Response by Labos et al to Letter Regarding Article, “Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression”
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Hartwig et al have raised important issues regarding the InSIDE (Instrument Strength Independent of Direct Effect) assumption because, as they correctly point out, violations of InSIDE would not permit a reliable causal estimate using the Egger approach used in our analysis.1
We agree that randomization to statin therapy in a clinical trial does not necessarily equate with taking the medication and that downstream effects along the causal pathway of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition could violate the InSIDE assumptions. These are valid concerns and should be taken into consideration when interpreting our results. However, we have several comments.
First, although compliance in randomized trials is not and never can be 100%, it is generally high. For example, in the HOPE-3 trial (Cholesterol Lowering in Intermediate-Risk Persons …