Transcript Step-down or Step-off

Step-down or Step-off:
How do we consider the warning
about LABA from the FDA?
Robert C. Strunk, MD
Strominger Professor of Pediatrics
Washington University School of Medicine
St. Louis Children’s Hospital
Division of Allergy, Immunology, and
Pulmonary Medicine
Disclosures

Employment


Research Interests


NHLBI
Financial Interests


Washington University School of Medicine
None
Chair, Pediatric Adjudication Committee,
GSK study of safety and benefit of
FP/salmeterol vs. FP
Areas to be discussed
• Importance of stepping down on therapy
when control achieved
• How to step down from ICS/LABA
• What is needed to help clinicians in
decision making
Focus on LABA
• LABA are effective in achieving improved
control when added to ICS
• ICS dose reduction greater when done in
the context of LABA
• How to step down from ICS/LABA
– Step-off LABA
– Step-down on ICS dosing
• What is the evidence for step-off LABA to
retain control
Why Step Down Asthma Care?
•
•
•
•
Minimization of Risks
Cost
Simplicity of regimen
To better define disease severity/phenotype
• The NAEPP/EPR3 Guideline say so
• The FDA says so
Why Step Down Asthma Care?
• The NAEPP/EPR3 Guideline Say So
– The Expert Panel recommends that, once asthma is well controlled
and the control is achieved and maintained for at least 3 months, a
reduction in pharmacologic therapy—a step down—can be
considered. This will be helpful to identify the minimum therapy for
maintaining good control of asthma (Evidence D).
– Reduction in therapy should be gradual and closely monitored,
because asthma can deteriorate at a highly variable rate and
intensity.
– Guidelines for the rate of reduction and intervals for evaluation
have not been validated, and clinical judgment of the individual
patient’s response to therapy is important.
– The opinion of the Expert Panel is that the dose of ICS may be
reduced about 25–50 percent every 3 months to the lowest dose
possible that is required to maintain control.
Why Step Down Asthma Care?
• The FDA Says So
– LABAs should not be used in patients whose asthma is adequately
controlled on low or medium dose inhaled corticosteroids.
– LABAs should only be used as additional therapy for patients with asthma
who are currently taking but are not adequately controlled on a long-term
asthma control medication, such as an inhaled corticosteroid.
– Once asthma control is achieved and maintained, patients should be
assessed at regular intervals and step down therapy should begin (e.g.,
discontinue LABA), if possible without loss of asthma control, and the
patient should continue to be treated with a long-term asthma control
medication, such as an inhaled corticosteroid.
– Pediatric and adolescent patients who require the addition of a LABA to an
inhaled corticosteroid should use a combination product containing both an
inhaled corticosteroid and a LABA, to ensure adherence with both
medications.
How to Step Down from
Combination Therapy?
• Potential Strategies
– Last med added, first med stopped
– Reduce or discontinue the medication with
the most concern for side effects/risks
• Reduce ICS first (to minimize ICS risks)?
• Eliminate (or reduce) LABA first (to minimize
LABA risks)?
– Replace one medication with another?
• Change from ICS to LTRA?
How to Step Down from
Combination Therapy?
• Potential Strategies
– Last med added, first med stopped
– Reduce or discontinue the medication with
the most concern for side effects/risks
• Reduce ICS first (to minimize ICS risks)?
• Eliminate (or reduce) LABA first (to minimize
LABA risks)?
– Replace one medication with another?
• Change from ICS to LTRA?
Why Step Down Combination
Therapy?
• Potential Strategies
– Last med added, first med stopped
– Reduce or discontinue the medication with
the most concern for side effects/risks
• Reduce ICS first (to minimize ICS risks)?
• Eliminate (or reduce) LABA first (to minimize
LABA risks)?
– Replace one medication with another?
• Change from ICS to LTRA?
How the issue of step-off
emerged in editorials after
a recent article
Step-up Therapy for Children with
Uncontrolled Asthma Receiving Inhaled
Corticosteroids
Lemanske and CARE Network
NEJM 2010;362:975
• Step-up therapies: +LABA, + LTRA, double ICS
• LABA step-up was significantly more likely to
provide the best response than either ICS or
LTRA step-up
• However, many children had a best response to
ICS or LTRA step-up
Primary Outcome: Probability of BEST
Response Based on Composite Outcome*
LABA step-up was more than 1.5 times as
likely to produce the best response
LABA
ICS
(p = 0.002)
LTRA
(p = 0.004)
*Covariate adjusted model
Accompanying editorial
von Mutius and Drazen
• Choice for a given patient should be based on
three things: surety of safety, price, and
convenience, in that order
• Given lingering about safety of LABA, first
choice would be either increasing dose of ICS or
adding LTRA
• Onus lies with the treating practitioner to follow
patients closely and to be sure that there is
improvement with therapeutic step-up
• If there is no improvement, the patient should be
switched to an alternative medication and again
closely monitored.
Other Recent Opinions
• Concern about safety, most notably death,
needs to be addressed by large safety
studies (Drazen and O’Byrne)
• LABAs should be used only in patients for
whom other controller medications alone
do not provide adequate (not optimal)
control (Drazen and O’Byrne)
• If step-up is done by adding LABA to ICS,
LABA should be withdrawn, of possible,
once stability is achieved (FDA 2/2010)
Step-Off: Remove LABA
• What is the evidence that it can be done
without compromising control?
• Who should be considered for step-off?
Overview of literature
• 5 articles report RCTs of patients with
stable asthma controlled on ICS/LABA
• Intervention:
– step-off to same dose of ICS without LABA
• Controls:
– ICS of same dose with continued LABA
– lower dose of ICS with continued LABA
Respiratory Medicine 2008;102:1124
Patients
• 18 years or older, N=476
• Eligibility
– Asthma controlled on dose of 1000 mcg CFC
beclomethasone or equivalent and a LABA
– Stable for at least 4 weeks
• During 8-week run-in period on open-label
fluticasone 250/salmeterol 50 (SFC250),
had “well-controlled” asthma
Methods
• Randomized to SFC 250, SFC 100, FP250
• Primary end-point variation in mean AM PEF
over 1st 12 weeks compared to last 2 weeks of
run-in
• Secondary outcomes:
–
–
–
–
–
–
–
PEF over last 12 weeks
Evening PEF
Daily symptoms
SABA use
FEV1at clinic visits
Asthma control (GOAL definitions)
Exacerbations: severe, moderate, mild
Primary efficacy analysis
Other outcomes
• Symptom-free days over 1st 12 weeks (change from
baseline)
– SFC 250: 90.2% to 89.4%
– SFC 100: 94.8% to 93.2%
– FP 250:
91.2% to 85.8% (p=0.012)
• Rescue-free days over weeks 5-12 (change from
baseline)
– SFC 250: 89.6% to 89.0%
– SFC 100: 95.7% to 93.6%
– FP 250:
93.6% to 88.2% (p=0.014)
• Moderate exacerbations (prednisone) similar in
groups
– SFC 250: 5.8%
– SFC 100: 7.7%
– FP 250: 10.4% (p=NS)
Overall Conclusion
• The better option for reducing treatment in
controlled asthma patient on an ICS/LABA
conbination was to reduce the ICS dose
and to maintain the LABA
• All published studies come to same
conclusion
Problems with all
published studies
• Poor control on ICS alone not
systematically demonstrated before
addition of LABA
• Group data only presented: Variability in
response to step-off not described
• Patient characteristics that might be
associated with variability in response to
step-off not part of any study
Conclusions
• Therapeutic nihilism is desired by patients
and should be a goal of all medical care
• Patients should continually be re-assessed
for degree of asthma control
• A discussion of therapeutic strategies,
including step-down of care, in the setting of
well-controlled asthma is essential
Conclusions
• Less (robust) data available to guide step-down
approaches than to guide step-up approaches
– Step-down of ICS within fixed dose inhaler of ICS/LABA
may be effective
– Step-off LABAs might put patients at risk for losing
asthma control
– Substituting LTRA+ICS for LABA+ICS has not been
studied
• All patients need close follow-up to evaluate
adequacy of step-down/step-off
References
• Koenig et al. Deterioration in asthma control when subjects
receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are
“Stepped-Down”. J Asthma 2008;45:681-687.
• Bateman et al. Asthma control can be maintained with fluticasone
propionate/salmeterol in a single inhaler is stepped down. JACI
2006;117:563-570.
• Godard et al. Maintaining asthma control in persistent asthma:
Comparison of three strategies in a 6-month double-blind
randomized study. Resp Med 2008;102:1124-1131.
• Berger et al. Efficacy and safety of budesonide/formoterol
pressurized metered-dose inhaler: Randomized controlled trial
comparing once- and twice-daily dosing in patients with asthma.
Allergy Asthma Proc 2010;31:49-59.
• Reddel et al. Down-titration from high-dose combination therapy in
asthma: Removal of long-acting beta2-agonist. Resp Med
2010;104:1110-1120.