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Modena, 6-7/8-9 Settembre 2011 CORSO DI FORMAZIONE PER PERSONALE MEDICO Nycomed Malattie cardiovascolari e BPCO Pietro Roversi, Alessia Verduri e Fabrizio.

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Presentation on theme: "Modena, 6-7/8-9 Settembre 2011 CORSO DI FORMAZIONE PER PERSONALE MEDICO Nycomed Malattie cardiovascolari e BPCO Pietro Roversi, Alessia Verduri e Fabrizio."— Presentation transcript:

1 Modena, 6-7/8-9 Settembre 2011 CORSO DI FORMAZIONE PER PERSONALE MEDICO Nycomed Malattie cardiovascolari e BPCO Pietro Roversi, Alessia Verduri e Fabrizio Luppi Clinica di Malattie dellApparato Respiratorio Azienda Ospedaliero – Universitaria Policlinico di Modena

2 Muscle Weakness / Wasting Metabolic Syndrome Type 2 diabetes Osteoporosis CRP Cardiovascular Events Liver ? Local Inflammation TNF IL-6 Fabbri LM, Luppi F et al, Eur Respir J 2008

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4 The American Journal of Medicine (2009) 122, 348-355 Prevalence of Comorbid Diagnoses and Symptoms Among a National Sample of Patients with COPD

5 Frequency distribution of comorbid conditions among patients with COPD. Barr, The American Journal of Medicine, 2009

6 The high prevalence of comorbidity in COPD is likely multifactorial and associated with age and multisystem impact of tobacco exposure COPD was less commonly treated than less symptomatic and less morbid conditions, such as hypertension and hypercholesterolemia, despite the increasing number of proven medications for the treatment of COPD Patients with COPD demonstrated better recall of their blood pressure and cholesterol than of their FEV1 This is not surprising in the context of the greater public education regarding hypertension and hypercholesterolemia Barr, The American Journal of Medicine, 2009

7 Prevention of exacerbations of chronic obstructive pulmonary diseases with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.Co-morbilità Vascolari (compresa lipertensione) 64% Cardiache 38% Gastrointestinali 48% Metaboliche o nutrizionali 47% Muscolo scheletriche o connettivali 46% Genito-urinarie 27% Neurologiche 22% Niewoehner et al, Ann Intern Med 2005;143:317-326

8 Role of co-morbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation. Crisafulli E, et al.,Thorax 2008;63: 487-492. 51% of the patients reported at least one chronic comorbidity added to COPD. Metabolic (systemic hypertension, diabetes and/or dyslipidaemia) and heart diseases (chronic heart failure and/or coronary heart disease) were the most frequently reported co-morbid combinations (61% and 24%, respectively)

9 Screening della comorbilità: alcuni esempi PatologiaIdentificazione CHFRx torace, BNP OsteoporosiDEXA, morfometria colonna dorsale DepressioneGeriatric Depression Scale Deficit cognitivo MMSE, Clock Drawing test GlaucomaTonometria oculare Insufficienza renale MDRD (stima indiretta GFR) GOLD Linee guida BPCO 2010

10 Cause of death on treatment Cardio- vascular PulmonaryCancerOtherUnknown Deaths (%) PlaceboSFC Calverley et al. NEJM 2007

11 Mannino et al, ERJ, 2007 What do COPD Patients Die From?

12 High CRP Severeobstruction and severe obstruction Cardiac infarction injury score P=0.001 Sin and Man, Circulation. 2003 0 1 2 3 4 5 6 7 8 Systemic Consequences of COPD Cardiovascular Morbidity

13 . Soriano, CHEST 2010 450 population participants without CVD 52 population participants with CVD, 119 hospital patients with CAD

14 . Soriano, CHEST 2010

15 1.One of every three patients with CAD recruited from the hospital clinic, and one of every five patients with CVD in the general population, suffer AL compatible with COPD 2.The majority of them are not diagnosed, and, therefore, they remain mostly untreated. 3.These observations are clinically relevant because COPD is now considered a preventable and treatable disease. Soriano, CHEST 2010

16 For every 10% decrease in FEV 1, cardiovascular mortality increases by approximately 28% and non-fatal coronary event increases by approximately 20% in mild to moderate COPD Anthonisen et al, Am J Respir Crit Care Med 2002 Cardiovascular mortality in COPD

17 Emphysema severity is associated with arterial stiffness in patients with COPD Similar pathophysiological processes may be involved in both lung and arterial tissue Further studies are now required to identify the mechanism underlying this newly described association MacNee W et al, AJRCCM 2007; 176:1208-1214 ARTERIAL STIFFNESS IS INDEPENDENTLY ASSOCIATED WITH EMPHYSEMA SEVERITY IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

18 ENDOTELIN-1 IL-6 LDL uptake CRP ( FIBRINOGEN) RELATIONSHIP BETWEEN COPD AND CARDIOVASCULAR DISEASE ICAM VCAM (adhesion molecules) Cytokines Complement activation Systemic Inflammation

19 The risk ratio of developing CHF in COPD patients is 4.5 (compared with age-matched controls without COPD after adjustments for cardiovascular risk factors ) (1) The rate-adjusted hospital prevalence of CHF is 3 times greater among patients discharged with a diagnosis of COPD compared with patients discharged without mention of COPD (2) (1) Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70. (2) Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD- related hospitalizations in the United States, 1979 to 2001. Chest 2005;128:2005–11.

20 How common is HF in COPD? Cazzola M. Respiration 2010; epub; Hawkins NM. Data on file. Italian Health Search Database n=341,329 7.9% preval ence HF in COPD overall Scottish Continuous Morbidity Record n=377,439 11.9% prevalen ce HF in COPD overall Prevalence (%)

21 How common is LVSD in COPD? Rutten FH. Eur J Heart Fail 2006: 8(7):706-711. Prevalence (%) high prevalence selected populations severe COPD suspected LVSD coronary disease

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23 Kaplan–Meier event-free survival curves according to chronic obstructive pulmonary disease coexistence Mascarenhas,Am Heart J 2008

24 Why is heart failure important? primary care patients with COPD 65 years (n=404) follow up for a mean duration of 4.2 (SD 1.4) years. HF doubles mortality of patients with COPD: adjusted HR 2.1 (1.2–3.6 C.I.) Boudestein LC. Eur J Heart Fail 2009; 11(12):1182-1188.

25 Mechanisms of Skeletal Muscle Atrophy in Patients With CHF or COPD M. Padeletti- LeJemtel : International Journal of Cardiology, 2008

26 PROGRESSION OF CHF AND COPD M. Padeletti- LeJemtel : International Journal of Cardiology, 2008

27 BMI > 29 Kg/m 2 BMI 24-29 Kg/m 2 BMI 20-24 Kg/m 2 BMI < 20 Kg/m 2 Weight loss is a prognostic factor in COPD Schols et al. AJRCCM 1998; 157: 1791-7

28 INSULIN RESISTANCE AND INFLAMMATION - A FURTHER SYSTEMIC COMPLICATION OF COPD Bolton CE et al, COPD. 2007 Jun ;4(2):121-6 This study demonstrates greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD

29 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).

30 a)diabetes, b) hypertension c) cardiovascular disease Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict death within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes, b) hypertension or c) cardiovascular disease

31 Results from Cox proportional hazard models (presented as hazard ratio with 95% confidence interval) that predict time to first hospitalisation within 5 yrs by modified Global Initiative for Obstructive Lung Disease (GOLD) category and the presence of a) diabetes b) hypertension or c) cardiovascular a)diabetes, b) hypertension c) cardiovascular disease

32 REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR BLOCKERS IN COPD The combination of statins and either ACE inhibitors or ARBs is associated with a reduction in COPD hospitalization and total mortality not only in the high CV risk cohort but also in the low CV risk cohort Mancini JB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60

33 Challenges in patients with coexistent COPD and CHF COPD is the one that most delays the diagnosis of CHF COPD is most often advocated for nonadherence to therapeutic guidelines, especially betablockade (BB) safety and efficacy of BB and bronchodilators in patients with COPD and HF M. Padeletti- LeJemtel : International Journal of Cardiology, 2008

34 cardiomegaliacardiomegalia congestioneematicacongestioneematica versamentopleuricoversamentopleurico gabbia toracica Ridotta compliance Aumento del lavoro respiratorio Ridotta compliance Aumento del lavoro respiratorio

35 Limitazione del flusso espiratorio alveoli bronchi

36 Caution diagnosing COPD in HF Airway compression Bronchialhyperresponsiveness always perform Spirometry… and always when euvolaemic misdiagnosis overestimateseverity inappropriatebronchodilators inappropriateavoidance of β-blockers

37 hyperinflation reduces cardiothoracic ratio pulmonary vascular remodeling masks alveolar shadowing asymmetric and regional patterns vascular bed loss causes upper lobe venous diversion Gehlbach BK. Chest 2004; 125:669-682. radiology COPD masks or mimics heart failure

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40 OUTCOMES bronchodilators heart failure devices smoking cessation beta-blockers Renin-angiotensin- aldosterone system inhibition COPD beta-agonists Why is diagnosis important?

41 THE IMPACT OF CARDIOSELECTIVE BETA- BLOCKERS ON MORTALITY IN PATIENTS WITH COPD AND ATHEROSCLEROSIS -blockers are often withheld from patients with chronic obstructive pulmonary disease (COPD) because of fear of pulmonary worsening Beta1-blockers may reduce mortality in COPD patients undergoing vascular surgery (1) In some patients with COPD selective beta1-blockers are safe and may reduce mortality (2) 1) Van Gestel, Am J Respir Crit Care Med. 2008 2) Salpeter S Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD003566.

42 Short PM et al., 2011 Baseline characteristics of 5977 patients at diagnosis of COPD, grouped according to final treatment.

43 Short PM et al., 2011 Effect of different treatment regimens* on FEV1 of patients with COPD during study period

44 Short PM et al., 2011 Adjusted hazard ratios for all cause mortality among patients with COPD in reference to the control group (who received only inhaled therapy with short acting β agonists or antimuscarinics)

45 Short PM et al., 2011 Kaplan-Meier estimate of probability of survival among patients with COPD by use of β blockers Β-blocker use was associated with a 22% reduction in mortality: hazard ratio 0.78 (95% confidence interval 0.67 to 0.92)

46 Conclusions β blockers may reduce mortality and COPD exacerbations when added to established inhaled stepwise therapy for COPD, independently of overt cardiovascular disease and cardiac drugs, and without adverse effects on pulmonary function. Short PM et al., 2011

47 Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD In-hospital mortality was 5.2% In-hospital mortality was 5.2% Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99) Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99) The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality Thorax. 2008 Apr;63(4):301-5. Dransfield MT, Thorax. 2008 Apr;63(4):301-5.

48 Hawkins NM. Eur J Heart Fail 2010 0.7 0.8 0.9 1.0 Survival Rate 0 0.5 1.0 1.52.0 2.5 3.03.5 Time (years) No bronchodilator and beta-blocker No bronchodilator and no beta- blocker Bronchodilator and beta-blocker Bronchodilator and no beta- blocker CHARM trial: patients with HF receiving bronchodilators (n=674 of 7599)

49 Celli B. et al., Chest 2010; 137: 20-30. Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis. Cumulative frequency of cardiovascular endpoint event 0 0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08 0,09 0,1 0612182430364248 Placebo Tiotropium Rate ratio = 0.83; 95% CI = (0.71-0.98) Time to first event (months) Patients at risk Tiotropium Placebo 10846 8699 6889 5506 4698 3599 2420 2240 2274 2068 2133 1917 2022 1787 1911 1681 1785 1571

50 Celli B. et al., Chest 2010; 137: 20-30. Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis. Cumulative frequency of cardiovascular death 0 0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08 0,09 0,1 0612182430364248 Placebo Tiotropium Rate ratio = 0.77; 95% CI = (0.60-0.98) Time to first event (months) Patients at risk Tiotropium Placebo 10846 8699 6933 5538 4737 3637 2456 2286 2322 2120 2193 1980 2087 1861 1986 1756 1863 1638

51 Primary analysis: all-cause mortality at 3 years Vertical bars are standard errors 152415331464148713991426 1293 Plc 1339 SFC Numberalive 0 2 4 6 8 10 12 14 16 18 01224364860728496108120132144156 Time to death (weeks) Probability of death (%) FSC 12.6% Placebo 15.2% HR 0.825, p=0.052 17.5% risk reduction 2.6% absolute reduction Calverley et al, NEJM, 2007

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54 Caratteristiche della TEP in BPCO 1.Nearly 30% of all exacerbations of COPD do not have a clear etiology 2.COPD patients are at a high risk for PE due to a variety of factors including limited mobility, inflammation, and comorbidities 3.Overall, the prevalence of PE was 19.9% (95% confidence interval [CI], 6.7 to 33.0%; p 0.014). 4.In hospitalized patients, the prevalence was higher at 24.7% (95% CI, 17.9 to 31.4%; p 0.001) than those who were evaluated in the emergency department (3.3%)

55 1.One of four COPD patients who require hospitalization for an acute exacerbation may have PE. 2.A diagnosis of PE should be considered in patients with exacerbation severe enough to warrant hospitalization, especially in those with an intermediate-to-high pretest probability of PE.

56 Polosa et al:Haematologica, 2008 IL-6: surrogate marker of inflammation vWF:Ag (von Willebrand Factor antigen): endothelium activation F1+2 (prothrombin fragment 1+2 ): clotting stimulation D-Dimer : fibrinolytic activation Endothelial-coagulative activation during COPD exacerbations

57 TEP in BPCO: FATTORI DI RISCHIO 1.precedente storia di neoplasia maligna (rischio relativo, RR 1.82, 95% CI, 1.3-2.92) 2.storia di TVP o EP (RR 2.43, 95% CI, 1.49-3.49) 3.riduzione della PaCO2 > 5 mm Hg COPATOLOGIE 1.cancro 2.scompenso cardiaco congestizio Tillie-Leblond I : Ann Intern med 2006

58 Riztkallah, CHEST 2009

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64 AE-COPD typical atypical TREATMENT improvement no improvement Pre test probability for PE HIGHINTERMEDIATELOW creatinine >1.5 <1.5 SPIRAL CT D-dimer NEG PE excluded POS PE confirmed POS Doppler US V/Q scan Kenneth E Wood International Journal of COPD 2008:3(2) 277–284

65 La BPCO è uno dei fattori di rischio per tromboembolia polmonare La TEP deve essere considerata tra le cause di riacutizzazione di BPCO e la sua frequenza varia in funzione della casistica studiata e del setting clinico, potendo arrivare fino al 25% dei casi La diagnosi è resa difficile dallaspecificità dei sintomi e dalla possibile sovrapposizione con quelli di una riacutizzazione e la formulazione di uno score clinico di probabilità è utile sia per porre il sospetto sia per laccuratezza diagnostica. La performance clinica delle indagini diagnostiche, con eccezione per la scintigrafia polmonare perfusionale\ventilatoria, non è influenzata in modo significativo dalla presenza di BPCO. TEP in BPCO: messaggi chiave I

66 TEP in BPCO: messaggi chiave II Lo studio del circolo polmonare arterioso con tomografia computerizzata (angioTC polmonare) è lindagine di riferimento un eccessivo impiego di esami TC con mezzo di contrasto può essere evitato escludendo i soggetti con score di probabilità medio-basso associato a D-dimero negativo. La valutazione del rischio di morte (stratificazione del rischio con ricerca dei segni di disfunzione ventricolare destra ) è utile a fini prognostici e terapeutici

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