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Aggiornamento concetti generali sulla componente respiratoria della BPCO Leonardo M. Fabbri
DEFINIZIONE Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease. It is characterized by chronic respiratory symptoms, particularly dyspnea and persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response of the airways and the lung to cigarette smoke and/or other noxious particles or gases. Exacerbations, significant concomitant disorders contribute to the overall severity in individual patients.
5-yrs mortality
The present study analysed data from 20,296 subjects aged >45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).
Clinical practice guidelines (CPGs) and quality of care for older patients with multiple comorbid diseases: implications for pay for performance
This review suggests that adhering to current CPGs in caring for an older person with several comorbidities may have undesirable effects Basing standards on existing CPGs could lead to inappropriate judgment of the care provided to older individuals with complex comorbidities Developing measures of the quality of the care needed by older patients with complex comorbidities is critical to improving their care
Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments
Hospital mortality
2.5%2.5%-10%
(5 days)
22%22%-32%
(14 days)
In outpatients
13%13%-33%
(14 days)
Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129; Adams et al. Chest. 2000; 117:1345-1352; Patil et al. Arch Int Med. 2003; 163:1180-1186.
THE PROGNOSTIC IMPORTANCE OF LUNG FUNCTION IN PATIENTS ADMITTED WITH HEART FAILURE
Prognostic importance for all-cause mortality allof lung function variables obtained by spirometry in an unselected group of patients admitted with heart failure (HF)
CARDIOVASCULAR MECHANISMS OF DEATH IN SEVERE COPD EXACERBATION: TIME TO THINK AND ACT BEYOND GUIDELINES
Patients hospitalized because of ECOPD should be carefully examined for the relevant biomarkers and for any concomitant abnormality that may call for specific therapy This in line with the recent editorial of FitzGerald20 and comment by the Editors of Thorax who recommends replacing the term exacerbations with the term lung attacks to emphasise their severity, dramatic consequences, and need for more aggressive, comprehensive and prolonged treatment
Mortality
Medication adverse effects
Activity
Lung function
COPD exacerbations
COPD
Chronic disease
progressive nature lung function symptoms comorbidities
Exacerbations
typically 1 - 3 per year frequency proportional to COPD severity the frequent exacerbator chronic decline resulting in poorer prognosis q HRQL o hospitalizations o mortality
ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP IN PATIENTS WITH COPD
50
Hospitalized for exacerbation in yr 1
47
% of patients
40 30
Frequent exacerbations
33 33
22
20 10 0 GOLD 2
(N=945)
18
GOLD 3
(N=900)
GOLD 4
(N=293)
STABILITY OF THE FREQUENT-EXACERBATION PHENOTYPE IN THE 1679 PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHO COMPLETED THE STUDY
Year 1
Patients with no exacerbation Patients with 1 exacerbation Patients with 2 exacerbations 0 20 40 60 80 100 Percent 0 20 40 60 80 100
5% 3% 1%
Year 2
0
Year 3
20 40 60 80 100
23 % 6% 2% 6% 3% 2% 2% 1%
20 40 60
80 100 2%
20 40 60
80 100 3%
2% 2%
20 40 60
80 100
2% 2% 3% 2% 1% 1%
20 40 60
80 100
20 40 60
80 100 2% 80 100
2% 3% 1% 4% 12 %
0 0 20 40 60 80 100 Percent 0
20 40 60
20 40 60 80 100 Percent
HER2+ 15-20%
Monotherapy
A-NSCLC
ComboTherapy
Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments
y y
y FEV1
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments
y y
y FEV1
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments
Optimal Pharmacotherapy
Rate of Exacerbations
1.13
number/patient/year
0.97 *
0.93 *
0.85 * #
0.5
0
Plc
* p< 0.001 vs Plc, p=0.002 vs SAL, # p=0.024 vs FP
SAL
FP
SFC
Assumes all patients lost to follow-up did not have exacerbations (4 for tiotropium, 2 for tiotropium + salmeterol, 2 for tiotropium + salmeterol/fluticasone)
0.3 Exacerbations/patient
0.2
0.1
0.052 0.030
0.052 0.030
0.084 0.052
0.088 0.055
0.0031
0.0031
0.0042
0.0032
Tiotropium Salmeterol
Hazard ratio = 0.83* (95% CI, 0.77, 0.90) P<0.001 (log-rank test)
10
*Cox regression adjusted for (pooled) centre and treatment.
Hazard ratio = 0.88* (95% CI, 0.78, 0.98) P=0.02 (log-rank test) 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days)
No. of patients at risk: Tiotropium 3707 3592 3501 3429 3382 3330 3299 3268 3225 3186 3158 3138 2841 Salmeterol 3669 3541 3436 3337 3291 3209 3181 3151 3111 3074 3054 3037 2703
Health Outcomes
SGRQ
Safety
Adverse events AEs of special interest All-cause Mortality
2 weeks Run-in
20
32
44
56
68
80
92 104
106 Follow-up
Treatment
Exacerbation rates
SFC (n=641) Rate of all HCU exacerbations HCU exacerbations using OCS HCU exacerbations (ab) Symptom defined exacerbations Total exacerbatoins 1.28 0.69 Tio (n=650) 1.32 0.85 0.976 (0.836,1.119)
0.814 (0.670,0.990)
P value 0.651
0.039
0.97
3.04
0.82 3.02
3.37
3.37
Time to Withdrawal
44 40 36 Probability of Event (%) 32 28 24 20 16 12 8 4 0 Number 656 at Risk 663 0 560 547 13 531 501 26 510 474 39 494 450 52 476 434 65 456 415 78 445 397 91 160 SFC 50/500 140 TIO 18 104
95% CI
p-value 0.005
(0.651,0.926)
p-value 0.088
0.736
456 415 78
(0.518,1.046)
445 397 91 160 SFC 50/500 140 TIO 18 104
Placebo
(n=432)
2 weeks
Baseline
52 weeks
Dahl et al. Thorax 2010
N.B. Indacaterol 150 g and 300 g once-daily are registered doses The recommended dose strength is 150 g once-daily, to be increased only on medical advice
Indacaterol 300 g provided significant improvement in trough FEV1 over 52 weeks, superior to formoterol
Placebo Indacaterol 300 g o.d. 1.55 1.50 Trough FEV1 (L) 1.45 1.40 1.35 1.30 1.25 1.20 1.15 Day 2 Week 12 Primary endpoint Week 52
1.31 1.31 1.28 1.43
Formoterol 12 g b.i.d.
***
***
1.48
***
1.43
***
***
*p<0.05, ***p<0.001 vs placebo; p<0.05, p<0.001 vs formoterol Data are LSM in the modified intent-to-treat population Trough = average of 23 h 10 min and 23 h 45 min post-dose values
200
***
*** ***
***
***
150 ***
***
100
***p<0.001 vs placebo. Data are LSM with 95% confidence intervals. The study was powered to detect an indacaterol-placebo difference of 120 mL (dotted line)
Improved clinical outcomes for patients: breathlessness significant improvements compared with formoterol (300 g) and salmeterol (150 g) health related quality of life Significant improvements compared with placebo significant improvements compared with salmeterol and numerical improvements vs formoterol reduction in need for rescue medication compared with salmeterol, formoterol and placebo
2.2 Inspiratory capacity (L) 2.1 2.0 1.9 1.8 1.7 1.6
2
10 12 14 16 18 20 22 24
Time post-dose
*p<0.05 indacaterol vs salmeterol; p0.015 for indacaterol vs placebo at all time points; p<0.05 for salmeterol vs placebo at all time points except 50 minutes, 3 hours, 8 hours, 10 hours, 11 hours 10 minutes LaForce et al. Pulm Pharmacol Ther 2011 and 23 hours 45 minutes. Data are LSMSE
n=90
Placebo
Placebo
21 days Washout
21 days Treatment 2
Indacaterol improved exercise endurance time on Days 1 and 21, compared with placebo
Placebo 12 Exercise endurance time (mins) 1.68 *** 11 10 9 8 7 6 5 Day 1
*p=0.011, ***p<0.001 Data are LSM and SE
9.75
8.07
7.92
Day 21
Day 21
Stage I
Indacaterol 75 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d. Indacaterol 600 g o.d. Placebo Formoterol 12 g b.i.d. Tiotropium* 18 g o.d.
Stage II
Placebo
Placebo
Tiotropium* 18 g
Stage I: 2 weeks, seven treatment arms Stage II: 26 weeks, four treatment arms (efficacy and safety) Stage III: 52 weeks, three treatment arms (safety and efficacy) *Open-label All drugs were delivered via proprietary SDDPIs
BLINDED 12 WEEK COMPARISON OF ONCE DAILY INDACATEROL AND TIOTROPIUM IN COPD Both bronchodilators demonstrated spirometric efficacy The two treatments were well tolerated with similar adverse event profiles Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes
Buhl R et al, Eur Respir J 2011, 24 May 2011
ONCE-DAILY BRONCHODILATORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: indacaterol versus tiotropium
Indacaterol was an effective once-daily oncebronchodilator As effective as tiotropium in improving clinical outcomes for patients with COPD
Donohue JF et al, Am J Respir Crit Care Med Vol 182. pp 155162, 2010
tiotropium
Improved clinical outcomes for patients for patients treated with
indacaterol compared to tiotropium: breathlessness health related quality of life reduction in need for rescue medication
Indacaterol has faster onset of action
INDORSE
Stage I
Indacaterol 75 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d. Indacaterol 600 g o.d. Placebo Formoterol 12 g b.i.d. Tiotropium* 18 g o.d.
Stage II
Placebo
Placebo
Tiotropium* 18 g
LONG-TERM SAFETY AND EFFICACY OF INDACATEROL, A NOVEL LONG-ACTING 2AGONIST, IN SUBJECTS WITH COPD: A RANDOMIZED, PLACEBO-CONTROLLED STUDY
During 1 year of treatment: indacaterol was well tolerated provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes
Chapman et et al, Chest 24 february 2011
Survival Rate
0.8
0.9
No bronchodilator and beta-blocker betaNo bronchodilator and no betabetablocker Bronchodilator and betabeta-blocker Bronchodilator and no betabetablocker
0.7 0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Time (years)
HEART FAILURE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE: THE QUANDARY OF BETABLOCKERS AND BETA-AGONISTS
-agonists are associated with incident heart failure in patients with pulmonary disease, and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing -agonists to patients with heart failure. Hawkins N et al, Am J Coll Cardiologist, 2011, in press
MORTALITY ASSOCIATED WITH TIOTROPIUM MIST INHALER IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: SYSTEMATIC REVIEW AND METAANALYSIS OF RANDOMISED CONTROLLED TRIALS
Our meta-analysis suggests an increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease Clinicians should inform patients about the possibility of this increased risk and exercise caution when prescribing tiotropium mist inhaler, particularly in patients with possible underlying cardiac disease
y y
y FEV1
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments
PDE4 inhibition
y y
y FEV1
FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure
Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add ICS OR/AND ROFLUMILAST in exacerbators
Add long term Add ROFLUMILAST oxygen if chronic respiratory failure. Consider surgical treatments
Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ACE INHIBITORS, AND ARBS IN PATIENTS WITH COPD These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials.
EFFECT OF BLOCKERS IN TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A RETROSPECTIVE COHORT STUDY blockers (predominantly cardioselective) may confer reductions in mortality, exacerbations, and hospital admissions in patients with COPD, in addition to the benefits attributable to addressing cardiovascular risk These additive benefits were seen on top of inhaled therapy, including inhaled corticosteroids and did not result in any worsening of pulmonary function
Philip M Short et Al BMJ 2011;342:d2549
Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments
Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments