Summary: In 112 veterans suspected of carrying a familial hypercholesterolemia (FH) variant, immediate return of clinically confirmed genetic results plus telegenetic counseling did not significantly reduce LDL-C versus delayed return at 6 months (between-arm difference -10.5 mg/dL; 95% CI -21.9 to 1.0; P=.07). The primary endpoint was not met, and the secondary intensification and target-achievement endpoints were also non-significant.
PICO Summary
| Element | Detail |
|---|---|
| Population | 112 Veterans Health Administration enrollees (Million Veteran Program) suspected to carry an FH-associated variant; randomized clinical trial across 28 US states; mean age 65.9 years, 83.9% men, baseline mean LDL-C 109.5 (SD 55.5) mg/dL, and 76.8% already receiving lipid-lowering therapy. |
| Intervention | Immediate return of clinically confirmed FH genetic results plus telegenetic counseling at baseline (immediate-results arm, n=55). |
| Comparison | Delayed return of the same results and counseling after 6 months (delayed-results arm, n=57). |
| Outcome | Primary outcome (6-month between-arm LDL-C reduction) was not statistically significant: difference -10.5 mg/dL (95% CI -21.9 to 1.0; P=.07; Cohen d=0.34). Treatment intensification: 20.0% (11/55) immediate vs 8.8% (5/57) delayed (P=.09). LDL-C target achieved: 27.3% (15/55) vs 24.6% (14/57) (P=.74). A pre-specified Bayesian analysis suggested a high probability of benefit but was explicitly exploratory. Among immediate-arm responders, 61.2% (30/49) shared results with a total of 98 relatives. No ARR or NNT was derived because the primary outcome was non-significant. |
Genomic FH Screening to Lower LDL-C
RCT · suspected FH · 6 months
Immediate return of confirmed FH results did not significantly lower LDL-C versus delayed return at 6 months; the primary and secondary efficacy endpoints were all non-significant.
Expert Commentary
This randomized trial is best read as a neutral result on its primary endpoint. The 6-month between-arm LDL-C difference of -10.5 mg/dL did not reach significance (P=.07), and the secondary endpoints of treatment intensification and target achievement were likewise non-significant. The direction of effect favoured immediate return of results, and a Bayesian analysis was interpreted as showing a high probability of benefit, but that analysis was pre-specified as exploratory and cannot substitute for a missed primary endpoint. The most consequential limitation is power: only 112 participants were randomized, the confidence interval crossed zero, and a population that was 76.8% already on lipid-lowering therapy with a near-target baseline LDL-C leaves limited room for a between-arm signal to emerge. Can I use this with my patients? Not yet as a justification for opportunistic genomic FH screening to lower LDL-C, because the trial did not demonstrate that benefit; the clearer, hypothesis-generating signal is cascade information sharing, with 61.2% of responders informing on average two relatives each. Clinically confirmed FH should still prompt guideline-based intensification and family screening through established pathways. A larger, adequately powered, outcomes-oriented trial with longer follow-up is needed before this delivery model is adopted as standard practice. The open-label design is unavoidable here, and although this was a publicly funded Veterans Affairs and Million Veteran Program study without commercial sponsorship, the modest single-system sample limits generalisability.
References
Vassy JL, Brunette CA, Yi T, et al. Opportunistic Genomic Screening for Familial Hypercholesterolemia to Improve Low-Density Lipoprotein Cholesterol: A Randomized Clinical Trial. JAMA Netw Open. 2026;9(1):e2549664. doi:10.1001/jamanetworkopen.2025.49664