Management of COPD and CHF: drugs that should be preferred or avoided

Management of COPD and CHF: drugs that should be preferred or avoided Dr John T. Parissis, Heart Failure Unit, Attikon University Hospital, Athens, Greece Disclosures: Research grants by Abbott USA and Orion-Pharma as a member of steering committee of ALARM-HF Survey

EPIDEMIOLOGY-PATHOPHYSIOLOGY Prevalence o COPD in HF is 20-33% (Medicare, Danish Diamond studies) COPD and HF have similar symptoms: exercise intolerance/dyspnea Obstructive pattern: acute HF Restrictive pattern: chronic HF (reduced lung volume due to cardiomegaly and alveolar and interstitial fluid, development of interstitial fibrosis, changes of lung compliance, weakness of the respiratory muscles) COPD causes HF exacerbation: increased pre-load, increased after-load, neurohormonal/inflammatory activation

Co-morbidities in ALARM-HF survey (n=4953) 90% 50% 61% 61% 63% 60% 54% 79% 46% 43% 38% EHS HF II All AHF ADCHF De novo AHF 25% 27% 17% 20% 19% 23% 14% 16% 18% 19% 15% 16% 10% 8% 9% 5% 7% 2% 0% J Parissis on behalf of ALARM-HF investigators Intensive Care Med 2011;37(4):619-26

% of patients Prevalence of COPD and COPD severity in patients with Chronic Heart Failure 100 80 29 % 60 71 % 40 20 CHF + COPD CHF 0 GOLD I GOLD II GOLD III GOLD: Global Obstructive Lung disease Boschetto, et al. ESC 2010

The impact of concurrent heart failure on prognosis in patients with COPD Rutten FH, et al. Eur J Heart Fail 2009;11:1182 1188

Hospitalizations After Heart Failure Diagnosis- A Community Perspective Predictors of Hospitalizations in multi-variate analysis Dunlay S, et al. JACC 2009;54:1695-1702

CHF and COPD: pathophysiologic links

Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease Andreas S, et al. CHEST 2005; 128:3618 3624

RESPIRATORY MUSCLE DYSFUNCTION IN CHF: PROGNOSTIC VALUE (Meyer et al. Circulation 2001)

EFFICACY AND SAFETY OF COPD DRUGS

Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV 1 /FVC < 70% FEV 1 /FVC < 70% FEV 1 > 80% predicted FEV 1 /FVC < 70% 50% < FEV 1 < 80% predicted FEV 1 /FVC < 70% 30% < FEV 1 < 50% predicted FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory failure Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with 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

COPD: Symptom-relieving drugs Beta2-adrenoceptor agonists: Eg Salbutamol, terbutaline, salmeterol, formoterol Airways are rich in B2-adrenoceptors (bronchial smooth muscle) Act via: Bronchodilation (generation of camp) Inhibition of mediator release from mast cells Enhanced mucociliary clearance Selectivity reduces adverse effects

Anti-muscarinics (anticholinergics) Eg. Ipratropium, tiotropium MoA: Based upon 3 types of cholingeric receptors: Parasympathetic ganglia Presynaptic cholinergic neurones (Ach) Postsynaptic mediators for bronchoconstriction Therefore, affect bronchial smooth muscle and mucus secretion Non-selective, anti-inflammatory (negate mediators) Mostly used for COPD No serious adverse effects

Drawbacks of drugs used for the treatment of COPD Fast-acting beta-2 adrenergic bronchodilators can cause tachycardia and increase myocardial oxygen consumption- These agents may increase risk of mortality and hospitalizations. Slow-acting agents (anticholinergics, etc) may be an adequate alternative although there are not prospective mortality data. Oral steroids lead to water retention and increase risk of HF exacerbations- Inhaled steroids may be safer. Theophylline products may increase risk of arrhythmias Rutten FH, et al. Eur J Heart Fail 2006;8:706-711

The Risk of Myocardial Infarction Associated with Inhaled b-adrenoceptor Agonists AM J RESPIR CRIT CARE MED 2000;161:827 830.

Association Between Inhaled b-agonists and the Risk of Unstable Angina and Myocardial infarction Au DH et al, Chest 2002;121:846

Risk of Mortality and HF Exacerbations Associated With Inhaled b - Adrenoceptor Agonists Among Patients With Known LVSD Au DH, et al. CHEST 2003; 123:1964 1969

A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD International Journal of COPD 2009:4

Anti-cholinergics and cardiac outcomes in COPD N Engl J Med. 2008;359:1543 1554.

Adjusted survival rate according to bronchodilator and beta-blocker use. Hawkins N M et al. Eur J Heart Fail 2010;12:557-565

EFFICACY AND SAFETY OF CHF DRUGS

Safety of CHF drug cocktails: ACE inhibitors Cornerstone of treatment in CHF Inhibit pulmonary airway constricting effects of Ang II Decrease pulmonary inflammatory response and pulmonary vascular constriction May prevent SM atrophy and improve respiratory muscle strength No increased risk of cough and bronchospasm Anker SD.Lancet 2003;361:1077-83. Packard A. Ann Pharmacother 2002;36:1058-67

Effects of enalapril on DLCO in CHF Guazzi, M. et al. Circulation 1997;95:1930-1936

ACE Inhibitor Therapy Improves Respiratory Muscle Strength in CHF Patients Individual (open circle) and mean ± SE (closed circle) values of Pimax and Pemax expressed as percentage of predicted values. Coirault C et al. Chest 2001;119:1755-1760

Changes in exercise tolerance measured in placebo and losartan groups by the mean number of shuttles completed in the shuttle walk test.

Spironolactone improves lung diffusion in chronic heart failure Agostoni P, et al. Eur Heart J 2005;26:159 164

Spironolactone-induced beneficial changes in pulmonary function were associated with increase of exercise tolerance in CHF patients Agostoni P, et al. Eur Heart J 2005;26:159 164

The EuroHeart Failure Survey programme - Predictors of under-prescription of beta-blockers Komajda M, et al. Eur Heart J 2003;24:464 474

Primary care burden and treatment of patients with HF and COPD in Scotland Hawkins N, et al. Eur J Heart Fail 2010;12:17

Effects of treatment on FEV1 for continued treatment studies Salpeter S R et al. Ann Intern Med 2002;137:715-725

Effects of treatment after use of β2-agonists on FEV1 for continued treatment studies. It has been suggested that beta- blockers may improve bronchodilator responsiveness by leading to upregulation of beta-receptors within the lung Salpeter S R et al. Ann Intern Med 2002;137:715-725

Kaplan-Meier estimate of probability of survival among patients with COPD by use of β blockers. P<0.001 Βeta-blocker use was associated with a 22% reduction in mortality Short P M et al. BMJ 2011;342:bmj.d2549

Effect of beta-blockers in treatment of COPD: a retrospective cohort study KEY MESSAGE Beta-blockers (predominantly cardioselective) reduced mortality and COPD exacerbations when added to stepwise inhaled therapy for COPD (including long acting beta-agonists and antimuscarinics) in addition to the benefits attributable to addressing cardiovascular risk The benefits observed occurred without adverse effects on pulmonary function These data support the use of beta- blockers in patients with COPD Short P M et al. BMJ 2011;342:bmj.d2549

Bisoprolol in patients with HF and moderate to severe COPD: a randomized controlled trial Initiation of bisoprolol in patients with HF and concomitant moderate or severe COPD resulted in a reduction in FEV1. However, symptoms and quality of life were not impaired Hawkins N. Eur J Heart Fail 2009;11:684 690

Comparative Effects of a Two-Week Treatment with Nebivolol and Nifedipine in Hypertensive Patients Suffering from mild/moderate COPD Nifedipine Nebivolol p=ns Respiration 2004;71:159 164

Tolerability of Carvedilol in patients with HF and concomitant COPD or asthma One among 31 pts with COPD and 4 among 12 pts with asthma did not tolerate carvedilol because of bronchocnstriction In patients who tolerated carvedilol, echocardiography at 12 months demonstrated a statistically improvement in LV dimensions and function accompanied by improvement in NYHA functional class in 68%. J Heart Lung Transplant 2002; 21: 1290-1295.

Differences Between Beta-Blockers in Patients With CHF and COPD: A Randomized Crossover Trial Jabbour A, et al. J Am Coll Cardiol 2010;55:1780 7

Differences Between Beta-Blockers in Patients With CHF and COPD: A Randomized Crossover Trial Jabbour A, et al. J Am Coll Cardiol 2010;55:1780 7

Differences Between Beta-Blockers in Patients With CHF and COPD: A Randomized Crossover Trial Conclusion Switching between 1-selective beta-blockers and the nonselective beta-blocker carvedilol is well tolerated but results in demonstrable changes in airway function, most marked in patients with COPD. Switching from 1-selective beta-blockers to carvedilol causes short-term reduction of central augmented pressure and N-terminal pro-hormone brain natriuretic peptide. Jabbour A, et al. J Am Coll Cardiol 2010;55:1780 7

Take Home messages (I) COPD medications Fast acting beta 2-adrenergic bronchodilators should be avoided (tachycardia, increase of MVO2, risk of adverse cardiac outcomes) Long acting drugs ( mainly anti-cholinergics, alternatively long-acting beta 2-adrenergic agonists) and/or inhaled steroids should be preferred.

Take Home Messages (II) HF medications Neurohormonal antagonists are recommended (ACEi, ARBS, Aldo antagonists)-reduce congestion and interstitial fibrosis; Improve respiratory function, muscle strength and lung diffusion. Selective β1 blockers (especially nebivolol /SENIORS trial, bisoprolol/cibis II trial and metoprolol succinate/ MERIT-HF trial) should be preferred and started if bronchospasm is not present. Carvedilol is tolerated in patients with mild/moderate COPD but may be contra-indicated in severe COPD or reversible obstructive airway disease. In general, beta-blockers should be avoided or given at reduced dose during COPD exacerbations. More prospective trials are needed in order to identify what is the best treatment strategy for patients with HF and concomitant COPD. High doses of loop diuretics should be avoided. High doses of these agents can cause excessive reduction of preload (risk of hypotension) and metabolic alkalosis (risk of hypoventilation and hypercapnia)* Digoxin may be no beneficial (risk of pulmonary vasoconstriction and arrhythmias)* * CHF. 2003;9:142 147