement at 7 years for SNS may be conservative, as newer smaller batteries, based on usage, last 2.9 to 5.4 years.

 More frequent battery replacement of every 5 years for SNS yields an even less favorable long-term cost ($43,946 for SNS over 10 years).

Furthermore, the SNS costing paradigm assumed that 49% of patients evaluated for SNS fail the testing phase and do not receive permanent battery implantation

; therefore, only 51% of patients incur the full cost of SNS therapy. The costs of SNS would increase significantly if the model assumed that 100% of patients ultimately receive permanent battery implantation.

One limitation to this analysis was the assumption of 100% adherence and persistence to treatments. The assumption of perfect adherence and persistence may overestimate the cost of treatments due to nonadherence or treatment discontinuation. In addition, no patient cost-sharing, product rebating, or discounts were included in the base case, which may overestimate the actual treatment costs to health plans. A discount factor was not applied to the 5- and 10-year time horizons. Moreover, this analysis only evaluated the direct treatment costs; therefore, potential cost savings due to healthcare resource offset associated with treatments were not considered in this analysis or included in the model. A future in-depth evaluation comparing the various approaches and assumptions across the relevant research conducted to date could provide a greater understanding of cost drivers in OAB.

Our findings that onabotulinumtoxinA may be cost-saving compared with branded OAB medications therapy are corroborated by a National Institutes of Health—funded cost-effectiveness model of onabotulinumtoxinA versus solifenacin- and trospium-branded anticholinergics.

 The economic endpoints used to populate the model were obtained from a randomized, double-blind, active-comparator study of the impact of onabotulinumtoxinA on UI (also referred to as the ABC study).

 In this cost-effectiveness model, the 6-month cost of onabotulinumtoxinA was $1270 compared with $1340 for anticholinergics, with better rates of UI resolution for onabotulinumtoxinA observed (eg, 27% of patients taking onabotulinumtoxinA achieved continence compared with 13% of patients on anticholinergics). The results of our analysis also support the findings of prior pharmacoeconomic studies evaluating the use of onabotulinumtoxinA for OAB patients. An analysis by Watanabe et al reported an average year 1 onabotulinumtoxinA cost of $2626 compared with $23,614 for SNS and $11,637 for augmentation cystoplasty (2007 US$).

 OnabotulinumtoxinA remained the least costly treatment option in the analysis of 2- and 3-year cumulative costs, and it was less costly than SNS in the all-scenario analyses. Siddiqui and colleagues evaluated the cost-effectiveness of onabotulinumtoxinA compared with SNS in OAB patients from a US societal perspective. The authors reported lower 2-year cumulative costs for onabotulinumtoxinA ($4392) compared with SNS ($15,743), and concluded that over a 2-year period, onabotulinumtoxinA was cost-effective compared with SNS for the treatment of refractory urgency UI.

 While the methods across all of these studies vary considerably, their overall conclusions are consistent with our findings.

This analysis suggests that short- and long-term costs of the current treatment options vary considerably in OAB patients who are inadequately managed on an anticholinergic. OnabotulinumtoxinA was the least costly option among the injection procedure and medical device treatments; when it was administered in the outpatient setting, it was less costly than all branded pharmaceutical treatments. Although cost is an important component when comparing these treatments, other aspects such as efficacy and safety must be considered when deciding on an appropriate treatment of OAB.

 Allergan, PLC (AY), Irvine, CA; Albany Memorial Hospital (BPM), Albany, NY; Cleveland Clinic (SPV), Cleveland, OH; and the University of Chicago (PKS), Chicago, IL.

Alon Yehoshua 854 Rim Crest Dr Westlake Village, CA 91361 E-mail: Yehoshua@usc.edu Phone: 818-621-0187

1. Haylen BT, de Ridder D, Freeman RM, et al; International Urogynecological Association; International Continence Society. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. 

2. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. 

3. Cheung WW, Khan NH, Choi KK, Bluth MH, Vincent MT. Prevalence, evaluation and management of overactive bladder in primary care. 

4. Coyne KS, Margolis MK, Kopp ZS, Kaplan SA. Racial differences in the prevalence of overactive bladder in the United States from the epidemiology of LUTS (EpiLUTS) study. 

2012;79(1):95-101. doi: 10.1016/j.urology.2011.09.010.

5. Ganz ML, Smalarz AM, Krupski TL, et al. Economic costs of overactive bladder in the United States. 

2010;75(3):526-532,532.e1-e18. doi: 10.1016/j.urology.2009.06.096.

6. Gormley EA, Lightner DJ, Faraday M, Vasavada SP; American Urological Association; Society of Urodynamics, Female Pelvic Medicine. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. 

2015;193(5):1572-1580. doi: 10.1016/j.juro.2015.01.087.

7. Chancellor MB, Migliaccio-Walle K, Bramley TJ, Chaudhari SL, Corbell C, Globe D. Long-term patterns of use and treatment failure with anticholinergic agents for overactive bladder. 

2013;35(11):1744-1751. doi: 10.1016/j.clinthera.2013.08.017.

8. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. 

2010;105(9):1276-1282. doi: 10.1111/j.1464-410X.2009.09036.x.

9. Jundt K, Schreyer K, Friese K, Peschers U. Anticholinergic therapy: do the patients take the pills prescribed? 

2011;284(3):663-666. doi: 10.1007/s00404-010-1720-x.

10. Medicare Payment Advisory Commission. Report to the Congress: Medicare payment policy. 2011. http://www.medpac.gov/docs/default-source/reports/Mar11_EntireReport.pdf?sfvrsn=0. Accessed December 4, 2017.

11. Chartier-Kastler E, Nitti V, De Ridder D, et al, Durable improvements in urinary incontinence and positive treatment response in patients with idiopathic overactive bladder syndrome following long-term onabotulinumtoxinA treatment: Final results of 3.5-year study, 

. 2015 Nov; 25 (13): 739. doi: 10.1016/j.purol.2015.08.047.

12. Botox [prescribing information]. Irvine, CA: Allergan, Inc; 2015.

13. Cipro [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2011.

14. Red Book Online®. MICROMEDEX® 2.0, Truven Health Analytics Inc. http://www.micromedexsolutions.com.ucsf.idm.oclc.org/micromedex2/librarian/CS/9446C9/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/CE12BC/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/redbook.FindRedBook?navitem=topRedBook&isToolPage=true. Accessed May 18, 2015.

15. Medicare pricing, data analysis, and coding. Noridian Healthcare Solutions, LLC, website. 

16. Ruff L, Bagshaw E, Aracil J, Velard ME, Pardhanani G, Hepp Z. Economic impact of onabotulinumtoxinA for overactive bladder with urinary incontinence in Europe. 

17. Burks FN, Diokno AC, Lajiness MJ, Ibrahim IA, Peters KM. Sacral neuromodulation reprogramming: is it an office burden? 

2008;19(8):1137-1140. doi: 10.1007/s00192-008-0601-3.

18. Arlandis S, Castro D, Errando C, et al. Cost-effectiveness of sacral neuromodulation compared to botulinum neurotoxin A or continued medical management in refractory overactive bladder. 

2011;14(2):219-228. doi: 10.1016/j.jval.2010.08.006.

19. InterStim and InterStim II neurostimulator features and specifications. Medtronic website. professional.medtronic.com/pt/uro/snm/prod/interstim/index.htm#.VvQSwuIrKUk. Accessed May 18, 2015.

20. Cameron AP, Anger JT, Madison R, Saigal CS, Clemens JQ; Urologic Diseases in America Project. National trends in the usage and success of sacral nerve test stimulation. 

2011;185(3):970-975. doi: 10.1016/j.juro.2010.10.060.

21. Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment of overactive bladder: 3-year results of the STEP study. 

2013;189(6):2194-2201. doi: 10.1016/j.juro.2012.11.175.

22. Zyczynski H. Comparison of cost-effectiveness of onabotulinumtoxin A and anticholinergic medications for the treatment of urgency urinary incontinence [paper presentation abstract 02]. 

2013;19(Suppl 2):S45. doi: 10.1097/SPV.0b013e3182a5ddf0

23. Visco AG, Brubaker L, Richter HE, et al; Pelvic Floor Disorders Network. Anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence. 

2012;367(19):1803-1813. doi: 10.1056/NEJMoa1208872.

24. Watanabe JH, Campbell JD, Ravelo A, Chancellor MB, Kowalski J, Sullivan SD. Cost analysis of interventions for antimuscarinic refractory patients with overactive bladder. 

2010;76(4):835-840. doi: 10.1016/j.urology.2010.01.080.

25. Siddiqui NY, Amundsen CL, Visco AG, Myers ER, Wu JM. Cost-effectiveness of sacral neuromodulation versus intravesical botulinum A toxin for treatment of refractory urge incontinence. 

2009;182(6):2799-2804. doi: 10.1016/j.juro.2009.08.031.

Articles

This cost analysis demonstrated that onabotulinumtoxinA is one of the least-costly treatment options for inadequately managed overactive bladder syndrome.