Reply to Polverino and Celli

From the Authors:

We thank Drs. Polverino and Celli for their response to our publication on losartan for treatment of emphysema (1). The study was negative, and this was largely due to the lower than expected progression of emphysema in the study population. Accordingly, we appreciate their suggestion that a biomarker for endothelial dysfunction such as microalbuminuria might select a population likely to respond. Unfortunately, the current state of science does not definitively identify one biomarker among many promising ones to predict whether an individual may be benefitted or harmed by a particular drug. The progression of emphysema, including patients with α-1 antiprotease deficiency, is the result of a complex network of processes, making it unlikely that a single biomarker can explain much of the variance in the progression of emphysema (1, 2). In a comprehensive review of biomarkers, clinical features explained 53% of the variance of emphysema progression in chronic obstructive pulmonary disease (COPD), whereas an optimized combination of serum biomarkers explained only 4.3% of the variance in emphysema progression (2, 3). The authors concluded: “Therefore, the field must acknowledge that statistically significant associations between biomarkers and outcomes that can be observed in large cohorts may be largely inadequate to explain remaining variance after strong clinical covariates are included in the models.” (3).

We faced other practical barriers to targeting a COPD population with microalbuminuria or underlying cardiovascular disease. Many such patients are already prescribed an angiotensin receptor blocker or an angiotensin converting enzyme inhibitor, or have a strong indication for such treatment. Therefore, we excluded such individuals on ethical grounds.

We join Drs. Polverino and Celli in looking forward to a time when a single laboratory test will predict which patients with COPD will show disease progression and which patients will respond to a targeted treatment. This is currently the case with some types of cancer. In the absence of this knowledge, we propose that the best approach is to enroll a relatively broad population into large COPD clinical trials, and to conduct post hoc analyses of biomarkers to test for those with disease progression and those who appear to be helped or harmed by the experimental treatment. Subsequent clinical trials enrolling specific subgroups can then be performed to test promising hypotheses. Indeed, we are in the process of testing a panel of biomarkers on specimens collected in LEEP, and, thanks to the helpful suggestion of the correspondents, we will add microalbuminuria to the list.