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Risk vs Benefit Considerations for the Long-Acting Beta-Agonists. Christine A. Sorkness, Pharm.D. Professor of Pharmacy and Medicine University of Wisconsin-Madison. Presentation Objectives. Provide an overview of the clinical pharmacology of the long-acting beta-agonists (LABAs)

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risk vs benefit considerations for the long acting beta agonists

Risk vs Benefit Considerations for the Long-Acting Beta-Agonists

Christine A. Sorkness, Pharm.D.

Professor of Pharmacy and Medicine

University of Wisconsin-Madison

presentation objectives
Presentation Objectives
  • Provide an overview of the clinical pharmacology of the long-acting beta-agonists (LABAs)
  • Discuss the selection of therapeutic outcomes for assessment of risks vs. benefits of the LABAs
  • Review selected clinical trials which provide insight into the risk/benefit of LABAs
  • Outline the controversies and remaining questions related to the role of LABAs
chemical structures of albuterol salmeterol and formoterol

Albuterol

HOH2C

OH

CH3

Salmeterol

HO

CHCH2NH-C

CH3

CH3

H3C

CHO

OH

(RS)

Formoterol

HN

NH

O

(RS)

HOH2C

HO

O

OH

OH

OCH3

2H2O

CH2

CH2

CH2

OH

HO

CHCH2

NHCH2

CH2

CH2

CH2

CH2

CH2

OCH2

2

Chemical Structures of Albuterol, Salmeterol, and Formoterol

Prescribing Information, GlaxoSmithKline.

Prescribing Information, Novartis.

comparison of b adrenergic agents

Duration of Action**

Selectivity

Bronchodilation

(h)

Protection

(h)

Pharmacologic

Profile

b2

Potency*

b1

b2

Drug

Full agonist

Partial agonist

Full agonist

Partial agonist

1

2

0.24

0.5

++++

++++

++++

++++

Isoproterenol

Albuterol

Formoterol

Salmeterol

++++

+

+

+

0.5-2

4-8

> 12

> 12

0.5-1

2-4

6-12

6->12

*Relative molar potency to isoproterenol, potency = 1

**Protection refers to the prevention of bronchoconstruction induced by exercise or nonspecific

bronchial challenges

Comparison of b–Adrenergic Agents

Kelly HW and Sorkness CA. Asthma. In: Pharmacotherapy—A

Pathophysiologic Approach, Sixth Edition, McGraw Hill 2005.

comparison of formoterol and salmeterol

Characteristic

Formoterol

Salmeterol

Equipotent Bronchodilating

Dose

Recommended Inspiratory

Flow Rate

Pregnancy Category

Indications

Onset of Action

  • 12 mcg via Foradil Aerolizer
  • 60 L/min for 2 secs.
  • C
  • Twice-daily maintenance
  • treatment of asthma and
  • prevention of bronchospasm
  • in adults and children

> 5 yrs

EIB prevention

Twice daily maintenance

treatment of broncho-

constriction in COPD

  • 80% max. bronchodilation
  • within 5-10 minutes
  • 50 mcg via Serevent Diskus
  • 60 L/min for 3 secs.
  • C
  • Twice-daily maintenance
  • treatment of asthma and
  • prevention of bronchospasm
  • in adults and children

> 4 yrs

EIB prevention

Twice daily maintenance

treatment of bronchospasm

associated with COPD

  • 90% max. bronchodilation
  • after 1 hr; median time to sig.
  • BD 30-40 minutes
Comparison of Formoterol and Salmeterol
slide8
What Therapeutic Outcomes Should be Used to Assess the Risks vs. Benefits of the Long-Acting Beta-Agonists?
slide9

Lung Function Measures

  • Longitudinal studies of lung health
  • “Gold-standard” measure for trial entry
    • FEV1 60-80% predicted with 15% reversibility
  • Primary endpoint to measure efficacy of controller therapies
  • Standardization of procedures for on-site and home measurements
slide10

Placebo

Placebo (n=56)

FEV1 >80%

TAA

Placebo

TAA (n=54)

PEF var

< 20%

Placebo

Salmeterol (n=54)

6 weeks

Run-in

6 weeks

Run-out

16 weeks

Treatment

Long-Acting b2-Agonist Monotherapy vs. Continued ICS Therapy

Lazarus S et al. JAMA 2001; 285:2583-2593 ACRN Group

slide11

500

Run-In

Double-Blind Treatment

480

Triamcinolone

Salmeterol

460

AM PEF (liters/min)

440

Placebo

420

400

2

6

10

14

18

22

26

Weeks

SOCS Primary Outcome: AM Peak FlowIntent-to-treat Analysis

Lazarus et al. JAMA 2001; 285:2583-2593 (ACRN Group)

slide12

SOCS Secondary Outcomes:Salmeterol versus Triamcinolone

Pulmonary Function

PM peak flow

FEV1

Methacholine PC20

Symptom Control

Asthma symptom scores

Rescue medication use

Quality of life

Markers of Inflammation

Sputum eosinophils

Sputum ECP

Sputum tryptase

Exhaled nitric oxide

P-value*

0.951

0.048

0.042

0.321

0.452

0.331

0.0003

0.005

0.0001

0.059

*significant = p < 0.016

slide13

Kaplan-Meier Survival Curves for Treatment Failure

and Asthma Exacerbations

Lazarus S et.al. JAMA 2001;285:2583-2593 ACRN Group

slide14

SOCS: Summary

  • Patients with persistent asthma well controlled by low doses of ICS cannot be switched to salmeterol monotherapy without risk of clinically significant loss of asthma control.
    • Clear disparity between lung function measures and other outcome measures
    • Multiple measurements and dimensions of control are needed to adequately assess therapies
slide15

Composite Measures of Asthma Control

  • Days of asthma control
  • Treatment failure
  • Asthma exacerbations
  • Improvement in NAEPP-defined asthma severity classification
  • “Total Control”
    • GINA 2002
    • Gaining Optimal Asthma Control (GOAL)
  • Patient surveys of asthma control and quality of life
    • Asthma Control Questionnaire (ACQ)
    • Asthma Therapy Assessment Questionnaire (ATAQ)
    • Asthma Control Test (ACT)
    • Asthma Quality-of-Life Questionnaire (AQLQ)
slide17

Low Dose Inhaled Budesonide and

Formoterol in Mild Persistent AsthmaThe OPTIMA Randomized Trial

O’Byrne PM et al. Am J Respir Crit Care Med 2001;164:1392-9

slide18

A

Group Patients not on inhaled steriods

Design Group A

Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

slide19

Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma: The OPTIMA Randomized Trial

Figure 1.  (A) Kaplan-Meier survival curve for the time to the first severe asthma exacerbation. (B) Proportion (%) of poorly controlled asthma days in Group A (corticosteroid-free patients). BUD 200 = budesonide 100 µg twice daily; F = formoterol 4.5 µg twice daily.

Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

slide20

Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma: The OPTIMA Randomized Trial

Figure 2.   Adjusted mean change from baseline in morning peak expiratory flow in Group A. BUD 200 = budesonide 100 µg twice daily; F = formoterol 4.5 µg twice daily.

Am. J. Respir. Crit. Care Med., 164(8):1392-1397, 2001

slide21

Addition of Salmeterol to Low-dose Fluticasone vs Higher-dose Fluticasone: An Analysis of Asthma Exacerbations

Matz J, Emmett A, Rickard K, Kalberg C.

JACI 107:783, 2001

slide23

FP/Salm vs FP alone:Effect of Disease Severity on Exacerbation Rates

Matz J et al. JACI107:783, 2001

slide24

**

1.0

Budesonide 100mcg/400mcg BID

0.9

Formoterol 12mcg BID

0.8

0.7

**

0.6

Severe Exacerbations/Patient/yr

**p=0.01

0.5

0.4

0.3

0.2

0.1

0.0

BUD 800mcg/day

BUD 200mcg/day

BUD 200mcg/day+F

BUD 800mcg/day+F

(n=213)

(n=214)

(n=215)

(n=210)

FACET Study: Formoterol and Budesonide in Moderate Asthma

Pauwels, et al. N Engl J Med 1997; 337: 1405-1411

slide25

Pharmacological Management to Reduce Exacerbations in Adults with Asthma—A Systematic Review and Meta-Analysis

Sinn DD et al. JAMA 2004; 292:367-376.

slide28

Can Guideline-defined Asthma Control Be Achieved? The Gaining Optimal Asthma Control Study

Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJH,

Pauwels RA, and Pederson SE for the GOAL Investigators Group.

Am J Respir Crit Care Med 2004; 170:836-844.

slide29

Total Control

Well-Controlled

All of:

Each Week

At least 2 of:

None

None

> 80% predicted daily

< 2 days with score > 1

< 2 days + < 4 occasions/wk

> 80% predicted daily

Daytime Sx

Rescue b2 agonist use

a.m. PEF

All of:

All of:

Nighttime awakening

Exacerbations

Emergency Visits

Tx-related AEs

None

None

None

None enforcing change in asthma Tx

None

None

None

None enforcing change in asthma Tx

Gaining Optimal Asthma Control (GOAL)

Research Question: Is GINA / NIH guideline-based control achievable, and in what proportion of patients, with SFC compared with FP alone?

Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

slide30

GOAL Study Design

  • 1 year, R, DB, PG, stratified study
    • Stratum 1: CS-naïve or CS-free x 6 months
    • Stratum 2: < 500 mcg BDP daily or equivalent
    • Stratum 3: > 500 - < 1000 mcg BDP daily or equivalent
  • > 12 yrs, asthma > 6 months, not well-controlled > 2/4 weeks during run-in, < 10 pack year smoking history, reversibility of >15%
  • At randomization: either SFC or FP alone via DiskusÒ; dose based on strata
  • Study Phase I: doses stepped up every 12 weeks until Total Control achieved or maximum dose reached
  • Study Phase II: dose of Total Control or maximum study dose (SFC 50/500 or FP 500 mcg bid) x 52 weeks

Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

slide31

BASELINE CHARACTERISTICS

Stratum 1

Stratum 2

Stratum 3

SFC

FP

SFC

FP

SFC

FP

N (ITT)

m Age (yrs)

FEV1, % pred

Revers., %

548

36.1

77

23

550

36.4

79

22

585

40.4

78

22

578

40.3

77

22

576

44.1

75

23

579

42.7

76

22

GOAL Study Population

Bateman ED et al. Am J Respir Crit Care Med 2004; 170:836-844.

slide34

GOAL Results

  • Significantly more patients achieved control with SFC vs FP in each stratum
  • In each stratum, the time to achieve the first individual week of Well-Controlled asthma was significantly lower with SFC than with FP alone (p < 0.001)
  • More patients achieved control at the same or lower dose of ICS in each stratum for SFC vs FP alone
  • The majority of patients who achieved Well-Controlled asthma in Phase I, maintained this status when reassessed in the last 8 weeks of the study; additional patients were able to gain control with sustained treatment
slide35

The Pediatric Asthma

Controller Trial (PACT)

A One-Year Prospective Comparison of Three Controller Medications for the Treatment of Mild-Moderate Persistent Asthma in Children

slide36

8 study encounters (5 clinic and 3

2 clinic visits

telephone) at 6

-

week intervals

All participants receive

:

Morning

Evening

Evening

Diskus

Diskus

Capsule

Albuterol prn

ICS

fluticasone

fluticasone

placebo

placebo diskus in the

morning and evening

ICS 50%

fluticasone/

salmeterol

placebo

placebo capsule in the

+ LABA

salmeterol

evening

LTRA

placebo

placebo

montelukast

Study Schematic

48-week treatment period

2-week run-in

Randomization

slide37

Inclusion Criteria

  • 6-14 year-old children with mild-moderate persistent asthma
    • Symptoms or b-agonist rescue use or PEF in the yellow zone on average of at least 3 days/wk during run-in
  • PC20 methacholine FEV1 12.5 mg/ml
  • FEV1 80% predicted at screen and  70% predicted at randomization
  • Nonsmoker within the past year
  • Naïve to controller medications for specified periods
  • Otherwise healthy
slide38

Primary Outcome

  • Percent of Asthma Control Days (ACD) during the 12-month treatment period
  • Using self-reported daily diary data, an ACD was defined as a day without:
    • Albuterol rescue use (pre-exercise treatment permitted)
    • Use of non-study asthma medications
    • Daytime asthma symptoms
    • Unscheduled health care provider visits for asthma
    • School absenteeism for asthma
slide40

Studies in the early 1990’s suggested that regular use of the ß-agonist fenoterol might produce adverse effects

Taylor et al., 1993. Thorax; 48:134-138

slide41

M

M

6 WKS

4 WKS

16 WKS

BAGS (ß-Agonist) TRIAL DESIGN

REGULAR ALBUTEROL + “AS NEEDED”

M

M

B

M

B

B

M

B

B

M

RUN-IN

RUN-OUT

PLACEBO INHALER+ “AS NEEDED”

Drazen JM for the ACRN. NEJM 1996; 335:841.

slide42

BAGS: AM Peak Flow

Drazen & the ACRN, NEJM, 1996

slide43

NH2

Gly

Arg 16

Thr 164

Ile

Gln 27

Glu

Cell membrane

Val 34

Met

COOH

2-Adrenoceptor (2-AR) Variants

Reishaus et al., 1993. AJRCMB; 8:334–339

slide44

BAGS Genetic Analysis

  • No effect seen at the B27 locus
  • No effect seen in B16 heterozygotes (Arg/Gly)
  • However, when B16 Arg/Arg patients (1/6 of the population) were compared to B16 Gly/Gly patients, a difference was found in the primary outcome variable - - AM PEF
slide45

Reg Arg/Arg

PRN Arg/Arg

Reg Gly/Gly

n=16

n=10

n=34

10

0

Change in AM PEF (L/min)

-10

-20

RUN OUT

-30

0

5

10

15

20

25

Scheduled vs ‘As Needed’ Albuterol Response by GenotypeBAGS— “Retrospective” Analysis

Weeks After Randomization

BAGS, Beta-agonist in mild asthma study.

Israel E, et al. Am J Respir Crit Care Med. 2000;162:75-80.

slide46

The Influence of Beta2-adrenergic Receptor Polymorphisms on Asthma Exacerbations

* †

* P=0.003 vs Gly/Arg.

†P=0.033 vs Gly/Gly.

Exacerbations

(per patient per year)

Taylor DR, et al. Thorax. 2000;55:762-767.

slide47

BARGE

  • Prospective randomized, placebo-controlled, double-blind trial of regular vs minimal albuterol in each genotype
  • To minimize beta-agonist use patients were provided with ipratropium bromide (IB) for rescue use and instructed only to use albuterol if symptoms were not relieved by IB

Israel E, et al. Lancet. 2004;364:1505-1512.

slide48

Crossover

Randomize

0

6

22

30

46

54

Regularly Scheduled Albuterol Response by GenotypeBARGE-Prospective Analysis

16 weeks placebo or active treatment

6 weeks run-in; all on placebo

8 weeks run-out;all on placebo

Screen and genotype

16 weeks active treatment or placebo

8 weeks run-out;all on placebo

Baselineweeks 0-2

PretreatmentBaseline 1weeks 3-6

PretreatmentBaseline 2weeks 27-30

BARGE, Beta-Adrenergic Response by GenotypE.

Israel E, et al. Lancet. 2004;364:1505-1512.

slide49

BARGE: Patient Population

  • Patients with mild asthma not using controller therapy
    • Mean age = 31 years
    • Mean FEV1 = 90% of predicted
  • Patients were matched in pairs for FEV1 according to whether they had Arg/Arg (n = 37)* or Gly/Gly (n = 41) genotype

*4 of the 41 matches withdrew from the study before randomization.

BARGE, Beta-Adrenergic Response by GenotypE.

Israel E, et al. Lancet. 2004;364:1505-1512.

slide50

Albuterol modelled

Albuterol raw means

Placebo modelled

Placebo raw means

Gly/Gly

Arg/Arg

Treatment

Washout

Treatment

Washout

20

20

P=0.029

P=0.0175

10

10

*

Morning PEFR (L/min)

Morning PEFR (L/min)

0

0

-10

-10

-20

-20

0

0

5

5

10

10

15

15

20

20

Time (weeks)

Time (weeks)

BARGE: Change in AM PEF by Genotype

BARGE, Beta-Adrenergic Response by GenotypE.

Israel E, et al. Lancet. 2004;364:1505-1512.

slide51

Mean Change in AM PEF by Genotype at Week 16

*

Albuterol Arg/Arg

Placebo Arg/Arg

Albuterol Gly/Gly

Placebo Gly/Gly

* Mean Arg/Arg minus Gly/Gly treatment difference= -24 (-37 to -12), P=0.0003.

† P=0.0209 vs Placebo Arg/Arg.

‡ P=0.0175 vs Placebo Gly/Gly.

Israel E, et al. Lancet. 2004;364:1505-1512.

slide52

FEV1Difference between Regular vs. Placebo Treatment-induced Changes over 16 Wk

P=0.002

P=0.094

Liters

P=0.002

Israel E for the ACRN, Lancet 2004; 364:1505-1512.

slide53

AM SYMPTOMS Difference between Regular vs. Placebo Treatment-induced Changes over 16 Wk

P<0.0001

P=0.001

P<0.0001

Israel E for the ACRN, Lancet 2004; 364:1505-1512.

slide54

INHALER USE Difference between Regular vs. Placebo Treatment-induced Changes over 16 Wk

P=0.0002

P<0.0001

P=0.019

P=0.043

PUFFS / WK

P<0.0001

P=0.0003

IB

Alb

Israel E for the ACRN, Lancet 2004; 364:1505-1512.

slide55

BARGE

  • AM & PM PEF, FEV1 , symptoms, and rescue inhaler use improved significantly in Arg/Arg patients with asthma when β-agonists were withdrawn and prn IB was substituted, as c/w regular albuterol use
  • The pattern was reversed in Gly/Gly patients with asthma
    • They improved with regular β-agonist use as c/w prn IB use
  • Suggested that Arg/Arg patients (1/6 of asthmatics) may benefit from minimizing short-acting β-agonist use

Israel E for the ACRN, Lancet 2004; 364:1505-1512.

slide56

Do Similar Effects Occur With Long-acting Beta2-agonists (LABA) and What Is the Impact of Concurrent Use of Inhaled Corticosteroids?

slide57

Methods

  • Genotype stratified retrospective analysis of 2 ACRN trials that used long-acting ß-agonists:
    • SOCS trial= Salmeterol Or CorticoSteroid
    • Well-controlled patients on ICS were randomized to LABA or continued ICS
    • SLIC trial=SalmeteroL +/- Inhaled Corticosteroid
    • Less well controlled patients on ICS were randomized to add LABA & continue ICS or add LABA & taper ICS
slide58
Does Regular Use of LABAs Delay Awareness of Asthma Progression or Effect Recovery From an Exacerbation?
slide59

FP/Salm vs FP Alone:Effect on Rate of Symptom Decrease following Exacerbation

Matz J et al. JACI107:783, 2001

evidence for increased asthma exacerbations with labas
Evidence for Increased Asthma Exacerbations with LABAs
  • Salmeterol
    • Serevent National Surveillance Study (SNS)

BMJ 1993; 306:1034-7

    • Salmeterol Multicenter Asthma Research Trial (SMART)
  • Formoterol
    • Review of 3 clinical studies submitted to the FDA

Chest 2003; 124:7074

summary
Summary
  • Strong evidence of the ability of ICS + LABA to achieve asthma control and reduce asthma exacerbations
  • More evidence in adults than children
  • Remaining concerns about safety
    • ? genotypic predictors
    • ? phenotypic predictors
    • ? need for larger and longer trials which incorporate multiple outcomes
    • ? class effect
    • ? dose effect