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 airwaysin which many cells and cellular elements play a role.The chronic inflammation is associated with airwayhyperresponsiveness that leads to recurrent episodes ofwheezing, breathlessness, chest tightness, and coughing,particularly at night or in the early morning. Theseepisodes are usually associated with widespread, butvariable, airflow obstruction within the lung that is oftenreversible 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 alternativeVariable 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 dosingvs fixed

Author Who adjusts?

Double-blind?

Exacerbations dosing

Leuppi 2003

patient Open label = lower

Aalbers 2004

patient Open label lower lower

Ind

2004

patient Open label = lower

Busse 2008

investigator Open label = lower

Previous Previous regular ICSregular ICS + +

SABA SABA as as neededneeded

Bud/Form 80/4.5 Bud/Form 80/4.5 g bid g bid aa + as needed + as needed

Bud/Form 80/4.5 Bud/Form 80/4.5 g bid g bid aa + terbutaline 0.4 mg as needed + terbutaline 0.4 mg as needed

Budesonide 320 Budesonide 320 g bidg bid aa + terbutaline 0.4 mg as needed+ terbutaline 0.4 mg as needed

a a Children <12 years received half the daily maintenance dose with a once daily regimenChildren <12 years received half the daily maintenance dose with a once daily regimen

RR

Run-inRun-in

STAY: Study Design

Visit:Visit: 11 2 3 2 3 4 4 5 5 6 6 7 7

Month: -0.5Month: -0.5 0 1 0 1 3 3 6 6 9 9 12 12

Bud/Form SMART Bud/Form SMART n=925n=925

Bud/Form Fixed Dose + SABA Bud/Form Fixed Dose + SABA n=909n=909

4 x Budesonide + SABA 4 x Budesonide + SABA n=926n=926

O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

Patient CharacteristicsBud/FormBud/FormBud/FormBud/Form4 x BUD4 x BUD

+ SABA+ SABA SMARTSMART

N=925N=925

+ SABA+ SABA

N=909N=909N=926N=926

score (0–6)score (0–6)Mean total asthma symptomMean total asthma symptom 1.51.51.41.41.51.5

Mean relieverMean relieverinhalations/24 hours (no.)inhalations/24 hours (no.) 2.52.52.42.42.42.4

Males, n (%)Males, n (%) 421 (46)421 (46)

Mean age, years (range)Mean age, years (range) 35 (4–77)35 (4–77)

Mean FEVMean FEV11, % predicted, % predicted 7373

394 (43)394 (43)

36 (4–79)36 (4–79)

7373

Long-acting Long-acting 22-agonists (%) -agonists (%) 2828 2727

416 (45)416 (45)

36 (4–79)36 (4–79)

7373

2727

Mean ICS at entry, Mean ICS at entry, g/day g/day 619619598598620620

CharacteristicCharacteristic

O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

Severe Exacerbations Total exacerbationsTotal exacerbations

Bud/Form SMARTBud/Form SMARTBud/Form + SABABud/Form + SABA4 x BUD + SABA4 x BUD + SABA

Exacerbation Exacerbation subtypessubtypes

00

100100

200200

300300

400400

500500

600600

p<0.001p<0.001

SteroidSteroid coursescoursesPEF fallsPEF falls

5050

150150

250250

350350

5050

150150

250250

350350

Hospitalisations/Hospitalisations/

ER treatmentER treatment

1010

2020

3030

4040303303

553553564564

O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

Maintenance + variable as needed (SMART) vs fixed

Author n Double-blind?

Exacerbations dosing

O’Byrne 2005

2760 yes lower =

Kuna

2007

3335 yes lower lower

Sears

2008

1538 yes lower lower

Demoly 2009

7855 no lower lower

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?

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Baseline SMART Treatment Baseline ConventionalTreatment

Sears et al. Eur Resp J 2008

ICS dose 748 mcg/dayICS dose 748 mcg/day ICS dose 1015 mcg/dayICS dose 1015 mcg/day

Spu

tum

Eosi

nophils

(%

)

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/Form SMART Bud/form FD Salm/FP

Male (%) 41 43 43

Age 38 38 38

FEV1 %pred 73 72 73

Reversibility 25 24 23

SABA rescue 2.3 2.3 2.3

ICS use at start 750 740 744

Mean costs / patient/ 6 monthsUnited Kingdom

₤ p value

Medical resource

-7 0.52

Study drugs -66 <0.001

Total direct -73 <0.001

Indirect -17 0.45

Total costs -91 0.001

Price et al, Allergy 2007

Australia

Aus$ p value

-24 0.07

-11 0.001

-35 0.16

-33 0.45

-70 0.20

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

ExacerbationsExacerbations[/100 patients/yr][/100 patients/yr]

Bud-Form SMARTBud-Form SMARTBud-Form + SABABud-Form + SABA

BUD + SABABUD + SABA

STEAMSTEAMChest 2006Chest 2006

00

1010

2020

3030

4040

5050

STEPSTEPAalbers et alAalbers et al

CMRO 2004CMRO 2004

STAYSTAY

O’Byrne et alO’Byrne et al AJRCCM 2005AJRCCM 2005

SMILESMILERabe et alRabe et al

Lancet 2006Lancet 2006

COMPASSCOMPASS

Kuna et alKuna et alIJCP 2007IJCP 2007

Salm-FP + SABASalm-FP + SABA

Bud-Form + formoterolBud-Form + formoterol

AHEADAHEAD

BousquetBousquetResp Med 2007Resp Med 2007

Reduction of Future Risk of Reduction of Future Risk of ExacerbationsExacerbations

Courtesy P.O’Byrne

The Goal of Asthma Management is:

Overall Asthma ControlOverall Asthma Control

Current ControlCurrent Control Future RiskFuture Risk

SymptomsSymptoms

ActivityActivity

Reliever useReliever use

Lung functionLung function

Instability/Instability/worseningworsening

Lung function Lung function lossloss

ExacerbationsExacerbations

Medication Medication adverse effectsadverse effects

achievingachieving reducingreducing

defined bydefined by defined bydefined by

GINA 2006; NIH/NAEPP Expert Report No.3 2007; ATS/ERS Task Force on Asthma Severity & Control 2008 GINA 2006; NIH/NAEPP Expert Report No.3 2007; 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; 171:129-136O’Byrne PM et al. Am J Respir Crit Care Med 2005; 171:129-136

Life has its ups & downs

2 October: No olympics for Chicago

9 October: Obama Nobel peace price