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Reply to S. Suissa et al.

We thank Suissa et al for their interest in our recently published article in which we found an association between statin use and a reduction in overall and multiple myeloma (MM) – specific mortality. Suissa et al raised important concerns regarding immortal time bias, which we would like to address. In observational studies, immortal time is the time between disease diagnosis and initiation of the exposure of interest. The use of time-fixed drug exposures in cohort studies can introduce immortal time bias. This can inappropriately prolong measured survival in the exposed population, because patients must live long enough to initiate the exposure of interest (in this case, a statin). Two methods were used to reduce immortal time within our study: statin exposure was assessed as a time-varying variable, and a 12-month landmark analysis was performed. Although the baseline demographic table categorized patients as never and ever statin users, all survival analyses (outside of the landmark analysis) defined statin exposure in a time-varying fashion. Use of time-varying methods removes the immortal time period. Using a timevarying definition, the time period from MM diagnosis to statin initiation is categorized as statin unexposed and thus contributes to survival time of statin nonusers. Once statin therapy is initiated, the time period from start of statin initiation contributes to the survival time of statin users. If a statin prescription is discontinued during the study time frame, the time after discontinuation then contributes to statin nonuser survival time until death or initiation of a subsequent statin prescription. In the 12-month landmark analysis, patients were defined as statin users if they had a prescription for a statin in the 3 months preceding MM diagnosis or within the first 12 months after MM diagnosis. All others were defined as statin nonusers. Patients who survived , 12 months from MM diagnosis were excluded. The association between statin use and survival was then assessed starting 12 months after MM diagnosis. Once again, the landmark analysis removed the immortal time period, because statin use was determined at the beginning of the 12-month survival landmark. We provided the numbers requested by Suissa et al to further characterize our cohort. Of the 4,957 patients in the cohort: 1,393 had a statin prescription in the 3 months before MM diagnosis, of whom 1,053 died; 901 had a statin prescription after MM diagnosis, of whom 624 died; and the remaining 2,663 were classified as nonusers, of whom 2,149 died. Person-years of follow-up for statin ever users were 8,079 person-years versus 7,678 person-years for nonusers. In the 901 patients who had a statin prescription after MM diagnosis, the mean time from MM diagnosis to first statin prescription was 11.2 months. Finally, we performed two additional sensitivity analyses looking at the association between statin use and survival. In both analyses, we defined statin exposure as time varying and used Cox proportional hazards regression to control for the same baseline MM prognostic factors as in our manuscript. First, we assessed the association between a first prescription for statin therapy after MM diagnosis (n 5 427) and survival. Patients who received any statin prescription before MM diagnosis, including remote prescriptions, were excluded. Statin nonuse was defined as never having received a prescription for statin therapy (n 5 2,198). Consistent with our article, in this supplemental analysis we found a 27% reduction in all-cause mortality with statin use (adjusted hazard ratio 5 0.73; 95% CI, 0.61 to 0.87; P, .001). Second, we assessed the association between statin use at MMdiagnosis and survival, defining statin use as a prescription at the time ofMMdiagnosis or within the 3months before diagnosis (n 5 1,416). Patients who received their first statin prescription after MM diagnosis or had a prescription before the defined use period were excluded. In this analysis, statin use was associated with a 28% reduction in all-cause mortality (adjusted hazard ratio 5 0.72; 95% CI, 0.65 to 0.79; P , .001) compared with statin nonusers. Overall, we found a consistent association between statin use and a reduction in all-cause and MM-specific mortality in patients with MM that was both clinically and statistically significant. Although we share the concerns of Suissa et al surrounding the threat of immortal time bias in observational studies, we considered this threat a priori and designed the analytic approach to reduce the risk of this bias. Regardless of our efforts to reduce the threat of biases such as immortal time, we acknowledge our results will need to be corroborated by prospective clinical trials before widespread clinical adoption.