Jun 022013
How to Prevent Acute COPD Exacerbations

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major problem for many people living with COPD. Acute exacerbations or attacks occur more often in people with more severe COPD (about 1-2 per year), and these disease flares may either signal or cause a more rapid progression of COPD over time.

COPD exacerbations are hard to define: the only accepted definition is a significant and persistent worsening of breathing in someone with COPD, requiring a change in medications -- usually including systemic corticosteroids (oral prednisone) and antibiotics to help the person recover. Although most COPD exacerbations don't require hospitalization, they can mean days or weeks of difficulty breathing, cough, and lost enjoyment of life. A person's pre-exacerbation lung function and exercise ability may not return completely, after recovery from the COPD attack.

So people with yearly COPD exacerbations are more likely to have worse disease, and more likely to have their COPD worsen in the future. Preventing COPD exacerbations, therefore, has always been a major goal of people with COPD, and their doctors. Nathaniel Marchetti, Gerard J. Criner, and Richard K. Albert have helpfully provided a Chest review and synthesis of the available evidence to teach us what treatments work best at preventing acute exacerbations of COPD.

Inhaled Steroids Alone to Prevent COPD Exacerbations

Although sometimes prescribed as first-line therapy for COPD, it's unclear whether inhaled corticosteroids prevent COPD exacerbations. If inhaled steroids do prevent COPD exacerbations, they are probably more effective for people with more airflow obstruction (lower FEV1). There is no strong proof that inhaled steroids don't prevent COPD flares -- it's more that the studies that have shown a benefit were flawed and inconsistent. The most optimistic cherry-picking of the data would be of the TORCH trial, in which inhaled steroids alone reduced exacerbations relative to placebo by 19% (number needed to treat: 5). There is fairly good evidence that inhaled corticosteroids do not reduce hospitalizations for COPD exacerbations. Authors used about 6 studies to draw these conclusions.

Long-Acting Beta Agonists Alone Prevent 15-20% of COPD Exacerbations

The best available data suggest that salmeterol alone reduces the rate of COPD exacerbations by 15% (in TORCH) to 20% (in the TRISTAN trial). In TORCH, salmeterol reduced hospitalizations by almost 20%. No good data exists on formoterol (the existing evidence is too flawed to conclude much). These trials enrolled people with moderate to severe COPD, who have the highest rates of exacerbations.

LABA + Inhaled Steroids Prevent 25% of COPD Exacerbations

In both the TRISTAN and TORCH trials, the combination of fluticasone/salmeterol (Advair) reduced the rate of COPD exacerbations by 25%, a number needed to treat of 4 patients for one year to prevent an exacerbation. In TORCH, hospitalizations were reduced by 17% as well, but no reduction in hospitalizations was seen in TRISTAN. Other combination products (Symbicort, Dulera) have not been tested against placebo in large trials, nor against Advair.

Tiotropium (Spiriva) Prevents COPD Exacerbations, Too

The largest study (UPLIFT) suggests tiotropium (Spiriva) prevents 14% of COPD exacerbations (or one exacerbation prevented for every 7 patients treated for a year). Other studies by Vincken, by Casaburi, and by Niewoehner were of widely differing methods, and suggested Spiriva prevented 14-25% of COPD exacerbations.

Tiotropium was compared head-to-head against salmeterol in the POET-COPD trial. Although most patients never had a COPD exacerbation in the trial, slightly fewer patients taking Spiriva had exacerbations than those taking salmeterol (0.64 per year, vs 0.72 per year). How can this be reconciled with salmeterol's 15-20% exacerbation reduction in TRISTAN and TORCH (supposedly superior to Spiriva)? It's a prime example of the pitfalls in comparing treatment effects between drugs across different trials, enrolling different patients and with different defined endpoints.

LABA + ICS vs Tiotropium: A Tie

The INSPIRE trial tested Advair (fluticasone/salmeterol) vs. tiotropium (Spiriva) in people with severe COPD; both drugs prevented COPD exacerbations equally well. Interestingly, more people taking Advair received antibiotics, while more people taking Spiriva received systemic corticosteroids, during the trial.

Triple Therapy with ICS, LABA, Tiotropium May Prevent Hospitalization

Adding Advair to Spiriva significantly reduced hospitalizations by almost 50%, without affecting the overall rate of COPD exacerbations (as compared to tiotropium alone, or tiotropium + salmeterol). The patients getting so-called triple therapy also had improved lung function and subjective dyspnea scores, compared to those taking Spiriva alone or with salmeterol. Many patients discontinued their treatments in this trial, potentially introducing bias.

Roflumilast Can Prevent COPD Exacerbations

Roflumilast (Daliresp), an oral phosphodiesterase inhibitor, reduced moderate or severe COPD exacerbations by 17% over one year in the largest clinical trial enrolling people with moderate or severe COPD. Daliresp did not reduce hospitalizations. Patients with regular heavy cough and mucus production (chronic bronchitis subtype) may benefit more from roflumilast.

Azithromycin Prevents COPD Exacerbations

Azithromycin taken regularly prevents COPD exacerbations by about 25% in people with severe COPD already taking maximum inhaler therapies (impressive compared to the above-described treatments, whose benefits were in relation to placebos). This comes with a still-undefined risk of sudden cardiac death with azithromycin resulting in an FDA warning, leaving doctors uncertain as to how best to use the drug for COPD exacerbation prevention. A NEJM review suggested limiting chronic azithromycin for COPD to thrice-weekly dosing, only in people without cardiac disease who've undergone a recommended workup first.

Preventing COPD Exacerbations Without Drugs

Lung volume reduction surgery is a drastic treatment that's only appropriate for certain people with COPD, but it may reduce COPD exacerbations and hospitalizations by 30%, as well as improve quality of life and breathing.

Pulmonary rehabilitation (supervised exercise) for people with COPD has definite benefits in exercise capacity and quality of life; however, studies are inconsistent as to its effects on preventing COPD exacerbations.

Conclusion and Caveats

Prevention of COPD exacerbations is not the only reason, or even the main reason, to prescribe or use a COPD treatment. This review did not examine the other benefits of COPD medications, like improved breathing or increased exercise capacity.

These numbers should be taken with a full dash of salt and kept in their proper context. COPD treatments have all been compared against placebo, but almost never against each other in clinical trials. Absent such a head-to-head comparison (as in the POET-COPD trial), it's an inappropriate stretch to say "Treatment X's effect was 20% in this trial, Treatment Y's was 26% in that other trial, therefore Y is better."

Nathaniel Marchetti; Gerard J. Criner; Richard K. Albert. Preventing Acute Exacerbations and Hospital Admissions in COPD. Chest. 2013; 143(5):1444-1454.

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How to prevent COPD exacerbations