Specification and Emulation of Target Trials Evaluating Statin Therapy Initiation Effectiveness on Mortality Following Diagnosis of Stage 3 or 4 CKD Using Observational Data From VA Electronic Health Records, January 1, 2005, to December 31, 2017
TIA, death, CKD, chronic kidney disease, Dialysis or stage 5, stroke, ASCVD, End-stage heart failure, dementia, Active liver disease, peripheral artery disease, andCKD stage
MYOCARDIAL INFARCTION, PERIPHERAL ARTERY DISEASE, TRANSIENT ISCHEMIC ATTACK, HYPERLIPIDEMIA, STROKE, CANCER, DISEASE, RHABDOMYOLYSIS, SENSITIVITY, SECONDARY, CKD STAGE 5, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, PERIPHERAL VASCULAR DISEASE, TYPE 2 DIABETES, ASCVD, TIA
Aged >65 y with a first diagnosis of stage 3 or 4 CKD between January 1, 2005, and September 30, 2015, inclusive.No prior diagnosis of ASCVD including myocardial infarction, coronary revascularization, transient ischemic attack, stroke, peripheral vascular disease, or peripheral artery disease at baseline.No prior exposure to statins before baseline.User of VA health care system within one year prior to baseline.No enrollment in hospice.Known body mass index within 1 year of baseline.No contraindications for statin therapy:Dialysis or stage 5 CKD,Rhabdomyolysis,Active liver disease,End-stage heart failure,Active chemotherapy, radiation indicating active cancer, andEnd-stage dementia.Same as for the target trial, except:Considered key criteria based on Initiation of a new statin therapy at baseline orNo statin therapy initiation at baseline.Same as for the target trial, except:Initiation defined by receipt or fill of any statin ≥30 d supply at baseline.Individuals randomly assigned to a treatment strategy at baseline. Individuals and their treating physicians are aware of assigned treatment.Patients were classified according to the treatment assignment that is compatible with the observed data at baseline. Randomization was emulated by adjusting for baseline covariates.Risk of death (all-cause mortality) over the follow-up period. Secondary outcome of MACE or death considered.Same as for the target trial.Follow-up starts at baseline and goes until death, outcome (specific to analysis), or the end of the study period (December 31, 2017), whichever happens first.Same as for the target trial.Intention-to-treat effect, ie, initiation of treatment.Observational analogue of the intention-to-treat effect, or the prescription and fill of statin therapy within the data sources available.Intention-to-treat analysis, Cox proportional hazards model to estimate the relative risks of outcome between treatment groups.Sensitivity analyses considered by entire analytic process to the following subgroups by:Age (66-74 and ≥75 y).Sex (male and female),Race (White, Black, and other),Cardiovascular disease risk (high and low),Frailty (frail and nonfrail),Prevalent type 2 diabetes (yes and no),Code for hyperlipidemia, andCKD stage (3 and 4).Same as intention-to-treat analysis, except that patients may be enrolled in multiple person-trials for statistical efficiency and confidence bounds estimated using non-parametric bootstrapping. To adjust for imbalance in baseline confounders, propensity score overlap weighting was used.Sensitivity analyses conducted, in full, within the trials corresponding to each subgroup.Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; Other race includes American Indian or Alaska Native, Asian, and Native Hawaiian or Pacific Islander individuals.Baseline, or time zero, would be defined as the date of randomization to initiating or not initiating statins. Only person-trials within the first 5 years following CKD diagnosis would be considered, and individuals who progressed to CKD stage 5 or requiring dialysis would be excluded, as these are considered contraindications for statin initiation. Those in the treatment group, or statin initiators, would receive at least one 30-day supply of a statin at the time of randomization. Those randomized to noninitiation would not receive any statins at the time of randomization, and both the clinician and patient would be aware of treatment assignment.The outcome for the target trial would be ascertained as the first date of death or end of study, whichever occurs first. In an analysis for secondary outcomes of MACE, the outcome would include any occurrence of MI, TIA, stroke, coronary revascularization, or death during follow-up. Time to MACE outcome would be measured as the first occurrence of a MACE, and follow-up would end at this date or end of study, whichever comes first.In a target trial study of statin initiation, the intention-to-treat analysis would include those who filled a statin prescription at baseline, while inclusion in the per-protocol analysis would be based on the patient’s adherence to taking the medication as directed.We additionally would conduct the following subgroup analyses by stratifying on key factors: age (66-74 vs ≥75 years), sex, race (Black or African American, White, other [American Indian or Alaska Native, Asian, or Native Hawaiian or Pacific Islander], vs unknown), specific CKD stage (3 vs 4), risk of ASCVD, frailty, and prevalent type 2 diabetes and hyperlipidemia.