Five-year cost analysis of intra-detrusor injection of botulinum toxin type A and augmentation cystoplasty for refractory neurogenic detrusor overactivity
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- Padmanabhan, P., Scarpero, H.M., Milam, D.F. et al. World J Urol (2011) 29: 51. doi:10.1007/s00345-010-0618-3
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Treatment options for antimuscarinic refractory neurogenic detrusor overactivity (NDO) are botulinum toxin type A injections (BTX-A) and augmentation cystoplasty (AC). We estimated initial and cumulative 5-year costs of these treatments.
Materials and methods
Base case is an individual with antimuscarinic refractory NDO and decreased bladder compliance. Primary analysis is from the health care payor perspective. Model probabilities and ranges were derived from literature and chart review. Reimbursements were derived from the average of insurance carriers. Complication cost calculations were based on standard practice. Decision-analysis model was made with TreeAge Pro Healthcare 2009 Software, Inc. and rolled back for cost calculation. One-way sensitivity analysis was performed on all variables, and two-way sensitivity analyses were based on these results.
Average reimbursement for one BTX-A injection and AC was $2,946.83 and $25,041.53, respectively. BTX-A treatment was less expensive over 5 years, costing $28,065. The model was only sensitive within a reasonable clinical range for Botox durability. BTX-A was more cost-effective over 5 years if the effect lasted for >5.1 months. The model was based on an AC complication rate of 40%. If the PAC complication rate < 14%, AC was cheaper over 5 years. The model was sensitive to surgeons costs of BTX-A ($3,027) and facility costs of BTX-A ($1,004) and AC ($17,100).
This is the first cost analysis of BTX-A and AC. BTX-A is cheaper at durations >5.1 months and AC was cheaper when the cost of BTX-A increases or the AC complication rate dropped below 14%.
KeywordsNeurogenic bladderOveractive detrusorBotulinum toxin type AEconomics
Key to management of neurogenic lower urinary tract dysfunction is preservation of renal function by avoidance of elevated storage pressure. The first-line treatment for achieving low pressure urine storage and appropriate urine evacuation is combination oral anticholinergic treatment and intermittent catheterization. There are a substantial percentage of patients with depressed bladder compliance, for whom anticholinergic treatment is ineffective. These individuals often have upper tract dilation and recurrent urinary infections requiring recurrent hospitalization. Augmentation cystoplasty (AC) has historically been an effective method for establishing a high capacity, low pressure reservoir and securing upper tract drainage, with intermittent catheterization frequently necessary as an adjunct for achieving optimal urinary continence. While effective, surgery is invasive and carries high complication and reintervention rates .
Detrusor injections with botulinum toxin type A (BTX-A) were first applied in March 1998 by Stohrer for treatment of neurogenic detrusor overactivity (NDO) . It has since reached rapid acceptance due to its simple administration, reliable efficacy and lack of adverse events. A single dose of 200–300 U of intra-detrusor BTX-A injection has been successfully used to treat neurogenic detrusor overactivity for up to 9 months in a number of patients in various countries . Prior studies indicate that repeat injections do not cause damage to the detrusor muscle or decrease detrusor compliance over time [4, 5]. Yet, the price of the toxin and inherent repetitive administration of BTX-A injections may have formidable cost implications. Long-term management requires understanding of the cost differential between these two options. We conducted a cost analysis of treatment options for refractory NDO. We estimated the average initial treatment costs and cumulative 5-year costs of BTX-A injections and AC for antimuscarinic refractory patients.
The base example for this cost analysis model was an individual with a neurogenic bladder and associated detrusor overactivity for whom anti-cholinergics and intermittent catheterization were not sufficient at maintaining safe bladder pressures and continence. These individuals often have decreased bladder compliance (mechanical elasticity), elevated storage pressures (>40 cm H2O) and detrusor overactivity associated with upper tract dilation and recurrent urinary tract infections. The example case does not include patients with decreased compliance from non-neurogenic causes or neurogenic patients in whom urodynamic evaluation reveals no detrusor activity.
The primary analysis was conducted from the perspective of the health care payor. Indirect costs, such as time lost from work, pain, emotional and personal distress were not included in this model. To this end, the patient or societal perspective was not assessed using this model.
Based on our practice, treatment with BTX-A injections assumed that 300 U of intradetrusor BTX-A injections using the technique described by Stohrer et al.  was given every 6 months over a 5-year period (total of 10 injections) when successful. In general, non-neurogenic DO patients were maintained at lower levels (200 U) of toxin administration, which could have cost implications. We did not explore the costs associated with other doses of toxin administration.
All dollar amounts were reported in 2008–2009 US dollars. Given the relatively short time frame and the fact that most of the costs were incurred in the first year of the model, discounting was not employed. Average reimbursement (physician and facility) from up to eight insurance carriers were used to estimate costs associated with initial BTX-A and AC. These costs include the laboratory work, radiologic evaluation, drugs, hospital stay, surgical care and follow-up provided during the appropriate global service coverage. Average costs of complications outside of the global service coverage were calculated based on our standard practices. The daily cost of antibiotics (fluoroquinolone), $12.63, anticholinergics (ditropan), $1.00, and anti-motility agents (immodium), $1.68, was obtained through drugstore.com. Radiologic costs (CT of abdomen and pelvis without or without contrast), $4,215, were based upon 2008–2009 reimbursements to Vanderbilt Hospital from local insurance carriers. Average hospital stay costs varied depending on the acuity of the care. Calculation of costs associated with UTI following BTX-A injection used an average of treatment for a single UTI (7 days) and daily antibiotics for prevention of chronic UTI over 5 years. Similarly, calculation of costs associated with AUR following BTX-A injection is an average of a transient (7 day) episode of urinary retention and daily clean intermittent catheterization. Following AC, the cost of UTI was an average of simple (daily antibiotic) and complex UTI costs (2 days regular room hospitalization + CT + 7 days of antibiotics). The cost of bowel dysfunction was calculated as an average of simple (daily anti-motility agent) and complex (3 days regular room hospitalization + CT). Complex UTI and complex bowel dysfunction both assume that the population had chronic symptoms requiring daily medications with an acute exacerbation requiring hospitalization. Costs associated with management of AC surgical complications (SBO, stone formation and perforation) were based on average reimbursements by all local insurance companies.
A decision-analysis model was developed using TreeAge Pro Healthcare 2009 Software, Inc, Williamston, MA. Successful treatment with either AC or BTX-A and no associated complications over 5 years was assigned a payoff value of one, with all other outcomes assigned a payoff of zero. The tree was then rolled back and the average cost for each treatment arm was determined. One-way sensitivity analyses were performed on all variables in the model. Selected two-way sensitivity analyses were performed based on the results of the one-way sensitivity analysis. This provided better understanding of the variables, their interaction and applicability in a clinical setting.
Estimates of probabilities used in model and ranges tested in sensitivity analysis
Probability of all complications following augmentation
UTI + bowel dysfunction
Probability of daily anticholinergic following augmentation
Probability of re-augmentation
Probability of botox failure
Probability of daily anticholinergics after failed botox
Probability of augmentation after failed botox
Probability of repeat botox
Probability of all complications after botox
Probability of daily anticholinergics after repeat botox
Estimates of costs used in model and ranges tested in sensitivity analysis
Point estimate of cost ($)
Low value in sensitivity analysis ($)
High value in sensitivity analysis ($)
Facility cost of BTX-A injection
Surgeon cost of BTX-A injection
Cost of UTI after BTX-A injection
Cost of urinary retention after BTX-A injection
Facility cost of AC
Surgeon cost of AC
Cost of UTI after AC
Cost of bowel dysfunction after AC
Cost of SBO after AC†
Cost of stone after AC
Cost of bladder perforation after AC
BTX-A and AC are the two treatment options for antimuscarinic-resistant NDO. Only two studies have analyzed the cost-effectiveness of BTX-A injections based on clinical outcomes. A study of 63 cases of neurogenic DO found BTX-A a more cost-effective option than standard of care in a UK secondary care setting for patients not planned for surgery in the time frame of the analysis . A German group found BTX-A injections decrease the costs of incontinence aids and UTI treatment by 50% . No study to date has compared cost implications of BTX-A to gold standard management with augmentation cystoplasty. This study shows that BTX-A is a less expensive option than AC over a 5-year period when success is defined as the same clinical state.
Following the FDA approval of BTX-A in 2,000, questions arose regarding the safety, durability and changes to bladder compliance with repeated injections. In the largest retrospective, multicenter European clinical trial , 200 neurogenic bladder patients were reported to have an increase greater than 50% of mean volume to first reflex detrusor contraction and maximum cystometric capacity, with proportional decrease in maximum detrusor pressure. This effect exceeded 6 months. Similar results with longer duration of effectiveness (12 months) were reported by Del Popolo et al. when 500–1,000 U were given . The clinical acceptance of BTX-A has increased with studies confirming the efficacy and safety of the toxin [4, 9–13]. A systematic review of 18 articles  evaluating the efficacy and safety of BTX-A in patients with neurogenic detrusor overactivity found injections effective for a minimum of 12–39 weeks [3, 4, 15–18] with significant quality of life improvements up to 12–24 weeks [15, 19–21]. Those studies finding faster decline in efficacy [3, 22] (<24 weeks) [3, 17, 23] may apply to patients with lower baseline bladder compliance . Our study found AC to be the cheaper option if the durability of BTX-A is less than 5.1 months. Preoperative urodynamics may help in differentiating those patients who would benefit from AC over BTX-A from a cost perspective. BTX-A may become less effective in patients with progressively decreasing bladder compliance secondary to changes in mechanical elasticity, rather than from the dynamic nature of overactivity. This may have cost repercussions beyond the scope of this analysis. Clearly, the timing and magnitude of reinjections and rationale (symptoms, urodynamic changes) for reinjection are essential in providing an effective yet cost-conscious solution. In longer-term follow-up (10 years), Pannek et al.  found evidence of impaired detrusor contraction strength over time and 25% rate of requiring surgical intervention. Our sensitivity analysis ranging from 5 to 60% for probability of botox failure did not find this variable to be significant in the cost differential. This indicates that even with injection-related changes in detrusor function, unless reinjections are necessary more than every 5.1 months, BTX-A remains cheaper than AC. Two-way sensitivity analysis of months until injection and BTX-A facility cost, not surprisingly, finds increasing cost of BTX-A (greater than $2,900) causes AC to be favored.
Benefits of AC are well established, as are the associated high complication and reintervention rates [1, 25–27]. This model was based on a 40% overall AC complication rate from the series with the longest mean follow-up . There is a great deal of variability in these rates within the reported literature, likely due to a lack of standardization. Sensitivity analysis reveals that AC is only cheaper than botox if the complication rate (including medical and surgical) is less than 14%. Even when performed at high volume academic centers, it is unlikely that the complication rate will be this low due to the population involved and nature of surgical intervention. The model in this study is based on the standard of care within our institution and from the reported literature. While costs were calculated based on facility and physician-related dollars, study was limited by inability to define costs to the individual or to the society. Specifically, we do not include indirect costs, such as time lost from work, lost wages, effects on personal relationships, costs of incontinence products, or quality of life impact. Calculations of medical complications were based on an average of extreme conditions (i.e. isolated UTI and complex UTI in setting of prophylaxis), which artificially simplifies the range of presentations. This study is also limited by the data available in the literature. There is a lack of standardization in the reporting of complication rates following AC. There are no large, randomized, prospective trial to evaluate efficacy, safety and duration of BTX-A effects. There remains variability in dosage, number and location of BTX-A injection sites. Our model was based on a 5-year perspective. BTX-A data are not as mature as AC data and the long-term duration of effects are still being accumulated. That being said, it is possible that the results of the analysis would have been quite different over a longer time horizon.
Bladder dysfunction associated with neurogenic detrusor overactivity impairs quality of life and often poses a threat to the upper urinary tracts, especially when the condition is unaddressed. Following failure of conservative measures, AC or BTX-A are used when some detrusor function remains. Due to the high complication and reoperation rate of AC, BTX-A injections are increasingly being used for management. This is the first study to date to perform a cost analysis of these two options. BTX-A proved to be cheaper at durations greater than or equal to 5.1 months and AC was cheaper when the cost of BTX-A increased or the AC complication rate was dropped below 14% in the model. Due to the variability in practices and detrusor compliance, there will be a subset of patients who may need BTX-A more often due to worsening of the detrusor function. Urodynamic parameters may help with counseling and the decision to pursue a surgical intervention to avoid excessive reinjections and greater financial burden. This information is a valuable adjunct in the clinical decision tree of NDO.
This research was funded by the Vanderbilt Department of Urologic Surgery and the Institute for Medicine and Public Health. Dr. Roger Dmochowski is a consultant for Allergan. None of the other authors have any relevant disclosures.