1. Strategies for asthma management VARIABLE ! Prof Huib Kerstjens Groningen Research Institute for Asthma and COPD University Medical Center Groningen

2. Florianópolis 2001 Life is not a fixed, straight line

3. Asthma is even more variable than life itself… Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment. Asthma is characterized by variability GINA 2007

4. Asthma is a disease characterized by variability…. … so fixed dosing is not logical ….and will frequently lead to either insufficient treatment (too low dose) or overtreatment (too high dose)

5. The alternative Variable dosing Concerns: Overtreatment? –Increased side effects? Sufficient treatment? –Inflammation? Costs?

6. What is variable dosing ? Confusion ? Variable dosing is NOT about Symbicort® contra Seretide®. –SMART = Steroid/LABA maintenance + reliever therapy Variable dosing IS about not using a fixed dose… of the same drug ! No studies of variable dosing of Salm/FP Therefore: data presented only of Bud/Form

7. Many types of variable dosing Maintenance dose + adjustments, e.g. 1-2 wks –Doctor adjusted dose –Patient adjusted dose Maintenance dose + as needed (totally variable) Majority of patients will do: no fixed dose; variable only

8. Adjustable maintenance dosing AMD Bud/F 320/9 bid FD Bud/F 320/9 bid FP/Salm 250/50 bid N= 1225 With AMD vs FD: 3 vs 4 puffs rescue med / day exacerbations Busse et al, JACI 2008

9. Adjustable maintenance dosing vs fixed AuthorWho adjusts? Double- blind? Exacerbationsdosing Leuppi 2003 patientOpen label=lower Aalbers 2004 patientOpen labellower Ind 2004 patientOpen label=lower Busse 2008 investigatorOpen label=lower

10. Previous regular ICS + SABA as needed Bud/Form 80/4.5  g bid a + as needed Bud/Form 80/4.5  g bid a + terbutaline 0.4 mg as needed Budesonide 320  g bid a + terbutaline 0.4 mg as needed a Children <12 years received half the daily maintenance dose with a once daily regimen R Run-in Run-in STAY: Study Design Visit:1 2 3 4 5 6 7 Month: -0.5 0 1 3 6 9 12 Bud/Form SMART n=925 Bud/Form Fixed Dose + SABA n=909 4 x Budesonide + SABA n=926 O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

11. Patient CharacteristicsBud/FormBud/Form 4 x BUD + SABA SMART N=925 + SABA N=909 N=926 score (0–6) Mean total asthma symptom 1.51.4 1.5 Mean reliever inhalations/24 hours (no.) 2.52.42.4 Males, n (%) 421 (46) Mean age, years (range) 35 (4–77) Mean FEV 1, % predicted 73 394 (43) 36 (4–79) 73 Long-acting  2 -agonists (%) 2827 416 (45) 36 (4–79) 73 27 Mean ICS at entry,  g/day 619598620 Characteristic O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

12. Severe Exacerbations Total exacerbations Bud/Form SMART Bud/Form + SABA 4 x BUD + SABA Exacerbation subtypes 0 100 200 300 400 500 600 p<0.001 Steroid courses PEF falls 50 150 250 350 50 150 250350Hospitalisations/ ER treatment 10 20 30 40 303 553 564 O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

13. Maintenance + variable as needed (SMART) vs fixed AuthornDouble- blind? Exacerbationsdosing O’Byrne 2005 2760yeslower= Kuna 2007 3335yeslower Sears 2008 1538yeslower Demoly 2009 7855nolower

14. From trials to daily clinical practice 6 RCT, open label SMART vs “conventional best practice” N=7855 Demoly et al, Respir Med 2009

15. Safety risk with self treatment? Sears et al. Eur Resp J 2008 ICS dose 748 mcg/day ICS dose 1015 mcg/day Sputum Eosinophils (%) Less ICS use, less SABA use, less costs Trend for less hospitalizations / ER visits

16. What about the costs? 6 months, double-blind, triple dummy, parallel RCT –Bud/form 160/4.5 bid + Bud/form 160/4.5 prn –Bud/form 320/9 bid + Terb prn –Salm/FP 50/250 bid + Terb prn Primary end-point rate of severe exacerbations (hosp/ER/oral steroids) Secondary outcome: costs Kuna et al, Int J Clin Pract 2007 Price et al, Allergy 2007

17. Patient characteristics Price et al, Allergy 2007 FD Bud/FormSMART Bud/formFD Salm/FP Male (%)4143 Age38 FEV 1 %pred737273 Reversibility252423 SABA rescue2.3 ICS use at start750740744

18. Mean costs / patient/ 6 months United Kingdom ₤ p value Medical resource -70.52 Study drugs-66<0.001 Total direct-73<0.001 Indirect-170.45 Total costs-910.001 Price et al, Allergy 2007 Australia Aus$ p value -240.07 -110.001 -350.16 -330.45 -700.20

19. Why would variable dosing be so efficient? Patients do variable dosing all the time! ­Mean inhaled drug use 25-40% of prescribed Compliance at the important moments goes up ­Patients recognize that they need it ­Patients recognize that the drugs work ­Patients become more in control over their own disease: implicit and explicit action plan

20. Has all been said? SMART scheme with other combination drugs ­Seretide ­Foster (Beclometason/formoterol) Only variable dosing (no maintenance dosing prescribed), in mild patients

21. Summary Asthma is a variable disease, so should treatment be With variable dosing compared to fixed: ­reduced exacerbations and less steroid use ­not more inflammation = safe ­less costs Tested so far only with Symbicort, but will probably work with other combinations

22. Brazil will have the olympics Our patients will enjoy variable dosing Muito obrigado

24. Exacerbations [/100 patients/yr] Bud-Form SMART Bud-Form + SABA BUD + SABA STEAM Chest 2006 0 10 20 30 40 50 STEP Aalbers et al CMRO 2004 STAY O’Byrne et al AJRCCM 2005 SMILE Rabe et al Lancet 2006 COMPASS Kuna et al IJCP 2007 Salm-FP + SABA Bud-Form + formoterol AHEADBousquet Resp Med 2007 Reduction of Future Risk of Exacerbations Courtesy P.O’Byrne

25. The Goal of Asthma Management is: Overall Asthma Control Current Control Future Risk Symptoms Activity Reliever use Lung function Instability/worsening loss Exacerbations Medication adverse effects achievingreducing defined by GINA 2006; NIH/NAEPP Expert Report No.3 2007; ATS/ERS Task Force on Asthma Severity & Control 2008

26. Steroid use in Stay study O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

27. Life has its ups & downs 2 October: No olympics for Chicago 9 October: Obama Nobel peace price