© 2005 American Thoracic Society
"Stop Right There...I Gotta Know Right Now!" Do Steroids Really Help for CAP?To the Editor:We read with interest about the randomized trial (n = 46) by Dr. Confalonieri and colleagues (1) reporting the benefits of treating severe community-acquired pneumonia (CAP) with hydrocortisone. Several poor prognostic factors were more common in the placebo group, including older age (66.6 versus 60.4 years), presence of preexisting comorbidities (20 versus 13), more positive bacterial cultures (18 versus 12), and more mechanical ventilation (19 versus 15). Two baseline imbalances favored the control group (PaO2:FIO2 ratio and chest radiograph score), but these can be misleading because both typically improve with application of positive end-expiratory pressure (PEEP), and greater numbers of control patients were ventilated. Due to the small patient numbers, none of these factors independently achieved statistical significance, but taken together they suggest that patients in the placebo group may have been sicker. Baseline imbalances such as these are frequently observed in small studies and threaten their validity; these prognostic factors generally become more balanced as study size increases. Sequential clinical trials with small numbers of patients may not be ideal for investigations in the intensive care unit, where marked heterogeneity among patients meeting study inclusion criteria may be observed. This trial was stopped early because of benefit in terms of PaO2:FIO2 ratio, and the assumption that continued enrollment would be unethical for control patients. This conclusion is difficult to reconcile with the authors' recommendation for a "larger, randomized trial ... to support the mortality findings," and raises important issues regarding early stopping rules. Clearly trials should not be allowed to continue if there is evidence of harm, but decisions to stop early for benefit must be made cautiously. The results must be sufficiently convincing to the medical community for the investigational therapy to be accepted (2). This is particularly true when surrogate endpoints are used instead of more meaningful clinical outcomes. Improvements in oxygenation have been associated either with no mortality benefit or with harm in a number of other studies (3–5). Confalonieri and coworkers (1) do report a statistically significant mortality benefit (a secondary outcome), but the occurrence of only a single death in the intervention group would have increased the mortality p value to 0.047, and two deaths to p = 0.13; given the baseline imbalances between groups the changes in mortality are certainly not robust. The results of this trial, in our view, must be considered hypothesis generating, and should not at this time lead to a change in therapy for patients with CAP, especially given the potential harm associated with steroids (6).
University of Toronto, Toronto, Ontario, Canada FOOTNOTES Conflict of Interest Statement: D.C.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.D.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.O.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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