Critical Appraisal

Pulmonary Hour
Clinical Scenario
• AZ, 41 year-old, male, with significant smoking history came in for
follow up. Patient is assessed with COPD. He asks if there is a
medication that could reduce exacerbation rate. You were introduced
to a new drug combination inhaler (LABA/LAMA/ICS) which is being
offered to COPD patients. You searched for evidence if this is
efficacious.
 Once Daily Single Inhaler
Triple versus Dual Therapy in
Patients with COPD
IMPACT Trial Phase III
Background
• Informing the Pathway of COPD Treatment (IMPACT) trial evaluated
the relative benefits and risks of these three regimens in patients with
symptomatic COPD and a history of exacerbations.
• Effectiveness of combination inhaled therapies has not been
comprehensively evaluated in patients with COPD who have the
highest symptom burden.
Appraising Directness
Does the study provide direct enough answer to your
clinical question in terms of type of patient,
exposure/intervention, and outcome?
• Population studied
• Intervention given
• Comparator given
• Outcome considered
Population
Exposure/Intervention

Intervention Comparator
• FF/UMEC/VI (100/62.5/25mcg) • FF/VI (100/25mcg)
• UMEC/VI (62.5/25mcg)
Outcome
Primary
• Annual rate of moderate or
severe exacerbations during
treatment (including 1 day after
the last dose was administered)
Secondary
• FEV1 change at 52 weeks
• SGRQ change at 52 weeks
• time to the first moderate or severe
COPD exacerbation during treatment
• time to the first moderate or severe
COPD exacerbation during treatment
among patients with a blood eosinophil
count of at least 150 cells per microliter
at baseline
• annual rate of severe exacerbations
Appraising Validity
Were patients randomly assigned to treatment groups?
Was allocation concealed?
Patients were randomised using the proprietary RandAll software
(GlaxoSmithKline).
Were baseline characteristics similar at the
start of the trial?
Were patients blinded to treatment
assignment?
• Patients were assigned to treatment using the Randomisation and
Medication Ordering System (RAMOS; GlaxoSmithKline).
Were outcome assessors blinded to treatment
assignment?
• Regimen were delivered via an identical ELLIPTA dry powder inhaler
• Only the IDMC will be authorised to review un-blinded interim safety
analyses during the trial, which will be performed and delivered to the IDMC
by an independent statistical data analysis centre.
• In addition, a separate adjudication committee will be established to
independently review and categorise the cause of each serious adverse event
(SAE) and death in the study.
• The committee members will remain blinded to treatment.

* Independent data monitoring committee (IDMC) Chair who is a pulmonologist, the IDMC comprises three people
(an independent statistician, an independent respiratory clinician with experience in COPD and a cardiologist).
Was follow-up adequate?
Appraising Results
 How large was the effect of treatment?
How precise was the estimate of the treatment effect?
Exacerbation Without Exacerbation
FF/UMEC/VI (Triple) 642 4145
FF/VI (Double A) 1228 4133
UMEC/VI (Double B) 1419 2069

= 0.155 = = 1- 0.522 = 0.478

= 0.297
= = 1- 0.226 = 0.774
= 0.686

𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑅𝑖𝑠𝑘 𝑅𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛𝑇𝑟𝑖𝑝𝑙𝑒 𝑣𝑠 𝐷𝑜𝑢𝑏𝑙𝑒 𝐴=𝑅𝑖𝑠𝑘 𝑇𝑟𝑖𝑝𝑙𝑒 − 𝑅𝑖𝑠𝑘𝐷𝑜𝑢𝑏𝑙𝑒 𝐴 =0. 155− 0.297=− 0.142
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑅𝑖𝑠𝑘 𝑅𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛𝑇𝑟𝑖𝑝𝑙𝑒 𝑣𝑠 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵=𝑅𝑖𝑠𝑘𝑇𝑟𝑖𝑝𝑙𝑒 − 𝑅𝑖𝑠𝑘 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵=0.155 − 0. 686=−0.531
 APPRAISING
APPLICABILITY
Are there biologic issues that may affect applicability of treatment?
(Consider the influence, co-morbidity, race, age, and pathology)

• None
Are there socio-economic issues affecting
applicability of treatment?
• Cost and benefit analysis was not done
• Accessibility is an issue. This drug is not readily available at our
pharmacy
• Cost may be an issue for low socio-economic population
INDIVIDUALIZING THE
RESULT
What is the likely effect of the treatment on
your individual patient?
• On triple therapy was 0.91 per year,
as compared with
• 1.07 per year among fluticasone
furoate–vilanterol
• 1.21 per year among umeclidinium–
vilanterol
What is the likely effect of the treatment on
your individual patient?
 Exacerbation Without Exacerbation
FF/UMEC/VI (Triple) 642 4145
FF/VI (Double A) 1228 4133
UMEC/VI (Double B) 1419 2069

= 0.155 = = 1- 0.522 = 0.478

= 0.297
= = 1- 0.226 = 0.774
= 0.686

𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑅𝑖𝑠𝑘 𝑅𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛𝑇𝑟𝑖𝑝𝑙𝑒 𝑣𝑠 𝐷𝑜𝑢𝑏𝑙𝑒 𝐴=𝑅𝑖𝑠𝑘 𝑇𝑟𝑖𝑝𝑙𝑒 − 𝑅𝑖𝑠𝑘𝐷𝑜𝑢𝑏𝑙𝑒 𝐴 =0. 155− 0.297=− 0.142
𝐴𝑏𝑠𝑜𝑙𝑢𝑡𝑒 𝑅𝑖𝑠𝑘 𝑅𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛𝑇𝑟𝑖𝑝𝑙𝑒 𝑣𝑠 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵=𝑅𝑖𝑠𝑘𝑇𝑟𝑖𝑝𝑙𝑒 − 𝑅𝑖𝑠𝑘 𝐷𝑜𝑢𝑏𝑙𝑒 𝐵=0.155 − 0. 686=−0.531

= = = 7.042 ~ 7
= = = 1.883 ~ 2
Would you offer the treatment to your
patients?
• Ideally if with funds
Always laugh while you can.
It is a cheap medicine.
– Lord Bryan -