PONE-D-20-30637

EFFECT OF COMBINED STATINS AND ACETYL SALICYLICACID TREATMENT ON INTRACRANIAL ANEURYSM RUPTURE

PLOS ONE

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Massimiliano Toscano

Academic Editor

PLOS ONE

Additional Editor Comments:

The main theme is interesting as the paper introduces a novel point of view in the scenery of unruptured intracranial aneurysms. Anyway, there are several major concerns, so that substantial reviews are needed. In the discussion section, findings were not really discussed according to the literature. Moreover, the introduction and methods are rather inaccurate.

Please reply accurately to the questions raised and, most of all, review the whole paper as well as the limitation section taking into account the reviewers’ comments (e.g. no follow-up period, no untreated patients, the small size of patients population and so on).

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Reviewers' comments:

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper from Terçeno et al. aimed to investigate the predictive role of the treatment with aspirin and statins in reducing the risk of rupture of intracranial aneurysms (IA).

This is a cohort study, retrospectively analysed, of 368 patients with 408 IA treated for 5 years, of which 52.5% unruptured at the time of diagnosis. Patients with unruptured IA more frequently had multiple aneurysms, more frequently taking ASA and statins. 9.3% of patients were receiving ASA and 20.3% were receiving statins at the time of diagnosis. In multivariable analysis, the association therapy of ASA and statins were independently associated with unruptured IA (OR 5.01, 95% CI 1.37-18.33). Other characteristics of the IA were correlated with unruptured IA (lobulated wall aneurysm, PComA/AComA location and multiple aneurysms) and were founded to be independently associated with unruptured IA. Mortality was around 20% at one-year follow-up in ruptured IA. Authors concluded for a potential protective role of the association of statins and ASA treatment in IA rupture.

Although the work is interesting and substantially in line with recent literature findings, the paper is inaccurate in some parts and should be implemented in its formal presentation.

Abstract- In conclusions section, authors stated that association treatment of statins plus ASA is more frequent in unruptured IA but this datum is not presented in the results section of the same abstract. It might be better to state that statins plus ASA association is independently associated with unruptured IA.

Main text

Background section should be more developed.

Methods.

• How authors defined mortality? Did they consider mortality for all causes? Or related to SAH?

• In the statistical analysis section, authors declared that risk factors were associated with IA rupture and Fisher 4 in ruptured IA, but the results of the association between IA rupture and Fisher 4 were not presented in text nor tables in the results section.

• Authors stated that a backward and forward stepwise procedure was used for multivariable logistic regression. Which approach was finally used in table 2?

Results.

• Authors stated that mortality is 19.6% in the ruptured IA at 12 months in the text and at 3 months in table 1. This discrepancy should be solved.

• Mean ASA dose should be reported.

Table 2. Statins treatment showed a significant different distribution in ruptured and unruptured IA (14.4 vs 26.2%, p=0.005) in univariate analysis (table 1). Why statins treatment alone was not inserted as independent variable in multivariable regression models?

Discussion section should be more fluent and less structured to be more enjoyable for readers.

Disappointingly, findings were not really discussed according to literature. Here, some examples:

• Why ASA alone did not result protective in this population, as expected from literature data? Is it in relation with sample size? Is it related to selection bias? Why patients were taking ASA at the time of diagnosis? All these aspects should be discussed. Moreover, ASA dose should be reported and discussed since an inverse dose-response relationship with SAH risk has been reported (Reference 9).

• The same should be done for statins alone, on which far less evidence is available.

• Another interesting point is that dome diameter of unruptured IA was significantly larger than ruptured IA, which is not expected. Moreover, the balanced distribution of high blood pressure between the two groups is not expected since well-controlled blood pressure are associated with a low risk of unruptured IA growth (Weng GC. Aspirin and Growth of Small Unruptured Intracranial Aneurysm: Results of a Prospective Cohort Study. Stroke. 2020 Oct;51(10):3045-3054. doi: 10.1161/STROKEAHA.120.029967. Epub 2020 Sep 3).

• Another main limitation that should be added is the cross- sectional nature of the study.

Reviewer #2: The authors presents a single institution study of cerebral aneurysms and report that a combination of ASA and a statin is associated with a lower incidence of aneurysm rupture. Given the general interest in ASA and statins for preventative care of cerebral aneurysms, this manuscript is worthy of publication if the following comments are addressed.

1) A major limitation to this study is that the patient population is limited to patients who underwent treatment of their aneurysms. This data can therefore not be generalized to all cerebral aneurysm patients. Please discuss this in the "limitations and strengths" section.

2) Please expand your final Conclusion to provide a brief summary of your data (ie, that the combination of ASA and a statin was more frequently seen in unruptured aneurysms).

3) Multiple aneurysms has been associated with a higher risk of aneurysm rupture, and yet you saw the opposite in your data. Do you have any thoughts on this?

4) Including Figure 1 places an emphasis on mortality data, although you found no statistically significant differences in mortality based on ASA and statin use. I would suggest either removing this figure and reporting this data in a table or text or adding error bars to the graph to make it more clear that there are no statistical differences.

Reviewer #3: The authors present a well-written manuscript on the effects of statins and ASA treatment on the rupture of intracranial aneurysms. This is a retrospective review that looks at risk factors and treatment with either statin, ASA or a combination in two groups of aneurysms- ruptured and unruptured. Based on rupture status alone, the authors observe a protective effect of combination treatment. This is a modestly sized study that is retrospective in nature. Additionally there is no follow-up period for patients. I think looking at the data in terms of predictors (ie treatment with statin and/or ASA) does provide some valuable information, and provides some of the seed data needed to perform an RCT of these two medications for treatment. However, I think we still don't truly know from this study if the medications are protective because there is no way of know how long any of the patients harbored an aneurysm, and there is no data available to perform survival analysis with a Cox model. Nonetheless, I think this manuscript serves as an excellent review of the potential effects of ASA and statin on the biology of intracranial aneurysms, and the data helps provide more impetus to move towards an RCT. I would ask that the authors include some of my comments in the limitations section, and flesh out the limitations of the study further in the discussion. I think the conclusions are appropriate for the study design and data.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Joshua W Osbun

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EFFECT OF COMBINED ACETYLSALICYLIC ACID AND STATINS TREATMENT ON INTRACRANIAL ANEURYSM RUPTURE

PONE-D-20-30637R1

Dear Dr. Silva,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Massimiliano Toscano

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: