Stesura Seveso Archivio Italiano di Urologia e Andrologia 2013; 85, 4200 InTrodUCTIon Lower urinary tract symptoms (LUTS) are common in aging men with a prevalence ranges from 10.3 to 25.1% depending on the severity threshold (1). Benign prostat- ic hyperplasia (BPH) and benign prostatic enlargement ORIGINAL PAPER Clinical effects and economical impact of dutasteride and finasteride therapy in Italian men with LUTS Luca Cindolo 1, Francesco Berardinelli 1, Caterina Fanizza 2, Marilena Romero 2, Luisella Pirozzi 2, Fabiola Raffaella Tamburro 1, Fabrizio Pellegrini 1, Fabio Neri 1, Andrea Pitrelli 3, Luigi Schips 1 1 S. Pio da Pietrelcina Hospital, Dept. of Urology, Vasto, Italy; 2 Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy; 3 Access to Medicine, GlaxoSmithKline spa, Verona, Italy. Objectives: To investigate differences in the risk of benign prostatic hyperplasia (BPH)- related hospitalization, for surgical and non-surgical reasons, and of new prostate can- cer (PCa) diagnosis between patients under dutasteride or finasteride treatment. Material and methods: A retrospective cohort study was conducted using data from record-linkage of administrative databases. Men aged ≥ 40 years old who had received a prescription for at least 10 boxes/year (index years: 2004-06) were included. The association of the outcomes was assessed using a multiple Cox proportional hazard model. Propensity score- matched analysis and a 5-to-1, greedy 1:1 matching algorithm were performed. The budget impact analysis of dutasteride vs finasteride in BPH-treated patient was performed. Results: From an initial cohort of about 1.5 million of Italian men, 19620 were selected. The over- all hospitalization for BPH-non surgical reasons, for BPH-related surgery and for new detection of PCa incidence rates (IRs) were 8.20 (95% CI, 7.62-8.23), 18.0 (95% CI, 17.12-18.93) and 8.62 (95% CI, 8.03-9.26) per 1000 person-years, respectively. The multivariate analysis after the propensity score-matching showed that dutasteride was associated with an independent reduced likelihood of hospitalization for BPH-related surgery (HR 0.82; 95% CI 0.73-0.93; p = 0.0025) and of newly detected PCa (HR: 0.76,95% CI, 0.65-0.85; p = 0.0116). The IR for BPH-non surgi- cal reasons was 8.07 (95% CI, 7.10-9.17) and 9.25 (95% CI, 8.19-10.44) per 1000 person-years, respectively. The IR for BPH-related surgery was 18.28 (95% CI, 17.17-20.32) and 21.28 (95% CI, 19.24-23.06) per 1000 person-years among patients under dutasteride compared with those under finasteride, respectively. For new-onset PCa, the IR was 8.01 (95% CI, 7.07-9.08) and 9.38 (95% CI, 8.32-10.58) per 1000 person-years The pharmacoeconomical evaluation showed that the net budget impact of the use of dutasteride vs. finasteride in 1000 BPH-treated patient for 1 year induces a saving of 3933 €. Conclusions: The clinical effects of dutasteride and finasteride are slightly different. The likeli- hood of hospitalization for BPH-related surgery and of newly detected PCa seems to be in favor of dutasteride. The budget impact analyses showed a slightly benefit for dutasteride. Comparative prospective studies are necessary to confirm these results. Key wORDs: Benign prostatic hyperplasia (BPH); Dutasteride; Finasteride; Epidemiology; Medical record-linkage. Submitted 14 April 2013; Accepted 5 October 2013 Summary (BPE) have been recognized as the major contributing factors to the development of LUTS. The first-line phar- macological therapy for moderate-to-severe non-neuro- genic male LUTS includes alpha-adrenoreceptor antago- DOI: 10.4081/aiua.2013.4.200 201Archivio Italiano di Urologia e Andrologia 2013; 85, 4 5ARIs comparison. Who is the best? nists (ABs) and 5alpha-reductase inhibitors (5ARIs) alone or in combination (2). ABs induce a rapid symp- tom relief, while the 5ARIs modify the BPH natural his- tory by delaying the disease progression (3-6). Finasteride and dutasteride are the two 5ARIs: finas- teride inhibits the 5-alpha-reductase isoenzyme type 2, whereas dutasteride inhibits both isoenzyme 1 and 2. The clinical value of the greater serum dihydrotestos- terone suppression achieved by dutasteride (7) remains unclear (2). Nowadays due to the limited literature (8- 11) the question of “what is the best 5ARI" remains unan- swered. Another point of uncertainty is about the eco- nomic impact of the use of dutasteride instead of finas- teride. In an attempt to clarify these aspects, we previ- ously performed an observational study on an unselect- ed population that showed a reduction in BPH-related hospitalization risk in dutasteride- compared to finas- teride-treated patients (12). In that paper (12) we also dealt with the hard issue of the detection of prostate can- cer (PCa) under 5ARIs treatments (13-16) showing a positive trend in favor of dutasteride. Herein, we report the new results of extended analysis investigating the clinical and economic differences between dutasteride and finasteride treatment in an Italian male population ≥ 40 years with LUTS. MaTerIaL and MeThodS A retrospective study was conducted based on informa- tion from three databases: Italian population registry, pharmaceutical prescription data, and hospital discharge record including information on about 1.500.000 male aged ≥ 40 years from 22 Local Health Units from Northern and Southern Italy for 6 consecutive years (January 1st 2004 and December 31st 2009). Data sources The Italian population registry provide demographic information (date of birth, sex and date of death if this occurred) on each subject. The pharmaceutical prescrip- tion database records all prescriptions reimbursed by the NHS (drugs coded according to the international Anatomical Therapeutic Chemical system - ATC) (17). The hospital records include detailed information on pri- mary diagnosis and up to five coexisting diagnoses, per- formed procedures, and admission/discharge dates. The diagnoses were classified according to the International Classification of Diseases-Ninth Revision, Clinical Modification (ICD9-CM) (18). A record linkage of these three databases was carried out and pharmacological and clinical history for each patients was obtained. The relia- bility of this strategy to produce an epidemiological sur- vey has been previously validated and reported (19-21). All security and protection measures for patient’s data was performed according to National laws on privacy protection. Patients and Drugs The cohort consisted of men aged ≥ 40 years, who received prescription for at least 10 boxes/year of finas- teride or dutasteride between 1 January 2004 and 31 December 2006 (index years). The first prescription of one of these drugs during the index years was considered as index date (Day 0). The exclusion criteria were either ABs monotherapy and/or short-term 5-ARI therapy (< 10 boxes/year). For all patients, the databases were searched during the 12-months period preceding the index date to verify the absence of BPH-complications and PCa. Specifically, patients with an urethral stricture (ICD9- CM: 598, 589.0, 598.00, 598.01, 598.1, 598.2, 598.8, 598.9) and/or with PCa diagnoses (ICD9-CM: 185, 198.82, 233.4, 236.5, 239.5, V10.46) and/or at least a prescription of LHRH analogues and/or antiandrogens, were not considered eligible. Patients using ABs (alfu- zosin, tamsulosin, terazosin) were included in the study. Patients with acute or chronic urinary retention second- ary to BPH and treated at the emergency department without hospital admission were not considered. Moreover, to assess the comorbidities, the Charlson Comorbidity Index (CCI) with the Dartmouth-Manitoba modification was used (22). Clinical outcomes Follow-up for each identified patient is extended from the index date to five years or until the occurrence of the following major events: 1) hospitalization for BPH-non surgical reasons); 2) hospitalization for BPH-related sur- gery; 3) new diagnosis of PCa. BPH-related hospitalization was considered when the hospital records included primary diagnosis and/or pro- cedures related to BPH. The presence of the ICD9-CM 600.xx (prostate hyper- plasia) and 222.2 (benign prostate tumor) codes as pri- mary diagnosis without surgical procedures was consid- ered hospitalization for “BPH-non surgical reasons”. The presence of ICD9-CM 57.0, 57.91, 57.92, 60.21, 60.29, 60.3, 60.4 codes (open or transurethral resection/abla- tion of prostate or bladder neck), as primary or second- ary surgical procedures with any primary diagnoses, was considered hospitalization for “BPH-related surgery”. The new diagnosis of PCa was identified through hospi- talization (ICD9-CM:185, 198.82, 233.4, 236.5, 239.5, V10.46) and/or PCa medical therapy (Gonadotripins releasing hormones agonists L02AE01, L02AE02, L02AE03, L02AE04; and/or antiandrogens: L02BB01, L02BB02, L02BB03). Analysis of health resources utilization The budget impact analysis of dutasteride vs. finasteride in BPH-treated patient according to the Italian NHS per- spective has been performed starting form an hypotheti- cal cohort of 1000 BPH-treated men under finasteride for one year, here and after “current scenario”; in our analysis this hypothetic cohort has been fully switched to dutas- teride, here and after “alternative scenario”. The incidence rates for 1000 person-years by outcomes after propensity score matching were used as source for the budget impact analysis model. Drug consumption has been calculated assuming an annual 80% compliance to both treatment (300 days of therapy); in both scenar- ios patients undergoing to BPH-related surgery with- drawn from treatment (assuming they don’t need further treatment for BPH). The health resources utilization in both scenarios has been calculated starting from the inci- Archivio Italiano di Urologia e Andrologia 2013; 85, 4 L. Cindolo, F. Berardinelli, C. Fanizza, M. Romero , L. Pirozzi, F.R. Tamburro, F. Pellegrini, F. Neri, A. Pitrelli, L.Schips 202 dence rates (both surgical and non surgical reasons) for 1000 persons/years after propensity score matching. Hospital records have been used to estimate the average hospitalization costs according to NHS perspective. The impact on NHS annual budget related to variation of PCa detection rate observed with dutasteride vs. finasteride was not analyzed. statistical analysis For the whole sample, patients’ characteristics were reported as frequency (percentage) and mean±standard deviation. Differences between patients’ treatment sub- groups were assessed using standardized difference. For major outcomes, crude incidence rates (IRs) per 1000 men-year were calculated as the number of events divid- ed by the number of person-years of follow-up. Furthermore, to check consistency of our results, a propensity score (PS)-matched analysis was performed (24-25). A logistic model -including the same covariates used in the multivariate Cox model, plus quadratic terms and a set of two-term interactions between the same covariates- was performed to predict the probability to be assigned to study drugs. PS logistic model was select- ed in a stepwise fashion and pair-wise comparisons were performed. A 5-to-1, greedy 1:1 matching algorithm (26) was used to identify a unique matched control for treat- ed patient according to their PS. Adequacy of covariate balance in the matched sample was assessed via stan- dardized difference between the two groups, considering differences less than 10% as good balance (27). The association of hospitalization for BPH, BPH-related surgery, PCa was assessed using a multiple Cox propor- tional hazard model. All multivariate analyses were adjusted for the following variables: age, Charlson co- morbidity score, previous hospitalization for BPH, previ- ous BPH-related surgery, pre-existing severity factors, previous pharmacological treatment with ABs. Results are expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). P-values < 0.05 were considered significant. All analyses were performed using SAS Statistical Package Release 9.2 (SAS Institute, Cary, NC, USA). reSULTS Patients characteristics From 1.417.969 men aged ≥ 40 years, 19620 were chronically exposed to 5ARIs; 13195 received finasteride and 6425 dutasteride. No significant differences were observed between these two groups with exception of previous ABs therapy (Table 1). Clinical outcomes during follow-up During 5 years, 841 patients were hospitalized for BPH- non surgical reasons, 2006 for BPH-related surgery and 749 were newly diagnosed with PCa. The overall hospital- ization IR for BPH-non surgical reasons and for BPH-relat- ed surgery were 8.20 (95% CI, 7.62-8.23) and 18.0 (95% CI, 17.12-18.93) per 1000 person-years, respectively. The matched analysis identified 6362 men under dutas- teride that were matched with a similar cohort under finasteride, without significant differences between groups (Table 2). Among patients under dutasteride compared with those under finasteride the IR for BPH-non surgical reasons was 8.07 (95% CI, 7.10-9.17) and 9.25 (95% CI, 8.19-10.44) per 1000 person-years, respectively. Moreover, the IR for BPH-related surgery was 18.28 (95% CI, 17.17-20.32) and 21.28 (95% CI, 19.24-23.06) per 1000 person-years Variable Finasteride (13195 pz) dutasteride (6425 pz) Standardized n (%) n (%) difference (%) Mean Age (mean ± SD) 72.25 (9.14) 71.62 (8.46 -7.1538 Age 40-55 509 (3.86) 178 (2.80) -5.9106 56-65 4917 (37.26) 2647 (41.61) 8.8940 66-75 5254 (39.82) 2589 (40.69) 1.7876 76-85 2515 (19.06) 948 (14.90) -11.0948 Charlson score 0 10945 (82.95) 5312 (83.50) 1.4657 1-2 1397 (10.59) 686 (10.78) 0.6326 >=3 853 (6.46) 364 (5.72) -3.1069 Previous hospitalization for BPH (non surgical reasons) 924 (7.00) 533 (8.38) 5.1632 Previous hospitalization for BPH-related surgery 39 (0.30) 32 (0.50) 3.2896 Previous BPH complications (severity factors) 583 (4.42) 272 (4.28) -0.7011 Previous alphablockers therapy 5519 (41.83) 3893 (61.19) 39.4960 Table 1. Patients' characteristics according to drug used (finasteride or dutasteride). * Standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. 203Archivio Italiano di Urologia e Andrologia 2013; 85, 4 5ARIs comparison. Who is the best? among patients under dutasteride compared with those under finasteride, respectively. For new-onset PCa, the IR was 8.01 (95% CI, 7.07-9.08) and 9.38 (95% CI, 8.32- 10.58) per 1000 person-years (Table 3). The multivariate analysis after the propensity score matching Cox model showed that dutasteride was asso- ciated with an independent reduced likelihood of hospi- talization for BPH-related surgery (HR 0.82; 95% CI 0.73-0.93; p = 0.0025) and of newly detected PCa (HR: 0.76, 95% CI, 0.65-0.85; p = 0.0116) (Table 4). Annual budget impact analysis In the “current scenario” an hypothetical cohort of 1000 BPH-treated patient for 1 year with finasteride generates a total annual impact on NHS budget of 1.017.444 €: 13,4% of this cost is related to finasteride cost (136.145 €), 66,4% is related to hospitalizations due to BPH-related surgery (675.423 €) and 20,2% is related to hospitalizations for BPH-non surgical reasons (205.872 €). In the “alternative scenario” is generated a total annual Variable Finasteride (6362 pz) dutasteride (6362 pz) Standardized n (%) n (%) difference (%) Mean Age (mean ± SD) 71.68 (8.42) 71.62 (8.46) 0.71092 Age 40-55 175 (2.75) 178 (2.80) 0.28712 56-65 2641 (41.51) 2647 (41.61) 0.19137 66-75 2589 (40.69) 2589 (40.69) 0.00000 76-85 957 (15.04) 948 (14.90) -0.39649 Charlson score 0 5294 (83.21) 5312 (83.50) 0.75957 1-2 695 (10.92) 686 (10.78) -0.45479 >=3 373 (5.86) 364 (5.72) -0.6056 Previous hospitalization for BPH (non surgical reasons) 528 (8.30) 533 (8.38) 0.28427 Previous hospitalization for BPH-related surgery 19 (0.30) 32 (0.50) 3.23449 Previous BPH complications (severity factors) 292 (4.59) 272 (4.28) -1.52745 Previous alphablockers therapy 3890 (61.14) 3893 (61.19) 0.09675 Table 2. Patients' characteristics according to drug used (finasteride or dutasteride) after propensity score matching. * Standardized difference greater than 10% represents meaningful imbalance in explored variables between treatment groups. outcome Finasteride dutasteride Incidence rate 95% CI Incidence rate 95% CI Hospitalization for BPH (non surgical reasons) 9.25 8.19-10.44 8.07 7.10-9.17 Hospitalization for BPH-related surgery 21.28 19.24-23.06 18.28 17.17-20.32 Newly detected prostate cancer 9.38 8.32-10.58 8.01 7.07-9.08 Table 3. Incidence rate for 1000 person-years by outcome considered in finasteride and dutasteride groups after propensity score matching. outcome hr 95% CI p value Hospitalization for BPH (non surgical reasons) 0.87 0.73-1.05 0.1377 Hospitalization for BPH-related surgery 0.82 0.73-0.93 0.0025 Newly detected prostate cancer 0.76 0.65-0.85 0.0116 Table 4. Results of propensity score matching Cox model: dutasteride vs. finasteride. Archivio Italiano di Urologia e Andrologia 2013; 85, 4 L. Cindolo, F. Berardinelli, C. Fanizza, M. Romero , L. Pirozzi, F.R. Tamburro, F. Pellegrini, F. Neri, A. Pitrelli, L.Schips 204 impact on NHS budget of 10.103.507 €: 25% of this cost is related to dutasteride cost (253.693 €), 57,2% is related to hospitalizations for BPH-related surgery (580.204 €) and 17,7% is related to hospitalizations for BPH-non surgical reasons (179.610 €) (Figure 1). The full switch from finasteride to dutasteride in an hypothetical cohort of 1000 BPH-treated patients for one year generates a net saving of 3.933 € to the NHS annu- al budget. dISCUSSIon Dutasteride and finasteride are the two currently avail- able 5ARIs, and are widely recommended in patients with moderate-to-severe BPH-related LUTS (2, 4-6). Large-scale clinical trials have demonstrated that dihy- drotestosterone (DHT) suppression with 5ARIs is effec- tive in the treatment of BPH and might have a role in the prevention of PCa (4, 5, 13, 14). Previous studies con- firmed that dutasteride consistently induces a near-max- imal suppression of both serum and intraprostatic DHT in men with BPH and those with PCa (7). Even if the two available 5-ARIs are considered to be virtually equivalent regarding the clinical outcomes (13, 14), unfortunately, a direct comparison of the two drugs evaluating the long term effects is still lacking. The EPICS study, the only randomized clinical trial comparing dutasteride vs. finas- teride, did not show significant differences between the drugs in terms of clinical efficacy. However, as pointed out by the authors, given the long-term, progressive nature of BPH, the one-year duration of EPICS may limit the potential to observe major differences between dutas- teride and finasteride treatment (11). In lack of relevant, prospective comparative studies, the purpose of this record-linkage study was to analyze the clinical effect of dutasteride and finasteride on BPH-relat- ed hospitalizations and on PCa diagnosis and the eco- nomical impact on NHS budget in an Italian cohort. After the propensity score matching Cox model, the mul- tivariate analysis showed that dutasteride was associated with a statistically significant lower likelihood of hospi- talization for BPH-related surgery (Table 4). These findings are in line with our previous study (12) and the reports from Issa (10) and Fenter (28. The results of the pharmacoeconomic analysis support health decision maker in the choice of whether or not to implement the treatment of BPH patient with dutasteride instead of less costly finasteride. In two papers Fenter and Naslund (28-29) made a real world economic evaluation of dutasteride vs. finasteride for the treatment of BPH patient analyzing restrictively medical and pharmacy claims in two large US adminis- trative databases. These studies were based on American Medicare-aged population and showed that dutasteride-therapy resulted in less medical costs than finasteride, suggesting that the higher price of dutasteride may be offset by decreased medical resource consumption. In our analysis we also estimated the cost consequence for the Italian NHS of the use of dutasteride instead of finasteride in a hypothetical cohort of 1000 BPH-treated patient for one year starting from the clinical differences in major outcomes (hospi- talization for surgical and non surgical reason). As a results of our analysis, even in a different NHS frame- work, the net budget impact of the use of dutasteride instead of finasteride is slightly in favor of dutasteride with a total annual saving of 3.933 €. This overall cost saving for men taking dutasteride could create a overall cost advantage for dutasteride despite its higher price. There is also significant additional value to patients who have a lower risk of BPH progression and than prostate surgery under dutasteride, although the Figure 1. Dutasteride vs finasteride: comparison of NHS costs for one year treatment of 1000 BPH patient. Finasteride € 1.200.000 - € 1.000.000 - € 800.000 - € 600.000 - € 400.000 - € 200.000 - € - dutasteride Hospitalization for BPH-related surgery Hospitalization for BPH Drug cost€ 205.872 € 675.423 € 136.145 € 179.610 € 580.204 € 253.693 205Archivio Italiano di Urologia e Andrologia 2013; 85, 4 5ARIs comparison. Who is the best? monetary value of these benefits is difficult to measure and quantify. As far as the new diagnosis of PCa is concerned, we found a PCa incidence lower in dutasteride- vs. finas- teride-treated patients. Although our previous study showed only a positive trend in dutasteride group with- out a statistical significance, however, in the current study, the wider cohort allowed to reach a statistically significant difference in reduction of PCa diagnosis (HR: 0.76, 95% CI, 0.65-0.85; p = 0.0116) (Table 4). All these evidence suggest that the clinical benefit of the dual 5a-reductase-isoenzymes inhibition might be slight- ly better. The two molecules are effective in BPH; never- theless, due to its peculiar pharmacokynetic and phar- macodynamic characteristics (longer half-life and dual inhibition of 5a-reductase-isoenzymes), dutasteride seems to be more active. Although our results suggest that there are differences between the two 5ARIs in terms of clinical and econom- ic outcomes, interpretation of the results is limited by the retrospective, non-randomized nature of the study. Moreover, no information about symptomatic burden of the disease, urodynamic parameters, baseline PSA val- ues, number and kind of core biopsies and Gleason score were available in our database. This is a main limitation of the study that hinders any inference about specific outcomes. However, the administrative database are widely used with all the inherent limitations and are con- sidered a valuable source of clinical information (19-21). Moreover, the pharmacoeconomic analysis contains fur- ther limitations. Firstly, in clinical practice physician pref- erences based on clinical characteristics can impact treat- ment selection which mathematical model can not account for. Secondly, our results are specific to Italy and are driv- en by local practice and healthcare costs and prices. ConCLUSIonS In conclusion, our results suggest slight differences in clinical and economic outcomes between dutasteride- and finasteride-treated patients. Further clinical trials are warranted in order to confirm these results and to evalu- ate the long term effectiveness of these drugs. aCknowLedgMenTS This study was financially supported by an uncondition- al grant from GlaxoSmithKline. reFerenCeS 1. Füllhase C, Chapple C, Cornu JN, et al. Systematic review of combination drug therapy for non-neurogenic male lower urinary tract symptoms. Eur Urol. 2013; 64:228. 2. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64:118. 3. 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Correspondence Luca Cindolo, MD, FEBU (Corresponding Author) lucacindolo@virgilio.it Francesco.Berardinelli, MD berardinelli.francesco@gmail.com Fabiola Raffaella Tamburro, MD fabiola.tamburro@libero.it Fabrizio.Pellegrini, MD fabriziopellegrini85@hotmail.it Fabio Neri, MD info@fabioneri.eu Luigi Schips, MD luigischips@hotmail.com S. Pio da Pietrelcina Hospital, Dept. of Urology, Vasto, Italy Caterina Fanizza, MD fanizza@negrisud.it Marilena Romero, MD romero@negrisud.it Luisella.Pirozzi, MD pirozzi@negrisud.it Department of Clinical Pharmacology and Epidemiology-Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy Andrea Pitrelli, MD andrea.n.pitrelli@gsk.com Access to Medicine, GlaxoSmithKline spa, Verona, Italy