Evidencia disponible acerca del uso del agonista B3- adrenoceptor selectivo mirabegrón para el tratamiento de la vejiga hiperactiva / Evidence available on the use of the selective B3- adrenoceptor agonist mirabegron for the treatment of overactive bladder

Contexto: Mirabegrón, agonista adrenoreceptor β3, supone el último desarrollo farmacológico para el tratamiento de la vejiga hiperactiva (VH).Objetivo: Presentar la evidencia disponible respecto a la eficacia y tolerancia de mirabegrón y discutir el potencial de dicho tratamiento en nuestro entorno. Adquisición de evidencia: Se revisan 11 estudios llevados a cabo con mirabegrón en pacientes con VH (2 fase II , 9 fase III ), todos en comparación con placebo y 6 de ellos incluyeron también tolterodina como brazo adicional. Se hace mayor énfasis en los principales ensayos fase III llevados a cabo en Europa, EE. UU. y Australia que evalúan la eficacia y seguridad a 12 semanas (NCT00662909, NCT00689104, NCT00912964) y la seguridad a 12 meses (NCT00688688). Se dispone también del análisis combinado de dichos estudios a 12 semanas, enfatizando en la eficacia global (FAS), la eficacia relativa a la incontinencia (FAS- I) y la seguridad (SAF). Más del 50% de los pacientes había abandonado previamente la medicación anticolinérgica para VH, lo que permite también obtener datos acerca de la efectividad de mirabegrón en pacientes tratados previamente con anticolinérgicos. Síntesis de evidencia: Mirabegrón es un fármaco eficaz que muestra una reducción estadísticamente significativa en número de episodios de incontinencia y en frecuencia miccional a partir de la 4.a semana, con mayor porcentaje tanto de pacientes secos como de pacientes con reducción ≥ 50% en número de episodios de incontinencia que placebo. La eficacia de mirabegrón 50 y 100 mg en la reducción en episodios de incontinencia sucede en pacientes nuevos y que han recibido antimuscarínicos, siendo la diferencia media ajustada y la mejora en la frecuencia miccional mayor en pacientes tratados. Su tolerancia es muy similar a placebo, particularmente para los efectos adversos de los antimuscarínicos (boca seca, estreñimiento y visión borrosa). Se aprecia un cambio mínimo no clínicamente significativo en la presión arterial sistólica, en la diastólica y en el pulso. Su eficacia se mantiene a largo plazo. Mirabegrón a dosis de 50 y 100 mg presenta mejoría frente placebo en la satisfacción del paciente, en la calidad de vida relacionada con la salud (HRQoL), en las molestias de síntomas y en la percepción del paciente de la condición vesical (PPBC). En el estudio europeo fase III a 12 semanas tolterodina proporcionó mejoría en menor medida que mirabegrón frente a placebo en la satisfacción del paciente, HRQoL, molestia de síntomas y PPBC (AU)

Context: Mirabegron, the selective β3-adrenoceptor agonist, heralds the latest development for the treatment of overactive bladder (OAB). Objective: To present the evidence available on the efficacy and tolerability of mirabegron and to discuss this treatment's potential in our setting. Evidence acquisition: We reviewed 11 studies conducted with mirabegron in patients with OAB (2 phase II, 9 phase III, all studies were compared to placebo with 6 studies also including tolterodine as an additional arm. Greater emphasis shall be given to the main phase III trials performed in Europe, the USA and Australia evaluating efficacy and safety after 12 weeks (NCT00662909, NCT00689104, NCT00912964) and safety after 12 months (NCT00688688). The combined analyses of these 12-week studies are also available, with emphasis on global efficacy (FAS), efficacy with regard to incontinence (FAS I ) and safety (SAF). More than 50% of patients had previously discontinued anticholinergics medication for OAB, thus allowing us to obtain data on the effectiveness of mirabegron in patients already treated with anticholinergics. Evidence synthesis: Mirabegron is an efficacious drug which presents a statistically significant reduction in the number of incontinence episodes and in urinary frequency as of 4 weeks, with a higher percentage of dry patients and a higher percentage of patients with reduction ≥50% in the number of incontinence episodes than placebo. The efficacy of mirabegron 50 and 100 mg in the reduction of incontinence episodes occurs in de novo patients and who have received antimuscarinics, with adjusted mean difference and improvement in urinary frequency greater in treated patients. Its tolerability is very similar to placebo particularly for the adverse effects of the antimuscarinics (dry mouth, constipation and blurred vision). A minimal, non-clinically significant change is observed in systolic and diastolic blood pressure and pulse. Its efficacy is long-term. Mirabegron at the doses of 50 and 100 mg presents an improvement versus placebo in patient satisfaction, health-related quality of life (HRQoL), symptom bother and patient's perception of bladder condition (PPBC). In the 12-week phase III European study tolterodine deliverred a lesser degree of improvement than mirabegron versus placebo in patient satisfaction, HRQoL, symptom bother and PPBC. Conclusions: Mirabegron is the first of a new class of compounds with a novel mechanism of action that is different to the antimuscarinics. It presents significant and clinically important efficacy in the treatment of the symptoms of OAB. It has advantages with regard to the results described by the patient in treatment satisfaction. Studies on its combined use with anticholinergics are ongoing (AU)

Evidence available on the use of the selective ß3-adrenoceptor agonist mirabegron for the treatment of overactive bladder.

CONTEXT: Mirabegron, the selective ß3-adrenoceptor agonist, heralds the latest development for the treatment of overactive bladder (OAB). OBJECTIVE: To present the evidence available on the efficacy and tolerability of mirabegron and to discuss this treatment's potential in our setting. EVIDENCE ACQUISITION: We reviewed 11 studies conducted with mirabegron in patients with OAB (2 phase II, 9 phase III), all studies were compared to placebo with 6 studies also including tolterodine as an additional arm. Greater emphasis shall be given to the main phase III trials performed in Europe, the USA and Australia evaluating efficacy and safety after 12 weeks (NCT00662909, NCT00689104, NCT00912964) and safety after 12 months (NCT00688688). The combined analyses of these 12 week studies is also available, with emphasis on global efficacy (FAS), efficacy with regard to incontinence (FAS i) and safety (SAF). More than 50% of patients had previously discontinued anticholinergics medication for OAB, thus allowing us to obtain data on the effectiveness of mirabegron in patients already treated with anticholinergics. EVIDENCE SYNTHESIS: Mirabegron is an efficacious drug which presents a statistically significant reduction in the number of incontinence episodes and in urinary frequency as of 4 weeks, with a higher percentage of dry patients and a higher percentage of patients with reduction ≥50% in the number of incontinence episodes than placebo. The efficacy of mirabegron 50 and 100mg in the reduction of incontinence episodes occurs in de novo patients and who have received antimuscarinics, with adjusted mean difference and improvement in urinary frequency greater in treated patients. Its tolerability is very similar to placebo particularly for the adverse effects of the antimuscarinics (dry mouth, constipation and blurred vision). A minimal, non-clinically significant change is observed in systolic and diastolic blood pressure and pulse. Its efficacy is long-term. Mirabegron at the doses of 50 and 100mg presents an improvement versus placebo in patient satisfaction, health-related quality of life (HRQoL), symptom bother and patient's perception of bladder condition (PPBC). In the 12 week Phase III European study tolterodine delivered a lesser degree of improvement than mirabegron versus placebo in patient satisfaction, HRQoL, symptom bother and PPBC. CONCLUSIONS: Mirabegron is the first of a new class of compounds with a novel mechanism of action that is different to the antimuscarinics. It presents significant and clinically important efficacy in the treatment of the symptoms of OAB. It has advantages with regard to the results described by the patient in treatment satisfaction. Studies on its combined use with anticholinergics are ongoing.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies.

INTRODUCTION: To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results. METHODS: This prespecified pooled analysis of three randomised, double-blind, placebo-controlled, 12-week studies, evaluated efficacy and safety of once-daily mirabegron 25 mg (safety analysis), 50 or 100 mg (efficacy and safety analyses) and tolterodine ER 4 mg (safety analysis) for the treatment of symptoms of overactive bladder (OAB). Co-primary efficacy measures were change from baseline to Final Visit in the mean number of incontinence episodes/24 h and mean number of micturitions/24 h. Key secondary efficacy end-points included mean number of urgency episodes/24 h and mean volume voided/micturitions, while other end-points included patient-reported outcomes according to the Treatment Satisfaction-Visual Analogue Scale (TS-VAS) and responder analyses [dry rate (posttreatment), ≥ 50% reduction in incontinence episodes/24 h, ≤ 8 micturitions/24 h (post hoc analysis)]. The safety analysis included adverse event (AE) reporting, laboratory assessments, ECG, postvoid residual volume and vital signs (blood pressure, pulse rate). RESULTS: Mirabegron (50 and 100 mg once daily) demonstrated statistically significant improvements compared with placebo for the co-primary end-points, key secondary efficacy variables, TS-VAS and responder analyses (all comparisons p < 0.05). Mirabegron is well tolerated and demonstrates a good safety profile. The most common AEs (≥ 3%) included hypertension, nasopharyngitis and urinary tract infection (UTI); the incidence of hypertensive events and UTIs decreased with increasing dose. For mirabegron, the incidence of the bothersome antimuscarinic AE, dry mouth, was at placebo level and of a lesser magnitude than tolterodine. CONCLUSION: The efficacy and safety of mirabegron are demonstrated in this large pooled clinical trial dataset in patients with OAB.

The rectal administration of lignocaine gel and periprostatic lignocaine infiltration during transrectal ultrasound-guided prostate biopsy provides effective analgesia.

INTRODUCTION: Transrectal ultrasound guided prostate needle biopsy (TRUS) is the standard procedure to diagnose or exclude prostate cancer. This procedure can be associated with significant discomfort, both on insertion of the ultrasound probe as well as on taking the biopsy. We evaluated a new technique for pain relief during TRUS biopsy. PATIENTS AND METHODS: In Group 1 (n = 60), the biopsies were taken without any analgesia. In Group 2 (n = 60), 11 ml of Instillagel (2% lignocaine) was administered rectally prior to probe insertion and 5 ml of 1% lignocaine periprostatic injection was administered before taking the biopsy. The discomfort encountered during the procedure was graded by the patient on a scale ranging from no discomfort to mild, moderate and severe pain. RESULTS: In Group 2, there was a marked reduction in the pain experienced during the procedure. The Chi-squared test for trend showed a significant association between the rectal administration of local anaesthetic gel and reduction in pain on probe insertion (P = 0.0001). There was also a significant association between the use of periprostatic lignocaine injection and reduction in pain on taking the biopsy (P < 0.0001). CONCLUSIONS: The use of lignocaine gel prior to probe insertion and periprostatic infiltration of lignocaine before taking the needle biopsy significantly reduces the pain experienced by the patient during TRUS-guided prostate biopsy.

Changes in cholinergic and purinergic neurotransmission in the diabetic rabbit bladder.

BACKGROUND: Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes in autonomic receptors and alterations in detrusor structure and function. The changes in cholinergic and purinergic neurotransmission in the DM rabbit bladder were evaluated. MATERIALS AND METHODS: DM was induced with alloxan in adult male New Zealand White rabbits. At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in organ baths. Transmural electrical field stimulation (EFS: supramaximal voltage, 0.1 ms duration, 10 s trains) was performed in the presence of atropine (10(-6) M) or alpha, beta-methylene ATP (10(-6) M), and after adding tetrodotoxin10(-6) M. Purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components were calculated independently and compared with those from controls. RESULTS: Both normal and DM detrusor and bladder neck strips contracted in a frequency-dependent fashion in response to transmural EFS. A plot of EFS vs. detrusor contractility showed a decrease (ANOVA < 0.001) in the cholinergic nerve-mediated component, whereas the purinergic nerve-mediated component was increased (ANOVA < 0.001) in the DM detrusor compared to the control. The total EFS- and KCl-induced responses were unaltered in the DM group compared to the controls. There was no difference in purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components in strips from the bladder neck for both normal and DM rabbits. CONCLUSION: These results suggest that an enhancement of purinergic and a reduction of cholinergic neurotransmission occur in the detrusor muscle of the diabetic rabbit. These changes may contribute to the pathophysiology of diabetic cystopathy.