Effect of disclosing a polygenic risk score for coronary heart disease on adverse cardiovascular events: 10-year follow-up of the MI-GENES randomized clinical trial.

Background: The MI-GENES clinical trial (NCT01936675), in which participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (FRS _g , n=103), or an integrated risk score (IRS _g , n=104) that additionally included a polygenic risk score (PRS), demonstrated that after 6 months, participants randomized to IRS _g had higher statin initiation and lower low-density lipoprotein cholesterol (LDL-C).
Objectives: In a post hoc 10-year follow-up analysis of the MI-GENES trial, we investigated whether disclosure of a PRS for CHD was associated with a reduction in adverse cardiovascular events.
Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain adverse cardiovascular events, testing for CHD, and changes in risk factors, by blinded review of electronic health records. The primary outcome was the time from randomization to the occurrence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Statistical analyses were conducted using Cox proportional hazards regression and linear mixed-effects models.
Results: We followed all 203 participants who completed the MI-GENES trial, 100 in FRS _g and 103 in IRS _g (mean age at the end of follow-up: 68.2±5.2, 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in FRS _g and 2 in IRS _g (hazard ratio (HR), 0.20; 95% confidence interval (CI), 0.04 to 0.94; P =0.042). In FRS _g , 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRS _g (HR, 0.51; 95% CI, 0.32 to 0.81; P =0.004). IRS _g participants had a longer duration of statin therapy during the first four years post-randomization and a greater reduction in LDL-C for up to 3 years post-randomization. No significant differences between the two groups were observed for hemoglobin A1C, systolic and diastolic blood pressures, weight, and smoking cessation rate during follow-up.
Conclusions: The disclosure of an IRS that included a PRS to individuals at intermediate risk for CHD was associated with a lower incidence of MACE after a decade of follow-up, likely due to a higher rate of initiation and longer duration of statin therapy, leading to lower LDL-C levels.
Competing Interests: Disclosure of Interest The authors declare no conflict of interest.