Critical Limitations
- Lack of Cause-Specific Mortality: The primary endpoint was all-cause mortality, meaning the researchers could not differentiate between cardiovascular deaths and cancer/infectious deaths. While low LDL is implicated in increased infectious mortality, failing to isolate ASCVD mortality weakens the direct challenge to the AHA guidelines.
- Residual Confounding & Ascertainment Bias: ASCVD events were only tracked within the UPMC hospital network. Events occurring out-of-network were missed, leading to an undercounting of the secondary ASCVD endpoints.
- Statin Ascertainment: Statin use was based on EMR patient-reported data, not hard prescription fill data, introducing potential misclassification bias.
- Latency of Pathology: Excluding deaths within one year may not be sufficient to eliminate reverse causality for slow-progressing pathologies like undetected cancers, which can suppress LDL-C for years prior to mortality.
