NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH

Abstract

Background and aims: NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study.

Approach and results: We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH. Patients were randomly assigned (2:1 ratio) to receive either an exercise training program or standard clinical care. The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1) level, an established thrombotic biomarker. Twenty-eight patients were randomly assigned (18 exercise training and 10 standard clinical care). PAI-1 level was significantly decreased by exercise training when compared to standard clinical care (-40 ± 100 vs. +70 ± 63 ng/ml; p = 0.02). Exercise training decreased MRI proton density fat fraction (MRI-PDFF; -4.7 ± 5.6 vs. 1.2 ± 2.8% absolute liver fat; p = 0.01); 40% of exercise subjects had a ≥30% relative reduction in MRI-PDFF (histological response threshold) compared to 13% for standard of care (p < 0.01). Exercise training improved fitness (VO₂ peak, +3.0 ± 5.6 vs. -1.8 ± 5.1 ml/kg/min; p = 0.05) in comparison to standard clinical care.

Conclusions: This clinical trial showed that, independent of weight loss or dietary change, exercise training resulted in a significantly greater decrease in thrombotic risk than standard clinical care in patients with NASH, in parallel with MRI-PDFF reduction and improvement in fitness. Future studies are required to determine whether exercise training can directly impact patient outcomes and lower rates of TE.

Figure 1.

NASHFit Trial CONSORT Diagram

Figure 2.. Change in PAI-1 comparing exercise training to standard clinical care

PAI-1 level was significantly decreased for the exercise training group when compared to the standard of care control group (−40+/− 100 vs. +70 +/− 63 ng/mL, p=0.02)

Figure 3.. Change in MRI-PDFF measured liver fat comparing exercise training to standard clinical care

(A) No significant change was observed in MRI-PDFF in standard of care subjects. (B) MRI-PDFF significantly decreased following exercise training. (C) Exercise training decreased liver fat as measured by MRI-PDFF (−4.7 +/− 5.6 vs. 1.2 +/− 2.8% absolute liver fat, p=0.01). (D) 40% of exercise subjects had ≥30% relative reduction in MRI-PDFF, the threshold for histologic response, compared to 13% of standard of care subjects.

Figure 4.. Change in cardiorespiratory fitness comparing exercise training to standard clinical care

(A) No significant change was observed in VO₂peak for standard of care subjects. (B) There was a trend towards significance in VO₂peak improvement following exercise training. (C) Cardiorespiratory fitness improved more with exercise training as greater gain in VO₂peak (+3.0 +/− 5.6 vs. −1.8 +/− 5.1 mL/kg/min, p=0.05) was observed in comparison to standard clinical care. (D) 44% of exercise subjects had ≥10% gain in VO₂peak, the threshold to improve overall mortality, compared to 0% of standard clinical care subjects.