Methodological Challenges of Emulating a Target Trial to Assess Effectiveness of Timing of PCSK9 Inhibitor Treatment...

Studies comparing treatment strategies based on initiation timing-such as starting PCSK9 inhibitor (PCSK9i) therapy sooner versus later after a myocardial infarction (MI)-are prone to immortal time bias. Clone-censor-weight methods can address these issues and allow the researcher to emulate a trial in which patients are assigned to protocols dictating when PCSK9i is initiated. This study aimed to evaluate the comparability of patients in a clone-censor-weight setup who initiated a PCSK9i within 12 months post-MI versus non-initiators.

We included adult patients hospitalized for MI in Sweden (2015-2021) and followed them for 3 years. We considered two treatment strategies: initiating PCSK9i within 12 months versus not initiating PCSK9i during the same period. We applied the clone-censor-weight method to address immortal time bias and assessed remaining bias using covariate balance metrics and negative control outcomes.

The primary study sample included 38  627 episodes of MI, with 561 (1.5%) initiating PCSK9i treatment within 12 months. These patients were younger, had higher baseline LDL-C levels, and were more frequently treated with ezetimibe during their post-MI follow-up compared to non-initiators. Although clone-censor-weight estimation was free of immortal time bias, it faced challenges in achieving adequate balance of covariates due to the high rates of censoring (relatively small number of people initiating a PCSK9i in the first year) and strong association between covariates and censoring. Truncation of weights provided more stable estimates but at the expense of some covariate imbalances.

The clone-censor-weight method is a promising approach that allows researchers to answer questions about the effect of treatment policies. But practical guidance is needed to address problems that arise from small, highly imbalanced groups, which is common with most newly introduced treatments.