Required warfarin dose and time in therapeutic range in patients with diagnosed Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH)

Abstract

Warfarin has been widely used to treat thromboembolism. The effect of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), on warfarin dosing remains unknown. This study aims to examine the effects of NAFLD/NASH on the average daily dose (ADD) of warfarin and the time in therapeutic range (TTR). This is a retrospective study utilizing an administrative data. We included patients with at least 2 months of warfarin dispensing and two subsequent consecutive INR measures. The ADD of warfarin to achieve therapeutic range INR levels, and TTR were compared between patients with and without NAFLD/NASH in four subgroups of patients accounting for the presence of obesity and diabetes. Generalized linear models (GLM) with Propensity score (PS) fine stratification were applied to evaluate the relative differences (RD) of warfarin ADD and TTR (>60%) in four subgroups. A total of 430 NAFLD/NASH patients and 38,887 patients without NAFLD/NASH were included. The ADD and TTR, were not significant in the overall cohort between those with and without NAFLD/NASH. However, GLM results in patients without diabetes or obesity (N = 26,685) showed a significantly lower warfarin ADD (RD: -0.38; 95%CI: -0.74–-0.02) and shorter TTR (OR: 0.71; 95%CI: 0.52–0.97) in patients diagnosed with NAFLD/NASH. The effects of NAFLD/NASH on warfarin dose or TTR were observed in patients without obesity and diabetes. Obesity and diabetes appear to be significant modifiers for the effects of NAFLD/NASH on warfarin dose and TTR.

Considerations for Physiologically Based Modeling in Liver Disease: From Nonalcoholic Fatty Liver (NAFL) to Nonalcoholic Steatohepatitis (NASH)

“…59 The average therapeutic daily dose of warfarin (S-warfarin), another CYP2C9 substrate, was not significantly different between NAFLD patients with and without cirrhosis compared with non-NAFLD control groups in two separate studies. 65,66 This is in line with nonsignificant changes in protein levels of CYP2C9 (involved in warfarin metabolism) and CYP4F2 (responsible for catabolism of vitamin K and associated with interindividual variability in warfarin response) in patients with non-cirrhotic NAFLD compared with non-NAFLD individuals with similar BMI. 39 Despite observing no change in warfarin daily dose relative to the control group, Zhang et al 66 reported a lower international normalized ratio to warfarin dose ratio in NAFLD (cirrhosis status not reported), suggesting potential NAFLDmediated alterations in vitamin K regulation or other pharmacodynamic factors that may impact warfarin response.…”

“…When controlled for CYP2C9 genotype, the plasma metabolite‐to‐parent ratio of losartan (a CYP2C9 substrate) was markedly lower in adolescents with NASH compared with a healthy cohort, although the corresponding ratio evaluated using urine samples was not affected by NAFLD disease status 59 . The average therapeutic daily dose of warfarin (S‐warfarin), another CYP2C9 substrate, was not significantly different between NAFLD patients with and without cirrhosis compared with non‐NAFLD control groups in two separate studies 65,66 . This is in line with nonsignificant changes in protein levels of CYP2C9 (involved in warfarin metabolism) and CYP4F2 (responsible for catabolism of vitamin K and associated with interindividual variability in warfarin response) in patients with non‐cirrhotic NAFLD compared with non‐NAFLD individuals with similar BMI 39 .…”

Nonalcoholic fatty liver disease and non-liver comorbidities

“…Anticoagulants like warfarin are frequently indicated in these patients to prevent thromboembolic events. Patients with NAFLD along with valvular disease are seen to require higher doses of warfarin and even then, they are less likely to stay in the therapeutic range as compared to patients without NAFLD [ 44 ].…”

Hypercoagulability in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD): Causes and Consequences

“…Furthermore, the activity of dabigatran has been related to a reduction in high-fat diet-induced weight gain [ 48 ]. Interestingly, possible interactions among anticoagulant activity, weight gain/obesity, and NAFLD were recently reported in humans by Wen et al [ 49 ]. Lower average warfarin daily dosage and shorter time in the therapeutic range were found in patients diagnosed with NAFLD/NASH [ 49 ].…”

“…Interestingly, possible interactions among anticoagulant activity, weight gain/obesity, and NAFLD were recently reported in humans by Wen et al [ 49 ]. Lower average warfarin daily dosage and shorter time in the therapeutic range were found in patients diagnosed with NAFLD/NASH [ 49 ]. Notwithstanding, this anticoagulation in patients with NAFLD has been poorly investigated.…”