Hypertriglyceridemic pancreatitis subphenotypes and differential responses to low-molecular-weight heparin: analyses from a cohort and a randomized controlled trial.

BACKGROUND/

OBJECTIVES

Hypertriglyceridemic pancreatitis (HTG-AP) is a heterogeneous disease, potentially diluting the apparent benefit of specific interventions. Characterizing this heterogeneity may help identify subgroups that benefit from particular treatments. We aimed to identify HTG-AP subphenotypes and explore differential responses to low-molecular-weight heparin (LMWH) across subphenotypes.

METHODS

HTG-AP subphenotypes were identified using latent class analysis based on admission clinical and laboratory variables from a prospective cohort (n = 1483). Associations between subphenotypes and clinical outcomes were assessed. These subphenotypes were independently validated in a multicenter randomized controlled trial (RCT, n = 533), in which differential treatment effects of LMWH on new-onset organ failure and/or mortality (primary outcome) were explored with and without adjustment for baseline covariates.

RESULTS

In the cohort, a two-class model provided the most appropriate solution, classifying 1135 patients (76.5%) as phenotype 1 and 348 (23.5%) as phenotype 2. Phenotype 1 could be described as a relatively homeostasis-preserved phenotype, whereas phenotype 2 represented a high-stress, multisystem-response phenotype. Phenotype 2 patients had more persistent organ failure, infected pancreatic necrosis, mortality, intensive care unit admission, and longer hospital stays (all P < 0.001) compared to phenotype 1. Validation in the RCT showed similar characteristics. In the RCT, the effect of LMWH plus insulin versus insulin alone on the primary outcome differed significantly between subphenotypes (phenotype 1: relative risk [RR] 1.04, 95% confidence interval [CI] 0.75-1.46; phenotype 2: RR 0.57, 95% CI 0.34-0.96; P for interaction = 0.04 unadjusted and 0.01 adjusted).

CONCLUSIONS

Two distinct clinical subphenotypes of HTG-AP are identified with heterogeneous treatment responses to LMWH.