Review for 10.1186/s12876-021-01704-w (2021)

Reviewer’s report
Title: 
A Systematic Review on Pharmacokinetics, Cardiovascular Outcomes and
Safety Profiles of Statins in Cirrhosis
Version: 
0 
Date: 
22 Jan 2021
Reviewer's report:
General
This manuscript is a systemic review that seeks to find answers to the three
critical questions facing the field *around* the use of statins in patients with
chronic liver disease: (1) How do the pharmacokinetics of statins change in
cirrhosis, (2) how to statins affect major adverse cardiovascular events in
patients with cirrhosis, and (3) do any of the currently used prognostic scores
predict when it is time to dose adjust or stop statin usage?
Data Source & Methods 
This systematic review searched multiple well-established databases
(MEDLINE, EMBASE, Cochrane, etc) with consultation from a University of
Alberta librarian. Articles were screened independently by two of the authors,
with the senior author serving to judge discrepancies, and rated based on quality,
bias, and heterogeneity using accepted tools such as Cochrane Risk of Bias and
Newcastle-Ottawa Assessment scale. Data were supplemented by searching the
Health Canada and FDA Drug Databases and product monographs. 
Strengths
As discussed in the background, there is now a breadth of retrospective data and
ongoing prospective trials evaluating the role of statins for chronic liver disease,
especially cirrhosis. However, there are many questions that remain before these
observations can be operationalized into clinical practice. This systematic review
identifies critical questions and seeks to answer them. The authors have
performed a high quality search and have been thorough and exhaustive in their
presentation of the data available to us. 
Weaknesses
The main weakness of this paper are limitations of the field itself. There is a lack
of high quality information on pharmacokinetics of statins, and most hepatically
cleared therapies, in the setting of cirrhosis and decompensated cirrhosis. The
authors did an admirable job summarizing the available data in tables and charts,
but the dearth of data makes extrapolation to clinical care difficult. 
A separate weakness of this paper involves its description of the biochemical
processing and degradation of the statins in the liver. In the introduction,
CYP450 is the main catabolic enzyme mentioned, whereas later mention of
organic anion transporters (OATPs) is only framed in the context of rosuvastatin
use. However, uptake of all statins is affected by OATPs, though there are
differences between statins due in part to interactions with different OATPs. For
example, the SLCO1B1 polymorphism of OATP1B1 has a large effect on
simvastatin, resulting in a 221% increase in AUC. (Niemi, M. Clin Pharm &
Ther. (2010); 87 1:130-133.) 
While the literature is not robust enough to formulate guidelines on weaning
protocols in the setting of advancing liver disease, there is enough data to urge
caution with statin use in decompensated cirrhosis. Consider additionally
mentioning the role of drug-drug interactions, especially for drugs that are
known to interact with CYP450, OATP and p-glycoprotein. (Francis P, Forman
L. Clin Liver Dis. 2020 Feb 25; 15(1):40-45).
Finally, as a minor point, the formatting of the tables is currently difficult to
read. Where possible, please try to standardize outputs of trials so as to paint a
clearer picture of the data.
Conclusions
In conclusion, the authors have identified three fundamental and pressing
questions regarding statin use and performed a thorough systematic review to try
to identify answers from the literature. While the literature lacks robust data, the
absence of high quality data is a useful piece of information. With improvements
to organization, corrections to statin metabolism mentioned above, and
consideration of offering more caution of use of statins in decompensated/Childs
Pugh C, this should be a worth contribution to the literature.
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Is the study design appropriate to answer the research question (including the use
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