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Three better than 1 or 2?
DISCLOSURE
Pam McLean-Veysey, Team Leader Drug Evaluation Unit DEU funded by the Drug Evaluation Alliance of NS. (DEANS).
DEU prepares Drug Evaluation Reports for the Atlantic Common Drug Review (ACDR)
Has no conflicts of interest
Faculty: Dr. Brian Moses
Relationships with commercial interests: Grants/Research Support: None
Speakers Bureau/Honoraria: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Novartis, NovoNordisk, Pfizer, Sanofi Aventis, and Servier.
Consulting Fees: AstraZeneca, Bayer, BMS/Pfizer, NovoNordisk, Eli Lilly, Novartis.
Other: None
OBJECTIVES
To review the evidence (benefits and harms) for triple therapy (LAMA+LABA+ICS) in COPD.
Based on a case, determine the characteristics of the patient population where triple therapy could be considered.
To review the positioning of triple therapy in Clinical Practice Guidelines
AN EXPLOSION OF INHALER DEVICES!
Turbuhaler
Genuair
Class GenericLong acting Beta2 agonists (LABA) Salmeterol
Formoterol
Indacaterol
Long Acting Muscarinic
Antagonists (LAMA)
aka Long Acting Anticholinergic
(LAAC)
Tiotropium
Aclidinium
Glycopyrronium
Umeclidinium
LAMA/LABA Combinations: Aclidinium + Formoterol
Glycopyrronium + Indacaterol
Tiotropium + Olodaterol
Umeclidinium + Vilanterol
LABA/ICS Combinations in one
inhaler
Budesonide/ formoterol
Fluticasone/ Salmeterol
Fluticasone/ Vilanterol
Mometasone/formoterol
LAMA+ICS+LAMA
Combination in one inhaler Fluticasone, umeclidinium, vilanterol
JB- COPD relevant medical history
74 y.o. male, 5’8” (1.7m) 130 lbs (59 kg); BP 140/90
Heavy smoker x 50 years stopped 5 years ago
FEV1 FVC 50% ; FEV1 60% predicted; no reversibility > 12% or 200 ml
COPD diagnosed 10 years ago; no signs of CHF
MRC =3
Treated for hypertension and hyperlipidemia
Insured through Pharmacare
Image: https://www.google.com/search?q=man+coughing&client=firefox-b&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiB3cPN4JLeAhVCZN8KHVvYAuQQ_AUIDigB&biw=1280&bih=664#imgrc=VMNhSqCEyJFcnM:
Past COPD medications (added therapy in response to persistent dyspnea)
Ipratropium 20mcg – 2 puffs qid (2008 -2012)
Tiotropium once daily x 5 years (2012- Dec 2017 (LAMA)
Tiotropium + olodaterol 2.5/2.5mcg
2 inhalations once daily (Dec 2017 ...) (LAMA/LABA)
+salbutamol prn
First AECOPD 2 weeks ago
Increased SOB, cough, sputum volume, purulence x 4 days
treated antibiotic doxycycline 200 mg one dose then 100 mg bid x 7 days and prednisone 40 mg x 5 days.
Image: https://www.google.com/search?q=man+coughing&client=firefox-b&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiB3cPN4JLeAhVCZN8KHVvYAuQQ_AUIDigB&biw=1280&bih=664#imgrc=VMNhSqCEyJFcnM
Has recovered from exacerbation, and dyspnea and energy almost at baseline
You do which of the following?
Prescribe the new triple therapy inhaler TRELEGY ELLIPTA (you have samples)
Keep on LAMA/LABA Respimat inhaler
Update his flu and pneumococcal vaccines
Check technique and adherence
Add an ICS inhaler - Fluticasone (Flovent) 250 mcg 2 puffs twice daily.
Switch to Advair 250mcg 2 puffs twice daily.
Stay on LAMA/LABA
Add an ICS (triple therapy)
Switch to a LABA/ICS
Exacerbations Mild
Moderate
Severe (hospitalizations)
All combined
Symptoms Dyspnea scores (TDI) MCID 1 point
SABA use
Quality of Life SGRQ SCORES (MCID 4 points)
Lung function Trough FEV1 (MCID? 100-140 ml)
Exercise tolerance
ADVERSE EFFECTS
Key ConceptsClinical vs. statistical significance
MCID
PICO FORMAT
Population
Intervention
Comparison
Outcome
CONSIDER SWITCH?
Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol–glycopyrronium versus salmeterol–fluticasone
for COPD. N Engl J Med 2016; 374:2222-34.
•FLAME TRIAL PRIMARY ENDPOINT N=3362
•All (mild, moderate, severe) exacerbations (rate/year)
MITT
•INDACATEROL+
GLYCOPYRRONIUM
110/50 mcg ONCE DAILY•n=1680
•SALMETEROL+
FLUTICASONE
50/500 mcg BID•n=1682
•RR 95% CI
•P VALUE
•ARR
•%
•3.59% •4.09%
•0.88
•(0.82, 0.94)
•p<0.001
•ARR 0.50
•LABA/LAMA shown to be non inferior to LABA/ICS•Met superiority standards also
ARR = absolute risk reduction
RR = Relative risk
INDACATEROL+GLYCOPYRRONIUM
110/50 mcgONCE DAILY
n=1680
SALMETEROL+FLUTICASONE
50/500 mcg BIDn=1682
RR 95% CI P VALUE
ARRNNT
95% CI
Secondary Exacerbation Endpoints (rate/year)
Mild 2.46 2.720.91
(0.83, 0.99)0.030 ARR 0.26
Moderate 0.81 0.980.83
(0.74, 0.92)<0.001 ARR 0.17
Severe 0.15 0.170.87
(0.69, 1.09)0.231 -
Pts with ≥ 1 exacerbation
77% 82%NNT 2013-44
VS LAMA
Outcomes with no statistically or clinically relevant difference
X Lung function:
X Severe exacerbation
X Dyspnea - insufficient information
√ Improved QoL:
Odds for MCID 50% vs 40% Rojas-Reyes,
TRINITY
? Moderate to severe exacerbations; vs. TIO:
low annualized rates
RR 0.80 (0.69-0.92) TRINITY
* Reference: Cochrane Review (Triple vs. Tio) Rojas-Reyes MX 2016 and 4 RCTS TRINITY, FULFIL, TRILOGY, GLISTEN
3 vs 1?
LABA/ICS
LAMA/LABA/ICS vs. LABA/ICS *
? Lung function: 1 of 4 trials showed clinically relevant difference FULFIL (171 mL)
√ QoL
Odds of MCID favored triple: OR1.33 (95%CI 1.11-1.59)
? Exacerbations: low annual rates; small ARR; clinical relevance?
X Symptoms: no difference – both treatments improved dyspnea scores
* References: 4 RCTS TRINITY, FULFIL, TRILOGY, GLISTEN
Most relevant comparator vs. triple?
After FLAME trial
LABA/LAMA or
LABA/ICS to confirm FLAME results or
Why not LAMA?
Insufficient evidence for benefit until these new trials
DB, PG, MC Trials
IMPACT 2018 Lipson DA, N Engl J Med. 2018;378:1671-80
TRIBUTE 2018 Papi A et al Lancet Lancet 2018; 391: 1076–84
KRONOS 2018 Ferguson GT Lancet Respir Med 2018;6: 747-58
Funded by GlaxoSmithKline.
Lipson DA, Barnhart F, Brealey N, et al; Once daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med.
2018;378:1671-80.
N=10,355, 52 weeks
Mean FEV1 < 56 %
PATIENTS: At least 1 moderate or severe exacerbation in the previous year, or an FEV1 50 to 80% predicted + at least two moderate exacerbations or one severe exacerbation in the-previous year.
Baseline:
Moderate or severe COPD exacerbation in previous year
1 - 45%
2 - 43%
3 or more 11%
Severe exacerbations in previous year (hospitalizations)
1 or more 26%
2 or more 4%
Run in – Continued own medication, (LAMA, LABA, or an inhaled glucocorticoid alone or in combination), during a 2-week run-in period before randomization.
38% using triple therapy at baseline
29% LABA/ICS
8% LAMA/LABA
More patients discontinued prematurely in the dual bronchodilator (27%) and LABA/ICS (25%) than triple therapy (18%) group.
77% completed trial taking medications and overall, 88% completed trial
18% -20% had reversibility of ≥ 12% and≥ 200 ml post bronchodilator –indicative of asthma.
Intervention and Comparators
LABA/ICS/ LAMA: FF 100 mcg, umeclidinium 62.5 mcg, vilanterol 25 mcg (Triple therapy in one inhaler)
LABA/ICS: FF 100 mcg, vilanterol25 mcg
LAMA/LABA: Umeclidinium 62.5 mcg, vilanterol 25 mcg
PICO
Primary outcome
Annual rate of moderate or severe COPD exacerbations during treatment
Symptoms recorded by patient in electronic diary each morning
Symptoms suggestive of an exacerbation over 48 hours - contacted investigator
MANY secondary outcomes
PICO
IMPACT RESULTS
IMPACT TRIAL
Event rates Rate Ratio/Hazard Ratio/Odds Ratio
Triple therapy vs comparators
(95% Confidence Interval)
LAMA/LABA
/ICS
N= 4151
LABA/
LAMA
N= 2070
LABA/ICS
N= 4134
LABA/
LAMALABA/ICS
Additional outcomes (not a complete list – 16 in total) Not adjusted for multiple comparisons
Annual rate of all
exacerbations1.05 1.4 1.25 RR 0.75 (0.70-0.81) RR 0.84 (0.79-0.89)
Health Status (SGRQ)
Change from baseline
MCID -4 pts
–5.5
(–5.9 to –5.0)
–3.7
(–4.4 to –3.0)
–3.7
(–4.2 to –3.2)- -
SGRQ proportion with
MCID -4 points42% 34% 34% 1.41 (1.26 to 1.57) 1.41 (1.29 to 1.55)
Lung Function Mean
change from baseline
(Trough FEV1)
94
(86 to 102)
40
(28 to 52
–3
(–12 to 6)
Difference
54 ml (39-69)
Difference
97 ml (85-109)
Dyspnea
% with MCID TDI ≥ 136% 30% 29% OR 1.33 (1.13-1.57) OR 1.36 (1.19-1.55)
All cause death – on
treatment 50 (1%) 39 (2%) 49 (1%)
0.58 (0.38 to 0.88)
Authors state a fragile result
NNT 121 (71 to 3450)
NS
All cause death on and off
treatment
(supplementary info)89 (2.14)% 60 (2.9%) 97 (2.35) HR 0.71 (0.51-0.99) NS
Pneumonia 8%
(Serious 4%)
5%
(Serious 3%)
7%
(Serious 4%)
Triple vs LAMA/LABA
HR 1.53 (1.22-1.92) NS
CADTH recommendation: July 2018
For the maintenance treatment of COPD, including chronic bronchitis and/or emphysema, if the following criteria and condition are met:
Criteria
Patients should not be started on triple inhaled therapy as initial therapy for COPD.
For use in patients who are not controlled on optimal dual-inhaled therapy for COPD.
Condition
Drug plan cost of FF/UMEC/VI should not exceed the drug plan cost of treatment with any triple therapies reimbursed for COPD (long-acting muscarinic antagonist [LAMA]/long-acting beta-2 agonist [LABA]/inhaled corticosteroid [ICS]).
https://www.cadth.ca/sites/default/files/cdr/complete/SR0562_cdr_complete_Trelegy_Ellipta_Aug_27_18.pdf
Similar design, primary outcome and severity as IMPACT population
N=1532, 52 weeks
All patients < 50% FEV1 pred.
20% ≥ 2 exacerbations in previous year; 80% 1 exacerbation
> 60% used ICS prior to study entry
Comparators: triple vs LAMA/LABA:
Budesonide extra fine/ formoterol/ glycopyrronium vs.
Indacaterol/ glycopyrronium (LAMA/LABA)
Funded by Chiesi Farmaceutici
TRIPLE VS LAMA/LABA (TRIBUTE OUTCOMES)
No statistically significant difference
• Moderate exacerbations
• Severe exacerbations
• Combined moderate and severe
• RR 0.85 (0.723-0.995) p=0.043
No difference in lung function or
quality of life (SGRQ) outcomes
No increased risk of pneumonia
Mortality not reported
Patients – moderate to severe COPD without a history of exacerbations N=1902
75% - no exacerbations in previous year
20% - 1 exacerbation in previous year
FEV1 % predicted 50% (cut-off for severe)
70% used ICS at baseline
~ 43% reversible (>200 ml and 12%)
Baseline inhaler use
LABA/ICS ~ 40%
LAMA/LABA/ICS ~ 28%
LAMA/LABA ~ 20%
Remaining - Short acting agents and other combos
Interventions / Comparisons
TRIPLE
budesonide/glycopyrrolate/formoterol fumarate MDI 320/18/9.6 μg (BGF),
Dual Glycopyrrolate/formoterol fumarate mdi 18/9.6 μg (GFF),
LABA/ICS budesonide/formoterol fumarate 320/9.6 μg (BFF MDI),
Open-label budesonide/formoterol fumarate DPI 400/12 μg (BUD/ FORM DPI).
Funded by Astra Zeneca
PICO
24 week trial
Primary outcomes (lung function)
FEV1 area under curve from 0-4 hours
Triple vs LABA/ICS AND Triple vs open label LABA/ICS
Pre dose FEV1 change from baseline
Triple vs LAMA/LABA
LABA/ICS vs open label LABA/ICS (non-inferiority )
Many secondary outcomes for symptoms, QoL and lung function, time to first moderate or severe exacerbation etc.
OUTCOME LAMA/
LABA/ICS n=639
LAMA/LABA
n=625
LABA/ICS
n=314
LABA/ICS open label
n= 318
FEV1 AUC 0-4
Difference (LSM)
- 16 mL (-6 to 38)
P=0.1448 NS
104 mL (77 - 131)
P<0.0001
91 mL (64-117)
P<0.001
FEV1 trough
LSM
- 22 mL (4-39)
P=0.0139
Clinically
Relevant?
74 (52-95)
P< 0.001
59 (38-80)
P< 0.001
Secondary outcomes
Model estimated
moderate to severe
exacerbations
per year (RR triple vs
comparator)
0.46 0.95
RR 0.48 (0.37-0.64)
P<0.0001
0.56
RR 0.82 (0.58-1.17)
NS
0.55
RR 0.83 (0.59- 1.18)
NS
No statistical and/or clinical relevant difference in dyspnea, health status (SGRQ), or rescue medication use.
No increased risk of pneumonia – trial short.
GLOBAL INITIATIVE FOR CHRONIC OBSTRUCTIVE LUNG DISEASE
CANADIAN THORACIC SOCIETY
GOLD 2018 Therapeutic Options
https://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf
Symptoms
Exacerbations
https://cts-sct.ca/wp-content/uploads/2018/01/Pharmacotherapy-of-COPD-2017.pdf
LAMA LABA LAMA/LABA LABA/ICS ICS
$50-53/month $45-59 $60-82 $67 -141 $20-85
Triple therapy in one inhaler:
Fluticasone furoate/umeclidinium/vilanterol (Trelegy)
Wholesale Cost $143.44
Recovered from exacerbation
You do which of the following?
Prescribe the new triple therapy inhaler TRELEGY ELLIPTA (you have samples)?
Keep on LAMA/LABA Respimat inhaler ?
Update his flu and pneumococcal vaccines
Check his inhaler technique and adherence
X Prescribe Advair 250 2 puffs twice daily
X Add an ICS inhaler - Fluticasone (Flovent) 250 mcg 2 puffs twice daily. ( not likely)
X Switch to Advair 250mcg 2 puffs twice daily. (FLAME trial)
Outcome Benefit or Harm
Moderate and severe exacerbations IMPACT, TRIBUTE and KRONOS (MODEL ESTIMATED)
Absolute differences small ARR 0.3%, 0.09%, 0.5%
Moderate exacerbations Not significant in TRIBUTE
Not reported in IMPACT, KRONOS
Severe exacerbations IMPACT - low rates - clinical relevance of ARR 0.06%?
Not TRIBUTE; not reported in KRONOS
Health Status SGRQ (% clinically meaningful) IMPACT ARI 8% (mean difference not MCID of 4 points)
Not TRIBUTE or KRONOS
Dyspnea IMPACT ARI 6%
Not TRIBUTE or KRONOS
Clinical relevance?
Increased Pneumonia IMPACT ARI 3% NNH 33
Not TRIBUTE or KRONOS
Mortality IMPACT, reported benefit for triple (low rates questionable outcome -
NNT 121 (71 to 3450)
KRONOS, TRIBUTE non sign.