Rol presente y futuro de la estrategia mantenimiento y rescate en el tratamiento del Asma. SIMPOSIO AZ: “Aportando nueva evidencia para la neumonología.

Presentación del tema: "Rol presente y futuro de la estrategia mantenimiento y rescate en el tratamiento del Asma. SIMPOSIO AZ: “Aportando nueva evidencia para la neumonología."— Transcripción de la presentación:

1 Rol presente y futuro de la estrategia mantenimiento y rescate en el tratamiento del Asma.
SIMPOSIO AZ: “Aportando nueva evidencia para la neumonología argentina” Día: Sábado 11 de Octubre de 2014, 19:15 hs ·         Datos epidemiológicos actuales de la EPOC en Argentina: Estudio PUMA. Dr Gustavo Zabert ·         Rol presente y futuro de la estrategia mantenimiento y rescate para el tratamiento del Asma. ·         Rol presente y futuro de la estrategia mantenimiento y rescate para el tratamiento del Asma. Dr Luis Nannini SIMPOSIO: ¿Qué hay hoy de nuevo en Asma y EPOC? FECHA: Jueves 25 de Septiembre de 2014 Lugar: Hotel Diplomatic Agenda: 20.30 hs. Apertura. Chairman: Dr. Ramón Alchapar 20:35 hs: El paradigma de los corticoides inhalatorios (CI) en EPOC: Si, No, Cuándo y Cual? o   Eficacia y efectividad comprobada de los CI en EPOC.  Dra. Ana López o   Riesgo/beneficio de los CI en EPOC. Dr. Carlos Luna 20:35 hs: Reconocimiento internacional a más de una década de evidencia: Estrategia mantenimiento y rescate en Asma. Dr. Luis Nannini 21:55 hs: Preguntas. Cierre. Dr. Ramón Alchapar 22:05 hs: Cena Luis J Nannini

2 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 Consejo asesor: Novartis y AstraZeneca 2

3 Durante este simposio, puede que exista información que esté referida a productos o indicaciones que no estén aprobadas en su país. La misma es presentada con el espiritu educacional y el derecho de la comunidad médica y científica de estar completamente informada de los avances médico-científicos, como se estipula en el código IFPMA. Bajo ningúna circuntancia debe tomarse esta informacióm como una recomendación para el uso de estos productos o indicaciones. Por favor, consulte el prospecto de prescripción, aprobado por la autoridad regulatoria local IFPMA, International Federation of Pharmaceutical Manufacturers and Associations 3

4 Estrategia M&R con 1 solo inhalador.
Una estrategia altamente efectiva que adecua la terapia anti inflamatoria en función de la actividad del asma «  si se elige un inhalador combinado que contiene budesonida y formoterol, éste puede ser utilizado para rescate y mantenimiento. Esta estrategia ha demostrado reducir las exacerbaciones y mejorar el control del asma en adultos y adolescentes con dosis realtivamente bajas de tratamiento (Evidence A) » KEY MESSAGE(s) FOR SLIDE : GINA fully endorses the SMART approach with budesonide and formoterol and highlights that it leads to improved asthma control at low doses. It indicates the evidence for this statement is (level A) which is the highest level of evidence possible. GINA 2006; página 60

5 www.ginasthma.org Sociedad Torácica Canadiense. Guía CTS
Sociedad Torácica Británica. Guía NICE GINA 2014

6 Step 3 – one or two controllers + as-needed inhaled reliever
*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, Step 3

7 ¿Por qué proponer una estrategia de M&Rx1?
Realidad y automanejo versus prescripción. ¿En una crisis hay más inflamación; por qué solo SABA entonces? ¿Actuar a tiempo o cada 3 meses (GOAL)? ¿Hubo exceso de confianza en ICS/LABA? ¿El aval científico es vasto y robusto? Luis J Nannini

8 ¿Qué hubiera ocurrido si en lugar de consumir 250 dosis de SABA en menos de una semana hubiera usado al menos Ventide?

9 Incrementando tempranamente la terapia combinada para prevenir las exacerbaciones
Estudio FACET - perfil de 425 exacerbaciones 100 Ventana de oportunidad para aumentar tratamiento anti inflamatorio y prevenir exacerbaciones? Broncodilatador β2-agonista FEP matutino 80 Síntomas nocturnos 60 …… Hipotética evolución % Cambio respecto día –14 40 Traditional exacerbation management usually consists of a course of oral steroids when symptoms are at their worst. The exacerbation is already fully manifested at this stage. A 20% increase in rescue beta-agonist use can be noted more than a day earlier than 20% change in PEF and almost 5 days earlier than a change in nighttime symptoms – the most specific indicator used indicator of worsening. Although the RATE of change was statistically similar, differences can be seen in onset. The Formoterol and Corticosteroids Establishing Therapy (FACET) 12-month, parallel-group study compared low and high doses of budesonide, with and without formoterol, in asthma patients (n=694). Severe exacerbations were defined as: the need for an oral steroid course (n=311 of study population), or a >30% reduction in morning peak expiratory flow (PEF) on 2 consecutive days. Exacerbations were characterised by: a gradual fall in PEF over several days, and more rapid changes over 2–3 days. An increase in symptoms and β2-agonist reliever use occurred in parallel and the severity and time course of the changes were similar in all treatment groups. Self-management programmes usually do not recommend an increase in anti-inflammatory treatment until: a 30% fall in PEF, or an increase in reliever use, or symptoms for 2 consecutive days. This study suggests that inceasing treatment during the 2–3 day window of opportunity when symptoms are deteriorating may help prevent exacerbations. Tattersfield AE, et al. Am J Respir Crit Care Med 1999;160:594–599. 20 –15 –10 –5 5 10 15 Días antes y después de una exacerbación Tattersfield AE, et al. Am J Respir Crit Care Med 1999;160:594–599.

10 Bud/Form es tan efectivo y bien tolerado como el salbutamol para tratar el asma aguda
Frecuencia Cardíaca (lpm) FEV1 (% D del basal) 45 93 35 91 25 89 Symbicort 1280/36 µg 15 87 Salbutamol 1600 µg To determine whether Symbicort is suitable for use both as daily maintenance and rapid reliever therapy, its efficacy and tolerability were compared with salbutamol, a SABA, in patients seeking medical attention for acute severe asthma. In this randomised, double-blind, double-dummy, parallel-group, 3-hour study, patients admitted to hospital with acute asthma (mean forced expiratory volume in 1 second [FEV1] 43% predicted normal) received a dose of Symbicort (320/9 µg, two inhalations) or salbutamol (100 µg, eight inhalations) 5 mins apart (n=103). All patients were given prednisolone (60 mg) at 90 mins. Symbicort was as effective as salbutamol in increasing FEV1. Mean FEV1 over 90 mins increased from baseline by 30% and 32% for Symbicort and salbutamol, respectively (p=0.66). There was no statistically significant difference in FEV1 between the two groups at 90 or 180 mins post-dose. High-dose Symbicort (budesonide/formoterol) is effective and well tolerated for the treatment of acute asthma, with rapid onset of efficacy and a similar safety profile as high doses of salbutamol. Balanag VM, et al. Pulm Pharm Ther 2006;19:139–147. 5 85 –5 0 30 60 90 120 150 180 -5 0 30 60 90 120 150 180 Tiempo después de la administración de la droga (minutos) FEV1 basal: 43% predicho Balanag VM, et al. Pulm Pharm Ther 2006;19:139–147.

11 10 dosis en sujetos ya tratados
Seguridad y tolerabilidad de 10 dosis sumadas a las 2 dosis habituales de la mañana en 14 sujetos con asma. This randomised, double-blind, double-dummy, crossover, placebo-controlled study assessed the acute tolerability of budesonide/formoterol in a single inhaler (Symbicortw Turbuhalerw, AstraZeneca) administered as a high dose. Fourteen patients with asthma receiving budesonide/formoterol maintenance treatment (two inhalations of 160/4.5 mg twice daily) inhaled 10 additional doses of budesonide/formoterol 1600/45 mg (total daily dose including morning dose of maintenance treatment 1920/54 mg) or formoterol 45 mg (Oxisw Turbuhalerw, AstraZeneca; total daily dose including morning dose of maintenance treatment 54 mg formoterol) or placebo in addition to the morning dose of maintenance treatment on 3 separate study days. Serum potassium, pulse rate, blood pressure and ECG were assessed at regular intervals over a 12-h period following dosing. Blood glucose and plasma lactate were assessed over 3 h following dosing. Changes in serum potassium, pulse rate, blood pressure, QTc, blood glucose and plasma lactate occurring with budesonide/formoterol, though statistically significantly different from placebo (P , 0:05), were considered clinically unimportant. No clinically relevant differences were identified between active treatments. In conclusion, budesonide/formoterol in a single inhaler is well tolerated at high doses such as might be used by patients using budesonide/formoterol for relief of symptoms of asthma. Ankerst J. Pulm Pharm Ther 16 (2003) 147–151

12 ¿M&R es efectiva en comparación con bud/form a dosis fijas+saba o LABA prn?

13 Bud/Form M&R: Tiempo a la 1ª exacerbación grave
Pacientes con exacerbaciones severas (%) Mantenimiento Bud/Form + a demanda: terbutalina TBH 25 formoterol TBH M&R P < 0.01 20 P < P < 0.005 15 10 All patients in the SMILE clinical trial received Symbicort as maintenance therapy and were randomised to receive either Bricanyl (terbutaline), Oxis (formoterol) or Symbicort as needed (Symbicort SMART). In this 12-month study, the time to first severe exacerbation was prolonged with as-needed Symbicort (Symbicort SMART) compared with Oxis (formoterol) (p<0.005) or Bricanyl (terbutaline) (p<0.0001) as needed. In addition, Symbicort maintenance therapy in combination with as-needed formoterol prolonged the time to first severe exacerbation compared with Symbicort plus terbutaline as needed (p<0.0001). Results from this study demonstrated that both of the monocomponents of Symbicort–budesonide and formoterol–as needed contribute to the enhanced protection from severe exacerbations. Rabe KF, et al. Lancet 2006;368:744–753. M&R reduce el riesgo en: 27% vs Bud/Form + Form 45% vs Bud/Form+ SABA 5 60 120 180 240 300 360 Días desde randomización Rabe KF, et al. Lancet 2006;368:744–753.

14 ¿M&R es más efectiva en comparación con fluticasona/salmeterol según el estudio GOAL?
“El camino” del rosarino Antonio Berni. La terapia fija no es flexible, no dobla ante los síntomas y se estampa en la curva (MUY LOCO!!!)

15 COSMOS evaluó dos conceptos de tratamiento
Medicación diaria para asma bud/for rescate (paciente) Salbutamol p r n 2 inh. 50/100 µg 2 inh. 50/500 µg 2 inh. 50/250 µg titulación (médico) 2 inh. 160/4.5 µg 4 inh. 160/4.5 µg titulación (médico) Grupo sal/flu Grupo bud/for (hasta 4 inhaladores diferentes) (1 inhalador) Vogelmeier et al Eur Respir J 2005

16 Tasa acumulada de exacerbaciones graves
Tasa de eventos Eventos/paciente/año FLU/SAL BUD/FOR M&R 0.24 0.32 SAL/FLU Reducción de la Tasa: 22% (CI: 9, 44%) p<0.01 BUD/FOR M&R 0.24 NNT = 14 0.16 0.08 Tiempo (días) 80 160 240 320 Fase de titulación Vogelmeier et al Eur Respir J 2005

17 COSMOS: Dosis de GCSi y uso de rescate
Dosis total de GCSi mg/día (BDP equivalente) Uso de rescate (inh./día) 1500 1.0 1250 0.75 Diferencia general 38% p>0.001 1000 750 0.50 500 Sal/Flu Bud/Form mantenimiento + rescate 0.25 250 Bud/Form mantenimiento solo 60 120 180 240 300 360 60 120 180 240 300 360 Fase de titulación Fase de titulación Período post randomización (días)

18 Tardío cambio de la dosis de Flut/Salm (GOAL) en comparación con Bud/Form M&R (STEAM)
Exacerbaciones/pacient/ año (phase 1 data) Dosis final de GCSi mg/day (FP) Exacerbaciones/pacient/ añor (6-month study) Dosis promedio de GCSi (BUD) 0.3 0.3 1000 1000 800 800 0.18 0.2 0.2 600 600 400 400 0.08 0.1 0.1 200 200 The slide above presents annual exacerbation rates based on the first 6 months of treatment in both the STEAM and GOAL studies (ie these are a simple doubling of the actual rates in the first 6 months). In addition, we present the ICS dose associated with these rates. The key premise of Symbicort SMART is that immediate intervention to prevent inflammation and bronchospasm at the first sign of symptoms provides superior asthma control. This has been demonstrated effectively in the Symbicort SMART studies and constrasts markedly with results from the GOAL study. This slide shows the number of exacerbations/patient/year in the GOAL1 and STEAM2 studies. The GOAL study involved fixed-dose Seretide, increased every 12 weeks until total asthma control or the maximum dose was achieved, whereas patients in the STEAM study received Symbicort SMART. Patients in the S2 sub-group of the GOAL study had very similar forced expiratory volume in 1 second (FEV1) values as those in the STEAM study, involving patients with mild to moderate asthma (FEV1 78% of predicted normal vs FEV1 75% of predicted normal in the GOAL S2 and STEAM patients, respectively). Patients in both studies had previously used less than 500 µg/day of ICS. The hatched bars show metered doses of ICS used in periods when exacerbation rates were assessed. For the GOAL study, these are the mean doses used in the last 12 weeks of phase I (Step-up phase). The data from this slide should be used with caution in the context of scientific debates, because it can be argued that different studies should not be compared in this way. However, these data build on the evidence from the previous slide (but this time in patients with mild to moderate asthma) that delayed adjustments in ICS treatment are less effective than patient-initiated adjustments in times of need, and they lead to less than optimal exacerbation control despite higher treatment levels. Aiming for total control in the step-up period of the GOAL study resulted in most patients receiving the maximum dose of Seretide. The mean dose of fluticasone used by the S2 population in the GOAL study was approximately 820 µg/day (metered dose). However, because most patients needed to step up their treatment twice, taking a total of 24 weeks, optimal exacerbation control was not seen in the first phase of the study, which lasted up to Week 36. The stepwise approach used in the GOAL study resulted in approximately double the number of exacerbations/patient/year compared with Symbicort SMART (0.18 vs 0.08 exacerabtions/patient/year, in the GOAL vs STEAM studies, respectively), despite most patients having been stepped up to the highest dose of Seretide. Moreover, patients receiving Symbicort SMART achieved superior asthma control; the budesonide dose remained low throughout the 6-month study (300 µg/day, metered dose; 3 inhalations of 80/4.5 inhaler). 1Bateman ED, et al. Am J Respir Crit Care Med 2004 (Article in press) 2Rabe KF, et al. J Allergy Clin Immunol 2004;113(Suppl 2):S116, A360 GOAL (S2) Pacientes tratados con dosis bajas de GCSi (Flut/Salm - periodo step-up[ phase I ] STEAM Pacientes tratados con dosis bajas de GCSi con Bud/Form M&R Bateman ED, et al. Am J Crit Care Med 2004 * Exacerbation definition identical in both studies all ICS doses in metered doses of FP or budesonide

19 Estadística de las exacerbaciones
Reducción (%) con bud/for M&R vs sal/flu 10 Visitas no programadas Días con esteroides orales Visita a guardias Días de hospitalización 37% a SAL/FLU (7.2 días/evento) vs BUD/FOR M&R (5.9 días/evento) 24% 34% 16% 154 a 117 2978 a 1980 45 a 38 94 a 59 a -10 -20 Exacerbation subtypes presented showing the total number of exacerbations that fulfilled each criteria, i.e. the same exacerbation could be included in more than one subtype if it fulfilled ≥1 criterion. -30 -40

20 Media de inhalaciones de bud/for por día
La utilización de rescate promedio fue baja en todos los niveles de severidad Media de inhalaciones de bud/for por día 4.0 rescate Utilización total (incluyendo mantenimiento) 0.6 3.1 2.6 1.1 0.7 2.7 3.0 2.0 1.0 This plot shows that the mean use of Symbicort for relief of symptoms during Symbicort SMART treatment and the total use including maintenance doses shown in the hatched bars. The increase in as needed medication use on going from mild to severe persistent asthma was only 0.5 inhalations per day with Symbicort SMART. Leve n=175 Moderada n=491 Severa n=1531 * Global Initiative for Asthma (GINA) NIH Publication No Combined (STEAM, STAY & STEP)

21 ¿M&Rx1 es más efectiva que la mejor práctica convencional según revisiones sistemáticas?

22 En crisis graves. Edwards y col Int J Clin Pract, Apr. 2010
Bud/Form M&R 40% menos crisis que las dosis fijas de Salm/Flut y Bud/Form a altas dosis.

23 46% menos crisis tratadas con corticoides orales
Analysis 3.2. Comparison 3 Adults using BDF single inhaler therapy versus fixed dose ICS, Outcome 2 Patients with exacerbations treated with oral steroids. Review: Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children Comparison: 3 Adults using BDF single inhaler therapy versus fixed dose ICS Outcome: 2 Patients with exacerbations treated with oral steroids Cates C. The Cochrane Library 2013, Issue 4

24 25% menos corticoides orales
Corticoides orales 25% menos

25 28% menos visitas guardia y
hospitalizaciones Kew Cochrane review dic 2013 crisis con internación. 28% menos riesgo con M&R Kew Cochrane review dic 2013

26 Budesonida/formoterol en el marco de productos respiratorios en desarrollo de AstraZeneca
Asma: tratamiento según pasos GINA EPOC: tratamiento según grupos GOLD GOLD 1 GOLD 2 GOLD 3 GOLD 4 m MRC 0-1 CAT < 10 m MRC ≥2 CAT ≥ 10 1 ≥2 or 1 hospitalisation C D B A Exacerbations per year PT010 LABA/LAMA/ICS PT001 LAMA PT003 LABA/ PT001 LAMA Budesonide + GINA 5 4 3 2 1 ’As Needed’ PT010 triple Traloki-numab (Anti IL13, Mab) Budesonida Pearl Pulmicort TBH Benrali-zumab (Anti IL5R, Mab) Budesonida/ formoterol Budesonida/formoterol PT010: budesonida/glicopirronium/fumarato formoterol, pMDI Pearl co-suspention PT001: glicopirronium pMDI, Pearl co-suspention PT003: glicopirronium/fumarato formoterol, pMDI Pearl co-suspention m MRC modified Medical Research Council dyspnea scale CAT COPD Assessment Test

27 Estrategia M & R en asma intermitente y leve. (Hay ensayos en curso)
J Allergy Clin Immunol 2014;133:39-41. Mantenimiento y Rescate con un solo inhalador de Budesonide+formoterol en asma leve o intermitente: ¿qué evidencias orientan esta hipótesis? Estrategia M & R en asma intermitente y leve. (Hay ensayos en curso)

28 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)

29 Edad 18-25 años. Inflamación subclínica
Control sano Asma remisión Prot Básica Mayor Figure 2. Bronchial biopsy specimen from a healthy control subject (top panel) and a subject in clinical remission of atopic asthma (bottom panel) immunostained with -Major Basic Protein (MBP). Notice the increased MBP-positive area (the red stain) and epithelial shedding in the subject in clinical remission. Clinical remission of atopic asthma was defined as reported complete absence of asthmatic symptoms in subjects not taking any asthma medication for at least 12 mo prior to the study. Eligible subjects were compared with patients with asthma who had persistent symptoms and used inhaled 2 -agonists on demand in order to relieve symptoms. Atopic asthma was previously diagnosed in all subjects according to ATS criteria Van Den Toorn.LM. Am J Respir Crit Care Med –2113, 2001

30 Asma leve. Bud intermitente 800 mcg x2 y 10 días.
Budesonide como monoterapia ante avance de síntomas hacían 1600 mcg diarios durante 10 días (tto intermitente) Boushey H. N Engl J Med 2005;352:

31 Treatment at the start of the late
El efecto anti-inflamatorio temprano de la budesonide redujo la respuesta asmática tardía. Budesonide 800 µg FEV1 (L) Placebo 4 * * * * * 3 2 Treatment at the start of the late response * p<0.05 1 -2 -1 1 2 3 4 5 6 7 8 9 10 Time (hours) Paggiaro PL, et al (1994)

32 Reducción óxido nítrico exhalado en asma leve
Reducción óxido nítrico exhalado en asma leve. Formoterol versus Bud/Form M&R Diferencia de 15.5 ppb= p<0.001; 95% CI 7.5–23.5 FIGURE 3. Mean fractional exhaled nitric oxide (FeNO) over time in the budesonide/formoterol (&) and formoterol ($) groups. The mean reductions in the two groups were 18.3 ppb and 2.8 ppb, respectively, with a significant difference of 15.5 ppb between the treatments (p,0.001; 95% CI 7.5–23.5). Haahtela T. Eur Respir J 2006; 28: 748–755

33 SABA&ICS en un solo inhalador en asma leve es una alternativa al tto diario con ICS.
Papi A; N Engl J Med May 17;356(20): In patients with mild asthma, the symptom-driven use of inhaled beclomethasone and albuterol in a single inhaler is as effective as regular use of inhaled beclomethasone and is associated with a lower inhaled steroid load Figure 3. Mean (±SE) Morning Peak Expiratory Flow (PEF) Rates in the Modified Intention-to-Treat Population. Missing values were replaced according to the last-observation-carried forward (LOCF) technique (Panel A) or the maximum likelihood technique (Panel B). As-needed combination therapy consisted of placebo twice daily plus 250 ìg of beclomethasone and 100 ìg of albuterol in a single inhaler as needed; as-needed albuterol therapy, placebo twice daily plus 100 ìg of albuterol as needed; regular beclomethasone therapy, 250 ìg of beclomethasone twice daily and 100 ìg of albuterol as needed; and regular combination therapy, 250 ìg of beclomethasone and 100 ìg of albuterol in a single inhaler twice daily plus 100 ìg of albuterol as needed. P values for comparison with the mean for the last week of the run-in period (baseline) are as follows. In Panel A, among patients receiving as-needed albuterol therapy, P<0.001 for weeks 5 and 6, P = for weeks 11 and 12, P = 0.01 for weeks 17 and 18, and P = 0.03 for weeks 23 and 24. In Panel B, among patients receiving as-needed albuterol therapy, P<0.001 for weeks 5 and 6, P<0.001 for weeks 11 and 12, P = for weeks 17 and 18, and P = for weeks 23 and 24; among patients receiving regular beclomethasone therapy, P = 0.01 for weeks 17 and 18, and P = for weeks 23 and 24. En asma leve, Beclometasona 250/albuterol 100 a demanda fue tan efectivo como el uso regular de beclometasona y la dosis total de ICS fue menor.

34 Broncoespasmo por ejercicio: Basal y 42 días post-tto
Dosis total ICS 2,5 veces menor Figure 2 Forced expiratory volume in 1 s (FEV1) before and after a 6 min standardised exercise test on a treadmill, while breathing dry air, before treatment (upper panel) and after 6 weeks of treatment (lower panel) with the three different treatments. Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg) + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT ). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Lazarinis N, et al. Thorax 2013;0:1–7

35 n engl j med 364;21 may 26, 2011

36 La broncoconstricción inducida por metacolina generó similares fenómenos inflamatorios y remodelatorios que la broncoc con alergenos y el control salina o salbutamol/metacolina no dio nada de eso !

37 La broncoconstricción pura genera remodelación!
Colágeno III BFC Basal BFC final 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!

38 Juntos B&F mayor efecto antiremodelación en fibroblastos
Budesonide Lizbet Todorova. BUD 108 M (dark gray bars); FORM 1010 M (light gray bars); their combination (hatched bars). Open bars represent 10% serum without drug treatment (with drug vehicle). Data are expressed as percent of control (0.4% serum with drug vehicle) and shown as mean SEM. P versus 0.4% serum; *P 0.05, **P versus positive control (10% serum minus 0.4% serum); §P 0.05, §§P versus BUD alone; #P versus FORM alone. We have also shown that the combination of BUD and FORM is more efficient than either drug alone in the inhibition of versican, biglycan, and perlecan (proteoglycans known as markers of an early-inflammatory ECM), as well as decorin (which is usually upregulated in the more fibrotic ECM). The drug effects were exerted primarily at the post-transcriptional level. We conclude that increased early and late deposition of proteoglycans in asthmatic airways may be limited by treatment with a combination of BUD and FORM. Formoterol Budes/Formoterol Todorova L. Am J Respir Cell Mol Biol Vol 34. pp 92–100, 2006

39 Estrategia M&R: porqué funciona?
Bud&Form M&R Formoterol Budesonide Neutrofilos Mastocitos Células epiteliales Eosinófilos Linfocitos-Th2 KEY MESSAGES FOR SLIDE : There is good evidence that both components of Symbicort when used as maintenance therapy contribute to the efficacy of Symbicort SMART and there is good evidence that both components when used as reliever therapy contribute to fine tuning overall asthma control/inflammatory control thus preventing asthma exacerbations. Both formoterol & budesonide have both long-lasting and rapid effects that make them well suited to be given for both mainteance and relief. This is not the case for other ICS/LABA combinations. Rapido alivio sintomático/broncoprotección (e.g. Estabilización de los mastocitos) Reduce inflamación por neutrófilos (infecc. Virales y asma) Reduces edema bronquial Previene exacerbaciones tanto como terapia de mantenimiento o de rescate Vasoconstricción dentro de 30 min Aumenta la función b2-receptor dentro de 2h Reduce los niveles de eosinófilos y óxido nítrico dentro de 6h Previene exacerbaciones tanto como terapia de mantenimiento o de rescate Barnes PJ Eur Respir J 2007 (Review)

40 Conclusiones para la práctica
Niños de 6-11 años: En forma transitoria, la dosis diaria máxima puede alcanzar a 8 inhalaciones. Adultos y adolescentes >11 años: Generalmente, no es necesaria una dosis cotidiana superior a 8 inhalaciones. Excepcionalmente y en forma transitoria, pueden utilizar hasta un máximo de 12 inhalaciones por día.

41 Una ventana aprovechable con Bud/Form M&R
Uso de SABA (frecuencia diaria) Se abre una oportunidad para mejorar el control incrementando la dosis según necesidad (a demanda) con BUD/FORM 3.2 2.8 2.4 2.0 1.6 Salm/Flut fijo + SABA Here again, this slide shows the profile of 50 asthma attacks occurring with fixed-dose Symbicort and 59 asthma attacks occurring with fixed-dose Seretide during a 7-month assessment period. The data show mean daytime use of SABA during the 30 days before and after the diagnosis and treatment of an exacerbation (SUND study1). It can be seen that SABA use increased on average 2 weeks before an exacerbation, even in patients using gold standard combination therapy. Therefore the Symbicort SMART approach provides an opportunity to intervene early with increased medication in order to prevent a potential asthma attack. As Symbicort delivers both ICS and a LABA with each inhalation, the Symbicort SMART provides patients with a timely increase in both anti-inflammatory and bronchodilatory medication. 1Aalbers R, et al. Curr Med Res Opin 2004;20:225–240 Bud/Form fijo + SABA 1.2 0.8 -30 -20 -10 10 20 30 Días antes y despues de una exacerbación (SUND Study) Aalbers R, et al 2004

42 La incredulidad de los hombres hace que nunca crean en lo nuevo hasta que adquieren una firme experiencia de ello. Nicolás Maquiavelo. Muchas gracias Hace más de 8 años que es evidencia “A” por GINA.

43 Demorar el ajuste de la dosis de GCSi lleva a una demora en alcanzar un óptimo control de las exacerbaciones (Estudio GOAL- GSK) Media de exacerbaciones/paciente/año 0.70 0.70 FP 0.7 0. 63 SFC 0. 60 0.6 0.5 P< 0.01 0.4 0.37 0. 31 0.3 0.27 0. 19 0.2 Delays in adjusting the dose of maintenance therapy based on clinical review have been identified as a weakness of traditional asthma treatment regimens (GINA 2002). Here we can see this weakness is also exemplified by data from the GOAL study in patients in stratum 3 previously on moderate doses of ICS > 500-< 1000 µg. No benefit on exacerbations was apparent until the second six months of the study, 3 months after step-up to maximum doses. This graph shows that the delays in providing adequate therapy resulted in substantially higher exacerbation rates during the first 6 months of treatment (stepping up period) compared with the second 6 months, when patients received the maximum doses of Seretide or fluticasone. During the first 6 months of treatment, the use of Seretide — even at maximal dose — was not associated with any increase in exacerbation control, compared with either baseline or with fluticasone treatment. This highlights that delays in stepping up treatment will often result in a need for long-term increased treatment, which might have been avoided if more rapid dose adjustments had been made. 1Bateman ED, et al. Am J Respir Crit Care Med 2004 (Article in press) 0.1 Baseline Step - up period maintained period Average of Study (1 st 6 - months) (2 nd 6 - months) (12 - months) Desde el mes 3 al 12, 97% de los pacientes con FP y 90% de los pacientes SCF recibieron dosis máximas de tratamiento, pero la mayoría de las exacerbaciones ocurrieron durante el período de aumento (step-up) primeros 6 meses Bateman ED, et al. Am J Crit Care Med 2004

44 %Crisis a 21 días de uso >6 inhalaciones rescate/día
Figure 3 Asthma exacerbations associated with episodes of high reliever use (>6 inhalations/day) A) in Study A, B) in Study B. i) Proportion of all patients (ITT population) with an index day of >6 inhalations/day in the three treatment arms over the study period; ii) Kaplan–Meier plot of time from first use of >6 as-needed inhalations/day to first exacerbation during the following 21 days; iii) percentage of patients with ongoing treatment for an exacerbation for each day following the index day. Note in panels ii) and iii) only a minority of the at risk subgroup of patients having an episode of high reliever use identified in panel i) developed a severe exacerbation requiring additional treatment. The majority of high reliever episodes resolved spontaneously on all regimens. When as-needed reliever use exceeded 6 inhalations on at least 1 day, exacerbation rates in the 21 days postindex increased at least eightfold compared with background rates in the ITT populations for all regimens. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG: Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006, 368:744–753 B) Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE, Buhl R: Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007, 61:725–736. Buhl et al. Respiratory Research 2012, 13:59