This piece of literature is incredibly important – not because of the specific clinical question it addresses, but, rather, because of the fundamental principle in medicine it illustrates.
In large, heterogenous populations – frequently clinical trials – the risks and benefits are not evenly distributed throughout the cohort. However, when the primary outcome reported, this is based on the aggregate results. This leads us to one of the primary flaws in evidence-based medicine, that statistical power typically comes at the expense of external validity to the individual patient.
This retrospective evaluation of the cohort from RE-LY, the trial comparing dabigatran to warfarin for the prevention of stroke in atrial fibrillation, evaluates genetic polymorphisms and their association with primary and safety outcomes. In short, each minor allele of CES1 SNP rs2244613 was associated with lower trough concentrations and statistically significant interaction between treatment with warfarin and bleeding – hazard ratio 0.59 (0.46 – 0.76) for carriers and hazard ratio 0.96 (0.81 – 1.14) for noncarriers. No difference in the primary stroke prevention outcome was apparent – but outcomes were infrequent and the study was underpowered to detect such a difference.
My take on these results is simple – the 32.1% of patients who are carriers for the rs2244613 allele account for most of the bleeding benefit seen in RE-LY, and the non-carriers have no bleeding advantage compared with warfarin. We ought to be specifically tailoring and reducing the dabigatran treatment population to this subgroup with the most favorable risk profile – and we need to be developing tools that support this kind of individualized treatment throughout medicine.
“Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding”
www.ncbi.nlm.nih.gov/pubmed/23467860