Table 1.
Target trial emulation |
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Protocol | Target trial specification | Cohort analysis | Case-control analysis |
Eligibility criteria |
|
Same as for the target trial We defined hepatic impairment as a code for hepatic failure or ALT ≥120 IU/L and myopathy as codes for its symptoms: muscle aches, pain or weakness We required information on laboratory values measured during the past year and lifestyle factors during the past 4 years |
Same as for the cohort analysis We performed incidence density sampling of the eligible individuals, selecting 1000 controls per 1 colorectal cancer case |
Treatment strategies |
(i) Initiation of any statin therapy at baseline and continuation over follow-up until the development of a contraindication (hepatic impairment or myopathy) (ii) No initiation of statin therapy over follow-up until the development of an indication (LDL cholesterol ≥5 mmol/L) Treatment is considered continuous if there is a gap of <30 days between successive prescriptions. When clinically warranted during the follow-up, patients and their physicians will decide whether to start stop or switch therapy. Participants must have a primary care consultation at least once every 4 years to assess prognostic factors associated with adherence and loss to follow-up |
Same as for the target trial We defined the date of medication initiation to be the first date of a prescription We calculated discontinuation dates using the daily dose and quantity of pills in the prescription |
Same as for the cohort analysis |
Treatment assignment | Individuals are randomly assigned to a strategy at baseline, and individuals and their treating physicians will be aware of the assigned treatment strategy | We classified individuals according to the strategy that their data were compatible with at baseline and attempted to emulate randomization by adjusting for baseline confounders | Same as for the cohort analysis |
Outcomes | Colorectal cancer |
Same as for the target trial Colorectal cancer diagnoses were recorded as Read codes and ICD-10 codes |
Same as for the cohort analysis |
Follow-up | Starts at baseline and ends at the month of colorectal cancer diagnosis, death, loss to follow-up (transfer out of the practice or incomplete follow-up [4 years after the last recorded prognostic factors]), 6 years after baseline or administrative end of follow-up (end of practice data collection or February 2016), whichever happens first | Same as for the target trial | Same as for the cohort analysis |
Causal contrasts | Intention-to-treat effect and per-protocol effect | Observational analogue of intention-to-treat and per-protocol effect | Same as for the cohort analysis |
Statistical analysis |
Intention-to-treat analysis: apply inverse-probability weights to adjust for pre- and post-baseline prognostic factors associated with loss to follow-up Per-protocol analysis: censor individuals if and when they deviate from their assigned treatment strategy and apply inverse-probability weights to adjust for pre- and post-baseline prognostic factors associated with adherence and loss to follow-up14 |
Same as for the target trial with adjustment for baseline confounders | Same as for the cohort analysis |
ALT, alanine transaminase; CPRD, Clinical Practice Research Database; LDL, low-density lipoprotein.