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. Treatment of Chronic Heart Failure in patients with COPD Claudio Ceconi, Ferrara Modena 2 March 2011 MANAGEMENT OF BPCO AND COMORBIDITIES

3. Clinical guidelines are... Definition: “Systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” Institute of Medicine, 1990 Other common names:  medical guidelines  clinical practice guidelines  clinical protocols

4. “ ”

7.  Frequent and challenging diagnosis  Prognosis is worsened  Natriuretic peptides may be useful  ACE-inh, BBlockers, ARBs are useful  Asthma contraindicates BBlockers  Re-habilitation appropriate to improve skeletal muscle function and fatigue No Evidence Based recommendation !

8. Global Strategy for Diagnosis, Management and Prevention of COPD n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations n Definition, Classification n Burden of COPD n Risk Factors n Pathogenesis, Pathology, Pathophysiology n Management Practical Considerations

10. PubMed: 1996 to date Chronic pulmonary disease = 2767 AND heart failure = 2767 Chronic pulmonary disease AND heart failure NOT Cor Pulmonale = 396 NOT BNP = 396

11. Factors determining different outcomes of Patients 1.Chance 2.Accuracy of data sources: do they describe accurately the real world? 3.Risk associated to specific diseases 4.Differences in the efficiency of care and therapies and of quality of the treatments Iezzoni I. “Risk adjustment for measuring healthcare outcomes” Health Administration Press, 1997

12. VariableRCT Age57-64 Sx M:F4:1 EF > 40%Exclusion criteria AF20% Renal DysfunctionExclusion criteria Co-morbidityUncommon DisabilityExclusion criteria DrugsAt target ComplianceHigh Therapy duration1-3 years Primary objectiveSurvival Mortality at 1 year9-12% Pts enrolled in clinical trials vs real world CHF

13. “Real World” ?

14. Comorbidity and guidelines conflicting interests  Guidelines are likely to introduce more problems than they solve when used in patients with comorbidity (25-50% of people with chronic diseases)  Given the problems of exclusion criteria, randomization, blinding etc…, studies that combine therapeutic approaches and/or report the natural course of patients with comorbidities are welcome. Lancet 2006; 367: 550

15. Comorbidity and guidelines conflicting interests  Guidelines are likely to introduce more problems than they solve when used in patients with comorbidity (25-50% of people with chronic diseases)  Given the problems of exclusion criteria, randomization, blinding etc…, studies that combine therapeutic approaches and/or report the natural course of patients with comorbidities are welcome. Lancet 2006; 367: 550

16. CHF&COPD: Ignored combination  Risk ratio of developing CHF is 4.5 in COPD  FEV 1 is as good predictor of cardiovascular mortality as serum cholesterol Rutten FH. Am Heart J 2002;143:412-7, O’Connor CM.J Card Fail 2005;11:200-5, Gustaffson F. Eur Heart J 2004;25:129-35 Tobacco use Global epidemics Almost half of people aged 65 yrs or more: at least 3 chronic medical conditions

17. Cross-sectional study, patients 65 years of age Of 405 participating patients with a diagnosis of chronic obstructive pulmonary disease, 83 (20.5%, 95% CI 16.7–24.8) had previously unrecognized heart failure

18. Prevalence of COPD in patients with HF ReferencePrevalence %Country n PopulationData source Bangdiwala 15 USA, Canada 6273 HF hospitalisationSOLVD Registry Auerbach 19 USA 1298 HF hospitalisationSUPPORT Study Vaccarino 27 USA 2445 HF hospitalisation Conneticut Peer Review Org Gambassi 19 USA 86 094 outpatientSAGE Database Baker 25 USA 23 505 HF hospitalisation Cleveland Health Quality Choice Program Kosiborod 33 USA 3 957 520 HF hospitalisationMedicare Havranek 33 USA 34 587 HF hospitalisation National Heart Failure Project Kamalesh 52 USA 495 outpatient Indianapolis Veterans Affairs Medical Centre Lee 21 Canada 2624 HF hospitalisationEFFECT study Brown 12 Scotland 27 477 HF hospitalisation Scottish Morbidity Record Gustaffson 22 Denmark 5491 HF hospitalisation DIAMOND-CHF Registry

19. Factors determining different outcomes of Patients 1.Chance 2.Accuracy of data sources: do they describe accurately the real world? 3.Risk associated to specific diseases 4.Differences in the efficiency of care and therapies and of quality of the treatments Iezzoni I. “Risk adjustment for measuring healthcare outcomes” Health Administration Press, 1997

20. Non-cardiac Comorbidity Increases Preventable Hospitalizations among Medicare Beneficiaries with CHF A survey of 122 630 Subjects Aged > 65 years ACSC = Ambulatory Care Sensitive (e.g. preventable) Condition Braunstein et al., JACC 2003;42:1226

21. Adjusted 5-year survival curves for patients with HF with and without COPD Rusinaru D et al AJC 2008

22.  A cohort of 118 patients consecutively screened in an outpatient HF clinic  New diagnosis of CHF  ≥ 65 years of age  Smoking history of ≥ 10 pack-years Centro Scompenso - Università Ferrara

23. Characteristics of the study population Total patients (n = 118) Age (yrs)72.6 ± 6.8 Male (n [%])86% Smoking status (n [%]) Ex-smokers79.6% Current smokers20.4% Etiology of HF (n [%]) Hypertension16% Coronary heart disease64% Idiopathic Cardiomyopathy18% Other and unknown2%

24. Prevalence of COPD and COPD severity 31% 69% GOLD: Global Obstructive Lung disease All but two of the patients were unaware of COPD % of patients

25. Characteristics of patients with CHF according to presence or absence of COPD COPD(n=36) No COPD (n=82) p value Age (yrs)73.8 ± 7.172.1 ± 6.6N.S. Pack-years49.2 ± 31 39.2 ± 22.2 0.16 Body mass index (Kg/m 2 )27.6 ± 3.828.4 ± 3.6N.S. Dyspnoea (MMRC score)1 ± 0.51 ± 0.4N.S. NYHA class I and II (%)83.394.5N.S. LVEF ≤ 40% (%)63.360.3N.S. Diabetes (%)23.324.7N.S. Hyperlipidaemia (%)6065.8N.S. Hypertension (%)10098.6N.S. Metabolic syndrome (%)6363.5N.S. Serum creatinine (mg/dL)1.7 ± 0.31.4 ± 0.2N.S. Hemoglobin (g/dL)13.1 ± 0.313.3 ± 0.2N.S. HsCRP (mg/dL)0.8 ± 0.30.6 ± 0.1N.S.

26. 85.6 79.3 PaO 2 p=0.004

27. Correlation between lung function and echocardiography data DT (ms) sPAP (mmHg) r value p value r value p value FEV 1 pre-bronchodilator (% predicted) 0.340.004-0.330.006 FEV1 post-bronchodilator (% predicted) 0.350.003-0.280.020 FVC pre-bronchodilator (% predicted) 0.360.003-0.340.005 FVC post-bronchodilator (% predicted) 0.330.01-0.450.001 TlCO (% predicted) 0.390.004-0.470.001 FEV 1 = forced expiratory volume in 1 second; FVC= forced vital capacity; Tl CO = diffusing capacity of carbon monoxide; DT= E velocity deceleration time; sPAP= systolic pulmonary pressure.

28. Baseline: Indexes of Severity 1640 3540 NT-proBNP P<0.01 375 333 6mwd P=0.05

29. FOLLOW UP %  NT-proBNP %  6mwd 25% 100% 15% -1% P<0.01

30. FOLLOW UP -0.2% -8% -0.5% -1% %  FEV1 Post % Predicted%  FEV1/FCV P<0.01

31. FOLLOW UP -0.2% -8% %  FEV1 Post % Predicted P<0.01 %  PaO 2 + 0.5% -3%

32. Survival Months 25152005 1 0,8 0,6 p = 0,12 CHF CHF+BPCO

33. SURVIVAL OF INCIDENT CASES OF HEART FAILURE Cowie et al. 2002

34. All Cause Death + Hospitalization Predictive power of anaemia Time to the first event

35. Factors determining different outcomes of Patients 1.Chance 2.Accuracy of data sources: do they describe accurately the real world? 3.Risk associated to specific diseases 4.Differences in the efficiency of care and therapies and of quality of the treatments Iezzoni I. “Risk adjustment for measuring healthcare outcomes” Health Administration Press, 1997

36. Carvedilol (n=696) Placebo (n=398) Survival Days 050100150200250300350400 1.0 0.9 0.8 0.7 0.6 0.5 Risk reduction = 65% p<0.001 Packer et al (1996) Lancet (1999) 0 200 400 600 800 1.0 0.8 0.6 0 Bisoprolol Placebo Time after inclusion (days) p<0.0001 Survival Risk reduction = 34% The MERIT-HF Study Group (1999) Months of follow-up Mortality % 036912151821 20 15 10 5 0 Placebo Metoprolol CR/XL p=0.0062 Risk reduction = 34% US Carvedilol Study  -blockers in heart failure - all-cause mortality CIBIS-II MERIT-HF

37. Cardioselective beta-blockers for chronic obstructive pulmonary disease FEV1 treatment effect S.R. Salpeter et al. Respiratory Medicine 2002

38. Safety of beta-blockers  Selective B1B should not be withheld in patients with moderate-to-severe COPD  Real life: less than 10% of CHF patients with COPD recieve BB

39. IN CHF Betablocker prescriptions by age from 1995 to 2004 18.1% 11.9% 7.4% 1.1% 14.1% 39.9% 25.1% 14.7% 8.8% 28.6% 65.9% 53.4% 41.1% 23.4% 53.6% <65 years65-74 years75-84 years  85 years Total p<0.0001 1995-1997 1998-2000 2001-2004 p<0.0001 2001-2004 BRING-UP 1-2

40. REASONS WHY TREATMENT WAS NOT STARTED (n. 1455) n. of pts CONTRAINDICATIONS540 (37.1%) COPD317 (59%) PVD76 (14%) First degree AV block (>28 sec)35 (6%) Advanced AV block22 (4%) CHF on treatment with IV inotropes 38 (7%) HR <50 bpm39 (7%) SBP  90 mmHg50 (9%) Note: It was possible to specify more than one reason BRING-UP Study

41. CHF+COPD CHF  Blockade in CHF COPD co-morbidity did not predict the tolerability nor the achievement of target dose of  -Blocker therapy

42. Concomitant use of BB with inhaled beta-agonists  B2B agonists (short acting?) increase risk for CHF decompensation and all-cause mortality in CHF  Combination with nonselective BB: beneficial?  Both selective and nonselective BB with alpha blockade are to be avoided during COPD exacerbation due to the insufficient safety data Au DH. Chest 2003;123:1964-9

43. ACE inhibitors  Cornerstone of treatment in CHF  May prevent SM atrophy and improve respiratory muscle strength  No increased risk of cough and bronchospasm

44. Morbidity/Mortality Reduction in COPD effect of RAS inhibition and Statins Mancini et al. JACC 2006 COPD Hospitalization Infarction or Death

45. From common pathways to novel treatment options (too early and too speculative?) Can all COPD patients profit from cardiovascular drugs? - Renin-Angiotensin-Aldosteron System (ACE-i or ARB) - Sympathic nervous system (betablockers) - Endothelial function and atherosclerosis (statins) => New generation mortality reducing drugs in COPD ? Rutten FH

46. Comorbidity, Ageing Chronic diseases and human illness

47. Research units Department of Cardiology University of Ferrara Ceconi C, Fucili A, Ferrari R Department of Respiratory Diseases University-Hospital of Ferrara Potena A, Ballerin L, Papi A Department of Clinical and Experimental Medicine University of Ferrara Boschetto P, Stendardo M, Concordia A Department of Respiratory Diseases University of Modena & Reggio Emilia Fabbri LM