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PHARMACOLOGICAL MANAGEMENT OF COPD IN PATIENTS WITH CHRONIC CO-MORBIDITIES

Professor Peter Calverley

University Hospital Aintree

Liverpool

UK

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?

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

BETA-BLOCKERS, COPD AND VASCULAR SURGERY

1205 COPD patients, 462 receiving therapy with BB pre-surgery

Van Gestel et al AJRCCM 2008

Why COPD is not asthma –bronchodilator testing is not helpful

Change in FEV1 (L), Post-bronchodilator

Subj

ect G

roup

Perc

ent

Smok

er C

ontr

ols

Perc

ent

Non

-sm

oker

Con

trPe

rcen

t

COPD

Sub

ject

s35

30

25

20

15

10

5

0

35

30

25

20

15

10

5

0

35

30

25

20

15

10

5

0

0.150.05-0.65 -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

THE STATIN STORY

COPD/Low Risk(Steroid Users)

Risk Ratio

0.0 0.5 1.0 1.5 2.0

Hospitalization for COPD

Myocardial Infarction

Death

Myocardial Infarction or Death

0.91 (.84, .99), p = .02600.86 (.78, .96), p = .00560.74 (.67, .81), p < .0001

0.70 (.62, .80), p < .0001

1.17 (.90, 1.52)1.10 (.79, 1.54)0.85 (.61, 1.18)

1.27 (.90, 1.78)

0.73 (.65, .83), p < .00010.55 (.46, .66), p < .00010.51 (.43, .62), p < .00010.35 (.28, .44), p < .0001

0.82 (.73, .92), p = .00080.68 (.58, .80), p < .00010.64 (.55, .75), p < .00010.48 (.40, .58), p < .0001

Combination

Statin

ACE Inhibitor

ARB

Combination

Statin

ACE Inhibitor

ARB

Combination

Statin

ACE Inhibitor

ARB

ACE Inhibitor

ARB

Statin

Combination

COPD/Low Risk

Risk Ratio

0.0 0.5 1.0 1.5 2.0

ACE Inhibitor

ARB

Statin

Combination

ACE Inhibitor

ARB

Statin

Combination

ACE Inhibitor

ARB

Statin

Combination

ACE Inhibitor

ARB

Statin

Combination

Hospitalization for COPD

Myocardial Infarction

Death

Myocardial Infarction or Death

0.87 (.76, 1.0), p = .0502

0.78 (.64, .95), p = .0150.65 (.55, .78), p < .0001

0.74 (.59, .92), p = .0062

0.97 (.63, 1.50)0.96 (.53, 1.73)0.87 (.51, 1.49)0.87 (.49, 1.54)

0.60 (.49, .73), p < .00010.52 (.38, .72), p < .00010.56 (.42, .74), p < .00010.38 (.27, .54), p < .0001

0.71 (.59, .85), p = .00020.64 (.49, .84), p = .00110.65 (.51, .83), p = .00060.49 (.36, .66), p < .0001

STATINS AND COPD OUTCOMES IN LOW RISK PATIENTS

Mancini et al JACC 2006

STATINS AND EXACERBATIONS

Mortenson E et al Respir Res 2009

Systemic Effects of COPD: Target Organs

Lung Infections Lung Cancer

Weight lossMuscle weakness

Osteoporosis

Angina Acute coronary syndromes

Depression

DiabetesMetabolic syndrome

Systemic Inflammation

Oxidatitive Stress DepressionPeptic ulceration/reflux Depression

From W MacNee

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

COPD safety poolCOPD safety pool

placeboplacebo(N=5,491)(N=5,491)

(%)(%)

rof500rof500(N=5,766)(N=5,766)

(%)(%)

Most frequently reported AEs

All AEsAll AEs 62.862.8 67.267.2

COPD exacerbationsCOPD exacerbations 23.123.1 19.819.8

Diarrhoea Diarrhoea 2.62.6 10.110.1Weight decreasedWeight decreased 1.81.8 6.86.8

Nasopharyngitis Nasopharyngitis 6.36.3 6.36.3

Nausea Nausea 1.41.4 5.25.2Headache Headache 2.02.0 4.64.6

Upper respiratory tract infectionUpper respiratory tract infection 4.34.3 3.83.8

Bronchitis Bronchitis 3.53.5 3.13.1

Back painBack pain 2.12.1 3.13.1

InsomniaInsomnia 0.90.9 2.62.6

Influenza Influenza 2.42.4 2.52.5

DizzinessDizziness 1.21.2 2.42.4

Decreased appetite Decreased appetite 0.40.4 2.22.2

PneumoniaPneumonia 2.02.0 1.81.8

ET=number of patient-years of exposureET=number of patient-years of exposure

PHARMACOLOGICALLY PREDICTABLE EFFECTS

Diarrhoea Nausea

<1 week ≥1 weekto <4

weeks

≥4 weeksto <13 weeks

≥13 weeksto <26 weeks

≥26 weeks<1 week ≥1 weekto <4

weeks

≥4 weeksto <13 weeks

≥13 weeksto <26 weeks

≥26 weeks

placebo (n=5491)

rof 500 mcg (n=5766

Eve

nts

in t

he

cate

go

ry (

%)

Eve

nts

in t

he

cate

go

ry

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

Body weight over time in the studies with available data

-4

-2

0

2

4

0 8 16 24 32 40 48

Bo

dy

We i

gh

t [k

g]

placebo

roflumilast 500µg

= -2.17 kg(CI –2.4;-1.9)

p < 0.0001

Timecourse: Mean change in kgBetween Treatment Differences least-squares means from ANCOVA

Weeks

Weight change by BMI

N =N = 127127 134134 605605 572572 462462 475475 316316 317317

UnderweightUnderweight NormalNormal OverweightOverweight ObeseObese

Mea

n C

ha

ng

e (%

)M

ean

Ch

an

ge

(%)

PlaceboPlacebo

Rof500Rof500

Percent weight change from baseline to end of treatment by BMI at baseline: Percent weight change from baseline to end of treatment by BMI at baseline: pivotal COPD studies pool (SAF) pivotal COPD studies pool (SAF)

Mas

s in

dic

es [

kg/m

2]

-1

0

0 4 8 12 16 20 24

Weeks

Tiotropium + placebo(FFMI)

Tiotropium + Daxas®

(FFMI)

Tiotropium + placebo(BMI)

Tiotropium + Daxas®

(BMI)

Wouters EFM, Teichmann P, Brose M, et al. Am J Respir Crit Care Med 2010;181:A4473.

Weight loss associated with roflumilast was primarily fat mass

-0.5

FFMI: Fat Free Mass Index; BMI: Body Mass Index

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)

BONES AND INHALED CORTICSTEROIDS

Database associations but confounded by disease severity

TORCH - Time to First FractureSafety Population

SFCN=1546

Non-Traumatic 20 (1.3%) 29 (1.9%) 21 (1.4%) 21 (1.4%)

39 (2.5%) 37 (2.4%) 45 (2.9%) 58 (3.8%)

FPN=1552

SALN=1542

PlcN=1544

Traumatic

SFC vs Placebo 1.22 (0.87, 1.72) 0.248

SFC vs SAL 1.23 (0.88, 1.72) 0.229SFC vs FP 1.16 (0.83, 1.61) 0.382

SAL vs Placebo 1.00 (0.69, 1.43) 0.977FP vs Placebo 1.06 (0.74, 1.51) 0.765

p95% CIHazardRatio

5.1% 5.1% 5.4% 6.3%KM Prob at 3 years

Prevalence of Osteoporosis & Osteopenia at Baseline

00

1010

2020

3030

4040

5050

Placebo Placebo SALM 50SALM 50 FP 500FP 500 SFC 50/500SFC 50/500

T score < -1 and > -2.5 for hip or spine: osteopaenia T score < -1 and > -2.5 for hip or spine: osteopaenia

T score < -2.5 for hip or spine: osteoporosis T score < -2.5 for hip or spine: osteoporosis

% patients% patients

SFC

US Safety sub-study : percent change in total hip BMD

Vertical bars are standard errors

161162158162

87105112118

Numberof subjects

72828095

52786582

0 48 108 158

Placebo SAL FP–5

–4

–3

–2

–1

0

1Adjusted mean change BMD hip

Time (weeks)

Ferguson et al Chest 2009

Time to First Pneumonia AE

Probability of event prior to wk 104 SFC 9.9% TIO 5.5%

Cox Hazard Ratio 95% CI p-valueSFC vs TIO 1.94 (1.19, 3.17) 0.008

Numberat Risk

0 13 26 39 52 65 78 91 104

01

23

456

78

1112

Pro

bab

ility

of

Eve

nt (

%)

Time to Event (Weeks)

Treatment

656 550 511 491 470 451 426 415 150 SFC 50/500664 543 497 468 4242 426 405 387 136 TIO 18

910

TIO 18

SFC 50/500

TIME TO FIRST PNEUMONIA AE OR SAE

Sin et al Lancet 2009

Cardiovascular Events with Tiotropium

Placebo Tiotropium

Rate Ratio1 (95 % CI)

n Rate2

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

Composite Endpoint* Used by Singh et al applied to UPLIFT

SALM FP

All-cause mortality at 3 years

Vertical bars are standard errors

18

16

14

12

10

8

6

4

2

0

Time to death (weeks)

Probability of death (%)

1524153315211534

1464148714811487

1399142614171409

1293133913161288

Placebo SFC

Numberalive

0 12 24 36 48 60 72 84 96 108 120 132 144 156

Calverley et al. NEJM 2007

CARDIOVASCULAR EVENTS AND THERAPY

Calverley et al Thorax 2010

CVS TREATED COPD AND THERAPY

Calverley et al Thorax 2010

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.

Pro

bab

ilit

y o

f ev

ent

0.00

0.02

0.04

0 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 strokeMACE : CV death, non-fatal MI, non-fatal stroke

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