Assessment of Frailty and Association With Progression of Benign Prostatic Hyperplasia Symptoms and Serious Adverse Events Among Men Using Drug Therapy.

Importance: Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy. Objective: To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE. Design, Setting, and Participants: This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021. Exposures: A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to <0.25), or frail (score ≥0.25). Main Outcomes and Measures: Primary outcomes were time to clinical BPH progression and time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regressions adjusted for demographic variables, treatment group, measures of obstruction, and comorbidities. Results: Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, 745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared with robust men, frail men were older (age ≥75 years, 12 men [2%] vs 62 men [13%]), less likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men [72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]). During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2 events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82; 95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received doxazosin or combination therapy, although the test for interaction between frailty index and treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for interaction = .76). Conclusions and Relevance: These findings suggest that frailty is independently associated with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering initiation of drug therapy should be counseled regarding their higher risk of progression despite combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.

Using Medicare Claims to Examine Long-term Prostate Cancer Risk of Finasteride in the Prostate Cancer Prevention Trial.

Background: Investigators have used administrative claims to better understand cancer outcomes when a research question cannot feasibly be examined within a study. The Prostate Cancer Prevention Trial (PCPT) showed that seven years of finasteride reduced prostate cancer (PC) risk by 25% in men age 55 years or older. However, it was unclear whether the observed reduction in PC for finasteride participants would be maintained after finasteride discontinuation. Methods: We examined PC diagnoses identified by PCPT study records and Medicare claims (finasteride = 9423, placebo = 9457). A Medicare-defined PC diagnosis algorithm was defined using diagnosis and procedure codes. Multivariable Cox regression was used to examine time to PC within prespecified follow-up windows (<6.5, 6.5-7.5, and >7.5 years) using time-dependent covariates interacting with intervention assignment to account for the PCPT protocol-specified end-of-study biopsy at seven years. All statistical tests were two-sided. Results: Median follow-up using the linked database was 16 years. Overall, finasteride arm participants had a 21.1% decrease in the hazard ratio of PC (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.74 to 0.84, P < .001). The beneficial effect of finasteride in reducing the hazard ratio of PC was most pronounced in the first 7.5 years (HR = 0.71, 95% CI = 0.66 to 0.77, P < .001), consistent with the original study findings; after 7.5 years, there was no increased risk of PC for finasteride arm participants (HR = 1.10, 95% CI = 0.96 to 1.26, P = .18). Conclusions: Finasteride provides a substantial reduction in PC through 16 years of follow-up. There was no strong evidence that the benefit of finasteride diminished after the end-of-study follow-up. Utilizing Medicare claims to augment PCPT follow-up illustrates how the novel use of secondary data sources can enhance the ability to detect long-term outcomes from prospective studies.

Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia.

PURPOSE: Clinicians use tamsulosin, an α1-adrenoceptor antagonist, to manage symptomatic benign prostatic hyperplasia (BPH). Because α1-adrenoceptors are also present in the brain, the potential exists for adverse effects on cognitive functions. We explored the association between tamsulosin use and dementia risk. METHODS: We used Medicare data (2006-2012) to conduct a cohort study among patients aged ≥65 years and diagnosed with BPH. Men taking tamsulosin (n = 253 136) were matched at a 1:1 ratio using propensity-scores to each of 6 comparison cohorts: patients who used no BPH-medication (n = 180 926), and patients who used the following alternative-BPH-medications: doxazosin (n = 28 581), terazosin (n = 23 858), alfuzosin (n = 17 934), dutasteride (n = 34 027), and finasteride (n = 38 767). Assessment began following the first fill of BPH-medication to identify incident dementia by ICD-9 diagnosis codes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for dementia using Cox proportional hazard regression for each of the 6 propensity-score-matched cohort-pairs. RESULTS: The median follow-up period for all cohorts was 19.8 months. After propensity-score matching, the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years compared with only 25.9/1000 person-years in the no-BPH-medication cohort. The risk of dementia was significantly higher in the tamsulosin cohort, when compared with the no-BPH-medication cohort (HR [95% CI]: 1.17 [1.14, 1.21]) and each of the alternative-BPH-medication cohorts: doxazosin (1.20 [1.12, 1.28]), terazosin (1.11 [1.04, 1.19]), alfuzosin (1.12 [1.03, 1.22]), dutasteride (1.26 [1.19, 1.34]), and finasteride (1.13 [1.07, 1.19]). The significance of these findings persisted in sensitivity analyses. CONCLUSION: Tamsulosin may increase the risk of dementia in older men with BPH.

Evaluación de efectividad y seguridad de finasterida, para el tratamiento en hiperplasia benigna de próstata / Evaluation of effectiveness and safety of finasteride, for the treatment in benign prostatic hyperplasia

Introducción: La hiperplasia prostática benigna (HPB) es una enfermedad cuya incidencia se ha incrementado con el aumento de la esperanza de vida conseguido en las últimas décadas. En Colombia alrededor del 30% de los hombres mayores de 50 años presentan hiperplasia prostática benigna. El objetivo del tratamiento en HPB va dirigido a aliviar o mejorar los síntomas del tracto urinario inferior. Los medicamentos que más frecuentemente se utilizan son los antagonistas alfa-adrenérgicos (doxazosina, alfuzosina, terazosina y tamsulosina) y los inhibidores de la 5 alfa reductasa (finasterida y dutasterida). Objetivo: Evaluar la efectividad y seguridad de finasterida para el tratamiento de HPB en comparación con dutasterida, terazosina, alfuzosina, tamsulosina, doxazosina y terapia combinada. Metodología: se realizó una evaluación crítica a través de una búsqueda sistemática en bases de datos electrónicas, diseñadas con vocabulario controlado y no controlado, además, de indagar con expertos sobre la disponibilidad de estudios publicados y no publicados, en inglés y español, la tamización de los resultados fue llevada a cabo por 2 revisores expertos. Los hallazgos de efectividad y seguridad fueron extraídos de los estudios con mejor calidad metodológica, buscando obtener información para todas las comparaciones y desenlaces de interés. Resultados: La efectividad de la finasterida comparada con la terazosina y doxazosina, mostró una mejoría en la puntuación de la escala IPSS a favor de terazosina -2.80 (IC 95% -3.88 a -1.72) (p < 0.01) y a favor de doxazosina (N = 489, DM: 1.70, IC 95%: 0.58, 2.82), (P=0,001), no mostro ninguna diferencia estadísticamente significativa con tamsulosina, alfuzosina y dutasterida. En relación a la seguridad, se presenta una mayor probabilidad de hipotensión en los pacientes tratados con terazosina que en los tratados con finasterida, pero no se presentan diferencias en seguridad con respecto a doxazosina, tamsulosina, alfuzosina y dutasterida. Conclusiones: La finasterida fue menos efectiva que la terazosina y la doxazosina en la disminución de puntos de la escala IPSS, pero igualmente efectiva que la tamsulosina, alfuzosina y dutasterida. Seguridad: La finasterida tuvo un menor riesgo de hipotensión postural al compararla con terazosina, pero no se presentó ninguna diferencia estadísticamente significativa entre finasterida y doxazosina, tamsulosina, alfuzosina y dutasterida.(AU)

Evaluación de efectividad y seguridad de finasterida, para el tratamiento en hiperplasia benigna de próstata / Evaluation of effectiveness and safety of finasteride, for the treatment in benign prostatic hyperplasia

Antecedentes: Descripción de la condición de salud de interés: La hiperplasia prostática benigna es una de las enfermedades benignas más comunes en el hombre. Se define histológicamente como el crecimiento de la \r\nglándula de la próstata a partir de la hiperplasia progresiva de sus células y estroma. Clínicamente, se refiere a los síntomas del tracto urinario inferior (STUI) asociados con el crecimiento benigno de la próstata que causa eventualmente obstrucción del tracto urinario inferior. Descripción de la tecnología: Está indicada en el tratamiento de la hiperplasia prostática benigna (HPB) sintomática en varones con aumento de tamaño \r\nde la próstata con objeto de: mejorar los síntomas, reducir el riesgo de retención urinaria aguda, reducir la necesidad de cirugía, incluidas la resección transuretral de la próstata (RTUP) y la prostatectomía. Información de la tecnología: La finasterida produce regresión del crecimiento prostático, mejora el flujo urinario y mejora los síntomas relacionados con la Hiperplasia beninga prostática. Evaluación de efectividad y seguridad: ¿Cuál es la efectividad y seguridad de finasterida en comparación con alfuzosina, doxazosina, tamsulosina y terazosina, para el tratamiento de Hiperplasia Benigna de Próstata? La pregunta de evaluación fue refinada y validada con base en: autorización de mercadeo de las tecnologías para la indicación de interés (registro sanitario INVIMA), listado de medicamentos vitales no disponibles, cobertura de las tecnologías en el Plan Obligatorio de Salud (POS) (Acuerdo 029 de 2011), revisión de grupos terapéuticos (clasificación ATC: Anatomical, Therapeutic, Chemical classification system), recomendaciones de guías de práctica clínica actualizadas, disponibilidad de evidencia sobre efectividad y seguridad (reportes de evaluación de tecnologías y revisiones sistemáticas de la literatura), uso de las tecnologías (listas nacionales de recobro, estadísticas de prescripción, etc), estudios de carga de enfermedad y consulta con un experto temático (especialista clínico). No se identificaron otros comparadores relevantes para la evaluación. Población: Pacientes con diagnóstico de Hiperplasia Benigna de Próstata. Metodología: Búsqueda de literatura, Búsqueda en bases de datos electrónicas. Conclusiones: Una revisión sistemática de buena calidad, que incluyó estudios para evaluar la efectividad y seguridad del finatesterida comparado con alfa-bloqueadores como la terazosina y doxazosina, mostro que existen diferencias estadísticamente significativas en desenlaces relacionados con síntomas obstructivos bajos, medidos con escalas validadas. No se encuentran diferencias significativas con la tamsulosina, no se encontraron estudios que realicen la comparación directa con la alfuzosina por lo cual sobre este último no se puede emitir una conclusión en esta revisión. En cuanto a los eventos secundarios reportados, excepto por una mayor probabilidad de presentar hipotensión en el grupo tratado con terazosina, en comparación con finasterida, no se evidencio ninguna otra diferencia estadísticamente significativa entre finasterida y otros alfa-bloqueadores.

A randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with prostate cancer. Efficacy monitored by karyometry.

OBJECTIVE: Presurgical, window of opportunity trials have been proposed as a model to assess the activity of preventive and therapeutic interventions in a cost-effective manner in prostate cancer (CaP). The aim of the study was to explore karyometry as a method for monitoring the efficacy of intervention with preventive agents in patients with CaP. MATERIALS AND METHODS: The material used in this investigation was from the 2F study, i.e., an Italian prospective randomized phase IIb presurgical study of finasteride vs. low-dose flutamide vs. placebo in men with CaP. Image analysis was performed in 16 cases treated with finasteride, 24 with flutamide, and 20 with placebo. For all these cases, CaP and normal looking secretory epithelium were present in the pretreatment biopsies as well as the post-treatment ex-vivo biopsies obtained from the radical prostatectomy specimens. RESULTS: To establish a direction of nuclear change from normal to malignancy, i.e., the so-called line of progression, a discriminant function was derived with the normal looking epithelium in the pretreatment biopsies as one endpoint, and the CaP in the pretreatment biopsies as the other. The discriminant function was then applied to the post-treatment groups. The increase in relative nuclear area was the dominant feature. In the placebo group, 15 out of 20 CaP (75%) cases had a higher discriminant function score at the end of study, with a significant increase of the mean score by 90%. The flutamide treated CaP cases had increased discriminant function scores in 19 out of 24 cases (79%) and an increase of the mean score by 43%; the 5 cases with lower scores involved only minor reductions. In contrast, the finasteride treated CaP cases had increased discriminant function scores for 8 out of 16 cases (50%), but the increase in the mean score was by only 8%. CONCLUSION: This exploratory study establishes that karyometric monitoring can track the results of subtle nuclear changes induced by preventive interventions in men with CaP, thus allowing assessment of agent activity in a cost-effective manner.

Global photographic assessment of men aged 18 to 60 years with male pattern hair loss receiving finasteride 1 mg or placebo.

BACKGROUND: Finasteride (1 mg) has been shown to increase vertex hair growth in men aged 18 to 60 years with male pattern hair loss and to increase frontal scalp hair growth in subjects aged 18 to 41 years. OBJECTIVE: A secondary efficacy analysis was conducted to determine effects of finasteride (1 mg) on scalp hair growth in the 4 distinct scalp regions affected by male pattern hair loss. METHODS: Multicenter, double-blind studies randomized patients with vertex hair loss (men aged 18-41 and 41-60 years) to finasteride (1 mg/d) or placebo. Efficacy was evaluated by review of standardized clinical photographs (global photographic assessment) of the vertex, anterior/mid scalp regions, and frontal and temporal hairlines over 24 months relative to baseline. RESULTS: At 24 months, treatment with finasteride resulted in statistically significant (P ≤ .05) hair growth versus placebo in all scalp regions. There was also a significant decrease in hair loss in the younger men treated with finasteride in all areas, but only in the vertex and anterior/mid scalp regions in the older men. A slightly higher incidence of drug-related sexual adverse experiences was reported in the finasteride group than in the placebo group, irrespective of age. LIMITATIONS: These studies enrolled men with vertex pattern hair loss; therefore, the findings may not be extrapolated to men with predominantly anterior/mid scalp, frontal, or temporal hair loss. CONCLUSION: Based on global photographic assessment, finasteride (1 mg) is able to increase hair growth in all areas of the scalp affected by male pattern hair loss.

What's wrong with chemoprevention of prostate cancer?

When prostate-specific antigen (PSA) testing was introduced, proponents expected it to cut prostate-cancer mortality and did not expect it to unleash an epidemic of unnecessary treatments. Now that evidence of a mortality benefit remains unclear while evidence of overtreatment in undeniable, there is understandable interest in reducing the human costs of the PSA system. Two related drugs, finasteride and dutasteride, both proven to reduce the incidence of prostate cancer and the "risk of diagnosis," are being promoted accordingly. However, if not for the flaws of the PSA system the use of these drugs for purposes of prevention would lose its rationale. Not only are the drugs in this sense dependent on a faulty system, but their own mortality benefits are as speculative as PSA's-in addition to which, they introduce new risks.

A rapid, simple, specific liquid chromatographic-electrospray mass spectrometry method for the determination of finasteride in human plasma and its application to pharmacokinetic study.

A fast, accurate, sensitive, selective and reliable method using reversed-phase high-performance liquid chromatography-mass spectrometry coupling with an electrospray ionization interface was developed and validated for the determination of finasteride in human plasma. After deprotienation with acetonitrile, centrifugation, evaporation to dryness and dissolving in mobile phase, satisfactory separation was achieved on a Hypersil-Keystone C(18) reversed-phase column using a mobile phase consisting of acetonitrile-water (46:54, v/v), 0.1% acetic acid and 0.1% trifluoracetic acid. Carbamazepine (IS) was used as internal standard. This method involved the use of the [M+H](+) ions of finasteride and IS at m/z 373 and 237 with the selective ion monitoring (SIM) mode. The calibration curve was linear in the range of 0.2-120 ng ml(-1). The limit of quantification for finasteride in plasma was 0.2 ng ml(-1) with good accuracy and precision. The intra-assay precision and accuracy were in the range of 2.1-11.2% and -1.3% to 8.5%, respectively. The inter-assay precision and accuracy were in the order of 3.4-12.1% and -1.5% to 11.5%, respectively. The mean sample extract recoveries of the method were higher than 85% and 74% for finasteride and internal standard (IS), respectively. The assay has been successfully used to estimate the pharmacokinetics of finasteride after oral administration of a 5mg tablet of finasteride to 24 healthy volunteers.