Table 1 Specification and emulation of a target trial of treat-to-target cholesterol-lowering interventions to prevent cardiovascular disease and all-cause mortality

From: Effectiveness of treat-to-target cholesterol-lowering interventions on cardiovascular disease and all-cause mortality risk in the community-dwelling population: a target trial emulation

Protocol component

Target trial specification

Target trial emulation

Eligibility criteria

Aged 35 years or older between January 1, 1992 and December 31, 1993

In-person examination at the baseline

No history of cardiovascular disease at the baseline

Triglyceride < 4.52 mmol/L (400 mg/dL) at baseline, defined as the recruitment date of study participants

Same as for the target trial

We defined a history of cardiovascular disease as a composite outcome comprising heart disease and stroke before the date of recruitment in the Chinese Multi-provincial Cohort Study

Treatment strategies

The natural course of no intervention

Treat-to-target cholesterol-lowering interventiona

Feasible treat-to-target cholesterol-lowering intervention, defined as 80% of eligible participants receiving the intervention at the follow-up examination over the study period

Same as for the target trial

Treatment assignment

Participants are randomly assigned to an intervention strategy at baseline or during the follow-up when the risk-based conditions are met

We implemented the hypothetical treat-to-target intervention by transforming the follow-up time into a one-year unit and initiating the hypothetical interventions when the risk-based conditions were met

Outcomes

The primary outcomes are cardiovascular disease and all-cause mortality

The secondary outcome is atherosclerotic cardiovascular disease

Competing events are defined as non-cardiovascular deaths before the occurrence of the outcome of interest (except for all-cause mortality)

Same as for the target trial

Follow-up

The follow-up period starts at baseline and ends at the year of recording cardiovascular deaths, non-cardiovascular deaths, loss to follow-up, 29 years after baseline, or administrative end of follow-up on 31 December 2020, whichever occurs first

Same as for the target trial

We defined the start of the follow-up period (i.e., time zero) as the initiation time of the intervention when the risk-based conditions are met

Causal contrasts

Per-protocol effect

Observational analog of per-protocol effect

Statistical analysis

Per-protocol analysis of the cholesterol-lowering effects under various strategies

Competing risk analysis of the total cholesterol-lowering effects in the presence of competing events

Subgroup analyses by sex (men vs. women), BMI ( < 24 vs. \(\ge\)24 kg/m2), smoking status (Yes vs. No), and anti-hypertensive drugs (Yes vs. No) at the baseline

Sensitivity analysis of the cholesterol-lowering effects under various model specifications and a range of adherence rates from 70% to 20%

Positive and negative control analyses of replicating the constant ~21% cardiovascular risk reduction with statin therapy per 1 mmol/L (39 mg/dL) reduction in plasma LDL-C levels and the null association of cholesterol-lowering interventions with cancer deaths.

Same per-protocol analysis with sequential emulation and adjustment for baseline covariates

Same competing risk analyses

Same subgroup analyses

Same sensitivity and positive/negative control analyses

  1. Note: aTreat-to-target cholesterol-lowering intervention is based on cholesterol-lowering targets recommended by the Chinese Society of Cardiology in 2020 on LDL-C and non-HDL-C levels, i.e., for participants with diabetes at high cardiovascular risk, lower the LDL-C to < 1.8 mmol/L (70 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 1.8 mmol/L) or LDL-C reduction to > 50% from baseline whichever is the lowest and non-HDL-C to < 2.6 mmol/L (100 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 2.6 mmol/L); for participants without diabetes who are at moderate-to-high cardiovascular risk lower the LDL-C to < 2.6 mmol/L (100 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 2.6 mmol/L) and non-HDL-C to < 3.4 mmol/L (130 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 3.4 mmol/L); for participants at low cardiovascular risk, lower LDL-C to < 3.4 mmol/L (130 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 3.4 mmol/L) and a non-HDL-C < 4.2 mmol/L (160 mg/dL, i.e., a fixed level drawed from a uniform distribution with a upper bound of 4.2 mmol/L).
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