Transcript The Long-Acting Beta Agonist: Friend or Foe

The Long-Acting Beta Agonist:
Asthma Therapeutic
Friend or Foe
Jason E. Knuffman, M.D.
Allergy & Immunology Fellow
Department of Medicine
July 19, 2006
No Disclosures
ICS – Inhaled corticosteroid
LABA – Long-acting beta agonist
Outline
• Introduction
• Asthma Clinical Research Network
(ACRN)
• Salmeterol Multicenter Asthma Research
Trial (SMART)
• Black Box Warning
• Controversy
• Conclusions
Long-Acting Beta Agonists
• Salmeterol xinafoate
(Serevent Diskus and
aerosol inhaler)
– 50 mcg DPI
– 1 puff BID
– Delayed onset of
action
• Advair Diskus
(salmeterol combined
with fluticasone)
Long-Acting Beta Agonists
• Formoterol fumarate
(Foradil Aerolizer)
– 12 mcg DPI
– 1 puff BID
– Immediate and
delayed onset of
action
• Symbicort Turbuhaler
(formoterol combined
with budesonide)
– Not available in U.S.
http://www.acrn.org/index.html
After adding LABA to the ICS, my
patient’s asthma is under good
control. How far can I cut back on
their ICS dose?
SLIC (ACRN)
• SaLmeterol with or without Inhaled
Corticosteroids Trial
– Hypothesis: “In patients with persistent asthma who
are suboptimally controlled with a regularly-scheduled
ICS, but subsequently controlled following the addition
of a scheduled LABA, can the dosage of ICS be
reduced or eliminated without increasing the risk of
treatment failure?”
JAMA.2001;285:2594-2603
SLIC
JAMA.2001;285:2594-2603
SLIC
• SaLmeterol with or without Inhaled
Corticosteroids Trial
– Conclusion: “In patients with persistent asthma
suboptimally controlled by triamcinolone therapy
alone but whose asthma symptoms improve after
addition of salmeterol, a substantial reduction (50%)
in triamcinolone dose can occur without a significant
loss of asthma control. However, total elimination of
triamcinolone therapy results in a significant
deterioration in asthma control and, therefore, cannot
be recommended.”
JAMA.2001;285:2594-2603
What about patients wellcontrolled on ICS, why not switch
them to LABA and avoid potential
ICS side effects?
SOCS (ACRN)
• Salmeterol Off CorticoSteroids Trial
– Hypothesis: “In patients with moderate persistent
asthma whose symptoms are well-controlled with
ICS, does continued treatment with ICS differ in
efficacy from a change of therapy with LABA?”
JAMA.2001;285:2583-2593
SOCS
JAMA.2001;285:2583-2593
SOCS
• Salmeterol Off CorticoSteroids Trial
– Conclusion: “In patients with persistent
asthma that is well controlled by low-dose
triamcinolone monotherapy cannot be
switched to salmeterol monotherapy without
risk of clinically significant loss of asthma
control.”
JAMA.2001;285:2583-2593
What about combination
(ICS + LABA) therapy and
exacerbations?
FACET
• Formoterol and Corticosteroids Establishing
Therapy Trial
– First trial to suggest that adding LABA to ICS could
reduce exacerbations
– Best way to decrease major exacerbations was to
increase ICS four-fold, but…
– Adding formoterol to either low- or high-dose ICS
(budesonide) further reduced both minor and major
exacerbations
– These findings supported by…
Optimal Treatment for Mild Asthma
(OPTIMA) Trial
Does regular use of LABA make
one tolerant to albuterol?
ER Study
• Patients seen for acute asthma exacerbations
– 57 patients taking salmeterol along with other
therapies for asthma
– 57 patients not taking salmeterol (controls)
– With nebulized albuterol, mean PEF increased from
45% of predicted to 62% in controls, while increasing
from 40% to 60% in salmeterol group (p=NS)
– No differences seen between length of ER stay,
admission to hospital or number of return visits
• This and other studies have been reassuring in
this matter
Can LABAs be harmful?
SMART
Salmeterol Multicenter Asthma
Research Trial
A Comparison of Usual Pharmacotherapy for
Asthma
or Usual Pharmacotherapy plus Salmeterol
Nelson HS et al. The salmeterol multicenter asthma research trial: a comparison of usual
pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26.
SMART Study Design
• 28-week, multicenter, randomized, doubleblind, placebo-controlled, observational
surveillance trial initiated in June 1996
• Target enrollment: ~60,000 patients
• Included patients >12 years with asthma
currently using a prescription asthma
medication
– No history of previous salmeterol or
formoterol use
Nelson HS et al. Chest. 2006;129:15-26.
SMART Study Endpoints
• Primary Endpoint
– Combined respiratory-related deaths or lifethreatening experiences (intubation and
ventilation)
• Key Secondary Endpoints
– Respiratory-related deaths
– Combined asthma-related deaths or lifethreatening experiences
– Asthma-related deaths
Nelson HS et al. Chest. 2006;129:15-26.
SMART Study Design (cont.)
Salmeterol MDI 42 mcg BID + Usual Care
• No inhaled longacting beta2-agonist
• ≥12 years of age
(n=13,176)
R
28-week treatment period
Phone contact every 4 weeks
Placebo MDI BID + Usual Care
(n=13,179)
Clinic Visit
28-week supply of study
medication provided
Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.
Baseline Characteristics
Salmeterol
(n=13,176)
Placebo
(n=13,179)
Age, mean
39.2
39.1
Sex, n (%)
Female
Male
8334 (64)
4703 (36)
8337 (64)
4686 (36)
Ethnic origin, n (%)
Caucasian
African American
Hispanic
Asian
Other
9281 (71)
2366 (18)
996 (8)
173 (1)
230 (2)
9361 (72)
2319 (18)
999 (8)
149 (1)
224 (2)
84.0
83.8
Peak expiratory flow (% predicted)
Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.
Baseline Asthma Characteristics in
Caucasians and African Americans
Caucasian African American
(n=4685)
(n=18,642)
Peak expiratory flow (% predicted)
85%
78%
Nocturnal symptoms present
59%
67%
 1 ER visit last 12 months
22%
41%
 1 ER visit lifetime
59%
72%
 1 hospitalization last 12 months
6%
15%
 1 hospitalization lifetime
30%
44%
 1 intubation for asthma lifetime
4%
8%
Baseline ICS use
49%
38%
Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.
Asthma Medications at Baseline
Concurrent Medications, n (%)
Salmeterol
n=13,176
Placebo
n=13,179
Patients using asthma medications
at Baseline
12,715 (97)
12,660 (96)
461 (3)
519 (4)
12,059 (92)
12,043 (91)
Inhaled corticosteroids
6127 (47)
6138 (47)
Methylxanthines
1766 (13)
1767 (13)
Leukotriene modifiers
1437 (11)
1402 (11)
Patients with no asthma medications
at Baseline
Inhaled or oral beta2-agonists
(excluding inhaled LABAs)
Nelson HS et al. Chest. 2006;129:15-26. Adapted with permission.
SMART Interim Analysis, 2002
• SMART did not reach predetermined stopping criteria at
the interim analysis
• Data Safety Monitoring Board recommended
– Timely completion (within 2 years)
If this was not possible:
– Discontinuation of study and rapid dissemination
of the interim results
• SMART was discontinued due to difficulties in enrollment
and findings in African American patients
Nelson HS et al. Chest. 2006;129:15-26.
Data on file, GlaxoSmithKline.
SMART Results
All Patients and Ethnic Subgroups
1° Endpoint
Combined
Respiratory-related
Deaths or
Life-threatening
Experiences
2° Endpoints
Respiratory-related
Deaths
Combined
Asthma-related
Deaths or
Life-threatening
Experiences
Asthma-related
Deaths
.031.062 .125 .25 .5
1
2
4
8
Nelson HS et al. Chest. 2006;129:15-26.
16 32 64 128
RR (95% CI)
SAL n
PLA n
1.40 (0.91, 2.14)
1.05 (0.62, 1.76)
4.10 (1.54, 10.90)
50
29
20
36
28
5
2.16 (1.06, 4.41)
2.29 (0.94, 5.56)
3.88 (0.83, 18.26)
24
16
8
11
7
2
1.71 (1.01, 2.89)
1.08 (0.55, 2.14)
4.92 (1.68,14.45)
37
17
19
22
16
4
4.37 (1.25, 15.34)
5.82 (0.70, 48.37)
7.26 (0.89, 58.94)
13
6
7
3
1
1
Total
Caucasian
African American
N=13,176
N=9281
N=2366
N=13,179
N=9361
N=2319
SMART: Summary of Results
• Total Population
– For the primary endpoint, 50 events occurred in patients receiving
salmeterol vs 36 events in those receiving placebo (RR=1.40,
95% CI [0.91, 2.14])
– A significant increase in respiratory-related deaths was observed in
patients receiving salmeterol vs those receiving placebo (RR=2.16, 95%
CI [1.06, 4.41])
– The number of combined asthma-related deaths or life-threatening
experiences was 37 in patients receiving salmeterol vs 22 in those
receiving placebo (RR=1.71, 95% CI [1.01, 2.89])
– A significant increase in asthma-related deaths was observed in patients
receiving salmeterol (13 of 13,176 pts) vs those receiving placebo (3 of
13,179 pts) (RR=4.37, 95% CI [1.24, 15.34])
SMART: Summary of Results
• African Americans
– For the primary endpoint, 20 events occurred in patients treated with
salmeterol vs 5 in those treated with placebo (RR=4.10, 95% CI
[1.54, 10.90])
– A higher number of respiratory-related deaths (8 vs 2, RR=3.88, 95%
CI [0.83, 18.26])
– A higher number of combined asthma-related deaths or lifethreatening experiences (19 vs 4, RR=4.92, 95% CI [1.68, 14.45])
– A higher number of asthma-related deaths (7 vs 1, RR=7.26, 95% CI
[0.89, 58.94])
SMART: Summary of Results
• Caucasians
– For the primary endpoint, 29 events occurred in patients treated
with salmeterol vs 28 in those treated with placebo (RR=1.05,
95% CI [0.62, 1.76])
– A higher number of respiratory-related deaths (16 vs 7, RR=2.29,
95% CI
[0.94, 5.56])
– The number of combined asthma-related deaths or lifethreatening experiences was 17 vs 16 (RR=1.08, 95% CI [0.55,
2.14])
– A higher number of asthma-related deaths (6 vs 1, RR=5.82,
95% CI [0.70, 48.37])
SMART: Key Findings
• Treatment with salmeterol compared with placebo
resulted in statistically significant higher incidence of
asthma-related deaths, combined asthma-related deaths
or asthma-related life-threatening experiences, and
respiratory-related deaths alone
• The data from SMART are not adequate to determine, nor
was the study designed to determine, whether concurrent
use of inhaled corticosteroids, such as fluticasone
propionate, modifies this risk of asthma-related death
• Given the similar mechanism of action of beta2-agonists,
it is possible that the findings of SMART may represent a
class effect
http://www.bagoliefriedman.com/news_item.asp?NewsID=382
Hi Dr. Salpeter:
This web page, presumably run by an attorney, quoted you as having stated the
following under the heading, "News You Can Use":
"We estimate that approximately 4,000 out of the 5,000 asthma deaths that occur in the
U.S. each year are actually caused by these long-acting beta-agonists, and we urge
that these agents be taken off the market," [Shelley Salpeter] added.
In the discussion portion of the meta-analysis, you stated, "This indicates that salmeterol
may be responsible for approximately 4000 of the 5000 asthma-related deaths that
occur in the United States each year (ref.)."
I am giving a talk to a large number of area primary care providers next week and your
explanation about this wording choice is requested. Thank you!
Jason E. Knuffman, MD
(608) 516-5645
Madison, WI
LARGE (ACRN)
• Long-Acting beta Agonist Response by
GEnotype study
– 60 week randomized, double-blind, crossover trial to
compare the effects of LABA in asthmatics receiving
ICS who express two distinct polymorphisms of the
beta2-adrenergic receptor
• Position 16 Arg/Arg vs. Gly/Gly
• Hypothesis: Subjects with the B16 Arg/Arg genotype will
experience inferior asthma control (by a.m. PEF rate) than
those with the B16 Gly/Gly genotype.
• Enrollment of around 80 subjects is now closed with the last
subjects finishing in September, 2007.
Conclusions
• First-line treatment is the inhaled corticosteroid
• LABAs, if selected, should be prescribed only in
conjunction with ICS
• There may be specific population subsets at
elevated risk for poor asthma outcomes while
taking LABAs
• Pharmacogenomic profiles need to be defined
• Documented, informed consent obtained?
• Diligent follow-up care is mandatory