Routine LDL Exam For Cancer Survivors

Cardiovascular disease is an important cause of long-term morbidity and mortality among cancer survivors. Current cardio-oncology and survivorship guidelines recommend periodic assessment of cardiovascular risk factors, including lipid profiles. However, limited evidence is available regarding whether routine LDL-C testing leads to greater initiation of preventive therapy or fewer cardiovascular events in cancer survivors.

This nationwide observational cohort study will evaluate the association between annual LDL-C testing and cardiovascular outcomes among statin-naive cancer survivors. The study will use routinely collected administrative health insurance and cancer registry data from Korea.

A sequential target trial emulation design will be used. Eligibility will be reassessed at a series of annual trial baselines beginning 1 year after cancer diagnosis. At each trial baseline, individuals will be eligible if they are alive, remain under observation, have no history of cardiovascular disease, myocardial infarction, stroke, familial hypercholesterolemia, percutaneous coronary intervention, or coronary artery bypass grafting, and are not receiving statin therapy. The same individual may contribute to more than one annual emulated trial if all eligibility criteria continue to be met.

At each eligible trial baseline, participants will be classified according to whether they undergo LDL-C testing. Participants in the active testing group will be compared with participants in the inactive testing group. Propensity scores will be estimated using demographic and clinical variables, including age, sex, cancer type, cancer diagnosis year, cancer stage, hypertension, diabetes mellitus, and dyslipidemia. One-to-one propensity score matching will be performed within each emulated trial.

The primary outcome will be major adverse cardiovascular and cerebrovascular events, defined as a composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization. Secondary outcomes will include the individual components of the composite outcome and initiation of statin therapy within 1 year after the trial baseline.

For the analysis of statin initiation, participants will be followed for up to 1 year. Follow-up will end at statin initiation, a major cardiovascular event, censoring, or the end of the observation period. For cardiovascular outcome analyses, follow-up will begin at the corresponding annual trial baseline. Participants in the inactive testing group who subsequently undergo LDL-C testing will be censored at the date of testing. Inverse probability-of-censoring weighting will be used in sensitivity analyses to address potential informative censoring.

Hazard ratios and 95% confidence intervals will be estimated using Cox proportional hazards models. Because individuals may contribute to multiple annual emulated trials, robust sandwich variance estimators clustered at the participant level will be used to account for within-person correlation. Competing-risk analyses will account for non-cardiovascular death when evaluating nonfatal cardiovascular outcomes.

Exploratory analyses will evaluate cardiovascular outcomes according to subsequent statin initiation after LDL-C testing. These analyses will be interpreted cautiously because statin use is determined after the trial baseline and is not a randomized treatment assignment. Prespecified subgroup analyses will be conducted according to sex, age, cancer stage, time since cancer diagnosis, cancer type, and diabetes status.

This study is observational. The investigators will not assign LDL-C testing, statin therapy, or any other clinical intervention.

Inclusion criteria

• Individuals with a diagnosis of cancer recorded in the nationwide cancer registry and health insurance database
• Alive and under observation at least 1 year after the initial cancer diagnosis
• Eligible for entry at an annual emulated trial baseline
• Not receiving statin therapy at the corresponding trial baseline
• Available information on age, sex, cancer type, year of cancer diagnosis, cancer stage, diabetes mellitus, hypertension, and dyslipidemia
• Continuous eligibility for outcome ascertainment in the national health insurance database

Exclusion criteria

• History of cardiovascular disease before the corresponding trial baseline
• History of myocardial infarction or stroke before the corresponding trial baseline
• History of familial hypercholesterolemia
• History of percutaneous coronary intervention or coronary artery bypass grafting
• Use of statin therapy before or at the corresponding trial baseline
• Missing information required to determine eligibility, exposure status, or prespecified baseline covariates