Beta blockers & COPD/asthma

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or asthma  Study sample:  Patients ≥65 years of age with a clinically confirmed AMI , defined as chart do

Quan Nguyen Anh, MDBeta blockers & COPD/asthma

Structure of presentation

 Case study

 Beta blockers – Overview

 COPD & heart diseases – Overview

 Under-use of beta-blockers in patients with ischaemic heart disease and concomitant COPD

 Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or asthma

 Use of Beta Blockers in CHF Patients with COPD and/or Asthma

 Cardioselective beta-blockers ?

 Non-cardioselective beta-blockers ?

 Non-selective alpha- & beta-blockers ?

=> Isolated systolic hypertension

=> First line agents:

- Thiazide diuretics

- ARB

- Long acting DHP CCB

- BB (???)

Case study 2

 Male, 79 years old

 3-vessel coronary heart disease – HF (LVEF: 28 %) – Asthma.

 Re-admission many times due to breathlessness, well tolerated with bronchodilatory, vasodilatory agents & diuretics.

 Prescription at discharge:

- Clopidogrel

- Berodual, Seretide, Bambec…

- Zestril, Furosemide, Nitrat…

- Not BB (!!!)

Case study 3

 Male, 50 years old

 Smoking – many years; occasional breathlessness related to weather, unconfirmed asthma,

no prevention His son is allergic to seafood with presentation of rash & itching.

 Admitted to Emergency Department: Anterior MI day 2 with bronchospasm appearance, well tolerated with bronchodilatory agents

-> C3: BP 130/80, HR: 85 bpm, no bronchospasm appearance at all.

=> Use of BB??? If yes, when & how???

Beta blockers – Overview

Beta blockers - contraindications

 Bradycardia, especially high degree AV block

Beta blockers – NOW: indications

 Hypertension (not recommended for patients ≥ 60 years old without another compelling indication)

 Coronary heart disease (Angina, UA, post MI)

 CHF (bisoprolol, metoprolol, carvedilol)

 Perioperative period (…)

Beta blockers – NOW: indications

 In a retrospective study of more than 200,000 patients with myocardial infarction, Gottlieb et

al found that beta-blockers were associated with a 40% reduction in mortality rates in

patients with conditions often considered a contraindication to beta-blocker therapy, such as congestive heart failure, pulmonary disease, and older age.

Gottlieb SS, McCarter RJ, Vogel RA Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction N Engl J Med 1998; 339:489–497.

Beta blockers - classification

 β1-Adrenoceptors are situated in the cardiac sarcolemma If activated, they lead to an increase in the rate and force of myocardial contraction (positive inotropic effect) by opening the calcium

channels.

 β2-Adrenoceptors are found mainly in bronchial and vascular smooth muscles If activated, they cause broncho- and vaso-dilatation There are, however, sizable populations of β2-Adrenoceptors in the myocardium, of about 20%–25%, which leads to the cardiac effects of any β2-Adrenoceptors stimulation There is a relative up-regulation of these receptors to about 50% in heart failure.

Beta blockers - classification

 The first generation agents (Propranolol, Sotalol, Timolol, Nadolol…): nonselective

- Blocking β1-receptors: affects the heart rate, conduction and contractility

- Blocking β2-receptors: tends to cause smooth muscle contraction -> bronchospasm.

 The second-generation agents (Atenolol, Bisoprolol, Metoprolol…): selective

- Block β1-receptors in low doses but are capable of blocking β2-receptors in higher doses.

Beta blockers - classification

 The third generation agents: selective (Nebivolol) or nonselective (Carvidolol and Labetolol)

- These agents have vasodilatory properties mediated either by nitric oxide release

(Nebivolol, Carvidolol) or by added alpha-adrenergic blockade (Labetolol, Carvidolol) or

- acts via β2-intrinsic sympathomimetic activity (ISA) (Pindolol, Acebutolol): capacity to stimulate as well as to block adrenergic receptors.

Beta blockers - classification

Int J Chron Obstruct Pulmon Dis 2007 December; 2(4): 535–540.

MECHANISMS OF INDUCED BRONCHOCONSTRICTION

BETA-BLOCKADE- Beta-adrenergic stimulation inhibits release of acetylcholine, a potent bronchoconstrictor, from cholinergic nerves in human airways.

 In patients with asthma, non-selective beta-adrenergic blockade may cause

bronchoconstriction by antagonism of inhibitory presynaptic beta-2-adrenoreceptors on cholinergic nerves.

 Patients with COPD, unlike those with asthma, experience equal or better bronchodilator responses to anticholinergic agents than to beta-adrenergic agonists.

MECHANISMS OF INDUCED BRONCHOCONSTRICTION

BETA-BLOCKADE- Beta-2-adrenoreceptors and cholinergic M2 receptors have opposite effects on adenylyl cyclase activity A rise in cAMP level relaxes smooth airway muscle Stimulation of

cholinergic M2 receptors reduces adenylyl cyclase activity, thereby counteracting agonist–induced airway smooth muscle relaxation.

beta-2- Accordingly, beta-adrenergic blockade may result in unopposed acetylcholine-mediated bronchoconstriction Considerable heterogeneity of cholinergic M2 receptors in patients with COPD may explain the variability in the airway response to beta-adrenergic blockade.

MECHANISMS OF INDUCED BRONCHOCONSTRICTION

BETA-BLOCKADE- Alternatively, the bronchoconstrictor effect of beta-blockers may not be directly related to beta-adrenoreceptor blockade.

 Alpha-1-adrenergic–blocking agents produce mild bronchodilation in patients with

obstructive airway disease.

 Thus, partial or complete beta-2-adrenoreceptor blockade with unopposed activation of alpha-receptors may be responsible for bronchoconstriction induced by non-selective beta- blockade.

COPD & heart diseases – Overview

 Many patients with COPD have concomitant conditions, mostly coronary artery disease

(CAD) – smoking (!), coexists in up to 27% of COPD patients.

Karoli NA, Rebrov AP Chronic obstructive lung disease and coronary heart disease Klin Med (Mosk) 2005;83:72–6.

Lung function in CHF & COPD

 The most common comorbid conditions associated with withholding BBs in elderly patients after myocardial infarction (MI) are COPD and asthma

Heller et al., Am Heart J 2000 Oct;140(4):663-71

 Many patients are diagnosed and treated for COPD with no objective evidence, such as pulmonary function tests or specialist assessment, to confirm the diagnosis => a significant number of patient are deprived the prognostic benefits of using BBs (???)

 COPD patients are at greater risk of ischaemic heart disease than asthmatics, so would benefit from the use of BBs

 On the other hand, they also have more severe airway obstruction, so may be more sensitive to small changes in FEV 1 due to beta-blockade.

Under-use of beta-blockers in patients with ischaemic heart disease and concomitant COPD

M EGRED, S SHAW, B MOHAMMAD, P WAITT and E RODRIGUES

From the Cardiothoracic Centre and Aintree Cardiac Centre, University Hospital Aintree, Liverpool, UK

Q J Med 2005; 98:493–497

Under-use of beta-blockers in patients with ischaemic heart disease and concomitant

Under-use of beta-blockers in patients with ischaemic heart disease and concomitant

COPD

 Results:

- Of 457 ACS patients studied, 246 (54%) were discharged on a BB.

- Cardiologists prescribed BB in ACS patients more frequently than did general physicians (70% vs 30%, respectively)

- The reasons for withholding BB were: not documented 27%, COPD 33%, heart failure 24%, others 16%

- 94 patients (21%) had a diagnosis of COPD; only 58 (62%) of these had been reviewed by a chest physician

or had previous pulmonary function tests Of the 94 patients with COPD, only 15 (16%) were prescribed BB during the admission: 9 by cardiologists and 6 by non-cardiologists BB were discontinued in two patients due

to an increase in dyspnoea.

Under-use of beta-blockers in patients with ischaemic heart disease and concomitant

COPD

 Conclusion: Many patients with a diagnosis of COPD have no objective evidence to support the diagnosis and are denied the prognostic benefits of BB when presenting with ACS

Before withholding beta-blockers, COPD and reversibility should be ascertained by

pulmonary function testing The overall use of beta-blockers remains sub-optimal and could

be improved in this setting.

American Medical Association Quality Care Alert: beta-blocker prophylaxis after acute myocardial infarction Chicago, IL:

American Medical Association, 1998.

 Both recommendations caution that the decision to begin beta-blocker therapy should be considered on a “case-by-case basis” in these patients.

 However, there are no data available to assist the physician in differentiating in which types

of patients with COPD or asthma beta-blockers should be considered, because these patients were largely excluded from the major randomized clinical trials

 For example, MIAMI trial excluded patients with “severe COPD, e.g requiring steroids or beta-agonists”; BHAT excluded patients with “asthma and COPD requiring therapy”; The Göteborg metoprolol trial and the Norwegian Timolol Study excluded patients with asthma and COPD.

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or asthma

Chen et al.,J Am Coll Cardiol 2001 Jun 1;37(7):1950-6

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

beneficiaries with AMI.

Chen et al.,J Am Coll Cardiol 2001 Jun 1;37(7):1950-6

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Study sample:

 Patients ≥65 years of age with a clinically confirmed AMI , defined as chart documentation of either a

creatine kinase (CK)-MB fraction >5%, lactate dehydrogenase (LDH) level more than 1.5 times normal and LDH1 > LDH2, or at least two of the following three criteria: chest pain, a twofold elevation of the CK level

or a new AMI on the official electrocardiogram report

 COPD or asthma based on the medical record, use of medications and prior admissions

 We defined a study sample of patients without chart-documented contraindications to beta-blockers other than COPD or asthma , based on the ACC/AHA clinical guidelines for the treatment of AMI.

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Methods: examined the relationship between discharge use of beta-blockers and one-year mortality in:

- patients with COPD or asthma who were not using beta-agonists,

- patients with COPD or asthma who were concurrently using beta-agonists

- patients with evidence of severe disease (use of prednisone or previous hospitalization for COPD or asthma)

compared with patients without COPD or asthma.

Chen et al.,J Am Coll Cardiol 2001 Jun 1;37(7):1950-6

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results: Of the 54,962 patients in the study sample:

- 12.1% had COPD or asthma but were not prescribed beta-agonist therapy.

- 5.2% had COPD or asthma and were prescribed beta-agonist therapy but were not prescribed oral steroids, or were hospitalized for COPD or asthma in the previous year.

- 2.7% had COPD or asthma and were on oral steroids or were hospitalized for COPD or asthma within the previous year.

- 80% patients did not have chart-documented disease or use of medications for COPD or asthma, or were not hospitalized for COPD or asthma in the year before the AMI admission.

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results - prescriptions:

46.4% were prescribed beta-blockers at discharge, over 91% were prescribed beta1-selective agents The rate of beta-blocker use declined as COPD or asthma severity increased (p < 0.001)

- 50.3% of patients without COPD or asthma

- 37.4% of patients with COPD or asthma not prescribed beta-agonists

- 25.2% of patients with COPD or asthma prescribed beta-agonists

- 12.5% of patients with severe COPD or asthma

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results: After adjusting for demographic and clinical factors, patients with COPD or asthma

continued to be less likely to be prescribed beta-blocker therapy compared with patients without pulmonary disease:

- for patients with COPD or asthma not prescribed beta-agonists (OR: 0,65, 95 % CI: 0,62-0,69)

- for patients with COPD or asthma prescribed beta-agonists but not prescribed oral steroids or admitted in the prior year (OR: 0,38, 95 % CI: 0,34-0,41)

- for patients with severe COPD or asthma (OR: 0.17; 95% CI: 0,14-0,20)

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results: Of the 45,322 patients not on beta-blocker therapy before admission, 39.9% were prescribed therapy at discharge Again, there were significant differences in the prescription of beta-blocker therapy at discharge by COPD or asthma status

- 31.1% of patients with COPD or asthma not prescribed beta-agonists

- 21.1% of patients with COPD or asthma prescribed beta-agonists

- 9.3% of the patients with severe COPD or asthma

(p < 0.001 compared with 43.8% of patients without COPD or asthma)

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

Chen et al.,J Am Coll Cardiol 2001 Jun 1;37(7):1950-6

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results – one year mortality:

- There were marked differences in one-year mortality (p < 0.001) among the four patient categories

- Beta-blockers were significantly associated with decreased one-year mortality among patients without COPD or asthma (p < 0.001), patients with COPD or asthma not prescribed beta-agonists (p

< 0.001), and among patients with COPD or asthma prescribed beta-agonists (p = 0.02)

- We did not find significant differences in one-year mortality associated with beta-blockers among patients with severe COPD or asthma (p = 0.72).

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results – one year mortality:

- In the adjusted analyses, the prescribed use of beta-blockers was associated with a reduced risk of mortality

in patients with COPD or asthma not prescribed beta-agonists (RR = 0.86, 95% CI 0.73 to 1.00, P = 0.048) that was similar to that of patients without COPD or asthma (RR = 0.86, 95% CI 0.81 to 0.92)

- Although not statistically significant in patients with COPD or asthma who were prescribed beta-agonists, the estimate for beta-blocker effectiveness was similar to that of patients in whom therapy was effective (RR = 0.88, 95% CI 0.69 to 1.14)

- We did not find a significant relationship between beta-blockers and mortality for patients with severe COPD or asthma (RR = 1.07, 95% CI 0.75 to 1.52).

Effectiveness of beta-blocker therapy after AMI in elderly patients with COPD or

asthma

 Results – re-admission:

- Beta-blocker therapy was not significantly associated with different rates of six-month re-admission for COPD or asthma in unadjusted comparisons for patients without COPD or asthma (0.2% for patients

prescribed beta-blockers vs 0.2% for patients not prescribed beta-blockers, P = 0.85), for patients with COPD

or asthma not prescribed beta-agonists (1.5% vs 1.9%, P = 0.21), and for patients with COPD or asthma prescribed beta-agonists (3.9% vs 5.1%, P = 0.53)

- Patients with severe COPD or asthma who received beta-blockers had lower re-admission rates (10.0% vs 18.5%, p < 0.01), although this is most likely due to selection effects in the unadjusted model.