LAMAs en asma; ¿cuándo, cómo y a quién? Solo tiotropio y umeclidinio tienen ensayos en ClinicalTrial.gov Cruz del Sur 2Simposiodomingo 12Enfermedades obstructivas e inmunología08:30 - 09:30"Avances en ASMA "PresidenteCarlos Sebastián WUSTTEN    SecretarioAlejandro RAIMONDI      08:30 - 09:00Novedades GINA 2014DisertanteFederico Daniel COLODENCO      09:00 - 09:30Uso de LAMAs en Asma , cuando , como y a quienDisertanteLuis Javier NANNINI   Luis J Nannini

Declaración de intereses de LJNannini Investigador principal en estudios clínicos de ASTRAZENECA, GENEXION, NOVARTIS, SCHERING PLOUGH, MSD, FOREST LAB. ROCHE-GENENTECH. Disertante de BI, MSD, Phoenix, Takeda, Novartis y AstraZeneca. Reuniones de Comité asesor: AZ y Novartis. 2

Nivel de evidencia D A propósito de un caso Mujer 73 años. 98 kg 160 cm (BMI=38). FEV1/FVC= 0,64 Flut500+Salm 50 BID + montelukast. Nunca fumó. Mprednisona 40 mg 3 cursos de 7 días; últimos 3 meses. DBT metaesteroidea. Hipertensión arterial Día cero pre tiotropio Día 50 de tiotropio FVC L (%teórico) 1,83 (65 %) 2,05 (73 %) FEV1 L (%teórico) 1.04 (49 %) 1,32 (62 %) ACQ 6+6+5+5+3+3= 4,7 0+0+0+0+0+1=0,16 la acción anti inflamatoria es nula? Alguien se animaría a los tres meses a retirar el Seretide? Si bien nunca fumó el Tiffenaou <0,7 la asemeja a una EPOC. Nivel de evidencia D

¿Cómo: LAMA o LABA más ICS o triple terapia, polvo seco, respimat? ¿Cuándo  en escalón 4 a 5? ¿Cómo: LAMA o LABA más ICS o triple terapia, polvo seco, respimat? ¿A quiénes: arg16/arg16, ACOS, obesidad? ¿Cuál LAMA? ya tenemos al menos 2! ¿Cómo reducen las crisis y a la vez no mejoran FEV1, ni B2 rescate, ni calidad de vida? L J Nannini

¿Cómo actúan estas moléculas en asma?

Interacción receptores Beta2 y M. Lipworth B Br J Clin Pharmacol 2013/ 77:1 / 55–62 Figure 1 In humans there is no direct sympathetic innervation of the smooth muscle, but b2ADR (b2) are available to circulating adrenaline. Pre-synaptically the sympathetic nerves lie close to the parasympathetic system and are thought to influence b2ADR here. It is thought both b2ADR and M2 receptors are inhibitory to the release of acteylchoine (ACh) and that there is crosstalk between these receptor types (broken line).The M2 receptor is stimulated by ACh to reduce further ACh secretion.This M2 autoreceptor is thought to be defective in asthma and in response to viruses, hence this negative feedback is lost and there is increased airway hyperreactivity (AHR). Post-synaptically the muscarinic M3 receptor is the main parasympathetic bronchoconstrictor mechanism. Although post-synapticM2 receptors are present their role is to prolongM3 initiated bronchoconstriction by opposing the actions of b2ADR.Hence the same receptors may have different actions pre- and post-synaptically exerting independent effects on AHR and airway tone respectively Lipworth B Br J Clin Pharmacol 2013/ 77:1 / 55–62

La acetilcolina regula quimiotaxis y activación de células inflamatorias Kistemaker. Life science Fig. 1. The regulatory role of acetylcholine in inflammatory cell chemotaxis and activation. Acetylcholine can be neuronally released or secreted as an autocrine or paracrine hormone from inflammatory cells and airway structural cells, most notably airway epithelial cells. In susceptible individuals, the release of acetylcholine may be enhanced in response to environmental factors such as cigarette smoke or allergens. As a consequence, pro-inflammatory cytokines including IL-6, IL-8 and LTB4 are produced, which attract and activate inflammatory cells, most notably neutrophils.MuscarinicM3 receptors expressed on airway smooth muscle and muscarinicM1–3 receptors expressed by airway epithelial cells mediate the release of these factors via activation of ERK1/2 and NF-κB signaling pathways. L.E.M. Kistemaker et al. / Life Sciences 91 (2012) 1126–1133

Acetilcolina en remodelación Fig. 2. The regulatory role of acetylcholine in airway wall remodeling. Acetylcholine is neuronally released and secreted as an autocrine or paracrine hormone from airway structural cells and inflammatory cells. In the inflamed airway, inflammatory cells and airway epithelial cells also secrete growth factors that in concerted action with acetylcholine activate cell proliferation and matrix production by airway mesenchymal cells, including airway fibroblasts and airway smooth muscle cells. Furthermore, acetylcholine activates smooth muscle contraction leading to airway wall compression, which activates inflammatory cells and promotes remodeling responses by airway epithelial cells. Acetylcholine also directly promotes mucus production by and cell proliferation of airway epithelial cells. L.E.M. Kistemaker et al. / Life Sciences 91 (2012) 1126–1133

Los 5 principales trabajos The effect of adding tiotropium (TIO) on FEV1 in all studies was less than the minimal important difference (MID) of 0.23 l, and on asthma quality of life questionnaire (AQLQ) was less than MID of 0.5. XO, crossover; PG, parallel group. Duration of treatment shown in weeks. TIO5/10 mg refers to dose via fine mist Respimat device, while TIO18 mg refers to dose via dry powder Handihaler device. Reversibility is the % change in FEV1 at baseline after salbutamol/ipratropium. The tiotropium effect is shown as the difference in FEV1 compared with either inhaled corticosteroid (ICS) or inhaled corticosteroid with long acting b-adrenoceptor agonist (ICS/LABA). Values for FEV1 are shown as means (95% CI): *P < 0.05, **P < 0.01,***P < 0.001, NS: not significant Lipworth BJ Br J Clin Pharmacol / 77:1 / 55–62

Conclusiones de Brian Lipworth En todos los estudios, el efecto sobre FEV1 fue menor a la diferencia mínima clínicamente importante de 230 ml. Tampoco alcanzó la Dif MI de 0,5 en los cuestionarios de calidad de vida The effect of adding tiotropium (TIO) on FEV1 in all studies was less than the minimal important difference (MID) of 0.23 l, and on asthma quality of life questionnaire (AQLQ) was less than MID of 0.5. XO, crossover; PG, parallel group. Duration of treatment shown in weeks. TIO5/10 mg refers to dose via fine mist Respimat device, while TIO18 mg refers to dose via dry powder Handihaler device. Reversibility is the % change in FEV1 at baseline after salbutamol/ipratropium. The tiotropium effect is shown as the difference in FEV1 compared with either inhaled corticosteroid (ICS) or inhaled corticosteroid with long acting b-adrenoceptor agonist (ICS/LABA). Values for FEV1 are shown as means (95% CI): *P < 0.05, **P < 0.01,***P < 0.001, NS: not significant

Cambio FEV1 de 110 ml no es clínicamente significativo. Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266 Peters SP N Engl J Med 2010;363:1715-26. Qvar (beclometasona) 40 mcgx2 cada 12. diseño cruzado y corto= 14 sem Figure 3. Primary and Secondary Outcomes. Shown are the mean differences among patients receiving tiotropium, those receiving double-glucocorticoid, and those receiving salmeterol with respect to the morning peak expiratory flow (PEF) (Panel A), the evening PEF (Panel B), the prebronchodilator forced expiratory volume in 1 second (FEV1) (Panel C), and the proportion of asthma-control days per 14-day period (Panel D). The I bars indicate 95% confidence intervals. Peters SP N Engl J Med 2010;363:1715-26.

139 (5µg) y 170 ml (10µg) a 8 semanas= recordar MCID Nada logró en Calidad de vida ni med rescate. Kerstjens HAM JACI 2011 FIG 2. FEV1 (A) and FVC (B) responses relative to baseline values within 3 hours after dosing after 8 weeks of treatment. The difference in level at 0:00 h is the trough effect of tiotropium administered 24 hours earlier. The measurement obtained at baseline (visit 2 before any maintenance or study medication) is defined as the baseline value. At the on-treatment visits, this was immediately followed by the usual medication (including ICS plus LABA), and this in turn was followed by the study medication. Error bars represent SEMs. Arrows indicate the timing of the maintenance medication: ICS plus LABA. Tiotropium R5, 5 mg of tiotropium; Tiotropium R10, 10 mg of tiotropium. Bud200&form 2 y 2 Kerstjens HAM JACI 2011

Al pico FVC 100 ml y al valle 80 ml Tian Jing- Wei. Resp Care 2014

Improvement in FEV1 was not nearly the minimum clinical important difference of 230 ml in asthma

Despertar nocturno y BD rescate: No

Reducción 21% riesgo de crisis Indice riesgo= 0.79; P = 0.03. 912 pacientes en tto Bud 800 + LABA y etc. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. 16 internados vs 20 en placebo. 3,5% estaban con omalizumab, otros cort orales. Huib A.M. Kerstjens.N Engl J Med 2012;367:1198-207.

Respimat en asma moderada >400ICS sin LABA Tiotropio 5 mcg fue mejor que las otras dosis (4 sem cruzado) Beeh et al. Respiratory Research 2014, 15:61 Tiotropium Respimat® in asthma: a double-blind, randomised, dose-ranging study in adult patients with moderate asthma Figure 3 Adjusted mean differences in lung function responses. (A) Peak FEV1(0-3h) response; (B) Trough FEV1 response; Response defined as change from study baseline (pre-treatment value measured at Visit 2 in the evening). Adjusted mean difference from placebo Respimat®: *P < 0.001; **P < 0.01; ***P < 0.05. Bars: standard error. FEV1, forced expiratory volume in 1 second; NS, not significant; peak FEV1(0-3h), peak forced expiratory volume in 1 second measured within the first 3 hours after dosing. ABSTRACT Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, when administered via Respimat® SoftMist™ inhaler (tiotropium Respimat®) significantly reduces the risk of severe exacerbations and improves lung function in patients with severe persistent asthma that is not fully controlled despite using inhaled corticosteroids (ICS) and long-acting β2-agonists. To further explore the dose–response curve in asthma, we investigated the efficacy and safety of three different doses of tiotropium Respimat® as add-on to ICS in symptomatic patients with moderate persistent asthma. Methods: In this randomised, double-blind, placebo-controlled, four-way crossover study, patients were randomised to tiotropium Respimat® 5 μg, 2.5 μg or 1.25 μg or placebo Respimat®, once daily in the evening. Each treatment was administered for 4 weeks, without washout between treatment periods. Eligibility criteria included ≥60% and ≤90% of predicted normal forced expiratory volume in 1 second (FEV1) and seven-question Asthma Control Questionnaire mean score of ≥1.5. Patients were required to continue maintenance treatment with stable medium-dose ICS for at least 4 weeks prior to and during the treatment period. Long-acting β2-agonists were not permitted during the treatment phase. The primary efficacy end point was peak FEV1 measured within 3 hours after dosing (peak FEV1(0-3h)) at the end of each 4-week period, analysed as a response (change from study baseline). Results: In total, 149 patients were randomised and 141 completed the study. Statistically significant improvements in peak FEV1(0-3h) response were observed with each tiotropium Respimat® dose versus placebo (all P < 0.0001). The largest difference from placebo was with tiotropium Respimat® 5 μg (188mL). Trough FEV1 and FEV1 area under the curve (AUC)(0-3h) responses were greater with each tiotropium Respimat® dose than with placebo (all P < 0.0001), and both were greatest with 5 μg. Peak forced vital capacity (FVC)(0-3h), trough FVC and FVC AUC(0-3h) responses, versus placebo, were greatest with tiotropium Respimat® 5 μg (P < 0.0001, P = 0.0012 and P < 0.0001, respectively). Incidence of adverse events was comparable between placebo and all tiotropium Respimat® groups. Conclusions: Once-daily tiotropium Respimat® add-on to medium-dose ICS improves lung function in symptomatic patients with moderate asthma. Overall, improvements were largest with tiotropium Respimat® 5 μg. Trial registration: ClinicalTrials.gov identifier NCT01233284. Beeh et al. Respiratory Research 2014, 15:61

1º estudio en edad 12-14 años. ICS 4 sem sin LABA *p < 0.05 ***p < 0.001 Figure 2 Evening peak FEV1 within 3 h post-dose from baseline and trough FEV1 responses to tiotropium Respimat and placebo Respimat (full analysis set). *p < 0.05; ***p < 0.001 versus placebo Respimat. aThe number of patients within the full analysis set for whom the end point measurement is available. FEV1, forced expiratory volume in 1 s. Results: From 139 enrolled patients, 105 were randomised to receive one of four treatment sequences. Peak FEV1(0e3h) response for tiotropium 5 μg was significantly greater versus placebo (p Z 0.0043). Trough FEV1 responses were significantly greater for tiotropium 5 μg (p < 0.00001) and 1.25 μg (p Z 0.0134) versus placebo, but not for 2.5 μg (p Z 0.0975), while FEV1 area under the curve(0e3h) responses were significant for all doses (p Z 0.00001e0.0398). Overall incidence of adverse events was balanced across treatment groups, with no dose dependent observations. The majority of adverse events were mild to moderate in intensity. Conclusion: This first study of tiotropium in adolescents with symptomatic asthma demonstrates that tiotropium is well tolerated and efficacious as add-on to maintenance treatment with ICS. Vogelberg C. Respiratory Medicine (2014)

Tiotropio no inferior a salmeterol en genotipo B16arg/arg FIG 1. Trial design. At all visits, pulse, blood pressure, and predose pulmonary function test results (determined by means of spirometry) were measured. Patients measured PEF and FEV1 each morning and evening with an electronic peak flowmeter and recorded asthma symptoms and rescue medication use in an electronic diary (5-point rating scale from 1 5 no impairment to 5 5 greatest impairment). Todos con Budesonide más de 400 a 1000 mcg. Conclusion: Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable Bateman ED. J Allergy Clin Immunol 2011;128:315-22

Homeokinesis y variabilidad del calibre vía aérea humana en corto plazo sanos asma Fig. 1. A: raw data of total respiratory impedance (Zrs) measured at 6 Hz over a 15-min period in a normal subject (RC, top trace) and an asthmatic patient (LC, bottom trace). B: probability density distributions of Zrs for data in A in a normal subject (left) and an asthmatic patient (right). It would seem that homeokinesis is a more appropriate term (38) than homeostasis. We tentatively define it as the ability of an organism functioning in a variable external environment to maintain a highly organized internal environment fluctuating within acceptable limits by dissipating energy in a far-from equilibrium state. sanos asma Que et al, JAP 2001; 91: 1131-41.

L-A (QD or BiD) versus S-A (QiD) BDs EFFECTS ON AIRWAY TONE Beeh KM & Beier J. Adv Ther 2010;27:150-9

¿A qué paciente o fenotipo? Respuesta (+) a salbutamol: SI NO PREDIJERON RESPUESTA a tiotropio: Respuesta + post ipratropio. IgE - Eosinófilos - óxido nítrico – atopía. Indice Masa Corporal. Duración del asma. Se puede personalizar? Aparentemente todavía no. Peters et al. J ALLERGY CLIN IMMUNOL NOV 2013

Am J Respir Crit Care Med 189;2014:A1312 912 pacientes. Estudio post hoc del publicado NEJM 2012 Kerstjens H Am J Respir Crit Care Med 189;2014:A1312

Stepwise management - pharmacotherapy *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy GINA 2014, Box 3-5 (upper part)

Criterios de inclusión: ACQ >1.4 FEV1 post 400 mcg= <79% y FVC <69% a pesar de Bud >800+LABA. Grupo 4 y 5 de fenotipos SARP? Atrapamiento aéreo, comienzo asma después de los 25 años. Conclusión: Asma sin control a pesar de ICS&LABA; Tiotropio aleja la 1ª crisis grave (282 vs. 226 días), con una modesta broncodilatación. The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P = 0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P = 0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups. Conclusions In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. N Engl J Med 2012;367:1198-207.

Moore WS. Am J Respir Crit Care Med 181; 315–323, 2010 Figure 1. Tree analysis. Using three variables (baseline FEV1 [with a bronchodilator withhold], maximal ‘‘Max’’ FEV1 after six to eight puffs of albuterol, and age of onset of asthma), subjects can be assigned to the five clusters that range from milder asthma (Cluster 1) to more severe disease (Clusters 4 and 5). Figure 2. Tree performance. Using the algorithm generated by the tree analysis, 80% of subjects are assigned to the correct cluster of asthma severity. Colors are maintained from the tree diagram (blue= mild atopic asthma; green= mild to moderate atopic asthma; yellow= late-onset non-atopic asthma; orange= severe atopic asthma; red= severe asthma with fixed airflow). Individual figure size is proportional to the frequency of a specific cluster. The percentage of subjects from that cluster that are correctly assigned is indicated numerically within the shape Moore WS. Am J Respir Crit Care Med 181; 315–323, 2010

La editorial de EH BEL Respimat mayor llegada distal. Mayor preocupación por efectos cardiovasculares (ACV). En EPOC 30-52% aumento en riesgo de muerte. Se internaron 16 vs 20. Crisis con corticoides pte/año= (0.53 vs. 0.66, P = 0.046). Los 3 eventos de riesgo vital ocurrieron en Tio El sabio jamás renuncia a su independencia. Aun, en medio de la suprema tempestad, se comporta como un vir fortis, sólido y tenaz en sus propósitos. Sus palabras pueden parecer contradictorias a los oídos de los demás y escuchará a su paso a los pedantes tildarlo de loco, sin perder por ello la tranquilidad de su ánimo. SÉNECA Bel EH. n engl j med 2012: 367;13

Mi conclusión editorial Selección de pacientes tal como se procede con asma de control difícil antes de C sist y omalizumab con FEV1 <60% Prueba terapéutica de 4 semanas. Del meta análisis revisado copio como sigue: Agregar tiotropio al tto habitual mejoró la función pulmonar sin aumentar eventos adversos en pacientes con asma inadecuadamente controlada. No se sabe efecto sobre exacerbaciones y mortalidad.

Muchas gracias Antonio Berni La experiencia más hermosa que tenemos a nuestro alcance es el misterio. Es la emoción fundamental que está en la cuna del verdadero arte y de la verdadera ciencia. Albert Einstein

Otra paciente no fumadora con asma de infancia, 58 años Otra paciente no fumadora con asma de infancia, 58 años. PRE= Fluticasona 2000+salmeterol+ Cort sistémicos+ tiotropio 18 mcg!!! Día cero pre indacaterol Día 30 indacaterol 300 FVC L (%teórico) 1,21 (46 %) 1,44 (55 %) FEV1 L (%teórico) 0.5 (24 %) 0,62 (31 %) ACQ 3+5+5+5+3+6= 4,5 1+2+0+2+0+1= 1

MABA (Acción dual) LABA & LAMA. TEI3252 GSK961081 400 μg-800 μg. 1º MABA. PF-3429281. THRX-198321. TEI3252. THRX-200495 AZD-2115. En marzo 2012 inició fase II. La parte inferior es el agonista beta

Acción dual= MABA (GSK961081) Fase IIb PLML Wielders. Eur Respir J feb 21 2013

n engl j med 364;21 may 26, 2011

TGF beta Colágeno III La broncoconstricción pura genera remodelación! Figure 3. Representative Photomicrographs of Respiratory Epithelium from Bronchial-Biopsy Specimens before and after Repeated Inhaled Methacholine Challenge. Panels A and C show the respiratory epithelium before the challenges, and Panels B and D show the epithelium after the challenges. Biopsy specimens were immunostained with an antibody to collagen type III (in Panels A and B) and with periodic acid–Schiff (in Panels C and D). The horizontal bar represents 30 μm. TGF beta La broncoconstricción pura genera remodelación!

Refutando los estudios de Kerstjens HAM: Cambios en FEV1 no clínicamente significativo Modesto -21% exacerbaciones (la mitad del logro de mepolizumab o el omalizumab). Nada alcanzado en calidad de vida y otros cuestionarios. Es como un LABA lento y tampoco anti-inflamatorio. Wenzel S. POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (11)

El grupo placebo en 2 se planchó! Tono colinérgico alto?

¿Pueden influir 2 años más de asma? Edad en trial 2 tiotropio 51 vs 53.6 y el asma les empezó 2 años después significa 4 años más de historia de asma en la rama placebo. Más remodelación, menos respuesta o mayor en rama tiotropio. En el trial 1 la rama placebo subió mucho más que la rama placebo del trial 2. Kerstjens H NEJM2012

Formoterol 10 Tiotropio 150 280

Criterios de inclusión: ACQ >1.4 FEV1 post 400 mcg= <79% ó FVC <69% a pesar de Bud >800+LABA. Grupo 4 y 5 de fenotipos SARP? Atrapamiento aéreo, comienzo asma después de los 25 años. N Engl J Med 2012;367:1198-207.