The Underutilization, Adverse Reactions and Efficacy of Statins after Liver Transplant: A Meta-Analysis and Systematic Review

Round 1

Reviewer 1 Report

Manuscript ID transplantology-1261916, entitled "The Underutilization, adverse reactions and efficacy of statins after liver transplant: a meta analysis and systematic review”.

Thank you for the opportunity to review this metanalysis and systematic review.

The study by Yeung Jek Ho et al deals with topic of interest and a question that, although not new, it is still under investigation and pertinent to our clinical practice.

The Authors, demonstrated that Statin therapy is safe and efficacious in post-liver transplant patients, and introduced the relevant issue regarding interactions between statins and immunosuppressant therapy.

I would like to ask for some clarifications:

Despite the full search syntax has been reported clearly, please be more specific about eligible study designs.

Usually eligible studies that do not contribute data suitable for meta-analysis are kept among the included studies. Were none of the outcomes of interest reported in these studies that were excluded for non-availability of outcome data?

Please report risk of bias of included studies in more depth. What were the relevant problems in the majority of studies,...

The principal nonimmune toxic effects of mTOR inhibitors include hyperlipidemia and hypercholesterolemia. The use of statins especially in those recipients undergoing therapy with mTOR inhibitors should be better specified.

In the discussion, the issues related to the link between statins and immunosuppressant therapy have the potential to be improved, and the literature discussed to be updated.

Author Response

Despite the full search syntax has been reported clearly, please be more specific about eligible study designs.

Thank you for the comment. We have elaborated on the eligible study designs in our methods section in lines 77-78.

Usually eligible studies that do not contribute data suitable for meta-analysis are kept among the included studies. Were none of the outcomes of interest reported in these studies that were excluded for non-availability of outcome data?

Thank you for the comment. Studies that we have identified for non-availability of outcome data in our screening process do not have outcomes of interest reported as well and hence were excluded.

Please report risk of bias of included studies in more depth. What were the relevant problems in the majority of studies?

Thank you for the comment. Range of quality assessment scores has been added to our Results section in line 123 and relevant problems were added in our limitations section.

The principal nonimmune toxic effects of mTOR inhibitors include hyperlipidemia and hypercholesterolemia. The use of statins especially in those recipients undergoing therapy with mTOR inhibitors should be better specified.

Thank you for the comment. We have included the number of patients reported to be on mTOR inhibitors in our Results section in line 119-122. However, due to the lack of studies reporting this data, we were unable to include this in our regression analysis.

In the discussion, the issues related to the link between statins and immunosuppressant therapy have the potential to be improved, and the literature discussed to be updated.

Thank you for the comment. We have refurbished our discussion section (lines 204-211) with the issues related to the link between statins and immunosuppressant therapy.

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors took on a a very difficult task to look at the use of statins in liver transplants.  Despite review of many citations, they ended up with 11 studies - 10/11 were retrospective.  Due to the nature of the studies, there are many flaws making true comparison difficult. The indications for starting statins, although obviously risk of CVD is the main factor, are varied - some use LDL numbers, some use diabetes etc.. Most patients' cholesterol  levels dropped only 25 mg/dl perhaps not enough to alter CVD related mortality. Additionally, the 95% CI for change in cholesterol ranged from -81.28 to 31.15 - not a significant difference in cholesterol which raises the question whether statins even had an impact on cholesterol values. The relationship between HCC and statin use was only looked at in one study, as was the risk of NODAT. 

There was a difference in mortality noted by the meta analysis but what was cause of the mortality in the non statin group? Could it be related in any way. Was follow up similar in the statin and non statin group. It was noted that one study did not find a significant difference in CVS events between statin and non-statin use. 

The conclusion that statins are underutilized is based on what?  do we have cholesterol numbers of the non statin users? is this based on historical data of % of people on statins in general population vs post-LT? 

I think its important to look at the use of statins in liver transplant given that the incidence of NASH cirrhosis as an indication for transplant is growing. however, I find this meta analysis, while it reassures us that there is not a significant number of adverse events, raises more questions about the efficacy.

Author Response

The authors took on a very difficult task to look at the use of statins in liver transplants.  Despite review of many citations, they ended up with 11 studies - 10/11 were retrospective.  Due to the nature of the studies, there are many flaws making true comparison difficult. The indications for starting statins, although obviously risk of CVD is the main factor, are varied - some use LDL numbers, some use diabetes etc.. Most patients' cholesterol  levels dropped only 25 mg/dl perhaps not enough to alter CVD related mortality. Additionally, the 95% CI for change in cholesterol ranged from -81.28 to 31.15 - not a significant difference in cholesterol which raises the question whether statins even had an impact on cholesterol values. The relationship between HCC and statin use was only looked at in one study, as was the risk of NODAT.

Thank you for the comment. We agree that the topic remains understudied and indeed can be limited. We have added this under our Limitation section in lines 232-235, 238-246. However, we believe that the paper adds to literature on the safety of statin post LT.

There was a difference in mortality noted by the meta-analysis but what was cause of the mortality in the non-statin group? Could it be related in any way? Was follow up similar in the statin and non-statin group. It was noted that one study did not find a significant difference in CVS events between statin and non-statin use.

Thank you for the comment. The cause of mortality difference in statin and non-statin groups is likely multifactorial but we postulate that it might be due to reduction in CVD-related mortality, immunomodulatory and anti-inflammatory properties of statins. There was only one study on CVD mortality, and the small  sample size could have resulted in the lack of significance.

The conclusion that statins are underutilized is based on what?  Do we have cholesterol numbers of the non-statin users? Is this based on historical data of % of people on statins in general population vs post-LT?

Thank you for the comment. The underutilizations was based on the lack of patients on statins after LT. The indications of statin use however, remains unclear in the included articles. Additionally, the studies included did not report LDL levels in non-statin users. We believe that statins are underutilised in post-LT patients as the benefits of statin usage greatly outweigh its associated risks.

I think it’s important to look at the use of statins in liver transplant given that the incidence of NASH cirrhosis as an indication for transplant is growing. however, I find this meta analysis, while it reassures us that there is not a significant number of adverse events, raises more questions about the efficacy.

Thank you for the comment. We agree that our analysis has shown the low incidence of adverse events and the efficacy of statins has yet to be proven conclusively in this patient population. Hence, more large-scale studies should be done to determine its efficacy.

Round 2

Reviewer 2 Report

authors acknowledge and address limitations of the study. The lack of serious adverse reactions to statins is an important piece of information that deserves to be published