1. Andrew McIvor MD, MSc, FRCP Firestone Institute for Respiratory Health
Dual Bronchodilators:
The New Foundation Treatment in COPD
Andrew McIvor MD, MSc, FRCP
Professor of Medicine
Firestone Institute for Respiratory Health

2. Faculty/Presenter Disclosure
CFPC CoI Templates: Slide 1
Faculty/Presenter Disclosure
Faculty: Andrew McIvor
Relationships with commercial interests:
Grants/Research Support: AstraZeneca, Novartis
Speakers Bureau/Honoraria: AstraZeneca, Boehringer Ingelheim,Merck, Novartis, Takeda.
Consulting Fees: AstraZeneca, Boehringer Ingelheim, GSK, Pfizer, Merck, Novartis, Takeda.
Other: Employee of McMaster University, St Joseph’s Healthcare Hamilton
This slide must be visually presented to the audience AND verbalized by the speaker.

5. Learning Objectives
Appreciate the current epidemiology and gaps in the management of COPD in Canada
Recognize why diagnosing and treating COPD is important for physicians and their patients
Differentiate the clinical characteristics and diagnostic criteria for COPD and asthma
Discuss current management strategies for patients with COPD, contrasting the new role of LAMA/LABA bronchodilators with anti-inflammatory agents in current guidelines
Further to participating in this program, physicians will be in a position to:
- Appreciate the current epidemiology and gaps in the management of COPD in Canada
- Recognize why diagnosing and treating COPD is important for physicians and their patients
- Differentiate the clinical characteristics and diagnostic criteria for COPD and asthma
- Discuss current management strategies for patients with COPD, contrasting the roles of bronchodilators and anti-inflammatory agents in current guidelines

9. Shortness of breath/inactivity downward spiral
Patients avoid shortness of breath by becoming less active, leading to a shortness of breath/inactivity downward spiral
Shortness of breath with activities
Becomes more sedentary to avoid activity that produces shortness of breath (decreases activity)1,2
References
Gysels M et al. J Pain Symptom Manage 2008;36:451–60.
ZuWallack R. COPD 2007;4:293–7.
Reardon JZ et al. Am J Med 2006;119:32–37.
De-conditioning aggravates shortness of breath; patients adjust by reducing activity further3
Figure adapted from Reardon JZ Am J Med 2006.
References.1Gysels M J Pain Symptom Manage 2ZuWallack R COPD 2007; 3 Reardon JZ Am J Med 2006.

10. Case Study
Mr. A.C. is a 61-year-old real-estate agent who has recently undergone angioplasty. Until 6 months ago, you saw him infrequently in your practice, perhaps because you usually tried to discuss smoking cessation with him.
Following an ER visit for chest pain he was managed by the cardiologists and underwent successful and uneventful angioplasty.

11. Case Study (cont’d)
Mr. A.C. is trying to make lifestyle changes recommended to him, including participation in a cardiac rehab program
During his rehab, he frequently feels breathless, earlier than others in the group
He finds the incline on the treadmill difficult
He has no history of lung disease but has cut down his smoking to one cigarette at bedtime 4 months ago and has a 35 pack-year smoking history

12. The Evolving Epidemiology of COPD in Canada

13. Growing Burden of COPD
Trends in age-standardized death rates for the 6 leading causes of death in the United States,
These graphs were developed based on analyses of vital statistics data on mortality in the United States from 1970 to 2002.
Reference:
Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, JAMA Sep 14;294(10):
Jemal A, et al. JAMA Sept. 14; 294(10):

14. Deterioration in Lung Function versus Symptoms in COPD
100 50 20
Severe
Mild
Symptoms
FEV1 (% of predicted)
Axis of Progression
Lung function normal
Asymptomatic
Lung function reduced
This slide highlights the fact that we must keep the diagnosis of COPD in mind. Patients don’t report symptoms until the lung function has significantly deteriorated. Early symptoms are often ignored. Thus, opportunity for early diagnosis and prevention may be lost.
COPD begins with an “asymptomatic phase” in which lung function deteriorates without associated symptoms or the symptoms are ignored.1 The onset of the subsequent “symptomatic phase” is variable but often does not occur until the FEV1 has fallen to approximated 50-60% (corresponding to moderate to severe disease) of the predicted normal value.2 Since substantial deterioration in airflow has already occurred by the time most patients present with symptoms, a chance for early intervention is lost.
Given that patients do not complain about the symptoms until significant lung function is lost, recognizing patients at risk for developing this disease and testing them with spirometry for early diagnosis are imperative.
References:
1. Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004 Jun 24;350(26):
2. Fabbri LM, Hurd SS; GOLD Scientific Committee. Global Strategy for the Diagnosis, Management and Prevention of COPD: 2003 update. Eur Respir J 2003 Jul;22(1):1-2.
Sutherland EM, et al. N Engl J Med 2004 Jun 24;350(26):

15. COPD: The Leading Cause of Hospital Admissions Today
18,000
16,000
14,000
12,000
10,000
8,000
6,000
4,000
2,000
COPD
Angina
Asthma
Heart Failure
Diabetes
Epilepsy
Ambulatory Care Sensitive Condition*
Number of Patients
Single Hospitalization
1 Repeat Hospitalization
2 or More Repeat Hospitalizations
In , COPD accounted for the highest per capita age-standardized hospitalization rate (96 per 100,000 population) in Canada (excluding Quebec) among all ambulatory care sensitive conditions (ACSC) (conditions that are normally manageable on an outpatient basis). COPD also accounted for the highest number of repeat admissions to hospital. Of the 17,200 patients who had COPD at first admission, 18% were readmitted once and 14% were readmitted two or more times for COPD or another ACSC.
Reference:
Canadian Institute for Health Information. Health Indicators Ottawa: CIHI; 2008.
*An ambulatory care sensitive condition is a condition that is normally manageable on an outpatient basis.
Data are for the Canadian population, excluding Quebec . Canadian Institute for Health Information. Health Indicators Ottawa: CIHI; 2008.

16. COPD is Underdiagnosed: Screening Spirometry in Primary Practice
Patients >40 years + 20 pack-year history of smoking
visiting a primary care physician for any reason (n=1,003)
Screening for COPD
Patients not meeting criteria for COPD*
(n=795; 79.3%)
Patients meeting criteria for COPD*
(n=208; 20.7%)
Previous diagnosis of COPD
(n=67; 32.7%)
No previous diagnosis of COPD
(n=141; 67.3%)
People with known risk factors for COPD are important targets for screening and early intervention. To determine the prevalence of COPD among high-risk individuals visiting a primary care practitioner for any reason, patients aged 40 years or older and with a 20 pack-year history of smoking were recruited from three primary care sites. Of the 1,003 participants who underwent spirometry, 208 (20.7%, 95% CI 18.3% to 23.4%) met the criteria for COPD. COPD was identified in approximately one of every five patients; however, two-thirds of these individuals were unaware of their diagnosis.
Reference:
Hill K, Goldstein RS, Guyatt GH, Blouin M, Tan WC, Davis LL, et al. Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care. CMAJ Apr. 20;182(7):673-8.
*Criteria for COPD: FEV1/FVC < 0.70
Hill K, et al. CMAJ Apr. 20;182(7):673-8.

17. Why is pursuing the diagnosis of COPD important for Mr. A.C.?

18. Comorbidities of COPD
Cardiovascular disease is a major comorbidity in COPD and probably both the most frequent and most important disease co-existing with COPD.
Other major comorbidities:
Osteoporosis
Depression
Lung cancer (most frequent cause of death in mild COPD)
The key point of this slide is that the disease may start in the lung, but it’s not confined to the lung. A number of co-morbidities are associated with the disease.
Reference:
Global Initiative for Chronic Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (Revised 2011).
often underdiagnosed and associated with poor health status and prognosis
Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2011.

19. Case Study (cont’d)
The rehab clinic placed him on salbutamol as needed and asked for him to follow up with his GP.

20. How would you proceed with Mr. A.C’s assessment?
Discuss history, physical examination and possible investigations, including reassessment of his cardiovascular status and ensuring that it is optimized.

21. Spirometry
For more information on spirometry in primary care, please visit:

22. Mr. A.C.: Spirometry Results
Parameter
Pred. value
Observed pre
% Pred.
Observed post
% pred.
% change
FVC (L)
5.64
5.23 93
5.77
102
10.3
FEV1 (L)
4.57
2.92 64
3.01 66
3.2
FEV1/FVC (%) 81 56 69 52
-6.4
FEF25-75 (L/S)
11.27
5.52 49
5.70 51
3.3
FEF50 (L/S)
2.02 36
1.73 31
-14.3
FEF75 (L/S)
2.82
0.75 27
0.59 21
-21.2
VE (L/min)
173 --
Raw insp. (cmH2O/l/s)
0.68
1.71
256
These results show that there is persistent obstruction (post ratio 52%) with less than 12% reversibility after bronchodilator.

23. Case Study (cont’d) His post bronchodilator spirometry
FEV1 66%
FVC 102%
FEV1/FVC 0.52
He is using his salbutamol 3-5 times a day.
How would you proceed?

24. Evaluating COPD Severity

25. Classification of COPD By Impairment of Lung Function*
Stage
Spirometry (post bronchodilator)
FEV1
FEV1/FVC
Mild
≥80% predicted
<0.7
Moderate
50-79% predicted
Severe
30-49% predicted
Very severe
<30% predicted
According to the classification system currently endorsed by the Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease, Mr. A.C.'s COPD is classified as moderate (FEV1 66% predicted, FEV1/FVC 0.52).
Reference:
O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease update - highlights for primary care. Can Respir J Jan-Feb;15 Suppl A:1A-8A.
*In keeping with current GOLD criteria
O'Donnell DE, et al. Can Respir J Jan-Feb;15 Suppl A:1A-8A.

26. MRC Dyspnea Scale and CTS COPD Classification
none
severe
Mild
Moderate
Severe
Grade 1
Breathless with strenuous exercise
Grade 2
Short of breath when hurrying on the level or walking up a slight hill
Grade 3
Walks slower than people of the same age on the level or stops for breath while walking at own pace on the level
Grade 4
Stops for breath after walking 100 yards
Grade 5
Too breathless to leave the house or breathless when dressing or undressing
The Canadian Thoracic Society COPD classification and/or the Medical Research Council dyspnea scale should be used to assess a patient’s breathlessness and severity of COPD. The diagnosis can only be made with spirometry. The MRC grade is an easy, in-office method of assessing severity of disease.
References:
Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J Aug 29;2(5147):
O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease Can Respir J May-Jun;10 Suppl A:11A-33A.
Fletcher CM, et al. Br Med J Aug 29;1:
O’Donnell DE, et al. Can Respir J May-Jun;10 Suppl A:11A-33A.

27. Lung Function and Symptoms: Both Are Tied to Outcomes
Survival by ATS Stage (based on FEV1)
Survival by Level of Dyspnea
100 80 60 40 20 10 30 50 70
Stage I (n=42)
Stage II (n=59)
Stage III (n=82)
p = 0.08
Months of Follow-Up
Cumulative Percent Survival (%)
100 80 60 40 20 10 30 50 70
Grade II (n=67)
Grade III (n=87)
Grade IV (n=26)
p < 0.001
Months of Follow-Up
Grade V (n=3)
The MRC class is very helpful, and in some ways more predictive of disease outcome. This would be another reason to use this scale.
Reference:
Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest May; 121(5):
Nishimura K, et al. Chest May; 121(5):

28. Mr. A.C.: CAT Score Scoring range 0-40 Mr. A.C.'s CAT score = 18 1 2 3
I never cough
I cough all the time 1 2 3 4 5
I have no phlegm (mucus) in my chest at all
My chest is completely full of phlegm (mucus)
My chest does not feel tight at all
My chest feels very tight
When I walk up a hill or one flight of stairs I am not breathless
When I walk up a hill or on flight of stairs I am very breathless
I am not limited doing any activities at home
I am very limited doing activities at home
I am confident leaving my home despite my lung condition
I am not at all confident leaving my home because of my lung condition
I sleep soundly
I don’t sleep soundly because of my lung condition
I have lots of energy
I have no energy at all
Scoring range
0-40
This slide shows an example of how the CAT can be used – to get the total score measuring overall severity, but also to very quickly identify the areas that are most affected (a surrogate measure of disability from illness).
Note that the CAT scores can be charted electronically as a simple and effective way to monitor response to therapy.
It does not, however, include exacerbations.
Mr. A.C.'s CAT score = 18

29. How would you treat Mr. A.C.?

30. Benefits of Smoking Cessation

31. Smoking Cessation and FEV120 40 60 80
100 30 50 70 90
FEV1 (%)
Age (Years)
Death
Disability
Symptoms
Quit age 45
age 55
This graphic shows where Mr. A.C., a 61-year-old smoker, is on the continuum of FEV1, graphed by age and smoking status.
Reference:
Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J Jun;1(6077):
Adapted from Fletcher C, et al. Br Med J Jun;1(6077):

32. In addition to pharmacotherapy, counselling and behavioural strategies are important components of a smoking cessation program.
Reference:
Wu P, Wilson K, Dimoulas P, Mills EJ. Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public Health Dec 11;6:300.

33. It is important to review examples of the various drug classes discussed in the slide to ensure that the group is familiar with the indicated therapies.
Reference:
O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease update - highlights for primary care. Can Respir J Jan-Feb;15 Suppl A:1A-8A.

34. Why do we use bronchodilators as first-line therapy?

35. Dynamic Lung Hyperinflation
Ventilation (L/min)
Volume (%pred TLC)
140
120
100 80 60 40 20
Normal
(n=25) RV
IRV IC
COPD
(n=105) VT
This slide illustrates why we use bronchodilators in COPD. They don't substantially impact FEV1 – they improve dynamic hyperinflation. This is the variable that we're trying to change, and all bronchodilators tested have been shown to improve dynamic hyperinflation.
Reference:
O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med Sep 1;164(5):770-7.
O'Donnell DE, et al. Am J Respir Crit Care Med Sep 1;164(5):770-7.

36. LAACs and LABAs Available in Canada
Mode of action
Individual agents
Long-acting anticholinergic (LAAC)
Also known as long-acting muscarinic antagonist (LAMA)
Tiotropium (Spriva)
Glycopyrronium (Seebri)
Aclidinium ( Tudorza)
Umeclidinium (Incruse )
Long-acting beta2-agonist (LABA)
Formoterol (Oxeze)
Salmeterol (Serevent)
LU 391
Indacaterol (Onbrez)
LU 443

37. LABA/LAMA, ICS/LAMA in Canada
Mode of action
Individual agents
LABA/LAMA
Indacaterol/Glycopyrronium (Ultibro)
LU 459
Vilanterol/Umeclidinium
(Anoro)
Formoterol/Aclidinium
(Duaklir)
Tiotropium/Olodaterol
(Inspiolt)
ICS/LABA
Fluticasone furorate/ Vilanterol
(Breo)
LU 456

38. Long-Acting Anticholinergics (LAACs)
Also known as long-acting antimuscarinics (LAMAs)

39. FEV1 from 5 Minutes to 4 Hours Post-dose on Day 1
Glycopyrronium bromide provided significant early bronchodilation following the first dose, and was significantly more effective than OL tiotropium 18 µg o.d.
FEV1 (L)
Time post-dose (h)
Placebo
Tiotropium
Glycopyrronium bromide
1.8
1.6
1.4
1.2 1 2 3
1.7
1.5
1.3 4
These data come from the GLOW2 study, which evaluated the efficacy and safety of the long-acting anticholinergic glycopyrronium bromide in moderate-to-severe COPD over 52 weeks. Patients in this study were randomised 2:1:1 to glycopyrronium bromide 50 mg, placebo or open-label tiotropium 18 mg for 52 weeks. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at 12 weeks.
As shown in the figure, glycopyrronium bromide provided significant early bronchodilation following the first dose, with significantly higher FEV1 from 5 minutes to 4 hours post-dose on Day 1 compared to both placebo and tiotropium.
On Day 1, the mean treatment difference in FEV1 between glycopyrronium bromide and placebo was 87 mL at 5 minutes and 143 mL at 15 minutes, following first dose.
Peak FEV1 (L) during 5 minutes to 4 hours post-dose on Day 1 was numerically superior in the glycopyrronium bromide group (1.662±0.0101) compared with placebo (1.462± ) and tiotropium (1.614±0.0124).
References:
Kerwin E, Hébert J, Gallagher N, Martin C, Overend T, Alagappan VK, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J Nov;40(5):
Novartis, data on file.
p<0.01 for glycopyrronium bromide versus tiotropium at all timepoints 5 min to 4 h
Kerwin E, et al. Eur Respir J Nov;40(5): ; Novartis, data on file.

40. GLOW2
Seebri® Breezhaler® delivered rapid and sustained improvements in lung function up to Week 52 vs placebo
Improvements in FEV1 with glycopyrronium were statistically superior compared with placebo at most time points at Weeks 12 and 52
Week 12*
Week 52†
1.70
1.70
1.60
1.60
FEV1 (L)
FEV1 (L)
1.50
1.50
1.40
1.40
1.30
1.30
1.20
1.20
GLOW2 study details
Design: 52-week, randomized, double-blind, placebo-controlled, parallel-group, open-label tiotropium.1
Patient population: N=1066.1
Key inclusion criteria: moderate to severe COPD (GOLD Stage II–III), age ≥40 years, at least 10-pack-year smoking history, post-bronchodilator FEV1 of <80% and ≥30% of predicted normal and post-bronchodilator FEV1/FVC ratio of <0.7.1
Key exclusion criteria: history/diagnosis of asthma, history of clinically significant cardiac abnormalities/prolongation of QTc interval1
Treatment groups: Seebri Breezhaler o.d., open-label tiotropium 18 µg o.d. and placebo (2:1:1).1
Primary outcome measure: trough FEV1 at 12 weeks.1
Key/important secondary outcome measures: TDI at 26 weeks, SGRQ at 52 weeks, time to first COPD exacerbation over 52 weeks, and daily rescue medication over 52 weeks.1
Additional secondary variables: trough FEV1 at Day 1, Week 26 and Week 52; serial spirometry on Day 1 and Weeks 12 and 52 (at time points 5, 15, 30 mins and 1,2,3 and 4 h post-dose); IC on Day 1 and Weeks 12 and 52 (time points 25 mins, 1 h 55mins and 3 h 55 mins post dose); rate of COPD exacerbations in the 52 weeks.1
76% completed the study.1
Reference
Kerwin E et al. Eur Respir J 2012;40:1106–14.
Time post-dose (hours)
Time post-dose (hours)
Glycopyrronium 50 μg o.d. (n=144)
Open-label tiotropium 18 µg o.d. (n=76)
Placebo (n=79)
*Differences were statistically significant at all time points except 16 h, 23 h 15 min, and 23 h 45 min (p<0.001, glycopyrronium vs placebo). †Differences were statistically significant at all time points (p<0.01, glycopyrronium vs palcebo). Data are from a subset of patients who underwent serial spirometry. o.d., once daily; FEV1, forced expiratory volume in one second.
Reference. Kerwin E Eur Respir J 2012.

41. Aclidinium provides effective bronchodilation over 24 hours on Day 1
Tiotropium 18 µg QD
Aclidinium 400 µg BID
Placebo BID
9 am
9 pm
9 am * * * * *
Change from baseline FEV1 (mL)
Evening dose
Notes
This was a Phase IIIb, multicentre, randomized, double-blind, double-dummy, placebo- and active comparator-controlled study in 414 patients with stable moderate to severe COPD. Patients were randomized (2:2:1) to aclidinium 400 µg via the Genuair® inhaler, once-daily (QD) tiotropium 18 µg via the HandiHaler® or placebo for 6 weeks.
Pulmonary function (FEV1) on Day 1 was an additional efficacy variable.
Aclidinium 400 μg BID and tiotropium 18 µg QD provided statistically significant improvements in FEV1 AUC0-24 , FEV1 AUC0-12 and FEV1 AUC compared with placebo on Day 1 (all p<0.05). Improvements in FEV1 AUC0-24 and FEV1 AUC12-24 were significantly greater with aclidinium 400 μg BID compared with tiotropium 18 μg QD (0.040 L and L, respectively; both p<0.05).
On Day 1, both aclidinium 400 μg BID and tiotropium 18 μg QD provided bronchodilation that was significantly greater at all time points compared with placebo (p<0.01 for both).
Improvements from baseline in FEV1 were generally numerically greater with aclidinium 400 μg BID compared with tiotropium 18 µg QD and were statistically significantly greater than tiotropium between 13 and 23 hours post-dose (p<0.05 at all time points).
Reference
Beier J, Kirsten AM, Mroz R et al. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled phase IIIb study. COPD 2013; 10:
Time (h)
Beier et al, COPD 2013
*p<0.05 vs tiotropium Both treatments statistically significantly higher than placebo at all time points

42. Once-Daily LABAs

43. Mean Change in FEV1 on Day 1 of Indacaterol Treatment
5 mins post-dose
Indacaterol, a long-acting, once-daily beta2-agonist bronchodilator, has been shown to have a very rapid onset of action, with a pronounced change in FEV1 evident as soon as five minutes post-dose with the 75 μg daily dose.
References:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).
Data are unadjusted means.
Adapted from:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).

44. Sustained Bronchodilation Over 24 Hours: Indacaterol vs. Placebo
Rapid onset within 5 minutes
Time (hours)
FEV1 (L)
1.30
1.35
1.40
1.45
1.50
1.55
1.60 4 8 12 16 20 24
1.20
1.25
Indacaterol 75 µg o.d.
Placebo
Improvement in FEV1 vs. placebo at every time point, measured by 24-hour spirometry
This figure illustrates the fact that indacaterol is a true once-daily drug, with similar separation from placebo evident at each time point throughout a 24-hour period.
References:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).
Adapted from:
Novartis Pharmaceuticals Inc. Onbrez* Breezhaler* Product Monograph. Date of Revision: October 24, 2012.
Novartis Pharmaceuticals Inc. Data on file (Study B2355).

45. Recommended Next Step for Mr. A.C.
It has been 6 months since you have seen him
He has been taking a once daily LAMA + Salbutamol prn
Mr. A.C. has not had an exacerbation of his COPD
He states that he is still an MRC 3 dyspnea and has been needing a breakthrough salbutamol a few times a week.
Perhaps LABA/LAMA should have been initial maintenace therapy?

46. Note that the Canadian recommendations from 2007 are essentially in line with the GOLD approach to classification – each involves a comprehensive assessment including both lung function and symptoms.
Reference:
O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease update - highlights for primary care. Can Respir J Jan-Feb;15 Suppl A:1A-8A.

47. This middle section of the guidelines is relevant for those patients with moderate-to-severe lung function/disability but with INFREQUENT EXACERBATIONS. For this group the treatment is that of symptoms and does not include exacerbation prophylaxis emphasis and thus does not include ICS.
Reference:
O'Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J, Marciniuk D, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease update - highlights for primary care. Can Respir J Jan-Feb; 15 Suppl A:1A-8A.

49. Patient Factors in COPD Management

50. 12-month Persistence with Inhaled Medications: Canadian Data
Ipratropium (Atrovent®) 8%
Ipratropium/salbutamol (Combivent®)
12%
Four times daily
Formoterol
(Oxeze®)
16%
Salmeterol (Serevent)®
18%
Twice daily
Formoterol-budesonide (Symbicort®)
25%
Salmeterol/fluticasone (Advair)®
32%
It should be noted that adherence, persistence and compliance may be measured in many different ways. When evaluating data like these, you need to know what the criteria are defining the results. In this case, the data represent the proportion of patients still taking the prescribed medication after one year.
Reference:
Cramer JA, Bradley-Kennedy C, Scalera A. Treatment persistence and compliance with medications for chronic obstructive pulmonary disease. Can Respir J Jan-Feb;14(1):25-9.
Once daily
Tiotropium (Spiriva®)
53% 10 20 30 40 50 60
% continuing for 12 months
Adapted from Cramer JA, et al. Can Respir J Jan-Feb;14(1):25-9.

52. Combining Bronchodilators in Mild to Moderate COPD

53. Dual Bronchodilation with Formoterol + Tiotropium
Trough FEV1: Change from baseline
Total COPD Symptom Score‡
Mean change in symptom score * AM PM
AM/PM average
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
Change from baseline in trough FEV1 (mL)
n=118
n=127 †
n=106
n=121
n=129 *
n=108
Week 4
Week 8
Week 12
Last visit
250
200
150
100 50
The objective of this study was to compare combination treatment with formoterol (a long-acting beta2-agonist bronchodilator) plus tiotropium (a long-acting anticholinergic bronchodilator) versus treatment with tiotropium alone in patients with COPD.
The subjects, 255 patients with diagnosed COPD, were randomized to 12 weeks of either the combination of formoterol 12 microg twice daily plus tiotropium18 microg once daily in the morning or monotherapy with tiotropium once daily in the morning.
The combination was found to be superior to tiotropium monotherapy both in terms of change in FEV1 from baseline (left panel) and in terms of reduction in COPD symptoms (right panel).
Reference:
Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD Feb;6(1):17-25.
Formoterol (12 µg b.i.d.) + tiotropium (18 µg o.d.)
Tiotropium (18 µg o.d.)
*p<0.05; †p<0.001 vs. tiotropium;
‡ sum of scores for dyspnea (0 = none to 4 = severe), wheezing, cough, and chest tightness (0 = none to 3 = very uncomfortable).
Tashkin DP, et al.:COPD Feb;6(1):17-25.

59. Does the device make a difference?

60. COPD Treatment Options
Tiotropium
Glycopyrronium bromide
Salmeterol / Fluticasone
Formoterol
Salmeterol
Indacaterol
Formoterol/ Budesonide
Mode of Action
LAAC/ LAMA
LAAC
LABA + ICS (FDC)
LABA
Devices
Handihaler (18 µg/ inhalation)
Breezhaler
(50 µg / inhalation)
Diskus DPI (50/250 µg and 50/500 µg / inhalation)
Aerosol MDI (25/50, 25/125 or 25/250 µg / inhalation)
Aerolizer (12 µg / capsule)
Turbuhaler DPI (6 & 12 µg / inhalation)
Diskus DPI (50 µg / inhalation)
Diskhaler Disk DPI (50 µg / inhalation)
Breezhaler (75 µg / inhalation)
Turbuhaler DPI (110/6 or 200/6 μg / inhalation)
This table shows the various long-acting bronchodilators available in Canada and the devices with which they are administered.
References:
Boehringer Ingelheim (Canada) Ltd. Spiriva product monograph. Date of Revision: August 21, 2012.
Novartis Pharmaceuticals Canada Inc. Seebri Breezhaler product monograph. Date of Revision: October 12, 2012.
GlaxoSmithKline Inc. Advair product monograph. Date of Revision: December 18, 2012.
AstraZeneca Canada Inc. Oxeze Turbuhaler product monograph. Date of Revision: May 31, 2011.
Novartis Pharmaceuticals Canada Inc. Foradil product monograph. Date of Revision: May 14, 2012.
Novartis Pharmaceuticals Inc. Onbrez Breezhaler product monograph. Date of Revision: October 24, 2012.
GlaxoSmithKline Inc. Serevent product monograph. Date of Revision: April 2, 2012.
Merck Canada Inc. Zenhale product monograph. Date of Revision: September 21, 2012.

62. Ultibro 1St LABA/LAMA Combo
Indacaterol
110 mcg
Glycopyrronium
50mcg

63. Flow Rates with Various Inhalers Used for COPD Medications20 40 60 80
100
120 2 4 6 8 10
Increasing Resistance
Breezhaler®
Diskus® /
Accuhaler®
Turbuhaler®
HandiHaler®
Flow rate (L/min)
kPa1/2 L-1 min
Breezhaler® 2.2 x 10-2
Diskus®/Accuhaler® 2.7 × 10-2
Turbuhaler® 3.4 × 10-2
HandiHaler® 5.1 × 10-2
The Concept1 device (aka the Breezhaler®) was designed to maximize its suitability for a wide range of patients, including those with limited inspiratory capacity. It is a relatively low airflow resistance inhaler compared with other marketed dry powder inhalers, which means less effort will be required to achieve the optimal flow rate to use the device.
Reference:
Singh D, Fiebich K, Dederichs J, Pavkov R, Schulte M, Sommerer K. Dose delivery characterization of indacaterol following inhalation by COPD patients. Am J Respir Crit Care Med. 2010;181:A4419 (+ additional material from poster).
Inspiratory effort (kPa)
Diskus® and Accuhaler® are registered trademarks of GlaxoSmithKline; Turbuhaler® is a registered trademark of AstraZeneca;
HandiHaler® is a registered trademark of Boehringer Ingelheim; Breezhaler® is a registered trademark of Novartis.
Singh D, et al. Am J Respir Crit Care Med. 2010;181:A4419 (+ additional material from poster).

64. LANTERN STUDY : Zhong et al. ERS
Once daily Ultibro 110/50 mcg vs. Advair 500mcg BID
Double-blind 26 week study in 744 Patients
Moderate to severe COPD and < 1 exacerbation in last year
Superior improvement in terms of lung function trough FEV L (p<0.001); AUC 0-4h L (p<0.001)
Reduced moderate-to-severe exacerbations by 31%
Adverse events were lower for Ultibro (40.17%) vs SFC (47.4%) and incidence of pneumonia was also lower with Ultibro (0.8%) vs SFC (2.7%)

65. Five Teaching Points
COPD should be considered in all patients over 40 with a smoking history of 20 pkt/yrs
Simple Spirometry is the GOLD standard for diagnosis
Smoking cessation, increased exercise crucial
Target Diagnosis and Optimal Bronchodilatation
Not all patients require ICS/LABA

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