No abstract

Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%‐97%) (EpiChron), 60% (26%‐88%) (SIDIAP), and 74% (60%‐85%) (Denmark); for the secondary ALI definition, 65% (45%‐81%) (EpiChron), 40% (19%‐64%) (SIDIAP), and 70% (64%‐77%) (Denmark); and for the tertiary ALI definition, 25% (18%‐34%) (EpiChron), 8% (7%‐9%) (SIDIAP), and 47% (42%‐52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Aims: To compare the effectiveness and safety of gliclazide modified release (MR) to sitagliptin as type 2 diabetes mellitus (T2D) treatments in a real-world patient population. Materials and Methods: This retrospective cohort study used records from the UK Clinical Practice Research Datalink. The cohort consisted of adult patients with T2D newly treated with either gliclazide MR or sitagliptin as second-line treatment added to metformin and with a glycated haemoglobin (HbA1c) level of ≥7.0% (53 mmol/mol). Patients were 1:1 matched using high-dimensional propensity score matching and followed to determine the time taken to reach an HbA1c <7.0%. Secondary outcomes included time to HbA1c ≤6.5% (48 mmol/mol), time to ≥1% (11 mmol/mol) HbA1c reduction from baseline, treatment persistence and durability, and hypoglycaemic events. Results: Among the 1986 patients included, those on gliclazide MR more likely achieved an HbA1c <7.0% [hazard ratio (HR): 1.35; 95% confidence interval (CI):

Background Agomelatine is a melatonin receptor agonist and serotonin 5-HT 2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). Objective The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. Method A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. Results We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19–0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20–1.07), and for the secondary (OR 0.40; CI 0.05–3.11) and tertiary (OR 0.79; CI 0.50–1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. Conclusion In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results. Electronic supplementary material The online version of this article (10.1007/s40263-019-00611-9) contains supplementary material, which is available to authorized users.