Review for 10.1186/s12876-015-0373-4 (2015)

Reviewer's report
Title:Hepatic Outcomes Among Adults Taking Duloxetine: a Retrospective
Cohort Study in a US Health Care Claims Database
Version:2Date:1 June 2015
Reviewer: Christine M. M Hunt
Reviewer's report:
The authors clearly defined the important study goal: to examine duloxetine
hepatic safety in a large, geographically diverse US insured population
(comprising 3-4% of US population). This 6 year propensity-matched cohort
study (2004-2010) appropriately compared the incidence of liver injury, liver
failure and liver-related death with initiation of duloxetine vs other
antidepressants in depressed patients without known baseline liver injury, and
additionally compared it to rates of liver injury in untreated patients with
depression. # 20,000-30,000 patients/drug-treatment group or control population
were compared, and were well-matched with propensity scoring (which included
assessment of 100 most common drugs coprescribed with duloxetine). The study
was designed similarly to Xue et al (2011), which examined the initial 2
post-marketing years in a population with #11,000 person-years of duloxetine
exposure (vs #7,000 in current 6 year study).
The study title and abstract are clear and explicit about the study aims,
population, and findings. The study is well-written and clear. The authors
appropriately cite prior work, including the 2 year post-marketing cohort study
(Xue 2011), which reported an increased risk of non-serious hepatotoxicity with
duloxetine in comparison to venlafaxine, as well as Shin (2013) who reported
adjusted rates of duloxetine-associated liver injuries in 2432 patients of 57.3 per
100 000 persons with 95%CI (0, 149.2).
Multiple study limitations are outlined in the discussion, including: insufficient size
to demonstrate a statistically significant difference across treatment groups, and
the post-hoc review of a clinically significant hepatic injury ascribed to duloxetine,
which was re-examined due to claims data – however, comparator events were
not re-examined, therefore, this decreased the incidence of clinically significant
duloxetine-induced hepatic injury.
1. The major study limitation is that it’s underpowered to assess differences in
clinically significant liver injury between groups, due to the large numbers of
patients needed to evaluate this rare event. For example, duloxetine-induced
liver injury is reported to affect:
• 26.2/100,000 patient-years (Voican CS et al. American Journal of Psychiatry
2014;171: 404-415).
• 57.3 per 100 000 persons with 95%CI (0, 149.2) adjusted rates of
duloxetine-associated liver injuries in 2432 patients (Shin J et al.
Pharmacoepidemiology and drug safety 2013; 22: 190–198)
However, only #7500-10,000 duloxetine person-years were captured in the
current study – inadequate to identify clinically significant liver injury between
groups.
2. An additional notable limitation is that the study followup was for only 15 days
after duloxetine treatment cessation. This limited study period precluded
assessment of potential duloxetine chronic liver injury, reported in Fontana RJ et
al. "Idiosyncratic drug-induced liver injury is associated with substantial morbidity
and mortality within 6 months from onset."Gastroenterol 2014;147:96-108. In this
prospective series, 2 duloxetine-induced chronic liver injury events were reported
among 113 chronic drug-induced liver injury events, in addition to 5
duloxetine-induced acute liver injury events within 484 acute drug-induced liver
injury events overall.
Other limitations include:
3. identifying potential cases on the basis of ICD-9 diagnosis or procedure codes.
Use of ICD-9 codes may under-estimate the event rate. As observed by
Jinjuvadia K et al. ("Searching for a needle in a haystack: use of ICD-9-CM codes
in drug-induced liver injury." The American journal of gastroenterology 2007;102:
2437-2443), <1% of acute liver injury ICD-9 codes are related to drug-induced
liver injury.
4. Additionally, few patients had liver chemistries evaluated, although Line 123
states: “The secondary outcome was non-serious asymptomatic hepatic enzyme
elevations.” Yet, Supplemental Table 2c reports that <1 in 20 (4.1%) duloxetine
patients had liver chemistries performed.
5. the apparent use of Lilly hepatologists to adjudicate cases. The authors should
indicate whether independent adjudication occurred to avoid potential bias.
6. Only 74% of medical records were obtained, limiting adjudication of potentially
important study events.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
In the past 5 years, the reviewer has been a consultant to Furiex, Otsuka and
was a full-time GSK employee until Aug 2012.
No stocks, patents or other financial competing interests affected by this paper.
No non-financial competing interests related to this paper.