Definition COPD def- A disease state characterized by air flow limitation that is not fully reversible It is expected to be the 3 rd leading cause of death by 2020 Approximately 14 million Indians are currently suffering form COPD The Indian J Chest Dis & Allied Sciences 2001; 43:139-47

The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.

RISK FACTORS Smoke from home cooking and heating fuel Occupational dust and chemicals Gender: More common in men. M:F ratio is 5%:2.7% (in India) Increasing age Others: Infection, nutrition and deficiency of  1 antitrypsin

PATHOPHYSIOLOGY Increased mucus production and reduced mucociliary clearance - cough and sputum production Loss of elastic recoil - airway collapse Increase smooth muscle tone Pulmonary hyperinflation Gas exchange abnormalities - hypoxemia and/or hypercapnia

PATHOGENESIS

Classification

TREATMENT Stable COPD Acute COPD

STABLE COPD Smoking cessation Oxygen therapy Bronchodilators- anticholinergics,beta agonists, inhaled steroids, xanthines

Pharmacotherapy for Stable COPD Bronchodilators Short-acting  2 -agonist – Salbutamol Long-acting  2 -agonist - Salmeterol and Formoterol Anticholinergics – Ipratropium, Tiotropium Methylxanthines - Theophylline Steroids Oral – Prednisolone Inhaled - Fluticasone, Budesonide

ACUTE EXACERBATION Bronchodilators Antibiotics Glucocorticoids Oxygen Ventilatory support

Post-bronchodilator FEV1 (% predicted) Management based on GOLD

JAMA sept 2008;300(12): Sonal Singh, Yoon k, Curt D

Need for this meta analysis COPD – 4 TH leading cause of chronic morbidity and mortality. CV disease is an important cause of morbidity and mortality.

Need for this meta analysis GOLD guidance-small increase in cardiovascular adverse events with anticholinergics US FDA-possible increased risk of stroke(8/1000/yr vs 6/1000/yr) No risk( chest 2006;130(6): )

OBJECTIVE Ascertain cardiovascular risks with long term use of inhaled anticholinergics compared with control therapies in patients with COPD in RCTs.

ELIGIBLITY CRITERIA More than 30 days of follow up Diagnosis of COPD of any severity Inhaled anticholinergics vs placebo or inhaled beta agonists and/or steroids Cardiovascular events reported

STUDY SELECTION 703 reports 17 RCTs- 12 tiotropium,5 ipratropium 5 long term trials(48weeks-5yrs) 12 short term(6weeks-26weeks)

RESULTS Primary outcome-increased risk of MI(1.2%vs0.2%) Significantly increased risk of cardiovascular death(0.9%vs0.5%) No significant increase in risk of stroke(0.5%vs0.4%)

Secondary outcome- no significant increase in all cause mortality

Long term trials- increased risk of cardio vascular events(2.9%vs1.8%) Short term trials-no statistically significant increase in cardiovascular event

NUMBER NEEDED TO HARM For MI-174/yr (baseline event 10.9/1000) For cardiovascular mortality-40/yr(31.9/1000)

MECHANISM COPD- inflammatory cytokines Inhaled tiotropium increases interleukin 8- destabilizes existing atherosclerotic plaques

CONCLUSSION Inhales anticholinergics used for >30 days significantly increases the risk of cardiovascular events by approx.58%- long term trials

Then Why to use it? Number needed to treat for tiotropium to prevent one COPD exacerbation is 21 Versus number needed to harm -40 for cardiovascular deaths and 174 for MI Treatment modalities are limited Baseline cardiovascular risks should be evaluated.