β-αγωνιστές – β-διεγέρτες: Μύθοι και πραγματικότητες ΠΕΤΡΟΣ ΜΠΑΚΑΚΟΣ ΑΝΑΠΛ. ΚΑΘΗΓΗΤΗΣ ΠΝΕΥΜΟΝΟΛΟΓΙΑΣ Α ΠΑΝ/ΚΗ ΠΝΕΥΜ/ΚΗ ΚΛΙΝΙΚΗ ΝΝΘΑ «ΣΩΤΗΡΙΑ»

ΧΑΠ ΚΑΙ ΚΑΡΔΙΑΓΓΕΙΑΚΑ ΝΟΣΗΜΑΤΑ Ο επιπολασμός της ΚΑ κυμαίνεται από 10-30% σε ασθενείς με ΧΑΠ έναντι 1-2% στο γενικό πληθυσμό 1-2 Ο επιπολασμός της ΧΑΠ ανέρχεται σε 13-39% σε ασθενείς με ΚΑ 3-4 Ο επιπολασμός της ΧΑΠ ανέρχεται σε 30% σε ασθενείς με επιβεβαιωμένη IHD και συνδυάζεται με αυξημένο κίνδυνο θανάτου 5-6 Ο επιπολασμός της ΚΜ κυμαίνεται από 5-15% σε ασθενείς με ΧΑΠ και 30% σε σοβαρή ΧΑΠ 7 Ο επιπολασμός της ΧΑΠ κυμαίνεται από 10-15% σε ασθενείς με ΚΜ 8 Συνοσηρότητες – μεγαλύτεροι σε ηλικία, άρρενες, καπνιστές, με περισσότερα συμπτώματα και άλλες συνοσηρότητες 1. Mullerova H et al, Chest 2013 5. Franssen FME et al, Am J Crit Care Med 2016 2. Chen W et al, Lancet Resp Med 2015 6. Enriquez JR et al, Chest 2011;140:604–610. 3. Mentz RJ et al, J Am Coll Cardiol 2014 7. Konecny T et al, Am J Cardiol 2014 4. Kwon BJ et al, Eur J Heart Fail 2010 8. January CT et al, J Am Coll Cardiol 2014

ΕΠΙΔΡΑΣΗ ΤΗΣ ΚΑΡΔΙΑΚΗΣ ΑΝΕΠΑΡΚΕΙΑΣ ΣΤΗΝ ΠΡΟΓΝΩΣΗ ΑΣΘΕΝΩΝ ΜΕ ΧΑΠ Patients aged 65 years or over with a general practitioner (GP)'s diagnosis of COPD but without a prior diagnosis of heart failure underwent an extensive diagnostic work-up including echocardiography and pulmonary function tests in the period 2001-03. An expert panel then confirmed the presence or absence of COPD according to the GOLD criteria and (previously undiagnosed) heart failure according to the criteria of the ESC heart failure guidelines. This cohort of 405 patients was followed up for a mean duration of 4.2 (SD 1.4) years.  The presence of newly detected heart failure significantly increased all-cause mortality independent of gender, age, history of ischaemic heart disease, hypertension, diabetes mellitus, atrial fibrillation, smoking, and cardiovascular drug use at baseline. Heart failure is a strong independent predictor of all-cause mortality in patients with a diagnosis of COPD. Boudestein LC et al, Eur J Heart Fail 2009

ΚΑΙ ΑΝΤΙΣΤΡΟΦΑ … Canepa M et al Eur J Heart Failure 2017 To describe the characteristics and assess the 1-year outcomes of hospitalized (HHF) and chronic (CHF) heart failure patients with chronic obstructive pulmonary disease (COPD) enrolled in a large European registry between May 2011 and April 2013. Overall, 1334/6920 (19.3%) HHF patients and 1322/9409 (14.1%) CHF patients were diagnosed with COPD. In both groups, patients with COPD were older, more frequently men, had a worse clinical presentation and a higher prevalence of co-morbidities.  At 1-year follow-up, the hazard ratios for COPD in multivariable analysis confirmed its independent association with hospitalizations both in HHF [all-cause: 1.16 (1.04-1.29), for HF: 1.22 (1.05-1.42)] and CHF patients [all-cause: 1.26 (1.13-1.41), for HF: 1.37 (1.17-1.60)]. The association between COPD and all-cause mortality was not confirmed in both groups after adjustments. In HHF, the increase in the use of heart failure (HF) medications at hospital discharge was greater in non-COPD than in COPD for angiotensin-converting enzyme inhibitors (+13.7% vs. +7.2%), beta-blockers (+20.6% vs. +11.8%) and mineralocorticoid receptor antagonists (+20.9% vs. +17.3%), thus widening the gap in HF treatment already existing between the two groups at admission. In CHF patients, there was a similar increase in the use of these medications after enrollment visit in the two groups, leaving a significant difference of 8.2% for beta-blockers in favour of non-COPD patients (89.8% vs. 81.6%, P < 0.001). Canepa M et al Eur J Heart Failure 2017

β-BLOCKERS Λίγες μελέτες ασχολούνται με την σύγκριση αποτελεσματικότητας και ασφάλειας των καρδιοεκλεκτικών και μη καρδιοεκλεκτικών β-αποκλειστών στη ΧΑΠ Εκλεκτικοί β-1 αποκλειστές όπως metoprolol, bisoprolol και nebivolol είναι ασφαλείς και προτείνονται από τις κατευθυντήριες οδηγίες αλλά και από τους ειδικούς Η τιτλοποίηση της δόσης σημαντική και ευκολότερη για την bisoprolol σε σχέση με την carvedilol Lainscak M et al, Resp Med 2011 One such trial was conducted in a small cohort of patients with COPD with HF and showed that, although NT-proBNP levels were lower with carvedilol than with metoprolol or bisoprolol, FEV1 was lowest with carvedilol and highest with bisoprolol. New York Heart Association functional class, 6-minute-walk distance, and LVEF did not change, and switching between a b1-selective to a nonselective b-blocker was well tolerated.

Οι διαφορές των β blockers retrospective, non-randomized, single center trial. Acute decompensated HF patients with COPD were classified according to the oral drug used at discharge into β-blocker (n=86; carvedilol [n=52] or bisoprolol [n=34]) and non-β-blocker groups (n=46). The mortality rate was higher in patients without β-blockers compared with those taking β-blockers. H bisoprolol σχετίστηκε με ελάττωση των παροξύνσεων της ΚΑ και της ΧΑΠ Kubota Y et al IJCOPD 2015

Ωφελιμότητα: Αδιαμφισβήτητη? Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2-4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). β-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction.  Bhatt SP et al, Thorax 2016

Cardiovascular Effects of β-Agonists in Patients With Asthma and COPD Cardiovascular Effects of β-Agonists in Patients With Asthma and COPD*: A Meta-Analysis Chest. 2004;125(6):2309-2321 A meta-analysis of randomized placebo-controlled trials of beta(2)-agonist treatment in patients with obstructive airway disease was performed, to evaluate the short-term effect on heart rate and potassium concentrations, and the long-term effect on adverse cardiovascular events. For trials lasting from 3 days to 1 year, beta(2)-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI, 1.59 to 4.05) compared to placebo. The included studies were of formoterol, fenoterol, terbutaline, salmeterol, salbutamol, albuterol, procaterol, levalbuterol and isoproterenol, either alone or in combination.

TORCH:LABA και καρδιαγγειακός κίνδυνος The probability of having a cardiovascular adverse event by 3 years was 24.2% for placebo, 22.7% for salmeterol, 24.3% for fluticasone propionate and 20.8% for SFC. Post hoc analysis of the 3-year TORCH dataset showed that salmeterol alone or in combination (SFC) did not increase the risk of cardiovascular events in patients with moderate to severe COPD. Calverley P M A et al. Thorax 2010;65:719-725

Νέοι Ultra-LABA: Καρδιαγγειακός κίνδυνος The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA). In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes. Brook RD et al, Heart 2017

SAMA? Adding ipratropium bromide or prednisone individually and then to the full model did not have significant effects on the point estimates (Table 4). For chronic heart failure hospitalizations, adding both ipratropium bromide and prednisone to a model that contained diabetes, acute coronary syndromes, other cardiovascular disease, alcohol abuse, and filling prescriptions for -blocker and ACE inhibitor had little effect on the point estimates: RR for one canister per month, 1.4 (95% CI, 0.9 to 2.1), RR for two canisters per month, 1.7 (95% CI, 1.1 to 2.5), and RR for three canisters per month, 1.9 (95% CI, 1.1 to 3.1) [Table 4]. We found similar results when examining the effects of adding ipratropium bromide and/or prednisone on risk for death: RR for one canister per month, 0.9 (95% CI, 0.5 to 1.6); RR for two canisters per month, 1.3 (95% CI, 0.8 to 2.1); and RR for three canisters per month, 1.8 (95% CI, 1.0 to 3.2) [Table 4]. Au DH et al Chest 2004

Καρδιαγγειακός κίνδυνος από Αντιχολινεργικά 0,00 0,02 0,04 0,06 0,08 0,10 0,12 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 Days after the initiation of reatment Probability of death Τio Respimat® 5 µg Τio Respimat® 2,5 µg Τio HandiHaler® 18 µg In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile (risk of death) and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD.LAMA προστατευτικοί Καταστολή ενδοθηλίνης 1 Μείωση Φλεγμονωδών κυτταροκινών Καταστολή της χημειοταξίας ουδετεροφίλων Καταστολή βλέννας Wise RA, et al, N Engl J Med. 2013

ΑΝΤΙΧΟΛΙΝΕΡΓΙΚΑ No additional risk of incident HF due newer long-acting antimuscarinic antagonists (LAMAs) Glycopyrronium1 Aclidinium2 Umeclidinium 3 LABA/LAMA combination indacaterol/glycopyrronium4 1. D’Urzo AD et al, Int J COPD 2015 2. Kerwin EM et al, COPD 2012 3. Trivedi R et al, Eur Respir J 2014 4. Wedzicha JA et al, N Engl J Med 2016 In conclusion, LAMA agents may be slightly preferred over b2-agonists to treat patients with COPD with HFrEF (113). It seems reasonable to suggest close follow-up during the first weeks of treatment with bronchodilators (95), particularly in those with HFrEF, but overall there is no direct evidence that COPD should be treated differently in the presence of HF (2)

Hillas G, et al. Int J Chron Obstruct Pulmon Dis 2016

Προγνωστική αξία καρδιακών βιολογικών δεικτών These associations persisted after adjusting for other clinical and laboratory predictors of mortality (arterial Paco(2), body mass index and CURB65 score). Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to hospital with acute exacerbations of COPD independently of other known prognostic indicators. The pathophysiological basis for this is unknown, but indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis. Chang CL et al, Thorax 2011

ΣΥΜΠΕΡΑΣΜΑΤΑ Καρδιακή ανεπάρκεια-ΚΜ-ισχαιμική καρδιοπάθεια και XAΠ: Συχνή συνύπαρξη Διαγνωστικοί αλγόριθμοι πρέπει να αφορούν και τα καρδιαγγειακά και τη ΧΑΠ Φάρμακα : β-blockers : Ναι Βρογχοδιασταλτικά – Ναι με προσοχή στους ασθενείς με κίνδυνο (κυρίως στα βραχείας δράσης). Προσοχή στο τι ακολουθεί μετά την παρόξυνση της ΧΑΠ

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