Effects of Inhaled Therapy on Mortality in COPD

Do inhaled corticosteroids and long-acting β-agonists lower mortality in patients with chronic obstructive pulmonary disease (COPD)? To answer this question, industry-sponsored researchers conducted the TORCH study, which included 6000 COPD patients (FEV₁ <60% of predicted; and reversibility with albuterol <10% of predicted FEV₁). Patients were randomized to receive twice-daily inhaled therapy with salmeterol plus fluticasone (Advair 50/500), salmeterol (Serevent) alone, fluticasone (Flovent) alone, or placebo (Journal Watch Feb 21 2007).

The primary endpoint, 3-year all-cause mortality, was lower with combined therapy than with placebo (12.6% vs. 15.2%), but the difference was of borderline statistical significance (P=0.052). Mortality with salmeterol alone (13.5%) was midway between rates seen with combined therapy and placebo, but mortality with fluticasone alone (16%) was slightly higher than mortality with placebo. Similarly, combined therapy and salmeterol alone — but not fluticasone alone — lowered hospitalization rates for COPD exacerbation. All three active therapies fared better than placebo for preventing COPD exacerbations, with combined therapy performing best. An unexpected outcome was a higher incidence of pneumonia in the steroid groups than in the salmeterol-alone and placebo groups.

Unfortunately, these findings don't yield a simple conclusion. The steroid-plus-β-agonist combination came close to lowering mortality significantly and did lower rates of exacerbation and hospitalization. For monotherapies, the overall balance of benefits and harm was more favorable for salmeterol than for fluticasone; a noteworthy finding in COPD patients, because it’s the opposite of generally accepted dogma in asthma, where monotherapy with long-acting β-agonists is not recommended. Finally, TORCH did not include a long-acting anticholinergic drug (e.g., tiotropium [Spiriva]), which can lower exacerbation rates but has not been evaluated in a long-term mortality study.

According to a new COPD guideline recently published by the American College of Physicians, clinicians should prescribe a maintenance monotherapy — long-acting β-agonist, long-acting anticholinergic, or inhaled corticosteroid — for patients with COPD and FEV₁ <60% of predicted (Journal Watch Dec 6 2007). However, the TORCH findings suggest that steroid monotherapy should be dropped from this recommendation. The guideline authors also state that clinicians “may consider” combination steroid and β-agonist therapy, and they cite the TORCH study to support this recommendation. However, clinicians should think about long-term side effects when they consider prolonged inhaled-steroid therapy for COPD patients.