Coagulation Factors in Ischemic Heart Disease: Answers From a Mendelian Randomization Study Inspire Further Questions

See Article by Zhao and Schooling In recent years, Mendelian randomization (MR) became the causal inference tool de rigueur in observational epidemiology. Originally proposed more than 3 decades ago,1 MR has risen in popularity because the evidence of spurious associations in observational studies emerged as a critical challenge to the validity of most epidemiological findings. Canonically, this problem has been illustrated by examples such as the Women’s Health Initiative, in which observational associations failed to reproduce in a randomized trial because of residual confounding and other forms of bias.2 MR promises to estimate unconfounded associations without requiring an actual randomized experiment, thus obviating many ethical and logistical hurdles—but relying on its own set of assumptions. In this issue of Circulation: Genomic and Precision Medicine , Zhao and Schooling3 used MR to explore potential causal associations between several coagulation factors and the risk of ischemic heart disease (IHD) using data from the CARDIoGRAM consortium (Coronary Artery Disease Genome Wide Replication and Meta-Analysis). Understanding the biology of thrombotic risk in patients with IHD has significant implications for clinical practice. Recently, the large-scale COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) (NCT01776424) demonstrated that an enhanced antithrombotic regimen that included addition of the factor Xa inhibitor rivaroxaban in patients with stable atherosclerotic vascular disease (90% of whom had a history of IHD) reduced the composite of cardiovascular death, stroke, or myocardial infarction by 24% relative to aspirin alone.4 However, the regimen also increased the …