BMJ Open: first published as 10.1136/bmjopen-2019-034361 on 22 July 2020. Downloaded from PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) Association between Topical Beta-Blockers and Risks of Cardiovascular and Respiratory Disease in Glaucoma Patients: a retrospective cohort study AUTHORS Chen, Hsin-Yi; Huang, Wei-Cheng; Lin, Cheng-Li; Kao, Chia-Hung VERSION 1 – REVIEW REVIEWER Marques-Neves, Carlos Ophthalmology University Clinic Faculdade de Medicina da Universidade de Lisboa REVIEW RETURNED 27-Oct-2019 GENERAL COMMENTS Some variables are difficult to control nevertheless, the point is achieved. REVIEWER Reza Razeghinejad Wills Eye Hospital, Philadelphia, PA REVIEW RETURNED 12-Nov-2019 http://bmjopen.bmj.com/ GENERAL COMMENTS A retrospective study on association between Topical Beta- Blockers and Risks of Cardiovascular, stroke, and Respiratory Diseases in Glaucoma Patients reporting higher rate of respiratory issues and stroke in those on beta-blockers. The reported correlations are valid under one condition, being on beta-blocker when the event (stroke, respiratory issues,…..) occurred. The major issue is not including the severity of the systemic diseases and also the severity of glaucoma. on September 25, 2021 by guest. Protected copyright. Although the frequency of DM, HTN, asthma,… were similar between both group, there is no data on the severity of these diseases, for example if the HbA1c of those taking beta blockers is higher it could be the cause of higher rate of stroke not the beta- blockers. Based on the presented data, higher number of those on beta- blockers were taking other groups of glaucoma medications which could indicate greater severity of glaucoma in the beta-blocker group. The hemorrohgic stroke was reported at a higher rate in the beta-blocker group. If it has been secondary to a fall, the chance of fall is greater in patients with severe glaucoma. Some of those who were on beta blockers had asthma. REVIEWER Dr. Khushwant Yadav SVKM’s NMIMS Deemed to be University, Mumbai, India REVIEW RETURNED 03-Dec-2019 1 BMJ Open: first published as 10.1136/bmjopen-2019-034361 on 22 July 2020. Downloaded from GENERAL COMMENTS A well written manuscript. Has explained the concept of linking the topical beta-blockers in Glaucoma with risks in cardiovascular and respiratory diseases. REVIEWER Syed Hamza Bin Waqar Dow Medical College, Pakistan REVIEW RETURNED 01-Jan-2020 GENERAL COMMENTS Perfectly balanced. REVIEWER Luis Puente Universidad Complutense de Madrid. Facultad de medicina Spain REVIEW RETURNED 09-Feb-2020 GENERAL COMMENTS This is a retrospective cohort study based in health records and so it has a series of inherent flaws: 1. In health records that have already been collected, not all pertinent risk factors are likely to have been identified and subsequently recorded. Therefore, as is typical of observational studies, only association and not causation can be inferred from the results of the above cohort study. This is because the observed association between glaucoma medications and the outcomes may have been the result of confounding. This is particularly worrisome when the associations are weak (RR< 2). In consequence the authors should be very cautious in their statements, because the evidence they provide is weak. 2. Many different healthcare professionals will have been involved in patient care, so the measurement of risk factors and outcome(s) throughout the database would probably not be fully accurate. It is possible that not all records were complete. 3. If patients who were part of the cohort identified in the above http://bmjopen.bmj.com/ study had incomplete records, it may have biased any observed associations. This will be particularly so if data were not missing at random—that is, if the reason for missing data was related to the risk factor ( medical treatment for galucoma or the outcome(s). 4. The period chosen for inclusion was long (10 years) and it may be difficult to ensure outcomes were measured consistently or using the same criteria. Furthermore the association between the risk factor(s) and the outcome or condition may have changed with time. What may have change the baseline hazard function. on September 25, 2021 by guest. Protected copyright. 5. The time lag between the exposition and the outcome is not shown. While these medications tend to be chronic, changes of treatment may have happened and 6. it is not clear if the patients were on beta blockers or the other medications at the moment at which the outcomes occurred. 7. The authors perform plenty of comparisons, but it is not clear if the adjusted their alfa-error for such a number of statistical tests Some but not all this limitations are recognized in the limitations section. Specific 1. Page 9, linr 40 : “Individuals without BBCD use were selected from the LHID2000 and matched to the BBCD cohort at a ratio of 1:1 based on the propensity score [15”]”. As the selection of the cohorts is key to understand potential biases, the authors need to explain very clearly what characteristic or characteristics were “matched” with this propensity score. What it at stakes here is 2 BMJ Open: first published as 10.1136/bmjopen-2019-034361 on 22 July 2020. Downloaded from whether the two populations belong to the same base population (i.e identical in all the characteristics except the expositions analyzed) or from the beginning they had differences which motivated different treatments and could be related to the outcomes. 2. Page 9, line 40 “The propensity score was calculated using a logistic regression model to estimate the probability of the BBCD status”. This is even more puzzling. Are the authors talking about patents without betablockers? 3. Page 9, line 20. Was the exposure to the drugs quantified ( I.e dose x time) 4. Page 10, line 34 We compared the distributions of demographic status…... Please clarify what do you mean by “distributions”. It appears that the authors wanted to mean groups. 5. Page 10,line 34 “demographic status” Do the authors mean demographic data? 6. Page 10, line 55 “The multivariable models were simultaneously adjusted for” I think that “also” fits better than simultaneously in this sentence. 7. Page 10,line 55 s the authors should describe how they managed the missing data 8. Page 10, line 55 s the authors should describe succinctly how they dealt with collinearity if it were present. 9. Page 10,line 55 s The authors must state what covariates were used in the adjusted models. 10. Page 10,line 55 The authors may check if they could find an exposure dependent association ( I.e the higher the exposure the higher the HR) to further strengthen the potential causal association between exposure an outcomes. 11. Table 1. The “p” values are meaningless since the authors matched the two samples, except for medications. None of the http://bmjopen.bmj.com/ differences is therefore the result of randomness, rather they are predetermined by the investigators to be similar or different. 12. Table 2. As the value of “p “is not a measure of the relevance of the differences and the authors already give the confidence interval , the asterisks should be omitted. 13. Table 2 abbreviations must be disclosed in the tables even it has been done in the text. The tables have to be self-reading. 14. Tables 3-4. The authors should clarify what information is on September 25, 2021 by guest. Protected copyright. presented in these tables. Can The “Beta-Blocker or combination drug” already contain any of the other drugs? 15. Tables 3-4. The authors should clarify what information is presented in these tables. Were these pairs of drugs used simultaneously or sequentially? 16. Page 17, line 56 “Second, selection bias was noted in this study. Because the NHIRD database only included patients who sought treatment, those who did not seek treatment may have been recruited into the control cohort”. Weren’t the control cohort also diagnosed from glaucoma? Then wasn’t the medications prescribed by the physicians?. Do you mean whether the patients retired the prescribed medication? 17. Page 13, line 52 “Our study demonstrated that in a large Taiwanese-Chinese population, topical beta-blocker use potentially increases risks of acute respiratory failure and stroke, 3 BMJ Open: first published as 10.1136/bmjopen-2019-034361 on 22 July 2020. Downloaded from but not CAD”. Unfortunately the design of the study does not allow to “demonstrate” causality. Use softer words such as “found an association” or something like that. 18. Page 15, line 19 “We believe that a different study will have a different outcome; thus, with regard to stroke, our results cannot be directly compared with the results of others”. This analysis is a bit escapist. If a true causal association between the exposition and an outcome exist, then the design of the study can’t be the reason for having opposite results, rather one of the two studies is biased. The authors have to convince the readers that it is not theirs. The same can be said with other commented associations for which the opposite was found in other studies such as for example CAD. 19. Page 16, line “This finding is very important; clinicians should be cautioned that the risk of respiratory failure increases when BBCD is combined with other glaucoma medications. Furthermore, we observed a statistically significant higher risk of stroke for patients who only used BBCD, both BBCD and CAI, or both BBCD and pilocarpine relative to those who did not use” the authors should be very cautious when recommending changes in clinical practice based in their retrospective observational study which found a weak association between medications and certain outcomes.