In COPD exacerbations, 5 days steroids seem as good as 14 (REDUCE trial)

For COPD Exacerbations, 5 Days Corticosteroids As Good as 2+ Weeks

COPD exacerbations -- worsening of shortness of breath and cough, often requiring medical treatment -- are a major problem for many people living with COPD. People with moderate or severe emphysema and chronic bronchitis (together called chronic obstructive pulmonary disease) experience an average of 1-2 COPD exacerbations a year, often feeling poorly for weeks and sometimes requiring hospitalization. People with frequent exacerbations tend to have a faster decline in lung function; proper treatment, it's hoped, could help slow this deterioration, and improve hundreds of thousands of people's daily lives. But "proper treatment" for COPD exacerbations has never been definitively established. It's known that the anti-inflammatory effects of systemic corticosteroids (prednisone, prednisolone, methylprednisolone) help people recover from COPD flares -- but at a cost of increased blood sugar and other side effects. Expert guidelines recommend 10-14 days systemic corticosteroids for treatment of COPD exacerbations. But this is based largely on one clinical trial done at the VA more than a decade ago, which did not examine shorter treatment courses. An underpowered Cochrane analysis  of a few randomized trials (n=288) could not establish equivalence between shorter (<7 days) and longer courses of steroids for COPD exacerbations, but a large observational database analysis in JAMA suggested patients treated with lower-dose oral steroids did just as well as those treated with higher-dose intravenous steroids. In the absence of strong data, you get wide variations in practice patterns -- from doctors prescribing 40 mg of oral prednisone on hospitalized COPD patients, to my (widely respected) former internal medicine attending's strategy of giving 125 mg of Solu-Medrol every 6 hours to people with COPD exacerbations until they improve. For those keeping score, that's a 15.5-fold difference in corticosteroid dosing for the same disease state. Steroids help resolve COPD exacerbations, and probably save lives. But steroids cause hyperglycemia, which can certainly be harmful, and regular (long-term) use of corticosteroids is linked to higher mortality in people with COPD. When it comes to corticosteroids for COPD exacerbations, how much is too much of a good thing? Swiss researchers Jörg D. Leuppi et al add their piece to the puzzle in the May 2013 JAMA.

What They Did

Investigators randomized 314 people mostly with severe COPD (mean FEV1 31%) having severe COPD exacerbations (all presenting to the emergency department, with 92% then hospitalized) to receive either 5 days of 40 mg prednisone followed by 9 days of placebo, or 14 days of 40 mg prednisone. All patients got one initial intravenous dose of 40 mg methylprednisolone (Solu-Medrol) to get things started, but no IV steroids after that. All patients also were given a broad-spectrum antibiotic for 7 days, nebulized bronchodilators as needed, and "triple therapy" with an ICS/LABA twice daily along with tiotropium/Spiriva once daily. The primary end point was time to the next COPD exacerbation (defined as any respiratory deterioration requiring a direct health care interaction), during a median of 6 months of follow-up. This was a noninferiority trial with a 15% absolute difference defined as the noninferiority threshold, which by their a priori calculations corresponded to a hazard ratio of 1.5 or less for the experimental (short-course prednisone) group experiencing a repeat COPD exacerbation.

What They Found

Longer courses of prednisone did not reduce the rate of repeat COPD exacerbations: 57 patients taking 14 days of prednisone had a repeat COPD exacerbation (37%), compared to 56 taking 5 days of prednisone (36%). Nor did extra prednisone prolong the time to the next COPD exacerbation, as shown in the groups' Kaplan-Meier plots: the short-course treatment group's median time to next COPD exacerbation was 45 days, vs. the long-course group's 29 days (non-significant). The findings met criteria for noninferiority. In numerous secondary end points -- lung function (FEV1), mortality, need for mechanical ventilation, dyspnea and quality of scores, there were no differences between groups. However, people given shorter courses of steroids left the hospital one day sooner (median 8 vs. 9 day hospital stay, p=0.04), and they took only about 1/3 the total steroid dose as the long-course treatment group (200 mg vs. 560 mg). Interestingly, patients given longer courses of steroids did not have significantly more hyperglycemia (both had a lot: 57% each). No difference was detected in potential adverse events attributable to glucocorticoids, like bleeding,  infections, psychatric disturbances or heart failure.

What It Means

This is the first study asserting noninferiority of shorter courses of systemic glucocorticoid for people with severe COPD experiencing severe COPD exacerbations. The most likely truth is that for most patients with COPD exacerbations, taking longer courses of prednisone probably doesn't help, and we should stop overtreating them. Since many patients experience multiple COPD exacerbations annually, reducing the per-COPD exacerbation steroid exposure could potentially prevent serious complications such as worsening of obesity, diabetes, and heart disease. Noninferiority trials have serious inherent limitations, the main one being that (unlike in a superiority trial), given a finding of noninferiority, it is impossible to distinguish between true equivalence and poor execution or faulty pretrial a priori assumptions regarding expectations of benefit and event rates. In this particular trial, a 15% absolute difference in the primary outcome was arguably too large to use as a noninferiority threshold. That threshold implies acceptance of 1 additional COPD exacerbation for each 7 patients treated. If a superiority trial showed a week's extra steroids prevented 1 COPD exacerbation for 10 or even 20 patients treated (i.e, a 5-10% noninferiority margin), I think many doctors and patients would endorse longer-course prednisone. This trial (as designed) would fail to detect that. Having said that, given their study size and findings of virtually the same absolute rate of COPD re-exacerbation in both groups, and greater delays in re-exacerbation in the short-course group, it would seem exceptionally unlikely that short-course treatment really is inferior. (Someone feel free to do the math on this one if you have SAS and a couple hours.) Back in the workaday world, all physicians with experience treating COPD exacerbations have anecdotes of patients who called or came back in with respiratory deterioration after being placed on a short course of prednisone. After a few of these experiences, the perceived increased efficacy and low downside to treating severe COPD patients with longer prednisone courses, along with the patient's discomfort and the aura of failure, create incentives to treat longer. Will this study change that? Share your thoughts in the poll below.

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Jörg D. Leuppi et al. Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: The REDUCE Randomized Clinical Trial. JAMA 2013;309(21):2223-2231. http://jama.jamanetwork.com/article.aspx?articleid=1688036