Table 3.

Estimand-to-Analysis Table for a Placebo-Controlled Clinical Trial

Primary Objective: To determine the effects of pitavastatin as a primary prevention strategy for major adverse cardiovascular events (MACE) in HIV.
Estimand: The cause-specific relative hazard of major adverse cardiovascular events (MACE) following prescribed pitavastatin (relative to no treatment) among people with HIV (PWH) on stable antiretroviral treatment (ART) who have low to moderate cardiovascular disease (CVD) risk according to 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines22 and no current indication for a statin.
Treatment a : Pitavastatin 4 mg PO daily
ESTIMAND	ANALYSIS
Target population	Analysis set
PWH on stable ART with low to moderate CVD risk according to 2013 ACC/AHA guidelines and no current indication for a statin.	All randomized participants. Participants assigned to pitavastatin through randomization will be the active treatment group. Participants assigned to placebo will be the comparator group.
Variable	Outcome measure
Time to the occurrence of any of the following MACE outcomes: atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, nonfatal stroke or transient ischemic attack, urgent peripheral artery disease ischemic event, death of undetermined cause.	Time to first MACE outcome or non-CV death where time is measured from randomization to the date of the event. Participants lost to follow-up or who otherwise discontinue study prematurely without experiencing any event will be censored at the date of last contact; deaths from known non-CV causes will be considered as competing risk events in the primary analysis.
Handling of intercurrent events	Handling of missing data
Premature treatment discontinuation: All follow-up included regardless of attribution to treatment (Treatment policy strategy). Deaths from known non-CVD cause: Follow-up is censored (While on treatment strategy, or “while alive”)b.	Unless censoring patterns appear otherwise, censoring will be assumed non-informative for the primary analysis. Sensitivity analyses: Inverse probability of censoring weights (IPCW) will be used to adjust for potentially informative censoring of participants discontinuing the study prematurely for reasons other than death. Information from vital status follow-up will be included, and event times will be imputed for any remaining unobserved follow-up times based on a range of event rates for each treatment group.
Population-level summary measure	Analysis approach
Cause-specific hazard ratio relative to without pitavastatin	The relative cause-specific hazard of pitavastatin versus placebo for MACE will be estimated using Cox proportional hazards model, where non-CVD deaths are competing events. Modification of the statin effect over time (non-proportional hazards) will be evaluated with treatment by time interaction; piecewise hazards will be used in case of failure of the proportional hazards assumption.

^aAn option is to present the Treatment attribute separately in the ESTIMAND and ANALYSIS columns for placebo-controlled trials to show that placebo, while not a treatment of interest in the estimand, is a treatment arm in the context of a trial for the analysis. In this option, Treatment under ESTIMAND would state the treatment of interest, and Treatment under ANALYSIS would include both the treatment and the placebo.

^bBecause response to treatment prior to the occurrence of the intercurrent event is of interest for while on treatment strategy, this is essentially “while alive” when considering death as an intercurrent event.