Title: Evaluation of antihypertensive medications use and survival in patients with ovarian
cancer: a population-based retrospective cohort study
Version: 1 Date: 30 Nov 2023
Reviewer's report:
General comments:
This study contributes to the growing body of literature suggesting a potential role for ACE
inhibitors in improving survival outcomes in ovarian cancer patients. However, the lack of
significant findings for other antihypertensive medications and the increased risk observed with
beta-blockers highlight the complexity of this research area.
The study's strengths include its comprehensive data source, detailed analysis, and focus on a
relatively unexplored area in ovarian cancer research.
The primary limitations include the study’s retrospective nature, the potential for unmeasured
confounding factors, and the limited statistical power due to the relatively low number of ovarian
cancer deaths in the cohort.
Specific comments:
1. The background provides a comprehensive overview of ovarian cancer statistics, risk factors,
and previous research on antihypertensive medications. However, it could be enhanced by
organizing the information more clearly, offering critical insights into previous research,
discussing biological mechanisms, balancing the global and local perspectives, and explicitly
stating the research gap.
However:
Discussing previous findings, especially around BBs, is somewhat confusing. The contrasting
results and the mention of different studies could be better organized for clarity. A
more structured approach, perhaps grouping studies by their findings (supportive, neutral,
contradictory), might help.
While many studies are cited, there's a lack of critical assessment of their methodologies or
potential biases. This could provide a stronger foundation for why further research (like the
current study) is needed.
There's little discussion on the possible biological mechanisms or pathways through which
antihypertensive drugs might influence ovarian cancer survival. Such information could add
depth to understanding why these drugs might have the observed effects.
Although implied, a more explicit statement about the research gap the current study aims to
fill would strengthen this section.
2. The statistical analysis appears well-conceived and executed with a thorough consideration
of important methodological aspects pertinent to this type of research. Yet, there is some room
for improvement:
• Please provide a rationale for the cut-point in dose stratification: While the median DDD is
used as a cut-point, it might be beneficial to provide a rationale for this choice, especially if the
distribution of DDD is skewed.
• Please provide more details on Competing Risks Analysis: While using Fine-Gray models
is mentioned, additional details on how competing risks were handled would provide deeper
insight into the analytical approach.
• Please address potential residual confounding: While many covariates are adjusted for,
acknowledging the possibility of residual confounding (unmeasured factors) would strengthen
the interpretation of results.
3. The results section is quite detailed, but there are several weak points to consider:
• There's a notable age difference between users and non-users of antihypertensive medications,
with users being older and having more comorbidities. This could introduce confounding factors
that may not be fully accounted for, despite adjustments in the analysis. The presence of
comorbidities and additional medication use (statins, anticoagulants, antidiabetic medications)
among users can also influence survival outcomes, complicating the interpretation of the results.
• Some results are reported as 'borderline significant' or with wide confidence intervals, such as
the increased risk observed in BBs users and the decreased risk in ARBs users. This indicates
a level of uncertainty in these findings, potentially due to small sample sizes in subgroups or
variability in the data.
• There are inconsistencies in the results, such as BBs showing an increased risk of ovarian
cancer death in certain subgroups but not others. These inconsistencies need further exploration
to understand the underlying factors.
• Some results are mentioned as being in supplementary tables or additional files, which might
not be immediately accessible to readers. Integrating key findings directly into the text could
improve the clarity and accessibility of the information.
• There seems to be an emphasis on findings that show significant associations, while less
attention is given to non-significant results. A more balanced reporting, including discussing
why certain expected associations were not observed, would strengthen the section.
4. The discussion provides a good overview of the study's findings in the context of existing
literature but could be improved by addressing the following points to enhance clarity, depth,
and applicability:
• The data on antihypertensive medication use is based on recorded medication purchases, which
does not necessarily confirm actual consumption. The discussion could benefit from a more
in-depth consideration of how this factor might affect the results, especially in the context of
medication adherence.
• The absence of information on lifestyle factors such as smoking, BMI, diet, and physical
activity is acknowledged. Still, the discussion could expand on how these factors might influence
the study's findings, considering their potential role in cancer progression and medication
efficacy.
• The study discusses the potential effects of non-selective and selective BBs on ovarian
cancer mortality. This section could be strengthened by providing more detailed mechanistic
explanations or hypotheses on why these differences might exist.