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The BMJ (formerly the British Medical Journal) is an international peer reviewed medical journal and a fully “online first” publication. Our "continuous publication" model means that all articles appear on bmj.com before being included in an issue of the print journal. The website is updated daily with The BMJ’s latest original research, education, news, and comment articles, as well as podcasts, videos, and blogs. The BMJ's team is based mainly in London, although we also have editors elsewhere in Europe, in the US, and in India.

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  • Reviewer(s)' Comments to Author:

    Reviewer: 1

    Recommendation:

    Comments: Overall well written, however, the major drawback relates to how the data are presented. On Page 12, authors state, "The baseline characteristics of all study participants are shown in Table 1." The groups shown in table 1 are the "outcome groups - All-cause mortality versus Cardiovascular mortality" whereas these should have been the "study groups Atenolol versus Metoprolol". I am a clinician first, and need to see data presented in the proper form. At present, it is unclear to determine if the two study groups at start of study was similar or not, as the analyses of the further data depends highly on this. I understand that there may not be significant baseline characteristics between the two study groups but the table 1, in its present form doesn't give information to the reader if there is a baseline difference or not. Table one should be presented properly and rewritten to describe the characteristics of the "study groups - Atenolol versus Metoprolol".

    It is fine to provide the number of co-morbidities present in each group and outcomes in relation to those, however, specific co-morbid diagnosis, like presence/absence of diabetes, ischemic heart disease(including angina, history of myocardial infarction, CABG) and presence of absence of congestive heart failure should be given for each group as indication and outcome may vary. The Table 2 should be modified both by identifying proper study groups and type of co-morbidities.

    Before considering this paper, this major drawback needs to be corrected and would not recommend its publication in present form.

    Additional Questions: Please enter your name: Malvinder Parmar

    Job Title: Associate Professor

    Institution: Northern Ontario School of Medicine

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: No

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here: No competing interests. None to declare.

    Reviewer: 2

    Recommendation:

    Comments: This paper describes a well conducted retrospective cohort study of 52,451 Chinese patients from Hong Kong who were treated with either metoprolol or atenolol for hypertension. Anonymized patients were taken from a electronic clinical management system in use in Hong Kong. Demographic information, prescription details and clinical diagnoses were available for most patients attending all public clinical settings. The patients were then followed for 5 years to assess the incidence of all-cause and cardiovascular mortality (composite of coronary heart disease, heart failure and stroke). The investigators found that hypertensive patients treated with metoprolol were 1.13 times as likely to die of any cause and 1.56 times as likely to die from a cardiovascular cause. The methods and analysis were appropriate for the research question. The discussion was well done and limitations acknowledged. I have only 2 minor concern that should be addressed. The authors state that the database has been validated for sociodemographic information and prescription profiles. They also should add whether the case definitions used to identify patients with hypertension and other chronic diseases have been validated. In the introduction there is reference to a paper by Joffres related to hypertension control. There is a more recent paper which shows hypertension control rates in Canada have improved. (Finlay A. McAlister, MD MSc⇓, Kathryn Wilkins, MSc, Michel Joffres, MD PhD, Frans H.H. Leenen, MD PhD, George Fodor, MD PhD, Marianne Gee, MSc, Mark S. Tremblay, PhD, Robin Walker, MSc, Helen Johansen, PhD, Norm Campbell, MD Changes in the rates of awareness, treatment and control of hypertension in Canada over the past two decades. CMAJ June 14, 2011 vol. 183 no. 9 First published May 16, 2011, doi: 10.1503/cmaj.101767)

    Additional Questions: Please enter your name: Richard Birtwhistle

    Job Title: Professor of Family Medicine and Public Health Sciences

    Institution: Queen's University, Kingston Ontario Canada

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: Yes

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here: I have received research funding from the Canadian Institutes for Health Research, the Public Health Agency of Canada and the Ministry of Health and Long Term Care of Ontario.

    Reviewer: 3

    Recommendation:

    Comments: Nicely done comparative effectiveness study using a new user design and appropriate adjustments including a propensity score-matched comparison conducted in Hong Kong; I've made suggestions for improving the clarity of the paper below.

    Main issue is the surprising results since other comparative effectiveness studies found no difference between atenolol and metoprolol (Arch Intern Med 2012;172:1406-12 for HTN patients and Am J Cardiol 2001;87:823-26 for AMI patients). In fact, indirect comparisons using RCTs suggested that, if anything, atenolol benefits were less than those seen with metoprolol (Lancet 2004;364:1684-89 and 2005;366:1545-53 for HTN) or no appreciable difference between BB (Ann Intern Med 2009;150:784-794 for CHF). So, I'm left wondering why the difference? I suppose different BB could have different effects in Chinese patients, but before making that statement I really think you'd need an RCT comparing atenolol vs. metoprolol in Chinese patients to make absolutely certain - given that most guidelines don't recommend BB as first line antihypertensive drugs for uncomplicated HTN anyway, I doubt this is an important enough question to warrant the cost of such a trial (not sure who would even fund it).

    Some suggestions for the authors:

    1. It would be helpful to include some statement about the validity of the prescribing data and what information is included in the Hong Kong Clinical Management System - they tell us the data field is 99.8% complete but does the prescribing data include drug, dose, and amount dispensed, does it include inpatient and outpatient prescriptions, does it include prescribing data for the entire population, etc?
    2. In the same vein, providing some statement about the accuracy of the comorbidity data and clinical data such as BP which are apparently in the electronic database would be helpful.
    3. How accurate is cause of death coding in their database?
    4. I am not clear on whether patients were censored when another antihypertensive agent was added or just when they had an event or stopped/switched away from atenolol or metoprolol? I'd encourage the authors to make this explicit in their analytic plan. I thought these patients were excluded in one of the sensitivity analyses after reading the methods section, but that's not what the last column in Table 4 implies.
    5. Was PDC calculated for all medications the patient(s) were on, or just the atenolol or metoprolol?
    6. I'd suggest re-doing Table 1 to show the baseline characteristics of those prescribed atenolol in one column and metoprolol in another column. I'd also suggest expanding the comorbidity section to describe the frequency of DM, CAD, CHF, COPD, CKD, etc in those prescribed atenolol vs. those prescribed metoprolol.
    7. I found Table 2 confusing. The title (and the text of the results section) implied the authors were going to provide the aHR for metoprolol users vs. atenolol users in each subgroup defined in the rows of Table 2, but that's not what is reported in each cell. Instead, the rows appear to report the aHR for each subgroup vs. the referent chosen within each row (ex. aHR for death was 11.13 for patients aged 70 or older compared to those aged <49). I think the authors either need to change the title and associated text in the results section or change the contents of the cells in the table.
    8. Same comment for Table 3.
    9. I'd suggest including subgroup analyses to examine outcomes in atenolol users vs. metoprolol users without DM or vascular disease at baseline (if Tables 2 and 3 are modified then this would correspond to the row for 0 comorbidities) as this would be closer to the population studied in Parker's study in Arch Inter Med 2012;172:1406-12.

    I'd welcome seeing a revision of this manuscript.

    Additional Questions: Please enter your name: Finlay McAlister

    Job Title: Professor

    Institution: University of Alberta

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: No

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here:

    If you elected during submission to send your article on to another journal the article will be transferred in 5 working days. If you intend to appeal against this decision please notify us before then. The journal(s) (if any) you have selected at submission are: If you want to speed up or stop this onward transmission please email the editorial office: papersadmin@bmj.com

    Reviewer: 1

    Recommendation:

    Comments: Overall well written, however, the major drawback relates to how the data are presented. On Page 12, authors state, "The baseline characteristics of all study participants are shown in Table 1." The groups shown in table 1 are the "outcome groups - All-cause mortality versus Cardiovascular mortality" whereas these should have been the "study groups Atenolol versus Metoprolol". I am a clinician first, and need to see data presented in the proper form. At present, it is unclear to determine if the two study groups at start of study was similar or not, as the analyses of the further data depends highly on this. I understand that there may not be significant baseline characteristics between the two study groups but the table 1, in its present form doesn't give information to the reader if there is a baseline difference or not. Table one should be presented properly and rewritten to describe the characteristics of the "study groups - Atenolol versus Metoprolol".

    It is fine to provide the number of co-morbidities present in each group and outcomes in relation to those, however, specific co-morbid diagnosis, like presence/absence of diabetes, ischemic heart disease(including angina, history of myocardial infarction, CABG) and presence of absence of congestive heart failure should be given for each group as indication and outcome may vary. The Table 2 should be modified both by identifying proper study groups and type of co-morbidities.

    Before considering this paper, this major drawback needs to be corrected and would not recommend its publication in present form.

    Additional Questions: Please enter your name: Malvinder Parmar

    Job Title: Associate Professor

    Institution: Northern Ontario School of Medicine

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: No

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here: No competing interests. None to declare.

    Reviewer: 2

    Recommendation:

    Comments: This paper describes a well conducted retrospective cohort study of 52,451 Chinese patients from Hong Kong who were treated with either metoprolol or atenolol for hypertension. Anonymized patients were taken from a electronic clinical management system in use in Hong Kong. Demographic information, prescription details and clinical diagnoses were available for most patients attending all public clinical settings. The patients were then followed for 5 years to assess the incidence of all-cause and cardiovascular mortality (composite of coronary heart disease, heart failure and stroke). The investigators found that hypertensive patients treated with metoprolol were 1.13 times as likely to die of any cause and 1.56 times as likely to die from a cardiovascular cause. The methods and analysis were appropriate for the research question. The discussion was well done and limitations acknowledged. I have only 2 minor concern that should be addressed. The authors state that the database has been validated for sociodemographic information and prescription profiles. They also should add whether the case definitions used to identify patients with hypertension and other chronic diseases have been validated. In the introduction there is reference to a paper by Joffres related to hypertension control. There is a more recent paper which shows hypertension control rates in Canada have improved. (Finlay A. McAlister, MD MSc⇓, Kathryn Wilkins, MSc, Michel Joffres, MD PhD, Frans H.H. Leenen, MD PhD, George Fodor, MD PhD, Marianne Gee, MSc, Mark S. Tremblay, PhD, Robin Walker, MSc, Helen Johansen, PhD, Norm Campbell, MD Changes in the rates of awareness, treatment and control of hypertension in Canada over the past two decades. CMAJ June 14, 2011 vol. 183 no. 9 First published May 16, 2011, doi: 10.1503/cmaj.101767)

    Additional Questions: Please enter your name: Richard Birtwhistle

    Job Title: Professor of Family Medicine and Public Health Sciences

    Institution: Queen's University, Kingston Ontario Canada

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: Yes

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here: I have received research funding from the Canadian Institutes for Health Research, the Public Health Agency of Canada and the Ministry of Health and Long Term Care of Ontario.

    Reviewer: 3

    Recommendation:

    Comments: Nicely done comparative effectiveness study using a new user design and appropriate adjustments including a propensity score-matched comparison conducted in Hong Kong; I've made suggestions for improving the clarity of the paper below.

    Main issue is the surprising results since other comparative effectiveness studies found no difference between atenolol and metoprolol (Arch Intern Med 2012;172:1406-12 for HTN patients and Am J Cardiol 2001;87:823-26 for AMI patients). In fact, indirect comparisons using RCTs suggested that, if anything, atenolol benefits were less than those seen with metoprolol (Lancet 2004;364:1684-89 and 2005;366:1545-53 for HTN) or no appreciable difference between BB (Ann Intern Med 2009;150:784-794 for CHF). So, I'm left wondering why the difference? I suppose different BB could have different effects in Chinese patients, but before making that statement I really think you'd need an RCT comparing atenolol vs. metoprolol in Chinese patients to make absolutely certain - given that most guidelines don't recommend BB as first line antihypertensive drugs for uncomplicated HTN anyway, I doubt this is an important enough question to warrant the cost of such a trial (not sure who would even fund it).

    Some suggestions for the authors:

    1. It would be helpful to include some statement about the validity of the prescribing data and what information is included in the Hong Kong Clinical Management System - they tell us the data field is 99.8% complete but does the prescribing data include drug, dose, and amount dispensed, does it include inpatient and outpatient prescriptions, does it include prescribing data for the entire population, etc?
    2. In the same vein, providing some statement about the accuracy of the comorbidity data and clinical data such as BP which are apparently in the electronic database would be helpful.
    3. How accurate is cause of death coding in their database?
    4. I am not clear on whether patients were censored when another antihypertensive agent was added or just when they had an event or stopped/switched away from atenolol or metoprolol? I'd encourage the authors to make this explicit in their analytic plan. I thought these patients were excluded in one of the sensitivity analyses after reading the methods section, but that's not what the last column in Table 4 implies.
    5. Was PDC calculated for all medications the patient(s) were on, or just the atenolol or metoprolol?
    6. I'd suggest re-doing Table 1 to show the baseline characteristics of those prescribed atenolol in one column and metoprolol in another column. I'd also suggest expanding the comorbidity section to describe the frequency of DM, CAD, CHF, COPD, CKD, etc in those prescribed atenolol vs. those prescribed metoprolol.
    7. I found Table 2 confusing. The title (and the text of the results section) implied the authors were going to provide the aHR for metoprolol users vs. atenolol users in each subgroup defined in the rows of Table 2, but that's not what is reported in each cell. Instead, the rows appear to report the aHR for each subgroup vs. the referent chosen within each row (ex. aHR for death was 11.13 for patients aged 70 or older compared to those aged <49). I think the authors either need to change the title and associated text in the results section or change the contents of the cells in the table.
    8. Same comment for Table 3.
    9. I'd suggest including subgroup analyses to examine outcomes in atenolol users vs. metoprolol users without DM or vascular disease at baseline (if Tables 2 and 3 are modified then this would correspond to the row for 0 comorbidities) as this would be closer to the population studied in Parker's study in Arch Inter Med 2012;172:1406-12.

    I'd welcome seeing a revision of this manuscript.

    Additional Questions: Please enter your name: Finlay McAlister

    Job Title: Professor

    Institution: University of Alberta

    Reimbursement for attending a symposium?: No

    A fee for speaking?: No

    A fee for organising education?: No

    Funds for research?: No

    Funds for a member of staff?: No

    Fees for consulting?: No

    Have you in the past five years been employed by an organisation that may in any way gain or lose financially from the publication of this paper?: No

    Do you hold any stocks or shares in an organisation that may in any way gain or lose financially from the publication of this paper?: No

    If you have any competing interests http://bit.ly/VW8GVB'target='_new'(please> see BMJ Group policy ) please declare them here:

    Submitted to
    Ongoing discussion
  • Comments: Overall well written, however, the major drawback relates to how the data are presented. On Page 12, authors state, "The baseline characteristics of all study participants are shown in Table 1." The groups shown in table 1 are the "outcome groups - All-cause mortality versus Cardiovascular mortality" whereas these should have been the "study groups Atenolol versus Metoprolol". I am a clinician first, and need to see data presented in the proper form. At present, it is unclear to determine if the two study groups at start of study was similar or not, as the analyses of the further data depends highly on this. I understand that there may not be significant baseline characteristics between the two study groups but the table 1, in its present form doesn't give information to the reader if there is a baseline difference or not. Table one should be presented properly and rewritten to describe the characteristics of the "study groups - Atenolol versus Metoprolol".

    It is fine to provide the number of co-morbidities present in each group and outcomes in relation to those, however, specific co-morbid diagnosis, like presence/absence of diabetes, ischemic heart disease(including angina, history of myocardial infarction, CABG) and presence of absence of congestive heart failure should be given for each group as indication and outcome may vary. The Table 2 should be modified both by identifying proper study groups and type of co-morbidities.

    Before considering this paper, this major drawback needs to be corrected and would not recommend its publication in present form.

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