Pharmacotherapy for neurogenic lower urinary tract dysfunction

Transcription

1 Pharmacotherapy for neurogenic lower urinary tract dysfunction Prof. Enrico Finazzi Agrò Unit of Functional Urology Tor Vergata University Hospital S. Lucia Rehabilitation Hospital Rome, ITALY

2 Enrico Finazzi Agrò Affiliations to disclose: Enter Organisation/Relationship Funding for speaker to attend: Enter X in appropriate box Self-Funded Institution (non-industry) funded X Sponsored by: ICS

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4 ANTIMUSCARINIC AGENTS

5 Antimuscarinic drugs on the market Oxybutynin (IR mg/day, IR 15 mg/day, TDS mg/day) Tolterodine (IR 2mg/day, IR 4 mg/day, ER 4mg/day) Propiverine, (IR 30mg/die, IR 45 mg/die, ER 20mg/die, ER 30 mg/die) Trospium, (40mg/die) Solifenacin (5mg/day, 10 mg/day) Darifenacin (7.15 mg/day, 15 mg/day) Fesoterodine (4 mg/day, 8 mg/day) Novara G., et al., Eur Urol, 2008

6 - - Membr. Cell. M 2 M 3 3 AC PLC + + camp Ca 2+ IP 3 relaxation contraction Ca 2+ contraction Chapple CR. Urology. 2000;55:33-46

7 In the denervated rat bladder, there is a 60% increase in M2 receptor density and these M2 receptors provide some contractile function. Braverman AS: Am J Physiol 1998 In the human bladder with NGB M2 receptors were found to mediate contractions in one study, but were found to play no part in bladder contractions in another. Pontari MA: Am J Physiol Regul Integr Comp Physiol 2004 Stevens LA: Eur Urol 2007

8 Thirty studies (16 RCT), 1479 patients Efficacy of AM in NDO, following 2 3 weeks of treatment no placebo effects manifested.

9 Other important parameters (impact on the upper urinary tract, continence, post-void residual urine, catheterization, urinary tract infections and quality of life) investigated to a limited extent only. Incidence rates of adverse events were comparable for NDO and IDO.

10 Most of the studies, especially RCT, were undertaken with oxybutynin immediate release (IR), trospium chloride IR, propiverine IR and propiverine extended release. In NDO, these drugs are best investigated.

11 Solifenacin 10mg significantly improved mean change from baseline MCC versus placebo (P<0.001) and was associated with improvements in bladder volume at first contraction and at first leak as well as detrusor pressure at first leak. Patient perception of bladder condition significantly improved with solifenacin 10mg versus placebo (P<0.041).

12 [NOME CATEGORIA]S [PERCENTUALE] [NOME CATEGORIA]S [PERCENTUALE]

13 [NOME CATEGORIA]S [PERCENTUALE] [NOME CATEGORIA]S [PERCENTUALE]

14 In the NGB population higher doses are required compared to the non-neurogenic population to be effective. Intravesical administration also used Bennett N: J Urol 2004 Buyse G: J Urol 1998

15 Dual therapy with AM Dual therapy (between combinations of oxybutynin, tolterodine and trospium) has been shown to be effective and well tolerated in a few patients with neurogenic bladder dysfunction Amend B et al Eur Urol. 2008

16 Safety and tolerability

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18 Oxybutynin associated with cognitive deficits MS and probably stroke and Parkinson s diseases pts may have an increase in permeability of BBB. New evidence that higher cumulative antimuscarinic usage is associated with an increase in the incidence of dementia and Alzheimer s Gray SL: JAMA Intern Med 2015

19 Prescriptions, in thousands Despite the Evidence, Fewer Men than Women Are Treated with Antimuscarinics OAB prescriptions BPH prescriptions Female Male 4 Times fewer OAB prescriptions are written for men Male Men with LUTS are treated mainly for prostate conditions Data collected over 12 months. OAB prescriptions include all antimuscarinics. BPH prescriptions include all alpha-blockers and 5- ARIs. Verispan Patient Longitudinal Data, MAT IMS NPA, MAT

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22 Safety of Tolterodine IR in Men with OAB/DO and BOO: AEs Urinary Symptom AEs Placebo (n = 72) Tolterodine IR (n = 149) n % n % Micturition disorder Urinary tract infection Dysuria Micturition frequency Micturition urgency Strangury AUR Bladder discomfort Urethral disorder Urinary incontinence Overall AE = adverse event. Abrams P et al. J Urol. 2006;175:

23 TIMES: Change in PVR Parameter Placebo (N = 215) Tolterodine ER (N = 210) Tamsulosin (N = 209) Tolterodine ER/ Tamsulosin (N = 217) Mean at baseline Mean at week Mean change to week

24 Significance of PVR PVR and Antimuscarinics in men It is common belief that antimuscarinics should not be used in men with BOO for a potential of AUR. Some placebo controlled clinical trial data suggest that antimuscarinics (alone or in combination with an alphablocker) do not increase the risk of AUR and do not produce a clinically significant increase of PVR in men, even in presence of BPO. Roehrborn CG,et al. Urology Nov;72(5):1061-7; discussion Athanasopoulos A, et al. Eur Urol Jul;60(1): However, patients with significant PVR were excluded from these studies and the safety of antimuscarinics in men remains to be confirmed. Teaching Module 24

25 Most studies recommend not utilizing AM drugs in patients with PVR >200 cc

26 MIRABEGRON

27 - - Membr. Cell. M 2 M 3 3 AC PLC + + camp Ca 2+ IP 3 relaxation contraction Ca 2+ contraction Chapple CR. Urology. 2000;55:33-46

28 Other drug classes to treat OAB? Despite intensive research, few new therapeutic principles have emerged and been demonstrated to have sufficient efficacy and adverse effect profiles to be accepted for approval and clinical use 1 Research indicated that stimulation of β 3 -receptors leads to bladder relaxation Discovery of β 3 -adrenoceptors, predominately present on the bladder wall development of β 3 -adrenoceptor agonist FDA-approval β 3 -agonist First FDA-approved antimuscarinic agent Andersson KE. Curr Urol Rep 2013;doi: /s ; 2. Kennelly MJ Rev Urol 2010;12:12-9; 3.

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30 EAU guidelines 2016

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32 Nitti VW et al. J Urol 2013; 190:

33 Mirabegron in BOO pts. Bladder Contractility Index Bladder Voiding Efficiency Nitti VW et al. J Urol 2013; 190:

34 American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (2012) Drugs with strong anticholinergic properties Antihistamines Antiparkinson agents Skeletal muscle relaxants Brompheniramine Chlorpheniramine Cyproheptadine Diphenhydramine Loratadine Antidepressants Carbinoxamine Clemastine Dimenhydrinate Hydroxyzine Meclizine Benztropine Trihexyphenidyl Antipsychotics Carisoprodol Cyclobenzaprine Orphenadrine Tizanidine Amitriptyline Clomipramine Doxepin Nortriptyline Protriptyline Amoxapine Desipramine Imipramine Paroxetine Trimipramine Antimuscarinics (urinary incontinence) Darifenacin Flavoxate Solifenacin Trospium Fesoterodine Oxybutynin Tolterodine Chlorpromazine Fluphenazine Olanzapine Pimozide Promethazine Thiothixene Antispasmodics Atropine products Belladonna alkaloids Dicyclomine Homatropine Hyoscyamine products Propantheline Scopolamine Clozapine Loxapine Perphenazine Prochlorperazine Thioridazine Trifluoperazine

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36 Mirabegron was well tolerated in older OAB patients with no difference in tolerability with age over a 1-year period. UTI and hypertension were the most frequent AE found in the population. However, in elderly subjects, these AE were more frequent in people treated with tolterodine than those under mirabegron over 12 months

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38 Nota Informativa Importante su mirabegron: nuove raccomandazioni relative al rischio di aumento della pressione arteriosa Pillole dal Mondo n /09/2015 L uso di mirabegron è ora controindicato nei pazienti affetti da ipertensione grave non controllata, intesa come Pressione Arteriosa Sistolica 180 mmhg e/o Pressione Arteriosa Diastolica 110 mmhg. È, quindi, necessario misurare la pressione arteriosa prima di intraprendere il trattamento e monitorarla regolarmente durante lo stesso, specialmente nei pazienti affetti da ipertensione

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40 Mirabegron CV Tolerability Pooled 12-week Phase III Studies (046, 047 and 074) CV Events Placebo (n=1380) 25mg (n=432) Mirabegron 50mg (n=1375) 100mg (n=929) Tolterodine ER 4mg (n=495) Incidence, n(%) of APTC/MACE 4 (0.3) (0.2) Relative risk of APTC/MACE (95% CI) - NE NE NE - 1-year Phase III Study (049) CV Events Mirabegron Tolterodine ER 4mg (n=812) 50mg (n=812) 100mg (n=820) Incidence, n(%) of APTC/MACE 6 (0.7) * 0 4 (0.5) ** Relative risk of APTC/MACE (95% CI) 1.50 (0.35, 7.27) NE - NE = not evaluated due to insufficient data * nonfatal stroke (3 patients), nonfatal myocardial infarction (2 patients) and CV death (1 patient) ** CV death (2 patients), nonfatal myocardial infarction (1 patient) and nonfatal stroke (1 patient) Rosa et al., Eur Urol Eur Urol Feb;69(2):311-23

41 The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents

42 ADD ON THERAPY?

43 ADD ON THERAPY? Incontinence episodes

44 DESMOPRESSIN

45 Spinal cord injured patients often have high urine output at night, particularly those with higher level lesions. Szollar S: Paraplegia 1995 Rule out UTI and glucosuria, congestive heart failure, improper timing of diuretic administration, sleep apnea and renal failure

46 Desmopressin Optimize bladder management Restrict fluids before bed Perform voiding diary Desmopressin treatment evaluated in few studies on SCI and MS patients with favorable results.

47 Desmopressin Check renal function and sodium levels Start with 120 mcg/day (in adults) Check sodium level and blood pressure frequently Not indicated for patients >65 years

48 ALPHA-BLOCKERS

49 1-receptors

50 Q max (ml/s) Alfa-blockers: Quick Qmax increase ,5* Alfuzosina 10 mg ,3 9,4 Placebo 6 4 Basal 8 hours *p=0, Mod. da Marks LS et al. Urology 2003; 62:

51 IPSS Alfa-blockers: LUTS improvement 0 *p<0,001 vs basale * -32% vs basale -6 * * * -7-8 Basal (n=2.777) M3 (n=2.662) M6 (n=2.385) M9 (n=1.575) M12 (n=2.055) Visite 8. Van Moorselaar RA et al. BJU Int 2005; 95:

52 Alpha-Blockers (filling phase) Can both improve storage and emptying symptoms in patients with NGB. Terazosin 5 mg showed good urodynamic improvement (reduction of detrusor pressure during filling) in a small group of SCI patients Swierzewski SJ J Urol 1994

53 Alpha-Blockers (voiding phase) In individuals who can spontaneously void alpha blockers have been shown to be effective. Symptomatic and urodynamic improvement in pts with DSD, SCI and MS. Stankovich E: Urologiia 2004 Kakizaki H: Int J Urol 2003 O'Riordan JI: J Urol 1995

54 Alpha-Blockers (autonomic dysr.) Terazosin has been shown to reduce the frequency of autonomic dysreflexia episodes and the severity of the symptoms in SCI pts with only minor side effects of fatigue and dizziness Chancellor MB: J Urol 1994

55 Conclusions

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