Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis.
OBJECTIVE
In recent years, safety alerts have been made warning of the risk of serious drug-induced liver injury (DILI) caused by cardiovascular drugs. The new oral anticoagulants (NOACs) have now reached the market. However, safety concerns have been raised about their hepatic safety. Therefore we aimed to evaluate NOAC liver-related safety.


METHODS
Systematic review and meta-analysis of phase III randomised controlled trials (RCTs). Medline and CENTRAL were searched to September 2013. Reviews and reference lists were also searched. Two reviewers independently searched for studies and retrieved data estimates. Primary outcome was DILI (transaminases elevations >3× upper limit of normal (ULN) with total bilirubin >2× ULN). NOACs were compared against any control group. Random-effects meta-analysis was performed, and pooled estimates were expressed as relative risk (RR) and 95% CI heterogeneity was evaluated with I(2) test.


RESULTS
Twenty-nine RCTs evaluating 152 116 patients (mean follow-up of 16 months) were included. All RCTs were rated as having low risk of bias. NOAC were not associated with an increased risk of DILI (RR 0.90, 95% CI 0.72 to 1.13, I(2)=0%). Similar results were obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, darexaban, edoxaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin (LMWH) and placebo). The risk of transaminases elevations (>3×ULN) was lower among NOAC-treated patients, in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85; I(2)=27%)


CONCLUSIONS
NOACs are not associated with an increased risk of DILI. The unexpected 'protective' effect of NOAC is probably due to LMWH-associated hepatotoxicity.
Clinical Pharmacology Unit, Instituto de Medicina Molecular, , Lisbon, Portugal.
Daniel
D
Caldeira
Márcio
M
Barra
Ana Teresa
AT
Santos
Daisy
D
de Abreu
Fausto J
FJ
Pinto
Joaquim J
JJ
Ferreira
João
J
Costa
D000925:Anticoagulants / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000209:etiology*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment
D000925:Anticoagulants