Knowledge of Genetic Risk for CAD Bolsters Prevention, Reduces MACE

Patients who learn their likelihood of developing CAD not only from the Framingham Risk Score but also from a more-personalized polygenic risk score experience fewer major adverse cardiovascular events over the next 10 years, according to an analysis of long-term data from the Myocardial Infarction Genes (MI-GENES) trial.

Mohammadreza Naderian, MD, MPH (Mayo Clinic, Rochester, MN), and colleagues, in a recent Circulation: Genomic and Precision Medicine paper, suggest that greater awareness spurred better outcomes through an uptick in statin therapy.

Polygenic risk scores (PRS) are used to calculate a person’s genetic susceptibility to a particular trait or disease based on single-nucleotide polymorphisms (SNPs). In the MI-GENES trial, which began randomizing participants in late 2013, the score for coronary heart disease (CHD) was based on 28 SNPs, whereas today’s PRS capture variations in thousands or even millions of these alleles.

“There is great interest in using PRS for CHD in the clinical setting but little data is available regarding whether such use reduces adverse cardiovascular events,” in part because a dedicated trial on the topic would need to be extremely large and follow patients for many years, the investigators note.

Here, the researchers instead decided to leverage a preexisting trial to explore the effect of disclosing PRS to patients at intermediate cardiovascular risk.

Michael Blaha, MD (Johns Hopkins University School of Medicine, Baltimore, MD), commenting on the new data for TCTMD, noted that the study was small and originally planned for 6 months, not 10 years. While it’s important to keep those limitations in mind, the results showing a benefit to personalized risk assessment still make sense, he said.

“The Framingham Risk Score or the pooled cohort equations, or even the newer [tools], are just starting points and not very personalized,” said Blaha. These more traditional scores “give someone just a general estimate of their risk, but not necessarily something they find actionable. It’s been a truism for the last 20 or 30 years, [and] this is just another example.”

The driver here isn’t so much the specific information provided by the PRS as it is the individualized perspective, he noted, highlighting the benefits of calcium scoring seen in the recently published CAUGHT-CAD trial.

As for PRS, Blaha predicted the tools will see the most clinical use as a way to gauge risk earlier in life and guide the aggressiveness of preventive efforts, particularly for people who have a family history and want to better understand their genetic makeup. “Later in life, things like your lifestyle risk and your accumulated risk factors, or even an imaging test to see if you have plaque, become bigger deals,” he explained, adding that PRS would thus be just one piece of the puzzle.

Four years ago, in 2021, the American Heart Association released a scientific statement exploring where PRS might fit in the management of cardiovascular disease.

More Statins, Fewer MACE

For their post-hoc analysis, Naderian et al turned to MI-GENES, a study that randomized 103 people being treated in the Mayo Clinic Health System to receive a conventional risk score (based on the Framingham equation) and 104 to receive an integrated risk score (Framingham score plus PRS) with the goal of seeing whether this knowledge impacted LDL cholesterol levels in the short term. At 6 months, the integrated-score group in fact did have higher statin initiation and lower LDL.

The investigators then reviewed electronic health records to identify any adverse clinical events, testing for CHD, and changes in cardiovascular risk factors over a 10-year window ending in late 2023. Mean age at the end of follow-up was 68.2 years, and 48% of patients were male.

In all, nine patients in the Framingham group and two in the integrated group had a first MACE (CV death, nonfatal MI, coronary revascularization, or nonfatal stroke), resulting in a hazard ratio of 0.20 (95% CI 0.04-0.94; P = 0.042). Nearly half (47%) of those who only knew their Framingham risk score underwent at least one diagnostic test for CHD compared with 29% of those given an integrated score (HR 0.51; 95% CI 0.32-0.81; P = 0.004).

Within the first 4 years after randomization, the proportion of patients on statin therapy was consistently higher among individuals given the integrated score, and this led to a greater reduction in LDL for up to 3 years. Yet there were no other significant differences over the years between the two groups when it came to traditional cardiovascular risk factors.

You talk about whatever test that you got and you make sense of it all. Michael Blaha

The investigators caution that their sample size is limited and the number of events is small. Additionally, the degree of MACE reduction is disproportionately large compared with the observed reduction in LDL, they point out. “One cannot, therefore, exclude the possibility that the results are due to chance,” they point out, calling for larger clinical trials “to confirm these findings and obtain a more precise estimate of effect size.”

Still, the results are plausible, the researchers say.

“Although the PRS utilized in the MI-GENES trial was specifically developed for CHD, the downstream interventions after CHD risk disclosure extended beyond statin initiation to include lifestyle modifications, such as increased physical activity, reduced dietary fat intake, and smoking cessation,” they write. On top of this, access to PRS appeared to encourage patients to seek information and share it with family members, friends, coworkers, and primary care providers, behavior that could have improved motivation and continuity of care.

For Blaha, the key factor isn’t so much the PRS itself but the in-person conversations.

“All of these [risk-assessment tools] only work if you discuss them with your patient. I’m not a big believer that if you mail someone their polygenic risk score, let’s say, [that it’s] going to make much difference unless they go talk to their physician. You know, I think it’s all part of a personalized visit. You talk about whatever test that you got and you make sense of it all,” he commented, adding that future studies should evaluate patient-reported outcomes in addition to hard events.

In MI-GENES, a genetic counselor disclosed risk estimates to patients during 30-minute sessions. Those who received an integrated score were shown a graphic displaying their 10-year risk before and after incorporating the PRS, with the counselor on hand to explain how the test works and to emphasize lifestyle changes. Patients then met with a preventive cardiologist or internist to discuss statin therapy using a decision aid that incorporated PRS and displayed details on CHD risk as well as the benefits and side effects of statins.

Controls initially just received results of their Framingham Risk Score, though 6 months after that disclosure they were mailed letters detailing their PRS.