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Effect of statins on the recurrence of hepatocellular carcinoma after liver transplantation: An illusion revealed by exposure density sampling

 Deok-Gie Kim  ;  Seung Hyuk Yim  ;  Eun-Ki Min  ;  Mun Chae Choi  ;  Myoung Soo Kim  ;  Dong Jin Joo  ;  Jae Geun Lee 
 LIVER INTERNATIONAL, Vol.43(9) : 2017-2025, 2023-09 
Journal Title
Issue Date
Carcinoma, Hepatocellular* ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use ; Illusions* ; Liver Neoplasms* ; Liver Transplantation* ; Neoplasm Recurrence, Local / epidemiology ; Retrospective Studies
exposure density sampling ; hepatocellular carcinoma ; immortal time ; liver transplantation ; statin
Background: Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias.

Methods: Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling.

Results: Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not.

Conclusion: Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Deok Gie(김덕기)
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Min, Eun-Ki(민은기)
Lee, Jae Geun(이재근) ORCID logo https://orcid.org/0000-0002-6722-0257
Yim, Seung Hyuk(임승혁) ORCID logo https://orcid.org/0000-0003-2146-3592
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
Choi, Mun Chae(최문채)
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