Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

This is a multicenter, prospective, randomized, double-blind, placebo-controlled trial that will enroll 1028 patients with at least moderately severe COPD over a three year period and follow them at regular intervals for one year. The primary endpoint is time to first acute exacerbation. Secondary endpoints include rates and severity of COPD exacerbations, cardiovascular events, all-cause mortality, lung function, dyspnea, quality of life and metoprolol-related side effects.

Hypothesis The primary hypothesis is that metoprolol succinate will reduce the risk of COPD exacerbations as compared to placebo. The secondary hypothesis is that metoprolol succinate will not adversely impact lung function, exercise tolerance, dyspnea or quality of life as compared to placebo.

Study Flow Patients will be screened and then randomized over a 2 week period and will then undergo a dose titration period for the following six weeks. Thereafter patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4 week washout period.

Specific Aims:

Primary: To determine the effect of once daily metoprolol succinate compared with placebo on the time to first exacerbation in moderate to severe COPD patients who are prone to exacerbations and who do not have absolute indications for beta-blocker therapy.

Secondary: To estimate the effect of metoprolol succinate compared with placebo on:

1. The rate and severity of COPD exacerbations over 12 months
2. Incidence and severity of metoprolol-related side effects including those that require cessation of drug
3. Lung function as assessed by spirometry, dyspnea as assessed by the Modified Medical Research Council Scale (MMRC) and San Diego Shortness of Breath Questionnaire, exercise tolerance as measured by six minute walk test (6MWD), and quality of life as assessed by the Short Form 36, St. Georges Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) and Personal HEART Score.
4. Hospitalizations
5. The rate of major adverse cardiovascular events (MACE) (defined by cardiovascular death, hospitalization for myocardial infarction, heart failure, or stroke), percutaneous coronary intervention or coronary artery bypass grafting
6. All-cause mortality

Secondary subgroup analyses for 1) cardiovascular risk based on Personal HEART Score and 2) age greater versus less than 65.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female subjects, ≥ 40 and less than 85 years of age
2. Clinical diagnosis of at least moderate COPD as defined by the Global Initiative for Obstructive Lung Disease (GOLD) criteria (53):

   * Post bronchodilator FEV1/FVC \< 70% (Forced expiratory volume in 1 second/ forced vital capacity),
   * Post bronchodilator FEV1 \< 80% predicted, with or without chronic symptoms (i.e., cough, sputum production).
3. Cigarette consumption of 10 pack-years or more. Patients may or may not be active smokers.
4. To enrich the population for patients who are more likely to have acute exacerbations (54), each subject must meet one or more of the following 4 conditions:

   * Have a history of receiving a course of systemic corticosteroids and/or antibiotics for respiratory problems in the past year,
   * Visiting an Emergency Department for a COPD exacerbation within the past year, or
   * Being hospitalized for a COPD exacerbation within the past year
   * Be using or be prescribed supplemental oxygen for 12 or more hours per day
   * Willingness to make return visits and availability by telephone for duration of study.

Exclusion Criteria:

1. A diagnosis of asthma established by each study investigator on the basis of the recent American Thoracic Society/European Respiratory Society and National Institute for Health and Care Excellence guidelines.
2. The presence of a diagnosis other than COPD that results in the patient being either medically unstable, or having a predicted life expectancy \< 2 years.
3. Women who are at risk of becoming pregnant during the study (pre-menopausal) and who refuse to use acceptable birth control (hormone-based oral or barrier contraceptive) for the duration of the study.
4. Current tachy or brady arrhythmias requiring treatment
5. Presence of a pacemaker and/or internal cardioverter/defibrillator
6. Patients with a history of second or third degree (complete) heart block, or sick sinus syndrome
7. Baseline EKG revealing left bundle branch block, bifascicular block, ventricular tachyarrhythmia, atrial fibrillation, atrial flutter, supraventricular tachycardia (other than sinus tachycardia and multifocal atrial tachycardia), or heart block (2nd degree or complete)
8. Resting heart rate less than 65 beats per minute, or sustained resting tachycardia defined as heart rate greater than 120 beats per minute.
9. Resting systolic blood pressure of less than 100mm Hg.
10. Subjects with absolute (Class 1) indications for beta-blocker treatment as defined by the combined American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons Guidelines which include myocardial infarction, acute coronary syndrome, percutaneous coronary intervention or coronary artery bypass surgery within the prior 3 years and patients with known congestive heart failure defined as left ventricular ejection fraction \<40%.(29, 30)
11. Critical ischemia related to peripheral arterial disease.
12. Other diseases that are known to be triggered by beta-blockers or beta-blocker withdrawal including myasthenia gravis, periodic hypokalemic paralysis, pheochromocytoma, and thyrotoxicosis
13. Patients on other cardiac medications known to cause atrioventricular (AV) node conduction delays such as amiodarone, digoxin, and calcium channel blockers including verapamil and diltiazem as well as patients taking clonidine.
14. Hospitalization for uncontrolled diabetes mellitus or hypoglycemia within the last 12 months.
15. Patients with cirrhosis
16. A clinical diagnosis of bronchiectasis defined as production of \> one-half cup of purulent sputum/day.
17. Patients otherwise meeting the inclusion criteria will not be enrolled until they are a minimum of four weeks from their most recent acute exacerbation (i.e., they will not have received a course of systemic corticosteroids, an increased dose of chronically administered systemic corticosteroids, and/or antibiotics for an acute exacerbation for a minimum of four weeks).