In COPD, Controlling Acute Exacerbations Remains Key to Survival

June 20, 2012

COPD exacerbations severe enough to require hospitalization are a red flag for mortality. Preventing or delaying the second after a patient is discharged, and each successive exacerbation, is crucial to extending lifespan.

The findings are enough to make anyone gasp. In a recent large study of patients hospitalized for the first time with chronic obstructive pulmonary disease (COPD), half were dead by 3.6 years, 75% were dead within 7.7 years, and 96% were dead by 17 years.1 In total, more than 50,000 of these 73,000 patients died over 17 years of follow-up.
The biggest contributor to these deaths? Exacerbations of COPD. Despite being part of the natural history of the condition, they extract a considerable toll. Consider these observations from the Canadian investigators:1

•  The mean rate of exacerbations severe enough to require hospitalization was 37.8 per 100 per year.
•  With each successive episode, the average interval between severe exacerbations shortened. The 5-year span between first and second COPD flare-ups shrank to less than 4 months between the ninth and tenth exacerbations.
•  After experiencing a second severe exacerbation of COPD, a patient’s risk of sustaining another increased threefold. By the ninth or tenth episode, the patient’s risk had escalated 24 times over that at baseline. To put it differently: The baseline rate for severe exacerbation was 3 per 10,000 per day for the first episode, increasing to 50 per 10,000 per day for the ninth episode.
•  Patients were at greatest risk for repeat exacerbation during the trimester following hospital discharge.
•  The death rate during the first week of hospitalization was by far the highest shortly after hospital admission, and reduced sharply if the patient could survive three months after discharge. Persons who experienced a severe exacerbation of COPD died at the rate of 40 per 10,000 per day during the first week of hospitalization. After 3 months, this declined to 5 deaths per 10,000 per day.
The bottom line:  Preventing or mitigating exacerbations of COPD is essential to prolonging life for someone who has COPD.  “Early identification and treatment of exacerbations is essential for optimal outcomes when managing patients who have COPD,” says M. Brad Drummond, MD, assistant professor of pulmonary and critical care medicine at Johns Hopkins University School of Medicine, who was not involved in the study.  “Close follow-up within 10 to 14 days of a flare, to confirm resolution, is beneficial.”

“Given the known morbidity and mortality associated with COPD,” Dr. Drummond advises, “primary care providers should quickly refer patients who have exacerbations to a pulmonary specialist, to ensure that medical therapy is being maximized.”

Several pharmacologic and nonpharmacologic strategies can be integrated into the patient’s care plan.

Pharmacologic intervention: The cornerstones of care for reducing exacerbations in patients with COPD are long-acting -agonists (salmeterol and formoterol, which are inhaled every 12 hours) and long-acting anticholinergics (tiotropium, inhaled once every 24 hours). Short-acting bronchodilators (albuterol, levalbuterol, pirbuterol, ipratropium) and combination medications (albuterol and ipratropium) are useful for short-term “rescue” use when patients feel out of breath or otherwise need additional help, such as during exercise. Inhaled corticosteroids may be helpful for some patients-primarily those whose symptoms are not controlled by maintenance therapy with one or more long-acting bronchodilators-but there is some concern that they increase the risk for pneumonia.2,3
Some new medications are expanding the COPD treatment tool kit. In March of 2011, the Food and Drug Administration approved the oral drug roflumilast for patients with severe COPD (forced expiratory volume in 1 second < 50% predicted), to manage symptoms of cough and excess mucus production and to reduce the frequency of exacerbations. Roflumilast is not indicated for treating COPD that is linked with emphysema.4 A member of a new class of medications for managing COPD exacerbations, roflumilast works by inhibiting phosphodiesterase type 4 (PDE-4), which regulates inflammatory activity preventing breakdown of cyclic AMP.3

Early experience suggests that this medication offers significant and sustained improvement in lung function, and reduces the incidence of COPD exacerbations.3 Roflumilast can be prescribed in conjunction with bronchodilator treatment. Possible side effects include mental health problems; changes in mood, thinking or behavior; headache; diarrhea; and unexplained weight loss.3,4
Another medication being studied in persons with COPD is azithromycin. Albert and colleagues5 showed that once-daily azithromycin delayed the time to a second COPD exacerbation by 266 days compared with 174 days in persons receiving placebo. Patients taking azithromycin also experienced fewer exacerbations (1.48 versus 1.83 per patient year) and had better respiratory function compared with those not taking azithromycin. On the down side, they reported more hearing loss than patients receiving placebo. Azithromycin has not been incorporated into therapeutic guidelines yet, but is a reasonable consideration for certain patients with COPD. 

Nonpharmacologic interventions: Medications can be supplemented with a several nonpharmacologic interventions to mitigate the risk of COPD exacerbations.2,3 These include:
•  Patient education, to make sure patients know how to use their medications correctly and understand the importance of remaining in full compliance with their prescribed regimen.
•  Regular pneumococcal and influenza vaccinations, to decrease the risk of superimposed viral and bacterial infection.   
•  Oxygen therapy for patients with hypoxemia.
•  Pulmonary rehabilitation, to improve quality of life and reduce the need for hospitalization.
•  Smoking cessation.



REFERENCES1. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. doi: 10.1136/thorax.jnl-2011-201518, Published online first. June 8, 2012.

2. Drummond MB. Strategies for preventing acute exacerbations of COPD. J Respir Dis. 2009:30. Available online at: Accessed June 16, 2012.

3. Price D, Chisholm A, Ryan D, et al. The use of roflumilast in COPD: a primary care perspective. Prim Care Resp J. 2010;19:342-351.

4. FDA News Release. FDA approves new drug to treat chronic obstructive pulmonary disease. March 1, 2011. Available online at: Announcements/ucm244989. Accessed June 17, 2012.

5. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.