Cost-Effectiveness of Medical Expulsive Therapy Using Alpha-Blockers for the Treatment of Distal Ureteral Stones

Transcription

1 european urology 53 (2008) available at journal homepage: Stone Disease Cost-Effectiveness of Medical Expulsive Therapy Using Alpha-Blockers for the Treatment of Distal Ureteral Stones Karim Bensalah a, Margaret Pearle a,b, Yair Lotan a, * a Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States b The Center for Mineral Metabolism and Clinical Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States Article info Article history: Accepted September 10, 2007 Published online ahead of print on September 18, 2007 Keywords: Kidney stones Ureteral stones MET Cost analysis Abstract Objective: Medical expulsive therapy (MET) has recently emerged as an efficacious and safe option for the initial management of ureteral stones. The objective of this study was to assess the cost-effectiveness of MET compared with conservative therapy for the treatment of ureteral stones using international cost data from the United States and four European countries. Material and methods: A decision analysis model was built with the use of TreeAge Pro 2004 software with linear success rate assumptions. The likelihood of spontaneous passage of ureteral stones according to their size and location was estimated with the use of data derived from a published meta-analysis. The estimated cost of ureteroscopy (URS) in the United States ($4973) was based on the mean cost of 121 consecutive cases performed at a large metropolitan hospital. URS costs for other countries were obtained from a published international survey. The cost of tamsulosin ($2.08 per day), currently the most commonly used medical expulsive agent, was estimated as a mean of the costs obtained from two national pharmacy chains. MET and conservative therapies were compared with the use of one-way and two-way sensitivity analyses. Results: In the United States, MET using tamsulosin resulted in a $1132 cost advantage over observation. MET maintained its cost advantage even in countries where the cost of URS is much lower than in the United States. Two-way sensitivity analysis showed that MET remained cost-effective even with very low rates of spontaneous passage, minimal benefit of MET, or low cost of URS. Conclusion: MET is a cost-effective strategy for the management of distal ureteral stones even those with a low rate of spontaneous passage providing another incentive for initial facilitated observation before embarking on surgical intervention. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX , United States. Tel ; Fax: address: yair.lotan@utsouthwestern.edu (Y. Lotan) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 412 european urology 53 (2008) Introduction The lifetime prevalence of stone disease in the United States has been estimated at 13% for adult men and 7% for adult women, with a peak incidence between the ages of 20 and 60 yr. Indeed, more than 1% of working-age adults were treated for a stone in the year 2000 [1]. It is estimated that total annual expenditure on stone disease that year was nearly $2.1 billion, including $971 million for inpatient services, $607 million for physician office and hospital outpatient services, and $490 million for emergency room services [2], values that are almost certainly underestimated. The optimal management of ureteral calculi depends on a variety of factors such as stone location and size, equipment availability, cost, patient preference, and surgeon experience. The likelihood of spontaneous passage is inversely related to stone size and improves the more distal the stone is located in the ureter at the time of diagnosis (Table 1) [3]. The majority of small distal ureteral stones will pass spontaneously [4]; consequently, a trial of conservative therapy is indicated if pain can be adequately controlled and there is no evidence for infection. Cost-effective treatment regimens aimed at resolving ureteral stones while minimizing cost are highly desirable. Medical expulsive therapy (MET) has been demonstrated in a number of randomized controlled trials (RCTs) to facilitate ureteral stone passage, diminish time to expulsion, and reduce the need for analgesics [5,6]. However, the cost-effectiveness of this treatment strategy, compared with simple observation, has not been established. We hypothesized that, if MET can increase the likelihood of stone passage and reduce the number of ureteroscopy (URS) procedures needed, then it might be cost-effective. The objective of our study was to compare the cost of observation versus MET for ureteral stones in five different countries. 2. Materials and methods 2.1. Decision model A decision analysis model was built to compare the cost of MET and initial observation for distal ureteral stones (Fig. 1). Decision trees were constructed with the use of TreeAge Pro 2004 software with linear success rate assumptions. The base case analysis was a patient with a distal ureteral stone who was a good candidate (no associated urinary infection or fever, well-controlled pain, tolerating oral intake) for either observation or MET. We assumed that patients who did not require emergent admission to the hospital would be managed on an outpatient basis and given an opportunity to pass their stone spontaneously. This assumption is consistent with recent findings in the Urologic Diseases of America project in which most patients with stones in the United States were managed on an outpatient basis [7]. Those patients who did not pass their stones were assumed to undergo an outpatient ureteroscopic procedure. For each arm of the model, the likelihood of spontaneous stone passage and the cost associated with treatment (observation or MET) and failure (need for URS) was utilized. Table 1 Spontaneous stone passages reported in the literature, according to stone size and location N Spontaneous passage rate for stones < 5mm Spontaneous passage rate for stones 5mm Spontaneous passage rate for proximal stones Spontaneous passage for distal stones Ueno et al [24] % 0 35% N/A N/A Segura et al [4] N/A N/A N/A 29 98% 71 98% Morse et al [25] 378 N/A N/A 22% 71% Hubner et al (meta-analysis) [3] % (<4 mm) 1.2% (>6 mm) 12% 45% Coll et al [26] % 25 60% 48% 75 79% Fig. 1 Decision analysis model. Model comparing the overall cost of observation versus medical expulsion therapy.

3 european urology 53 (2008) Assumptions Base rate of spontaneous stone passage We reviewed the literature to identify studies of spontaneous stone passage (Table 1). We utilized the meta-analysis of six natural history studies comprising 2704 patients to estimate the spontaneous passage rates of ureteral stones on the basis of stone size and location [3]. Stones less than 4 mm and greater than 6 mm at any location in the ureter were associated with spontaneous passage rates of 38% and 1.2%, respectively. The likelihood of spontaneous passage was higher for stones located in the distal ureter (45%) compared with stones located in the middle (22%) and proximal (12%) ureter Benefit of MET We utilized a recently published meta-analysis comprising nine RCTs including 693 patients [6]. In this study, patients receiving calcium-channel blockers or alpha-blockers had a 65% (absolute risk reduction, 0.31; 95% confidence interval [95%CI], ) greater likelihood of stone passage than untreated control patients (pooled risk ratio 1.65; 95%CI, ). In subgroup analysis, the pooled risk ratio for treatment with alpha-blockers was 1.54 ( ). Because our perception is that alpha-blockers comprise the most commonly employed MET regimen, we used this regimen for our model Cost The cost of treatment, whether observation or MET, takes into account not only the cost of drug treatment and medical care, but also the cost of surgical management of observation or MET failures. For the purposes of the model, we assumed that failures were treated with URS since this modality was shown in a previous cost study to be more cost-effective than shock wave lithotripsy (SWL) for the management of ureteral stones in all locations [8]. The cost of URS ($4773) in the United States was derived as the mean cost of 121 consecutive cases at a large metropolitan hospital. Cost centers included operating room, operating room supplies, day surgery, recovery room, laboratory costs, professional fees, and anesthesia costs. Professional fees were obtained from 2007 Medicare reimbursement rates in Texas, rather than from charge data. Costs for other countries were obtained from an international cost survey [9]. The cost of initial diagnosis and follow-up was excluded from calculation since it was presumed to be identical among the two treatment groups. We assumed that all treatments were performed on an outpatient basis, and any prior procedures such as stent placement were excluded from the cost analysis. Complications were not included in the cost analysis owing to the infrequent need for posttreatment intervention. Indeed, even major complications requiring surgical intervention, such as late ureteral stricture formation, have little impact on cost owing to the infrequency of the event. For the model, we assumed that the alpha-blocker used was tamsulosin at a dosage of 0.4 mg daily. The cost of the drug was calculated as an average of the costs obtained from two national pharmacies (Walgreens and Costco) and was $2.08 per 0.4 mg tablet Sensitivity analysis Using the success rates and derived costs for MET and observation as well as the cost of treating failures with URS, a series of one-way sensitivity analyses were performed to evaluate the effect of varying individual probabilities and costs, by varying one parameter while holding the others fixed. The cost threshold (point at which the treatment pathways were equal in cost) was determined for a range of treatment costs and success rates. One-way sensitivity analyses were utilized to determine points at which MET and observation were of equivalent cost in the United States. Two-way sensitivity analyses were performed by evaluating two variables over a wide range of values to allow determination of the most cost-effective therapy. 3. Results The initial model was based on United States costs for URS, medication, and emergency room visits and a presumed 54% increased risk of spontaneous stone passage on medication. MET was associated with a $1132 cost advantage over initial observation ($1493 vs. $2625, respectively). Because of the high cost of URS ($4773) and the low cost of medication ($28), even a 1% greater likelihood of stone passage with MET makes this strategy cost advantageous. Similarly, the cost of URS would have to decrease dramatically to $115 in order for observation to reach cost equivalence with MET. Furthermore if MET improves the likelihood of spontaneous stone passage by more than 1%, then MET is more costeffective because it precludes the need for URS, which is 170 times more costly than medication. In light of the high cost of URS in the United States compared with other countries, we performed an international comparison. An international cost survey [9] showed that the cost of URS was significantly lower in other countries compared with the United States. As such, we performed a secondary analysis to evaluate the cost-effectiveness of MET in four European countries for which cost data were available. As shown in Table 2, in countries such as Germany, where URS costs are approximately 5% of US costs, MET is marginally superior to observation. In such a scenario, the medical benefit (increased likelihood of spontaneous stone passage) would have to exceed 40% in order for MET to be cost-effective. On the other hand, in a country like Italy where the cost of URS is approximately one third the cost of URS in the United States, MET would need only to confer a 4% benefit over observation. Tables 3 and 4 show the model outcomes for observation and MET with varying cost of URS and

4 414 european urology 53 (2008) Table 2 Comparison of model outcomes in different countries Germany * Turkey UK Italy USA URS and stone fragmentation cost [9,23] $160 $491 $926 $1685 $4773 Model outcomes ** ($) Medical expulsive therapy $77 $179 $312 $545 $1493 Observation $88 $270 $509 $927 $2625 Point of cost-effectiveness for MET benefit # 40% 10% 7% 4% 1% UK, United Kingdom; USA, United States; URS, ureteroscopy; MET, medical expulsive therapy. * Ureteroscopy in Germany costs $160 as an outpatient but $800 per day as an inpatient procedure with 2 d in hospital on average. ** Assuming spontaneous stone passage rate of 45% [3] and medication cost of $28 ($2 per pill). # Incremental increase in spontaneous stone passage rates with MET. improved spontaneous stone passage with MET (Table 3), and with varying cost of URS and cost of medication (Table 4). In Table 3, one can see that the low cost of medication results in MET being more cost-effective, even with a 10% increased rate of spontaneous stone passage, as long as URS costs exceed $600. Table 4 shows that, unless URS is very cheap and medication is expensive, then MET is more cost-effective than observation. In Fig. 2, the increased likelihood of stone passage with MET is evaluated over a range of URS costs. Observation is cost-effective only if URS is very inexpensive or MET is no better than observation. Similarly, with varying rates of spontaneous stone passage and URS costs (Fig. 3), MET may be cost-effective, even for treatment regimens associated with relatively little additional benefit with respect to stone passage, provided the cost of URS is high. Table 3 Model outcomes for MET and observation, with varying cost of URS and increased likelihood of stone passage with MET 4. Discussion In this cost-effectiveness study, we found that, along with an improvement in stone passage rates, MET offers a significant cost advantage over observation alone. This observation holds true even in settings where URS is very inexpensive or MET provides only a marginal benefit in improving stone passage rates. The management of ureteral calculi represents a significant economic burden in industrialized countries owing to direct (surgical operations, medications, office visits, radiographic evaluation) and indirect (loss of work in working-age adults) costs. Many patients admitted to the hospital for renal colic due to ureteral stones are treated conservatively in anticipation of spontaneous stone passage. According to data from the Agency for Health Care Policy and Research spanning the time period from 1980 to 1987, Clark and colleagues [10] found that, among 6406 US patients discharged from the hospital with a primary diagnosis of calculus Table 4 Model outcomes for MET and observation, with varying cost of URS and medication

5 european urology 53 (2008) Fig. 2 Two-way sensitivity analysis varying ureteroscopy costs and the increased likelihood of stone passage with medical expulsion therapy (MET). Shaded areas represent points at which observation is more cost-effective than MET. of the kidney or ureter, only 24% underwent a definitive surgical procedure. Likewise, Saigal and colleagues [11], using data from the Urologic Disease in America project, found that only 25% of individuals with a diagnosis of nephrolithiasis submitted a claim for surgical treatment, suggesting that most patients are managed conservatively. There are several options for the management of ureteral stones, including conservative therapy (observation alone), SWL [12,13], and URS [14]. The optimal treatment in part depends on the size of the stone and the location of the stone in the ureter, both of which influence outcomes regardless of the treatment modality (Table 1). A meta-analysis of six Fig. 3 Two-way sensitivity analysis varying ureteroscopy costs and probability of spontaneous stone passage. Shaded areas represent points at which observation is more cost-effective than medical expulsion therapy.

6 416 european urology 53 (2008) natural history studies comprising 2704 patients evaluated the spontaneous passage rate of untreated ureteral stones [3]. The likelihood of spontaneous passage was shown to correlate inversely with stone size; stones less than 4 mm and greater than 6 mm had spontaneous passage rates of 38% and 1.2%, respectively. In addition, spontaneous passage rates were highest for stones in the distal ureter (45%) followed by middle ureter (22%) and finally proximal ureter (12%). Moreover, two thirds of the stones passed spontaneously within 4 wk of the onset of symptoms. These findings were confirmed by numerous studies (Table 1). Therefore, conservative therapy appears to be particularly suitable for the management of small distal ureteral calculi that have a high probability of passing spontaneously. Nevertheless, it should also be considered that, in the absence of spontaneous expulsion, URS done after a long time of conservative therapy may be much more difficult and may lead to more complications owing to the impaction of the stone [14]. There is now growing evidence that some pharmacological treatment regimens facilitate spontaneous stone passage [5,15]. A recent metaanalysis of nine RCTs (693 patients) [6] assessed the utility of alpha-blockers or calcium-channel blockers in promoting spontaneous passage of ureteral stones. Hollingsworth et al showed that patients given calcium-channel blockers or alpha-receptor antagonists were 65% (absolute risk reduction, 0.31) more likely to pass their stones than untreated control patients. Moreover, additional secondary benefits associated with MET included shortened time to stone passage, fewer pain episodes, and less need for analgesics, hospitalization, and/or endoscopic treatment [15 18]. Of note, side effects due to medication use were few and generally mild. However, it should be mentioned that the use of alpha-blockers in the setting of MET is off label. With health care expenditures reaching record levels, medical decision making is increasingly influenced by economic factors. Conservative therapy, although a seemingly inexpensive strategy, may prove to be more costly than firstline URS because of loss of more workdays or need for more frequent office or hospital visits. On the other hand, MET, by increasing the success rate of conservative therapy, has the potential to reduce overall cost. In the current study, we found that MET was the most cost-effective approach for ureteral stones, with an $1132 benefit over observation alone. The economic benefit of MET over conservative treatment seems logical because expulsive therapy reduces the number of urgent or planned physician s visits as well as the likelihood of needing a surgical procedure or experiencing complications. The cost-effectiveness of conservative versus surgical strategies for ureteral stones depends on the likelihood of spontaneous stone passage (which depends on stone size and location) and on the success rates of SWL or URS. Lotan and coworkers [8] used a cost-effectiveness model taking these factors into account and found that observation was the most cost effective approach to ureteral stones; the high likelihood of spontaneous passage of distal ureteral stones resulted in a $1200 cost advantage. Despite a much lower probability of spontaneous passage for proximal ureteral stones, a $400 cost advantage was realized in the model. The model assumed outpatient treatment in all cases and did not take into account additional visits to the emergency room (at an average cost of $625) or loss of work secondary to pain in patients treated conservatively. While our study of MET utilized a meta-analysis evaluating increased likelihood of spontaneous stone passage almost exclusively for distal stones, a benefit in patients with proximal and middle ureteral stones might also be realized if MET proves to be effective for stones in these locations. This possibility is suggested by the presence of alpha-1 binding receptors in the proximal and middle ureter [19]. This study suggests that, if conservative management is the strategy utilized for managing a patient with a ureteral stone, then even a small increase in the likelihood of spontaneous stone passage makes MET cost-effective. According to the 2001 Census of Population and Housing from the United States Census Bureau, the average American worker earned approximately $141 per day in 2000 dollars. As such, although observation for patients with small distal ureteral calculi may be a cost-effective strategy, for patients with proximal ureteral stones that are unlikely to pass, observation can result in rapid accrual of additional costs owing to loss of work, emergency room visits, and follow-up radiographs, which may ultimately render this approach cost ineffective. Improving the likelihood of spontaneous stone passage, however, favors the cost-effectiveness of observational strategies. The cost-effectiveness of particular treatment strategies may vary from country to country because of differences in the relative cost of surgery and medication in different parts of the world (Table 2). Most patients in the United States with acute stones are managed on an outpatient basis with pain medication and observation. Worldwide, however, there is more variability in admission rates for

7 european urology 53 (2008) an acute stone event. For example, approximately 69% of patients with urolithiasis receive inpatient hospital care in Germany [20] compared with only 29% in the United States [21] and 38% in Sweden [22]. Nevertheless, even in the countries with relatively low health care costs such as Germany and Turkey, MET appears to be cost-effective compared with URS and conservative therapy (assuming a 45% passage rate). The variation in cost and subsidization between health care systems can make it difficult to perform cost-effectiveness analyses that are easy to generalize [23]. Using Tables 3 and 4, one can identify the cost of ureteroscopy and medication at a particular institute and determine whether MET is cost-effective in that setting. We recognize that this study has several limitations. First, we did not include indirect costs such as lost wages in our analysis, although earlier stone passage with MET would lead to fewer missed workdays. Second, we did not incorporate the cost associated with complications of URS (such as stent pain, ureteral strictures, bleeding, perforation)whenusedinthecaseofobservationormet failures. However, this additional cost would also favor MET because it is associated with a reduced need for surgery. Third, there are inevitable differences from country to country in the management of ureteral stones. In settings where all patients with ureteral stones are managed in the hospital, then an observation strategy including use of MET may not be cost-effective. Finally we did not take into account noncompliance with or intolerance of the medication regimen; however, one-way sensitivity analyses suggest that even substantially reduced effectiveness of MET would still render it a more cost-effective strategy. The meta-analysis by Hollingsworth and colleagues [6] noted a low complication rate (< 5%) for MET, and consequently noncompliant patients would simply stop the medication and revert to the spontaneous passage rate of the observation arm. 5. Conclusion MET is a cost-effective strategy for the management of ureteral stones compared with conservative therapy, even in countries where the cost associated with surgery is lower than in the United States. These findings, along with the established effectiveness of MET, suggest that MET should be systematically considered as first-line treatment for patients with ureteral calculi in whom up-front surgery is not a necessity. Conflicts of interest Karim Bensalah is supported by the Association Française d Urologie. References [1] Ljunghall S, Lithell H, Skarfors E. Prevalence of renal stones in 60-year-old men. A 10-year follow-up study of a health survey. BJU 1987;60:10 3. [2] Pearle M, Curhan G, Calhoun E. Urolithiasis. In: Department of Health and Human Services NIoH, National Institute of Diabetes and Digestive and Kidney Diseases, editor. Washington (DC): US Government Publishing Office; p. 3. [3] Hubner WA, Irby P, Stoller ML. Natural history and current concepts for the treatment of small ureteral calculi. Eur Urol 1993;24: [4] Segura JW, Preminger GM, Assimos DG, et al. Ureteral Stones Clinical Guidelines Panel summary report on the management of ureteral calculi. The American Urological Association. J Urol 1997;158: [5] Healy KA, Ogan K. Nonsurgical management of urolithiasis: an overview of expulsive therapy. J Endourol 2005;19: [6] Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a metaanalysis. Lancet 2006;368: [7] Pearle MS, Calhoun EA, Curhan GC. Urologic diseases in America project: urolithiasis. J Urol 2005;173: [8] Lotan Y, Gettman MT, Roehrborn CG, Cadeddu JA, Pearle MS. Management of ureteral calculi: a cost comparison and decision making analysis. J Urol 2002;167: [9] Chandhoke PS. When is medical prophylaxis costeffective for recurrent calcium stones? J Urol 2002;168: [10] Clark JY, Thompson IM, Optenberg SA. Economic impact of urolithiasis in the United States. J Urol 1995;154: [11] Saigal CS, Joyce G, Timilsina AR. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005;68: [12] Argyropoulos AN, Tolley DA. Optimizing shock wave lithotripsy in the 21st century. Eur Urol 2007;52: [13] Seitz C, Fajkovic H, Waldert M, et al. Extracorporeal shock wave lithotripsy in the treatment of proximal ureteral stones: does the presence and degree of hydronephrosis affect success? Eur Urol 2006;49: [14] Seitz C, Tanovic E, Kikic Z, Fajkovic H. Impact of stone size, location, composition, impaction and hydronephrosis on the efficacy of holmium:yag-laser ureterolithotripsy. Eur Urol 2007;52: [15] Porpiglia F, Destefanis P, Fiori C, Fontana D. Effectiveness of nifedipine and deflazacort in the management of distal ureter stones. Urology 2000;56: [16] Borghi L, Meschi T, Amato F, et al. Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebo-controlled study. J Urol 1994;152:

8 418 european urology 53 (2008) [17] Yilmaz E, Batislam E, Basar MM, et al. The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. J Urol 2005;173: [18] Dellabella M, Milanese G, Muzzonigro G. Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol 2003;170: [19] Sigala S, Dellabella M, Milanese G, et al. Evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn 2005;24: [20] Strohmaier WL. Socioeconomic aspects of urinary calculi and metaphylaxis of urinary calculi. Der Urologe Ausg 2000;39: [21] Resnick MI, Persky L. Summary of the National Institutes of Arthritis, Diabetes, Digestive and Kidney Diseases conference on urolithiasis: state of the art and future research needs. J Urol 1995;153:4 9. [22] Ahlstrand C, Tiselius HG. Renal stone disease in a Swedish district during one year. Scand J Urol Nephrol 1981;15: [23] Lotan Y, Cadeddu JA, Pearle MS. International comparison of cost effectiveness of medical management strategies for nephrolithiasis. Urol Res 2005;33: [24] Ueno A, Kawamura T, Ogawa A, Takayasu H. Relation of spontaneous passage of ureteral calculi to size. Urology 1977;10: [25] Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol 1991;145: [26] Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR 2002;178: Editorial Comment on: Cost-Effectiveness of Medical Expulsive Therapy Using Alpha-Blockers for the Treatment of Distal Ureteral Stones Vassilis Poulakis Section of Laparoscopic, Robotic and Minimal Invasive Urology, Athens Medical Center, Athens, Greece vaspou@otenet.gr This study [1] deals with an important economic issue in the conservative treatment of distal ureteral stones. The authors used a decision analysis model (TreeAge Pro 2004 software) with linear success rate assumptions to calculate the estimated cost of watchful waiting, medical expulsive therapy (MET), and ureteroscopy for small ureteral stones in the United States and four European countries. After the statistical analysis, they were able to show that MET is a cost-effective strategy for the management of distal ureteral stones. The authors concluded that MET should be systematically considered as firstline treatment for patients with ureteral calculi in whom up-front surgery is not a necessity. Although the authors are known for their past publications on similar topics and the statistical analysis was based on data of other published studies and meta-analyses, the following critical points must be kept in mind: 1. Despite growing evidence from clinical, prospective, randomized studies of the efficacy of MET, in clinical practice MET is rarely used for the treatment of small ureteral stones. The reason for this is obvious: urologists are not yet persuaded because the effects of a-blockers are probably overestimated because they are derived from only a few pilot studies with a relatively low number of participants. It should also be mentioned that MET using a-blockers is an off-label use of these drugs. Furthermore, a-blockers have several side effects (dizziness, hypotension, retrograde ejaculation, flushes), which may make their tolerance difficult. In several studies a not-negligible drop-out rate due to severe side effects was shown. 2. The calculations, which the authors did in the statistical analysis, cannot easily be followed and duplicated even by an experienced reader. Furthermore, several important economic aspects are underestimated in the calculation model. The cost effectiveness of MET versus observation was evaluated taking into account the lower number of patients who underwent ureteroscopic management of ureteral stones. Economic benefits obtained by the reduction of the time of the patient cannot work and the costs of follow-up medical visits (ie, ultrasound examination) should also be considered. 3. Assuming that MET is an efficacious and safe option for the initial management of patients with distal ureteral stones, the present study shows that MET is also cost effective. However, a search in the guidelines of the European Association of Urology yielded no recommendation on the use of MET. This does not mean that the urologist should not have any guidelines on this topic. The use of a-blockers in the conservative treatment of distal ureteral stones is surely not contraindicated, but it is not the first-line therapy for all patients with ureteral stones. Despite its efficacy and cost effectiveness, MET should be

9 european urology 53 (2008) applied with caution in the patients in whom it is truly indicated. the treatment of distal ureteral stones. Eur Urol 2008;53: Reference [1] Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expulsive therapy using alpha-blockers for DOI: /j.eururo DOI of original article: /j.eururo