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

Florianópolis 2001 Life is not a fixed, straight line

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

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)

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

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

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

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

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

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: Month: 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:

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

Severe Exacerbations Total exacerbations Bud/Form SMART Bud/Form + SABA 4 x BUD + SABA Exacerbation subtypes p<0.001 Steroid courses PEF falls Hospitalisations/ ER treatment O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:

Maintenance + variable as needed (SMART) vs fixed AuthornDouble- blind? Exacerbationsdosing O’Byrne yeslower= Kuna yeslower Sears yeslower Demoly nolower

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

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

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

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

Mean costs / patient/ 6 months United Kingdom ₤ p value Medical resource Study drugs-66<0.001 Total direct-73<0.001 Indirect Total costs Price et al, Allergy 2007 Australia Aus$ p value

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

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

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

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

Exacerbations [/100 patients/yr] Bud-Form SMART Bud-Form + SABA BUD + SABA STEAM Chest 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

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 ; ATS/ERS Task Force on Asthma Severity & Control 2008

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

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