1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. Professor Peter Calverley University Hospital Aintree Liverpool UK
PHARMACOLOGICAL MANAGEMENT OF COPD IN PATIENTS WITH CHRONIC CO-MORBIDITIES
Professor Peter Calverley
University Hospital Aintree
Liverpool UK

3. A RUMSFELD MOMENT!
Does having COPD influence the choice of therapy for a co-morbidity?
Does taking a treatment for a co-morbidity improve the outcome in COPD?
Does taking a treatment for COPD affect the co-morbidity?

4. BETA –BLOCKERS AND COPD
Good data for the benefits of selective beta-blockade in congestive heart failure, rate control of AF
Longstanding worry that beta-blockade might precipitate bronchospasm
So most people avoided beta-blockers in COPD
Now we have evidence for safety and a reason why this is the case

5. BETA-BLOCKERS, COPD AND VASCULAR SURGERY
1205 COPD patients, 462 receiving therapy with BB pre-surgery
Van Gestel et al AJRCCM 2008

6. Why COPD is not asthma –bronchodilator testing is not helpful
Subject Group
Percent
Smoker Controls
Non-smoker Contr
COPD Subjects 35 30 25 20 15 10 5
0.15
0.05
-0.65
-0.55
-0.25
-0.05
0.25
0.35
0.45
0.55
0.65
0.75
0.85
0.95
1.05
1.15
1.25
1.35
-0.45
-0.35
-0.15
Change in FEV1 (L), Post-bronchodilator

7. THE STATIN STORY

8. STATINS AND COPD OUTCOMES IN LOW RISK PATIENTS
Mancini et al JACC 2006

9. STATINS AND EXACERBATIONS
Mortenson E et al Respir Res 2009

10. Systemic Effects of COPD: Target Organs
Angina
Acute coronary
syndromes
Weight loss
Muscle weakness
Lung Infections
Lung Cancer
Diabetes
Metabolic syndrome
Osteoporosis
Systemic
Inflammation
Oxidatitive Stress
Depression
Depression
Peptic ulceration/reflux
Depression
From W MacNee

11. TREATMENT AND COMPLICATIONS
Depression –common, often associated with fatigue. Interaction with therapy more likely with systemic treatment. Corticosteroids possibly –roflumilast unproven
Reflux – GI issues with theophyllines and PDEIV inhibitors
Metabolism and diabetes –ocs associated with hyperglycaemia but this is a feature of acute exacerbations. More data from roflumilast
Muscles

12. Most frequently reported AEs
COPD safety pool
placebo (N=5,491)
(%)
rof500 (N=5,766)
All AEs
62.8
67.2
COPD exacerbations
23.1
19.8
Diarrhoea
2.6
10.1
Weight decreased
1.8
6.8
Nasopharyngitis
6.3
Nausea
1.4
5.2
Headache
2.0
4.6
Upper respiratory tract infection
4.3
3.8
Bronchitis
3.5
3.1
Back pain
2.1
Insomnia
0.9
Influenza
2.4
2.5
Dizziness
1.2
Decreased appetite
0.4
2.2
Pneumonia

13. PHARMACOLOGICALLY PREDICTABLE EFFECTS
5/26/ :49 AM
PHARMACOLOGICALLY PREDICTABLE EFFECTS
Diarrhoea
Nausea
Events in the category
Events in the category (%)
Importantly, CCL3 and CXCL9 in lungs of patients afflicted from COPD were shown to correlate with COPD disease severity.
(Freeman et al. AJPathol. 2007) and CXCL10 was found augmented in induced sputum of COPD patients (Costa et al. Chest. 2008).
<1 week
≥1 week
to <4 weeks
≥4 weeks
to <13 weeks
≥13 weeks
to <26 weeks
≥26 weeks
<1 week
≥1 week
to <4 weeks
≥4 weeks
to <13 weeks
≥13 weeks
to <26 weeks
≥26 weeks
placebo (n=5491)
rof 500 mcg (n=5766
ET=number of patient-years of exposure
SAFETY (BU)

14. Weight loss
Noted as a self-reported finding more often with roflumilast
Not just confined to patients reporting GI intolerance
Monitored with regular weight measurement in pivotal one year trials
In one 6 month study bioimpedance data were available

15. Body weight over time in the studies with available data4
placebo
roflumilast 500µg 2
 = kg
(CI –2.4;-1.9)
p <
Body Weight [kg] -2 -4 8 16 24 32 40 48
Weeks
Timecourse: Mean change in kg
Between Treatment Differences least-squares means from ANCOVA

16. 5/26/ :49 AM
Weight change by BMI
Percent weight change from baseline to end of treatment by BMI at baseline: pivotal COPD studies pool (SAF)
Placebo
Rof500
Mean Change (%)
Objective: differential loss by BMI
Punchline: Obese patients on roflumilast lose the greatest percentage of weight. Underweight lose the least amount of weight
N =
127
134
605
572
462
475
316
317
Underweight
Normal
Overweight
Obese
SAFETY (BU)

17. Weight loss associated with roflumilast was primarily fat mass
Tiotropium + placebo (BMI)
Tiotropium + placebo (FFMI)
Tiotropium + Daxas® (FFMI)
Mass indices [kg/m2]
-0.5
Tiotropium + Daxas® (BMI)
Speaker notes
In the 6-month clinical study in which patients received Daxas® or placebo in addition to tiotropium, the mean weight loss was 2.1kg more in the Daxas® group compared with placebo group (95% CI -2.5, -1.7; p<0.0001).1,2
BMI fell gradually in Daxas®-treated patients, until reaching a plateau at 18 weeks of treatment (mean decrease –0.73 kg/m2). No significant change in BMI was observed in patients taking placebo during the 24-week treatment period (mean decrease 0.03 kg/m2).2
The overall mean difference in BMI between Daxas®-treated and placebo-treated patients was –0.76 kg/m2 (95% CI –0.89, –0.62; p<0.0001).2
Bioimpedance measurements indicated a decrease in fat free muscle mass during the first 4 weeks of Daxas® treatment. There was no significant difference between the change in FFMI in Daxas®-treated and placebo-treated patients (mean difference kg/m2, 95% CI to ; p=0.0059).2
These data indicate that the weight loss associated with Daxas® was primarily fat mass and probably not owing to continued loss of muscle mass.
References
Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695–703.
Wouters EFM, Teichmann P, Brose M, et al. Effects of roflumilast, a phosphodiesterase 4 inhibitor, on body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:A4473. -1 4 8 12 16 20 24
Weeks
Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473.
FFMI: Fat Free Mass Index; BMI: Body Mass Index 17

18. MUSCLES Loss of muscle bulk vs weakness
A marker for more health care expense and mortality but the thresholds may vary
A clear relationship of weakness to ocs use long term –not seen with ics
Anabolic steroids reverse this process but only in people taking oral corticosteroids (Kreutzberg E et al)

19. BONES AND INHALED CORTICSTEROIDS
Database associations but confounded by disease severity

20. TORCH - Time to First Fracture Safety Population
26/05/ :49
TORCH - Time to First Fracture Safety Population
Plc
N=1544
SAL
N=1542 FP
N=1552
SFC
N=1546
Non-Traumatic
20 (1.3%)
29 (1.9%)
21 (1.4%)
21 (1.4%)
Traumatic
39 (2.5%)
37 (2.4%)
45 (2.9%)
58 (3.8%)
5.1%
5.1%
5.4%
6.3%
KM Prob at 3 years
SFC vs Placebo
1.22
(0.87, 1.72)
0.248
SFC vs SAL
1.23
(0.88, 1.72)
0.229
SFC vs FP
1.16
(0.83, 1.61)
0.382
SAL vs Placebo
1.00
(0.69, 1.43)
0.977
FP vs Placebo
1.06
(0.74, 1.51)
0.765 p
95% CI
Hazard Ratio
Safety Pop, Source table: ,

21. Prevalence of Osteoporosis & Osteopenia at Baseline10 20 30 40 50
Placebo
SALM 50
FP 500
SFC 50/500
T score < -1 and > -2.5 for hip or spine: osteopaenia
T score < -2.5 for hip or spine: osteoporosis
% patients

22. US Safety sub-study : percent change in total hip BMD
Adjusted mean change BMD hip 1 –1 –2 –3 –4
Placebo
SAL FP
SFC
OSS population.
BMD examination was conducted on 658 patients from 88 US sites.
BMD at the total hip was expressed as a log transformed ratio to baseline prior to analysis. The data were analysed using repeated measures ANCOVA where treatment group was fitted as the explanatory variable, and terms for age, gender, smoking status, log baseline BMD, BMI (fitted as a continuous term), baseline BMD therapy, and visit will be fitted as covariates. An unstructured variance-covariance matrix was used, unless there were problems with model fitting, in which case a model requiring fewer covariance parameters was fitted.
Patients included in this analysis had those who had BMD measurements taken both at baseline and at 158 weeks
A supportive analysis was performed on absolute change from baseline BMD at the total hip assessment, using the same ANCOVA model.
The repeated measures analysis of the Ophthalmic and Skeletal Safety population was of primary interest:
In this sub-study population, there was no difference in BMD between the treatment groups
A significant proportion of this population had osteoporosis/osteopoenia at baseline.1
Reference
Pauwels R, Celli B, Ferguson G, et al. Osteopenia and osteoporosis in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167(7): A235. –5 48
108
158
Time (weeks)
Number of subjects
161
162
158 87
105
112
118 72 82 80 95 52 78 65 82
Vertical bars are standard errors
Ferguson et al Chest 2009

23. Time to First Pneumonia AE12
Probability of event prior to wk 104 SFC 9.9% TIO 5.5% 11
SFC 50/500 10 9 8 7
Probability of Event (%) 6
TIO 18 5 4
Treatment 3 2 1
Number
at Risk
SFC 50/500
TIO 18
Time to Event (Weeks)
Cox Hazard Ratio 95% CI p-value
SFC vs TIO 1.94 (1.19, 3.17) 0.008

24. TIME TO FIRST PNEUMONIA AE OR SAE
Sin et al Lancet 2009

25. Cardiovascular Events with Tiotropium
Composite Endpoint* Used by Singh et al applied to UPLIFT
Placebo
Tiotropium
Rate Ratio1 (95 % CI) n
Rate2
UPLIFT
Composite endpoint
246
2.89
208
2.25
0.78 (0.65, 0.94)
Fatal composite
124
1.42 98
1.04
0.73 (0.56, 0.95)
1 rate ratio tio vs. placebo; 2per 100 person-years of time at risk to tiotropium or placebo
*SOC cardiac (fatal), SOC vascular (fatal), MI (fatal+nonfatal), stroke (fatal+nonfatal), sudden death, sudden cardiac death

26. All-cause mortality at 3 years
Probability of death (%) 18 16 14 12 10 8 6 4 2
SALM FP
Placebo
SFC
There was a total of 875 deaths in the ITT population up to 3 years.
Patients receiving FP or SAL alone had a similar risk of death to those patients receiving placebo.1
Patients receiving FP had a similar risk of death to those patients receiving placebo:
The study was not powered to detect a difference between SFC and FP or between SFC and SAL
The results in the FP arm differ from those suggested from database studies or pooled data analysis conducted in studies where mortality was not the primary endpoint2,3
This is unlikely to be due to a true biological effect, as deaths from a wide range of causes were recorded
These results suggest that SAL and FP should be combined for maximum benefit.
References
Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8):
Sin DD, Wu L, Anderson JA, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005;60:992–7.
Soriano JB, Vestbo J, Pride NB, et al. Survival in COPD patients after regular use of FP and SALM in general practice. Eur Respir J 2002;20:819–25. 12 24 36 48 60 72 84 96
108
120
132
144
156
Time to death (weeks)
Number
alive
1524
1533
1521
1534
1464
1487
1481
1399
1426
1417
1409
1293
1339
1316
1288
Calverley et al. NEJM 2007
Vertical bars are standard errors

27. CARDIOVASCULAR EVENTS AND THERAPY
Calverley et al Thorax 2010

28. CVS TREATED COPD AND THERAPY
Calverley et al Thorax 2010

29. Time to onset of first major adverse CV event (MACE*)
5/26/ :49 AM
Time to onset of first major adverse CV event (MACE*)
roflumilast 500 mcg, od, p.o. + roflumilast 250 mcg, od p.o.
placebo, od, p.o.
Probability of event
0.00
0.02
0.04 30 60 90
120
150
180
210
240
270
300
330
360
390
Days post-randomisation
0.01
0.03
MACE : CV death, non-fatal MI, non-fatal stroke
SAFETY (BU)

30. CONCLUSIONS Beta–blockers and other cardiac drugs are safe in COPD
Statins may improve COPD outcomes but proper trial data are needed
Oral therapies produce more GI upset, oral corticosteroids long term are hazardous
Inhaled corticosteroids do not seem to accelerate osteoporosis but some may induce pneumonia
LAMA and LABA treatment is safe in COPD – anti-inflammatory therapy may improve cardiac outcomes
On balance our treatments are more friend than foe