Letter by Hartwig et al Regarding Article, “Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression”
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To the Editor:
It was with interest that we read the publication by Labos et al1 on applying an adaptation of Egger regression to evaluate pleiotropic effects of drugs. They interpret their reanalysis of randomized controlled trials (RCTs) as indicating that the effect of statins on cardiovascular disease (CVD) and diabetes mellitus are mediated primarily, if not entirely, because of reducing low-density lipoprotein cholesterol (LDL-C) levels. We think that this approach has potential, but here, we point out 2 main conceptual limitations of it, which we think question the authors’ conclusion.
Labos et al essentially did a meta-regression of the randomization status (RS)-outcome association (ie, intention-to-treat analyses) on RS-LDL-C association. By RS, we mean whether participants were assigned to statin or control groups, irrespective of compliance with these assignments. Given that perfect compliance is unlikely in real RCTs, RS and statin intake should not be treated as interchangeable. For example, an intention-to-treat analysis would be expected to be robust against confounding by prerandomization factors, but the same is not true for the association between actual statin intake and the outcome.
Suppose that LDL-C has no causal effect on CVD but that statins nevertheless have a causal effect on CVD (that is not mediated by LDL-C) as depicted in the graphical abstract of Labos et al. In this situation, statin intake confounds the association between LDL-C levels and CVD, and therefore, both the association of RS with LDL-C and the association …