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Economic Issues in the Treatment of BPH
european urology supplements 5 (2006) 1018–1024
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Economic Issues in the Treatment of BPH Pierre Teillac a,*, Roberto M. Scarpa b a b
L’Hoˆpital Saint-Louis, Paris, France Department of Urology, San Luigi Hospital, University of Turino, Turin, Italy
Article info
Abstract
Keywords: a1-Blockers BPH Cost economics 5a-Reductase inhibitors TURP
The long-term cost of effective management for benign prostatic hyperplasia (BPH) remains an important issue in pharmacoeconomics because about 25% of men aged 50 yr and older experience voiding problems due to BPH. With the ageing population and the increase in the percentage of patients with BPH for whom any type of treatment can be considered, a substantial increase in total costs to society can be expected. The up-front costs of interventional approaches to BPH are being replaced by a pattern of long-term medical and preventive therapy. The age-adjusted rate of transurethral resection of the prostate (TURP) reached a high point in 1987 and TURP rates, but not costs, have been in decline ever since. Mean 1-yr treatment costs (medical therapy and TURP) have been estimated in a pan-European study to be 858 Euros per patient, 75% of which were medication costs. Using a 2-yr time frame for treatment, Medicare costs for finasteride, terazosin, and TURP have been estimated as $3874, $2161, and $1820, respectively. The available models of the total long-term cost for all therapies for BPH remain compromised by a lack of inclusion of indirect costs, the lack of true long-term data and, critically, the lack of human cost information (patient preference). Only medical therapy provides a preventive as well as symptomatic potential and, if all of the issues were fully incorporated, it is likely that medical therapy would be increasingly recognised as economically preferable. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, L’Hoˆpital Saint-Louis, 1, Avenue ClaudeVellefaux, 75475 Paris Cedex 10, France. Tel. +33 1 42 49 96 14; Fax: +33 1 42 49 96 16. E-mail address: [email protected] (P. Teillac).
1.
Introduction
In the early 1990s the cost of managing benign prostatic hyperplasia (BPH) was dominated by the cost of performing transurethral resection of the prostate (TURP). By 1996, in the United States and Northern Europe, the annual rates of TURP were decreasing significantly but TURP remained the
economic benchmark of the disease (Table 1). TURP remains the standard by which other procedural interventions for BPH should be judged economically and in terms of risks and benefits. For example, the cost issues of introducing holmium laser resection are easily compared with those for TURP with an expectation of being able to act on the information [1]. TURP, however, presents a complex
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.08.011
european urology supplements 5 (2006) 1018–1024
1019
Table 1 – Use of transurethral resection of the prostate at the advent of effective medical therapy—indirect comparisons made among different regions over time US (Medicare)
1990 1995 1996
221,000 TURP 121,000 TURP ($928 million) [20] TURP represented 96% of all BPH surgery plus 38% of all major urologic procedures [21]
France
1997
66,431 surgical procedures for BPH 81% TURP (229 million Euros) [22]
Germany Italy UK
1995 1989 1990s
60,000 TURP (150 million Euros) [23] 68,448 TURP (229 million Euros) [24] 40,000 TURP (not declining) (54 million GBP) [25]
TURP = transurethral resection of the prostate; BPH = benign prostatic hyperplasia.
standard of comparison for medical therapies because of the importance of patient choice, perceptions, and the entirely different medical, financial, and industrial infrastructure required. Cost-effective management for BPH remains an important issue in pharmacoeconomics because about 25% of men aged 50 yr and older experience voiding problems due to BPH. The advent of medical therapies and less invasive procedure-based interventions has resulted in a decrease in age-adjusted TURP rates and also in an increase of the total number of men treated for BPH [2]. A large number of studies attest to the absolute superiority of TURP (and holmium resection) in terms of improvements in voiding parameters. The minimally invasive treatments may consume fewer domiciliary hospital services but generally fall short of the full clinical benefits of TURP and universally have been subjected to shorter periods of follow-up. Medical management of BPH collects data in a wholly different way and very detailed information is available on who should receive what dose with what expectation of benefit and risk and over what period. Some medical and minimally invasive treatments may eliminate the need for eventual surgical treatment, but the lifetime studies are not available at this time. The up-front costs of the interventional approaches to BPH are being inexorably replaced by a sustained medical and preventive therapy paradigm. Furthermore, there is an inherently dynamic nature of modern BPH treatment that, with the lack of long-term data, makes the true costs of treatment difficult to assess. It is clear that with the ageing population and the increase in the percentage of patients with BPH for whom any type of treatment can be considered, a substantial increase in total financial costs can be expected. Long-term prospective studies are needed to continue to supply the clinical data and at the same time more flexible scenarios and modelling are necessary to gain insight into the true overall and financial cost implications of treatments for different patient groups. The fact that there is a very active debate
in this area indicates that when financial and personal costs are considered there is no single dominant treatment method and that medical and surgical treatments remain competitive options.
2. The costs and trends of TURP and other interventions As the world population increases and gets older the number of patients who will be candidates for treatment for clinical BPH or to prevent the progression of symptoms will steadily increase. The average ages in the Medical Therapy of Prostatic Symptoms (MTOPS) study and the dutasteride trials lie in the decade from 60 to 70 yr old (62.6 yr for the MTOPS study [3] and 66.1 yr for the dutasteride trial [4]). The number of men in this decade is expected to grow by 40–48% over the next 20 yr [5]. The population and age range changes projected for the next 20 yr are shown in Fig. 1 for the population of the United Kingdom. This population is representative with respect to expected changes in demographics relevant to Western medicine. Current data on the frequency of surgery for BPH is available from the United States from the Healthcare Cost and Utilization Project (HCUP), a family of health care databases and related software tools and products developed through a federal/ state/industry partnership and sponsored by the Agency for Healthcare Research and Quality. HCUP data can be obtained online and the following statistics were obtained directly from it [6]. Although these statistics refer to the US medical environment, there is a reasonable degree of similarity of practice across Western health care systems (as can be seen in Table 1) and the availability and continuously updated nature of the data provide an unmatched relevance. Surgical procedures are uniquely identified for medical financial purposes by diagnostic-related groups (DRGs) after some work originated at Yale by Fetter and Thompson [7]. The statistics for
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european urology supplements 5 (2006) 1018–1024
Fig. 1 – Population and age range changes projected for the next 20 yr in the United Kingdom, taking this as a representative population with respect to Western medicine (source: US Census Bureau [5]).
complicated (DRG336) and uncomplicated (DRG337) TURP show that although the numbers of procedures are on the decline, the overall costs are not; trends over a recent 6-yr period are shown in Fig. 2 [6]. Data indicate a steady rate of decline in complicated TURP, particularly in the key group aged 65–84 yr. The number of TURP procedures in the uncomplicated under 65-yr-old group is not declining steadily, possibly reflecting the irreducible need to perform TURP in these patients due to anatomic factors, failure of medical therapy, or other medical factors. The growth in the cost to the country of TURP over the same period despite the decrease in numbers of discharges is shown in Fig. 3. Furthermore, this increasing bill in the face of declining performance of the procedure is captured in the dynamics of cost changes by risk category (Fig. 4). The steep rate of rise for complicated TURP exceeds that for the uncomplicated surgery.
The age-adjusted rate of TURP reached a high point in 1987 and TURP rates, but not costs, have been in decline ever since [8]. Similar trends were observed for all age groups. It has been calculated that in 1990 the rates of TURP were approximately 25/1000 for men over 75 yr, 19/1000 for men 70–74 yr, and 13/1000 for men aged 65–69 yr. During 1984– 1990, mortality and the performance of a second procedure decreased, suggesting an improvement in outcomes. Other studies have examined of the fate of patients undergoing TURP particularly to establish comparable benchmarks for competing therapies. In a study of Swedish patient data, the cost of TURP including reinterventions (TURP and bladder-neck incisions) continued to rise for at least 3 yr after the procedure [9]. In another study, the 3-yr risk of retreatment was 13.2% for TURP [10]. Although these data were largely compiled to address the issue of
european urology supplements 5 (2006) 1018–1024
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Fig. 3 – The ‘‘National Bill’’ for both complicated (DRG336) and uncomplicated (DRG337) transurethral resection of the prostate (TURP) combined over the most recent 6-yr period for which data are available in the United States (source: HCUPnet [6]).
Fig. 2 – Discharge statistics by age category for complicated (DRG336) and uncomplicated (DRG337) transurethral resection of the prostate (TURP) in the United States during the years 1997–2003 (source: HCUPnet [6]).
postpones costs. A delay in surgical intervention reduces current costs and changes the picture of opportunity costs. The 5a-reductase inhibitors (5ARIs) have been shown to reduce the risk of acute urinary retention (AUR) and surgical intervention, the most expensive events related to BPH treatment. AUR, associated with physician visits, catheterisation, hospital charges, and a possibility of surgical intervention, in the placebo group in the MTOPS study occurred 18 times with a rate of 0.6/100
comparability with alternative interventions, the retreatment rates are vital considerations in economic models looking at medical therapy cost comparisons where it is important to have current (total cost of care) not just historical (cost of surgery) data.
3. The evidence for risk reduction with medical therapy One key to an economic analysis of BPH treatment is how the benefit side of the balance is constructed. The actual costs of medication and medical visits are relatively straightforward to establish. The expansion of costs as multiple treatment alternatives are implemented also need to be considered. Medical therapy that does not reduce the lifetime chance of surgical intervention for BPH simply
Fig. 4 – The rise in the cost per discharge for patients after transurethral resection of the prostate (TURP) for both complicated and uncomplicated procedures (source: HCUPnet [6]).
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person-years. These numbers were reduced to a statically significant degree both for finasteride monotherapy (6 events; rate, 0.2/100 person-years) and for combination therapy group (4 events; rate, 0.1/100 person-years) [3]. The risk of AUR increased with increasing serum prostate-specific antigen (PSA) level in all groups, but the risk of AUR proved to be very low for men with low baseline PSA levels (<1.1 ng/ml). Surgical rates have been determined but there was scope for discretionary choice in intervention in the MTOPS study. At 4 yr, most of the surgical interventions were endoscopic (84%) and most patients underwent TURP. In the placebo group, there were 37 surgical interventions (rate, 1.3/100 person-years), whereas in the finasteride group there were 14 interventions (rate, 0.5/100 person-years), and with combination therapy, 12 interventions (rate, 0.4/100 person-years), a significant (64%) reduction. It was calculated that the number of men with BPH who needed to be treated to prevent one patient from interventional therapy was 29.0 for finasteride, 25.9 for combination therapy, and 15.9 for combination therapy in men with high baseline serum PSA levels (>4.0 ng/ml) and volumes (>40 ml). The data for dutasteride are similar [4]. AUR occurred 90 times (incidence 4.2% over the 24-mo study) in the placebo group and only 39 times (incidence 1.8%) in the dutasteride group, showing a 59% risk reduction. When the baseline prostatic volume was 30 to 40 ml, the risk reduction was 85% and for glands 40 ml dutasteride reduced the risk of AUR by 55%. Surgical intervention in the placebo group occurred 89 times (incidence 4.1%) and only 47 times (incidence 2.2%) in the dutasteride group, showing a 48% risk reduction for surgery. Among patients with baseline prostatic volumes 30–40 ml, dutasteride reduced the risk of surgical intervention by 35% and for those with prostates 40 ml, the reduction in surgical intervention was 52% [11]. The indirect costs of BPH that may be reduced with the use of medical therapies for BPH have been studied. Using claims data and absentee records from large employers, the costs associated with BPH were estimated in working-age men (a privately insured, non-elderly US-based population) [12]. The estimated cost of work loss was linked to medical claims related to treatment for BPH. The average employee with a diagnosis of BPH missed 7.3 h of work and 10% of men reported work loss related to a medical visit for BPH. The annual spending was $5729 for men with a claim for BPH compared with $4193 without a medical claim for BPH, giving an incremental cost associated with a diagnosis of BPH of $1536 per annum; this overall figure includes
medical and surgical care for BPH. The same authors emphasised the overall size of the direct and indirect costs related to BPH treatment and estimated them to be $3.9 billion in the US private sector.
4.
Risk reduction and the a-blockers
In the MTOPS study, doxazosin delayed the time to AUR but did not significantly reduce the cumulative incidence when compared with placebo nor was there a significant reduction in the cumulative incidence of invasive therapy [3]. Furthermore, the number of men with BPH who needed to be treated to prevent one patient from interventional therapy, when that treatment was doxazosin monotherapy, was 60.1 (the comparable number for combination therapy was 25.9).
5. A brief review of current models of 5ARI pharmacoeconomics In any comparison of costs, the results will be strongly influenced by the factors evaluated. The comparisons here have been limited to the broader cost considerations for methods of treatment that are approved for the effective treatment of BPH and its symptoms and no comparative evaluation has been attempted of the relative effectiveness. The following studies reveal some of the comparative cost issues but do not attempt to quantify cost effectiveness. However, it is worth noting that longterm and retreatment costs inherently account for some of the cost-effectiveness issues of the initial treatment choice. Economic studies of the therapy of BPH have been conducted to show the relative financial burden of a range of therapeutic options. Typically these have focused on direct costs and comparisons of the costs between modalities. They have not included weighting for patient preference nor have they been able to use more than 4-yr data in projecting the outcomes of therapy. Patient preference, were it to be included, would almost certainly assign a high value to avoiding AUR and surgery [13]. Only a fraction of that ‘‘cost’’ is captured because at 4 yr the risk of surgical intervention is 0.4/100 man-years for combination therapy, significantly reduced from placebo treatment but a rate with or without medical treatment that men would much rather avoid. In one study, the 2-yr time frame for costs associated with BPH was investigated using a
european urology supplements 5 (2006) 1018–1024
decision tree analysis of clinical intervention and available database estimates of outcomes [14]. The costs of finasteride, terazosin, and TURP were compared in men with symptoms of BPH of at least moderate severity. The chance of symptomatic improvement over 1 yr was highest for surgery followed by terazosin and finasteride (88%, 74%, and 67%, respectively). The corresponding estimated 24-mo costs for private insurance were $6411, $2860, and $2422, respectively, and for Medicare, $3874, $2161, and $1820, respectively. The sensitivity to the cost environment for surgical therapy and the duration of the period of cost accrual have been shown to be a critical factor in the findings of all comparative estimates of the costs of managing BPH. A recent study has looked at the average cost of treating BPH; therapies included not only surgery but also a variety of medical therapies [15]. The Trans European Research into the Use of Management Policies for BPH in Primary Healthcare (TRIUMPH) project was organized in 1999 and examined treatment costs for BPH in 5057 men across six European countries—France, Germany, Italy, Poland, Spain, and the United Kingdom—during a 1-yr follow-up period. Mean age at inclusion was 66 yr and mean International Prostate Symptom Score was 11.5. Mean 1-yr treatment costs were moderate and estimated to be 858 Euros per patient, 75% of which were medication costs. The study also revealed that daily practice and associated costs varied considerably from country to country. Long-term data on actual outcomes are critical in the pharmacoeconomic analysis of BPH. The Proscar Long-Term Efficacy and Safety Study (PLESS) demonstrated a reduction by finasteride monotherapy in the risk of developing AUR by 57% and the need for BPHrelated surgery by 55% [16]. This study has been used to update the understanding of the cost issues for the medical therapy of BPH by providing long-term failure rates and an adjustment for prostatic size [17]. The authors applied a medical management decision tree and used real or well-supported probabilities for outcomes in a detailed direct cost analysis. The resource utilisation was calculated on the basis of current practice determined by a custom survey of practising urologists. The remaining cost elements (medications, facility fees by DRGs, other hospital utilisation, and physician fees) were all based on current estimates but excluded indirect costs. The study found that 20% of finasteride monotherapy costs were recouped by avoiding surgery over the first 4 yr. When finasteride was compared with the then current medication costs for a-blockers, the costs were comparable in a low-cost scenario and sensitive to the total costs associated
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with surgery as well as numbers of visits, etc. The effect of prostate size was also investigated and the advantage for finasteride increased with prostate size and a high cost environment, such that up to 65% of the finasteride costs in the first year could be saved by avoiding complications and intervention. An early evaluation of the potential costs of funding finasteride was conducted in Canada with the finding that the cost, compared with conservative or surgical therapy, would depend on the initial symptom severity and the anticipated duration of treatment with finasteride [18]. The value of an incremental quality-adjusted life-year (QALY), in 1994 Canadian dollars, ranged from $3000 to $97,000 depending on symptom severity and duration of treatment. A later study in the same medical cost environment harnessed the new data from the MTOPS study and PLESS. A decision analytic model was used to estimate the clinical consequences, costs, and cost utility of doxazosin, finasteride, and combination therapy. The cost-to-utility ratio was sensitive to PSA (and thus prostate volume) but, owing to the unique single cost environment of the study, there was no sensitivity assessed for variable surgical costs. The study suggested that combination therapy was cost effective compared with doxazosin and that the value of a QALY in this scenario should be <$40,000 in 2004 Canadian dollars [19].
6.
Conclusions
The cost estimates for medical therapy of BPH remain compromised by a lack of inclusion of indirect costs, the lack of true long-term data and, critically, the lack of patient preference weighting. All of these factors, if included, would tend to increase support for the case for medical therapy by more adequately reflecting the true costs of failing to manage BPH in a preventive as well as symptomatic way. However, all the analyses are agree that the argument for combination therapy is well supported in men with larger, higher PSA, more symptomatic prostates. There is also agreement that the pharmacoeconomic picture is sensitive to the exact cost of surgical intervention and that no form of management of BPH is without financial cost. References [1] Fraundorfer MR, Gilling PJ, Kennett KM, Dunton NG. Holmium laser resection of the prostate is more cost effective than transurethral resection of the prostate: results of a randomized prospective study. Urology 2001;57:454–8.
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[2] Stoevelaar HJ, McDonnell J. Changing therapeutic regimens in benign prostatic hyperplasia. Clinical and economic considerations. Pharmacoeconomics 2001;19: 131–53. [3] McConnell JD, Roehrborn CG, Bautista O, et al. The longterm effects of doxazosin, finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [4] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G, ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434–41. [5] US Census Bureau, International Data Base, April 2005 version, accessed on Dec. 15, 2005 at http://www.census. gov/ipc/www/idbnew.html. [6] HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD., accessed on Dec 12, 2005 at http://www.ahrq.gov/ HCUPnet/. [7] Barnard C, Esmond T. DRG-based reimbursement: the use of concurrent and retrospective clinical data. Med Care 1981;19:1071–82. [8] Lu-Yao GL, Barry MJ, Chang CH, Wasson JH, Wennberg JE. Transurethral resection of the prostate among Medicare beneficiaries in the United States: time trends and outcomes. Prostate Patient Outcomes Research Team (PORT). Urology 1994;44:692–8. [9] Kobelt G, Spangberg A, Mattiasson A. The cost of feedback microwave thermotherapy compared with transurethral resection of the prostate for treating benign prostatic hyperplasia. BJU Int 2004;93:543–8. [10] de la Rosette JJ, Floratos DL, Severens JL, Kiemeney LA, Debruyne FM, Pilar Laguna M. Transurethral resection vs microwave thermotherapy of the prostate: a cost-consequences analysis. BJU Int 2003;92:713–8. [11] Boyle P, Roehrborn CG, Marks L, Vela-Navarette R, Nickel JC. The novel dual 5a-reductase inhibitor dutasteride is effective for the treatment and prevention of complications in men with a PV 3040 cc and 40 cc. Eur Urol Suppl 2003;2(1):160 (abstract 632). [12] Saigal CS, Joyce G. Economic costs of benign prostatic hyperplasia in the private sector. J Urol 2005;173:1309–13. [13] Kawakami J, Nickel JC. Acute urinary retention and surgery for benign prostatic hyperplasia: the patient’s perspective. Can J Urol 1999;6:819–22.
[14] Lowe FC, McDaniel RL, Chmiel JJ, Hillman AL. Economic modelling to assess the costs of treatment with finasteride, terazosin and transurethral resection of the prostate for men with moderate to severe symptoms of benign prostatic hyperplasia. Urology 1995;46:477–83. [15] Van Exel NJA, Koopmanschap MA, McDonnell J, Chapple CR, Berges R, Rutten FFH. Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six European countries: report of the TRIUMPH study. Eur Urol 2006;49:92–102. [16] McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998;338:557–63. [17] Albertsen PC, Pellissier JM, Lowe FC, Girman CJ, Roehrborn CG, for the PLESS Study Group. Economic analysis of finasteride: a model-based approach using data from the Proscar Long-Term Efficacy and Safety Study. Clin Ther 1999;21:1006–24. [18] Baladi JF, Menon D, Otten N. An economic evaluation of finasteride for treatment of benign prostatic hyperplasia. Pharmacoeconomics 1996;9:443–54. [19] McDonald H, Hux M, Brisson M, Bernard L, Nickel JC. An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia. Can J Urol 2004;11:2327–40. [20] Holtgrewe HL, Bay-Neilsen H, Carlsson P, et al. The economics of the management of lower urinary tract symptoms and benign prostatic hyperplasia. In: Dennis L, Griffiths K, Khoury S, et al., editors. Proceedings of the Fourth International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth, United Kingdom: Plymbridge Distributors; 1998. p. 61–81. [21] Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1988;51:1–7. [22] Lukacs B. Management of symptomatic BPH in France: who is treated and how? Eur Urol 1999;36:14–20. [23] Berges RR, Pientka L. Management of the BPH syndrome in Germany: who is treated and how? Eur Urol 1999;36:21–7. [24] Tubaro A, Montanari E. Management of symptomatic BPH in Italy: who is treated and how? Eur Urol 1999; 36:28–32. [25] McNicholas TA. Management of symptomatic BPH in the UK: who is treated and how? Eur Urol 1999;36:33–9.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Economic Issues in the Treatment of BPH Pierre Teillac a,*, Roberto M. Scarpa b a b
L’Hoˆpital Saint-Louis, Paris, France Department of Urology, San Luigi Hospital, University of Turino, Turin, Italy
Article info
Abstract
Keywords: a1-Blockers BPH Cost economics 5a-Reductase inhibitors TURP
The long-term cost of effective management for benign prostatic hyperplasia (BPH) remains an important issue in pharmacoeconomics because about 25% of men aged 50 yr and older experience voiding problems due to BPH. With the ageing population and the increase in the percentage of patients with BPH for whom any type of treatment can be considered, a substantial increase in total costs to society can be expected. The up-front costs of interventional approaches to BPH are being replaced by a pattern of long-term medical and preventive therapy. The age-adjusted rate of transurethral resection of the prostate (TURP) reached a high point in 1987 and TURP rates, but not costs, have been in decline ever since. Mean 1-yr treatment costs (medical therapy and TURP) have been estimated in a pan-European study to be 858 Euros per patient, 75% of which were medication costs. Using a 2-yr time frame for treatment, Medicare costs for finasteride, terazosin, and TURP have been estimated as $3874, $2161, and $1820, respectively. The available models of the total long-term cost for all therapies for BPH remain compromised by a lack of inclusion of indirect costs, the lack of true long-term data and, critically, the lack of human cost information (patient preference). Only medical therapy provides a preventive as well as symptomatic potential and, if all of the issues were fully incorporated, it is likely that medical therapy would be increasingly recognised as economically preferable. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, L’Hoˆpital Saint-Louis, 1, Avenue ClaudeVellefaux, 75475 Paris Cedex 10, France. Tel. +33 1 42 49 96 14; Fax: +33 1 42 49 96 16. E-mail address: [email protected] (P. Teillac).
1.
Introduction
In the early 1990s the cost of managing benign prostatic hyperplasia (BPH) was dominated by the cost of performing transurethral resection of the prostate (TURP). By 1996, in the United States and Northern Europe, the annual rates of TURP were decreasing significantly but TURP remained the
economic benchmark of the disease (Table 1). TURP remains the standard by which other procedural interventions for BPH should be judged economically and in terms of risks and benefits. For example, the cost issues of introducing holmium laser resection are easily compared with those for TURP with an expectation of being able to act on the information [1]. TURP, however, presents a complex
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.08.011
european urology supplements 5 (2006) 1018–1024
1019
Table 1 – Use of transurethral resection of the prostate at the advent of effective medical therapy—indirect comparisons made among different regions over time US (Medicare)
1990 1995 1996
221,000 TURP 121,000 TURP ($928 million) [20] TURP represented 96% of all BPH surgery plus 38% of all major urologic procedures [21]
France
1997
66,431 surgical procedures for BPH 81% TURP (229 million Euros) [22]
Germany Italy UK
1995 1989 1990s
60,000 TURP (150 million Euros) [23] 68,448 TURP (229 million Euros) [24] 40,000 TURP (not declining) (54 million GBP) [25]
TURP = transurethral resection of the prostate; BPH = benign prostatic hyperplasia.
standard of comparison for medical therapies because of the importance of patient choice, perceptions, and the entirely different medical, financial, and industrial infrastructure required. Cost-effective management for BPH remains an important issue in pharmacoeconomics because about 25% of men aged 50 yr and older experience voiding problems due to BPH. The advent of medical therapies and less invasive procedure-based interventions has resulted in a decrease in age-adjusted TURP rates and also in an increase of the total number of men treated for BPH [2]. A large number of studies attest to the absolute superiority of TURP (and holmium resection) in terms of improvements in voiding parameters. The minimally invasive treatments may consume fewer domiciliary hospital services but generally fall short of the full clinical benefits of TURP and universally have been subjected to shorter periods of follow-up. Medical management of BPH collects data in a wholly different way and very detailed information is available on who should receive what dose with what expectation of benefit and risk and over what period. Some medical and minimally invasive treatments may eliminate the need for eventual surgical treatment, but the lifetime studies are not available at this time. The up-front costs of the interventional approaches to BPH are being inexorably replaced by a sustained medical and preventive therapy paradigm. Furthermore, there is an inherently dynamic nature of modern BPH treatment that, with the lack of long-term data, makes the true costs of treatment difficult to assess. It is clear that with the ageing population and the increase in the percentage of patients with BPH for whom any type of treatment can be considered, a substantial increase in total financial costs can be expected. Long-term prospective studies are needed to continue to supply the clinical data and at the same time more flexible scenarios and modelling are necessary to gain insight into the true overall and financial cost implications of treatments for different patient groups. The fact that there is a very active debate
in this area indicates that when financial and personal costs are considered there is no single dominant treatment method and that medical and surgical treatments remain competitive options.
2. The costs and trends of TURP and other interventions As the world population increases and gets older the number of patients who will be candidates for treatment for clinical BPH or to prevent the progression of symptoms will steadily increase. The average ages in the Medical Therapy of Prostatic Symptoms (MTOPS) study and the dutasteride trials lie in the decade from 60 to 70 yr old (62.6 yr for the MTOPS study [3] and 66.1 yr for the dutasteride trial [4]). The number of men in this decade is expected to grow by 40–48% over the next 20 yr [5]. The population and age range changes projected for the next 20 yr are shown in Fig. 1 for the population of the United Kingdom. This population is representative with respect to expected changes in demographics relevant to Western medicine. Current data on the frequency of surgery for BPH is available from the United States from the Healthcare Cost and Utilization Project (HCUP), a family of health care databases and related software tools and products developed through a federal/ state/industry partnership and sponsored by the Agency for Healthcare Research and Quality. HCUP data can be obtained online and the following statistics were obtained directly from it [6]. Although these statistics refer to the US medical environment, there is a reasonable degree of similarity of practice across Western health care systems (as can be seen in Table 1) and the availability and continuously updated nature of the data provide an unmatched relevance. Surgical procedures are uniquely identified for medical financial purposes by diagnostic-related groups (DRGs) after some work originated at Yale by Fetter and Thompson [7]. The statistics for
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Fig. 1 – Population and age range changes projected for the next 20 yr in the United Kingdom, taking this as a representative population with respect to Western medicine (source: US Census Bureau [5]).
complicated (DRG336) and uncomplicated (DRG337) TURP show that although the numbers of procedures are on the decline, the overall costs are not; trends over a recent 6-yr period are shown in Fig. 2 [6]. Data indicate a steady rate of decline in complicated TURP, particularly in the key group aged 65–84 yr. The number of TURP procedures in the uncomplicated under 65-yr-old group is not declining steadily, possibly reflecting the irreducible need to perform TURP in these patients due to anatomic factors, failure of medical therapy, or other medical factors. The growth in the cost to the country of TURP over the same period despite the decrease in numbers of discharges is shown in Fig. 3. Furthermore, this increasing bill in the face of declining performance of the procedure is captured in the dynamics of cost changes by risk category (Fig. 4). The steep rate of rise for complicated TURP exceeds that for the uncomplicated surgery.
The age-adjusted rate of TURP reached a high point in 1987 and TURP rates, but not costs, have been in decline ever since [8]. Similar trends were observed for all age groups. It has been calculated that in 1990 the rates of TURP were approximately 25/1000 for men over 75 yr, 19/1000 for men 70–74 yr, and 13/1000 for men aged 65–69 yr. During 1984– 1990, mortality and the performance of a second procedure decreased, suggesting an improvement in outcomes. Other studies have examined of the fate of patients undergoing TURP particularly to establish comparable benchmarks for competing therapies. In a study of Swedish patient data, the cost of TURP including reinterventions (TURP and bladder-neck incisions) continued to rise for at least 3 yr after the procedure [9]. In another study, the 3-yr risk of retreatment was 13.2% for TURP [10]. Although these data were largely compiled to address the issue of
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Fig. 3 – The ‘‘National Bill’’ for both complicated (DRG336) and uncomplicated (DRG337) transurethral resection of the prostate (TURP) combined over the most recent 6-yr period for which data are available in the United States (source: HCUPnet [6]).
Fig. 2 – Discharge statistics by age category for complicated (DRG336) and uncomplicated (DRG337) transurethral resection of the prostate (TURP) in the United States during the years 1997–2003 (source: HCUPnet [6]).
postpones costs. A delay in surgical intervention reduces current costs and changes the picture of opportunity costs. The 5a-reductase inhibitors (5ARIs) have been shown to reduce the risk of acute urinary retention (AUR) and surgical intervention, the most expensive events related to BPH treatment. AUR, associated with physician visits, catheterisation, hospital charges, and a possibility of surgical intervention, in the placebo group in the MTOPS study occurred 18 times with a rate of 0.6/100
comparability with alternative interventions, the retreatment rates are vital considerations in economic models looking at medical therapy cost comparisons where it is important to have current (total cost of care) not just historical (cost of surgery) data.
3. The evidence for risk reduction with medical therapy One key to an economic analysis of BPH treatment is how the benefit side of the balance is constructed. The actual costs of medication and medical visits are relatively straightforward to establish. The expansion of costs as multiple treatment alternatives are implemented also need to be considered. Medical therapy that does not reduce the lifetime chance of surgical intervention for BPH simply
Fig. 4 – The rise in the cost per discharge for patients after transurethral resection of the prostate (TURP) for both complicated and uncomplicated procedures (source: HCUPnet [6]).
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person-years. These numbers were reduced to a statically significant degree both for finasteride monotherapy (6 events; rate, 0.2/100 person-years) and for combination therapy group (4 events; rate, 0.1/100 person-years) [3]. The risk of AUR increased with increasing serum prostate-specific antigen (PSA) level in all groups, but the risk of AUR proved to be very low for men with low baseline PSA levels (<1.1 ng/ml). Surgical rates have been determined but there was scope for discretionary choice in intervention in the MTOPS study. At 4 yr, most of the surgical interventions were endoscopic (84%) and most patients underwent TURP. In the placebo group, there were 37 surgical interventions (rate, 1.3/100 person-years), whereas in the finasteride group there were 14 interventions (rate, 0.5/100 person-years), and with combination therapy, 12 interventions (rate, 0.4/100 person-years), a significant (64%) reduction. It was calculated that the number of men with BPH who needed to be treated to prevent one patient from interventional therapy was 29.0 for finasteride, 25.9 for combination therapy, and 15.9 for combination therapy in men with high baseline serum PSA levels (>4.0 ng/ml) and volumes (>40 ml). The data for dutasteride are similar [4]. AUR occurred 90 times (incidence 4.2% over the 24-mo study) in the placebo group and only 39 times (incidence 1.8%) in the dutasteride group, showing a 59% risk reduction. When the baseline prostatic volume was 30 to 40 ml, the risk reduction was 85% and for glands 40 ml dutasteride reduced the risk of AUR by 55%. Surgical intervention in the placebo group occurred 89 times (incidence 4.1%) and only 47 times (incidence 2.2%) in the dutasteride group, showing a 48% risk reduction for surgery. Among patients with baseline prostatic volumes 30–40 ml, dutasteride reduced the risk of surgical intervention by 35% and for those with prostates 40 ml, the reduction in surgical intervention was 52% [11]. The indirect costs of BPH that may be reduced with the use of medical therapies for BPH have been studied. Using claims data and absentee records from large employers, the costs associated with BPH were estimated in working-age men (a privately insured, non-elderly US-based population) [12]. The estimated cost of work loss was linked to medical claims related to treatment for BPH. The average employee with a diagnosis of BPH missed 7.3 h of work and 10% of men reported work loss related to a medical visit for BPH. The annual spending was $5729 for men with a claim for BPH compared with $4193 without a medical claim for BPH, giving an incremental cost associated with a diagnosis of BPH of $1536 per annum; this overall figure includes
medical and surgical care for BPH. The same authors emphasised the overall size of the direct and indirect costs related to BPH treatment and estimated them to be $3.9 billion in the US private sector.
4.
Risk reduction and the a-blockers
In the MTOPS study, doxazosin delayed the time to AUR but did not significantly reduce the cumulative incidence when compared with placebo nor was there a significant reduction in the cumulative incidence of invasive therapy [3]. Furthermore, the number of men with BPH who needed to be treated to prevent one patient from interventional therapy, when that treatment was doxazosin monotherapy, was 60.1 (the comparable number for combination therapy was 25.9).
5. A brief review of current models of 5ARI pharmacoeconomics In any comparison of costs, the results will be strongly influenced by the factors evaluated. The comparisons here have been limited to the broader cost considerations for methods of treatment that are approved for the effective treatment of BPH and its symptoms and no comparative evaluation has been attempted of the relative effectiveness. The following studies reveal some of the comparative cost issues but do not attempt to quantify cost effectiveness. However, it is worth noting that longterm and retreatment costs inherently account for some of the cost-effectiveness issues of the initial treatment choice. Economic studies of the therapy of BPH have been conducted to show the relative financial burden of a range of therapeutic options. Typically these have focused on direct costs and comparisons of the costs between modalities. They have not included weighting for patient preference nor have they been able to use more than 4-yr data in projecting the outcomes of therapy. Patient preference, were it to be included, would almost certainly assign a high value to avoiding AUR and surgery [13]. Only a fraction of that ‘‘cost’’ is captured because at 4 yr the risk of surgical intervention is 0.4/100 man-years for combination therapy, significantly reduced from placebo treatment but a rate with or without medical treatment that men would much rather avoid. In one study, the 2-yr time frame for costs associated with BPH was investigated using a
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decision tree analysis of clinical intervention and available database estimates of outcomes [14]. The costs of finasteride, terazosin, and TURP were compared in men with symptoms of BPH of at least moderate severity. The chance of symptomatic improvement over 1 yr was highest for surgery followed by terazosin and finasteride (88%, 74%, and 67%, respectively). The corresponding estimated 24-mo costs for private insurance were $6411, $2860, and $2422, respectively, and for Medicare, $3874, $2161, and $1820, respectively. The sensitivity to the cost environment for surgical therapy and the duration of the period of cost accrual have been shown to be a critical factor in the findings of all comparative estimates of the costs of managing BPH. A recent study has looked at the average cost of treating BPH; therapies included not only surgery but also a variety of medical therapies [15]. The Trans European Research into the Use of Management Policies for BPH in Primary Healthcare (TRIUMPH) project was organized in 1999 and examined treatment costs for BPH in 5057 men across six European countries—France, Germany, Italy, Poland, Spain, and the United Kingdom—during a 1-yr follow-up period. Mean age at inclusion was 66 yr and mean International Prostate Symptom Score was 11.5. Mean 1-yr treatment costs were moderate and estimated to be 858 Euros per patient, 75% of which were medication costs. The study also revealed that daily practice and associated costs varied considerably from country to country. Long-term data on actual outcomes are critical in the pharmacoeconomic analysis of BPH. The Proscar Long-Term Efficacy and Safety Study (PLESS) demonstrated a reduction by finasteride monotherapy in the risk of developing AUR by 57% and the need for BPHrelated surgery by 55% [16]. This study has been used to update the understanding of the cost issues for the medical therapy of BPH by providing long-term failure rates and an adjustment for prostatic size [17]. The authors applied a medical management decision tree and used real or well-supported probabilities for outcomes in a detailed direct cost analysis. The resource utilisation was calculated on the basis of current practice determined by a custom survey of practising urologists. The remaining cost elements (medications, facility fees by DRGs, other hospital utilisation, and physician fees) were all based on current estimates but excluded indirect costs. The study found that 20% of finasteride monotherapy costs were recouped by avoiding surgery over the first 4 yr. When finasteride was compared with the then current medication costs for a-blockers, the costs were comparable in a low-cost scenario and sensitive to the total costs associated
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with surgery as well as numbers of visits, etc. The effect of prostate size was also investigated and the advantage for finasteride increased with prostate size and a high cost environment, such that up to 65% of the finasteride costs in the first year could be saved by avoiding complications and intervention. An early evaluation of the potential costs of funding finasteride was conducted in Canada with the finding that the cost, compared with conservative or surgical therapy, would depend on the initial symptom severity and the anticipated duration of treatment with finasteride [18]. The value of an incremental quality-adjusted life-year (QALY), in 1994 Canadian dollars, ranged from $3000 to $97,000 depending on symptom severity and duration of treatment. A later study in the same medical cost environment harnessed the new data from the MTOPS study and PLESS. A decision analytic model was used to estimate the clinical consequences, costs, and cost utility of doxazosin, finasteride, and combination therapy. The cost-to-utility ratio was sensitive to PSA (and thus prostate volume) but, owing to the unique single cost environment of the study, there was no sensitivity assessed for variable surgical costs. The study suggested that combination therapy was cost effective compared with doxazosin and that the value of a QALY in this scenario should be <$40,000 in 2004 Canadian dollars [19].
6.
Conclusions
The cost estimates for medical therapy of BPH remain compromised by a lack of inclusion of indirect costs, the lack of true long-term data and, critically, the lack of patient preference weighting. All of these factors, if included, would tend to increase support for the case for medical therapy by more adequately reflecting the true costs of failing to manage BPH in a preventive as well as symptomatic way. However, all the analyses are agree that the argument for combination therapy is well supported in men with larger, higher PSA, more symptomatic prostates. There is also agreement that the pharmacoeconomic picture is sensitive to the exact cost of surgical intervention and that no form of management of BPH is without financial cost. References [1] Fraundorfer MR, Gilling PJ, Kennett KM, Dunton NG. Holmium laser resection of the prostate is more cost effective than transurethral resection of the prostate: results of a randomized prospective study. Urology 2001;57:454–8.
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[2] Stoevelaar HJ, McDonnell J. Changing therapeutic regimens in benign prostatic hyperplasia. Clinical and economic considerations. Pharmacoeconomics 2001;19: 131–53. [3] McConnell JD, Roehrborn CG, Bautista O, et al. The longterm effects of doxazosin, finasteride and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387–98. [4] Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G, ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434–41. [5] US Census Bureau, International Data Base, April 2005 version, accessed on Dec. 15, 2005 at http://www.census. gov/ipc/www/idbnew.html. [6] HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD., accessed on Dec 12, 2005 at http://www.ahrq.gov/ HCUPnet/. [7] Barnard C, Esmond T. DRG-based reimbursement: the use of concurrent and retrospective clinical data. Med Care 1981;19:1071–82. [8] Lu-Yao GL, Barry MJ, Chang CH, Wasson JH, Wennberg JE. Transurethral resection of the prostate among Medicare beneficiaries in the United States: time trends and outcomes. Prostate Patient Outcomes Research Team (PORT). Urology 1994;44:692–8. [9] Kobelt G, Spangberg A, Mattiasson A. The cost of feedback microwave thermotherapy compared with transurethral resection of the prostate for treating benign prostatic hyperplasia. BJU Int 2004;93:543–8. [10] de la Rosette JJ, Floratos DL, Severens JL, Kiemeney LA, Debruyne FM, Pilar Laguna M. Transurethral resection vs microwave thermotherapy of the prostate: a cost-consequences analysis. BJU Int 2003;92:713–8. [11] Boyle P, Roehrborn CG, Marks L, Vela-Navarette R, Nickel JC. The novel dual 5a-reductase inhibitor dutasteride is effective for the treatment and prevention of complications in men with a PV 3040 cc and 40 cc. Eur Urol Suppl 2003;2(1):160 (abstract 632). [12] Saigal CS, Joyce G. Economic costs of benign prostatic hyperplasia in the private sector. J Urol 2005;173:1309–13. [13] Kawakami J, Nickel JC. Acute urinary retention and surgery for benign prostatic hyperplasia: the patient’s perspective. Can J Urol 1999;6:819–22.
[14] Lowe FC, McDaniel RL, Chmiel JJ, Hillman AL. Economic modelling to assess the costs of treatment with finasteride, terazosin and transurethral resection of the prostate for men with moderate to severe symptoms of benign prostatic hyperplasia. Urology 1995;46:477–83. [15] Van Exel NJA, Koopmanschap MA, McDonnell J, Chapple CR, Berges R, Rutten FFH. Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six European countries: report of the TRIUMPH study. Eur Urol 2006;49:92–102. [16] McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med 1998;338:557–63. [17] Albertsen PC, Pellissier JM, Lowe FC, Girman CJ, Roehrborn CG, for the PLESS Study Group. Economic analysis of finasteride: a model-based approach using data from the Proscar Long-Term Efficacy and Safety Study. Clin Ther 1999;21:1006–24. [18] Baladi JF, Menon D, Otten N. An economic evaluation of finasteride for treatment of benign prostatic hyperplasia. Pharmacoeconomics 1996;9:443–54. [19] McDonald H, Hux M, Brisson M, Bernard L, Nickel JC. An economic evaluation of doxazosin, finasteride and combination therapy in the treatment of benign prostatic hyperplasia. Can J Urol 2004;11:2327–40. [20] Holtgrewe HL, Bay-Neilsen H, Carlsson P, et al. The economics of the management of lower urinary tract symptoms and benign prostatic hyperplasia. In: Dennis L, Griffiths K, Khoury S, et al., editors. Proceedings of the Fourth International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth, United Kingdom: Plymbridge Distributors; 1998. p. 61–81. [21] Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1988;51:1–7. [22] Lukacs B. Management of symptomatic BPH in France: who is treated and how? Eur Urol 1999;36:14–20. [23] Berges RR, Pientka L. Management of the BPH syndrome in Germany: who is treated and how? Eur Urol 1999;36:21–7. [24] Tubaro A, Montanari E. Management of symptomatic BPH in Italy: who is treated and how? Eur Urol 1999; 36:28–32. [25] McNicholas TA. Management of symptomatic BPH in the UK: who is treated and how? Eur Urol 1999;36:33–9.