Use of Beta-Blockers as a First-Line Treatment for Primary Hypertension
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This systematic review aims to elucidate the effectiveness of beta-blockers in treating hypertension, given their removal from the JNC 8 report.
I have several criticisms:
Introduction.
Major:
I believe the introduction should be redrafted. It’s hard to follow the ideas in each paragraph and the main idea can't be found until the study's objective is highlighted in the last paragraph.
As it is, the introduction looks like the positioning of the authors about the JNC 8 report. Particularly, in the second paragraph, the authors should concisely explain why the panel members of the JNC 8 added back to the guidelines ACE-I inhibitors as first-line drugs for treating hypertension. The reasons why beta-blockers were removed from the JNC 8 report should also be highlighted. These actions could pave the way for the premises of the review.
Minor:
Why do the references in the introduction start with the number 10?
Methods.
Major:
I cannot say that the review shows up-to-date information about the use of beta-blockers as a first-line treatment for primary hypertension.
Why was the search for information from 1990 to February 2nd, 2021? This means that the scientific evidence published in the last three and a half years was not included in the study (other systematic reviews or meta-analyses, for instance). I’m wondering how this would impact the conclusions of the manuscript. I recommend searching for such information, reanalyzing the data, and supporting the conclusions with additional bases.
Minor:
A figure (or algorithm) showing the key steps of the methodology is recommended.
Results:
Major:
Introduce MAPHY and HAPPY studies to make these terms (acronyms) clear. Furthermore, as it is, the table in 3.1 cannot be interpreted. This scenario is repeated in the following points (3.2–3.5).
Discussion:
Major:
This section is underdeveloped. The main ideas should be discussed in individual paragraphs.
I got confused. Why do the authors intend to clarify the efficacy of beta-blockers for treating hypertension and claim that “the blood will stay static and form clots in the chambers, which might be the reason for the higher incidence of stroke in patients on beta-blockers (lines 297–298)?” Is this the main conclusion of the review?
The authors should discuss their findings, considering why beta-blockers were removed from the JNC 8 report.
Comments on the Quality of English Language
Extensive editing of the English language is required.
Author Response
Greetings and thank you for your valuable feedback. I have made an effort to correct all of the issues.
This systematic review aims to elucidate the effectiveness of beta-blockers in treating hypertension, given their removal from the JNC 8 report.
I have several criticisms:
Introduction. Major:
I believe the introduction should be redrafted. It’s hard to follow the ideas in each paragraph and the main idea can't be found until the study's objective is highlighted in the last paragraph.
As it is, the introduction looks like the positioning of the authors about the JNC 8 report. Particularly, in the second paragraph, the authors should concisely explain why the panel members of the JNC 8 added back to the guidelines ACE-I inhibitors as first-line drugs for treating hypertension. The reasons why beta-blockers were removed from the JNC 8 report should also be highlighted. These actions could pave the way for the premises of the review.
Introduction
It remains disappointing that high blood pressure continues to be the leading risk factor for global disability and death. Current monotherapy drugs are not very effective in lowering blood pressure [1]. Although treating hypertension in elderly patients has been shown to decrease cardiovascular morbidity and mortality in prospective intervention studies [2], treated hypertensive patients still have significantly higher rates of hypertension-related cardiovascular complications compared to people without hypertension [3]. According to the guidelines provided by the Eighth Joint National Committee (JNC 8) for managing hypertension in adults, there are currently four groups of medications recommended as the first-line treatment for primary hypertension [4].
The medications listed include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and calcium channel blockers. Beta-blockers were part of the previous evidence-based guideline released by the seventh Joint National Committee, JNC 7, but were removed in JNC 8. Although beta-blockers have been used as a first-line therapy for hypertension since the late 1960s [5] and have been widely used by physicians due to their cardioprotective properties in managing cardiac arrhythmias and preventing a second heart attack [6], they are no longer recommended as the first choice for initial treatment of most patients. Additionally, despite being recommended as the drug of choice in treating primary hypertension in JNC 6[7], angiotensin-converting enzyme inhibitors also faced a similar fate in recent years.
Similar to beta-blockers, Angiotensin-converting enzyme inhibitors, which are currently recommended as the preferred medication for treating primary hypertension, were previously removed from and then reinstated in the Joint National Committee's guidelines [7]. It is therefore reasonable to approach the panel board's decision with skepticism and investigate whether beta-blockers can still be used as first-line treatment for primary hypertension. As the evidence regarding the use of beta-blockers as first-line therapy for primary hypertension remains controversial, this article aimed to clarify the efficacy of beta-blockers by incorporating the data from all relevant randomized clinical trials and meta-analyses, using the composite outcome of major cardiovascular events. To find the reason behind the diverse effects of beta-blockers, a different approach was used. The study included similar trials with diverse inclusion criteria, such as different genders, nationalities, and other potential risk factors associated with primary hypertension [8, 9]. Furthermore, the article attempted to explore the variability in the results of beta-blocker trials by comparing outcomes in younger and older patients, as the pathophysiology of hypertension differs between these age groups [8, 10, 11].
Minor:
Why do the references in the introduction start with the number 10?
Corrected
Methods.
Major:
I cannot say that the review shows up-to-date information about the use of beta-blockers as a first- line treatment for primary hypertension.
Why was the search for information from 1990 to February 2nd, 2021? This means that the scientific evidence published in the last three and a half years was not included in the study (other systematic reviews or meta-analyses, for instance). I’m wondering how this would impact the conclusions of the manuscript. I recommend searching for such information, reanalyzing the data, and supporting the conclusions with additional bases.
I mentioned that beta-blockers used to be included in the previous evidence-based guidelines released by the seventh Joint National Committee (JNC 7), but they were removed in the JNC 8 guidelines. In fact, it was around the time when beta-blockers were removed from the guidelines.
Minor:
A figure (or algorithm) showing the key steps of the methodology is recommended.
Added already
Results:
Major:
Introduce MAPHY and HAPPY studies to make these terms (acronyms) clear. Furthermore, as it is, the table in 3.1 cannot be interpreted. This scenario is repeated in the following points (3.2–3.5).
I gave the references for both study which are number 16, 21
Discussion:
Major:
This section is underdeveloped. The main ideas should be discussed in individual paragraphs.
I got confused. Why do the authors intend to clarify the efficacy of beta-blockers for treating hypertension and claim that “the blood will stay static and form clots in the chambers, which might be the reason for the higher incidence of stroke in patients on beta-blockers (lines 297–298)?” Is this the main conclusion of the review?
The authors should discuss their findings, considering why beta-blockers were removed from the JNC 8 report.
Rewrite the discussion:
Discussion
In conclusion, despite the fact that all sources were peer-reviewed, published articles, additional information is necessary to identify the gaps between the studies. The primary gap identified was the age group. Most studies didn’t include patients aged 18 to 45. It is essential to conduct a thorough analysis of the specific effects and benefits of beta-blockers in each age group. While this study utilized meta-analyses to address this gap, further research is needed to validate the results. Another notable gap was the lack of exploration of the impact of race or ethnicity in all studies except for the systemic review study, as the majority of trial participants were white men. Each study had at least one major limitation. For instance, a few studies compared the combination of beta-blockers and diuretics to other medications, rather than examining the effectiveness of beta-blockers alone. These two drugs have different mechanisms of action. Beta-blockers directly affecting the heart receptors, B2, and slowing the heart rate.
On the other hand, diuretics decrease the body's fluid load, leading to a lower blood load for the heart to pump. Therefore, it is impossible to precisely differentiate the effect of each drug when they are added together. Additionally, some studies have defined primary hypertension as a diastolic blood pressure of 100 mm Hg, rather than using a systolic blood pressure of 140 mm Hg. Furthermore, one study included left ventricle hypertrophy as an inclusion criterion, while another study only included male participants. These factors can significantly impact the results. Most studies confirmed the additional myoprotective effects of beta-blockers in reducing myocardial infarction. However, these studies have concluded that beta-blockers are more effective and safer compared to diuretics but are less effective than angiotensin receptor blockers. Beta-blockers were found to be equally safe and effective as calcium channel blockers and angiotensin-converting enzyme inhibitors in reducing coronary heart disease, fatal and non-fatal myocardial infarction, congestive heart failure, and sudden death. However, they were found to be less effective than calcium channel blockers in reducing fatal and non-fatal strokes, which can be explained by the different mechanisms of action of these two groups of medications.
Calcium channel blockers function by blocking calcium channel receptors and preventing calcium from entering the heart muscle which is essential for muscle contractions. In contrast, beta-blockers target beta receptors on the heart, reducing heart contractions and protect the left ventricle from overwork and thickening. This is why beta-blockers have been used as a main treatment of congestive heart failure for decades, as they can reduce heart remodeling and prevent left ventricle hypertrophy. However, this reduced pumping action may lead to blood stay static and form blood clots in the chambers, potentially elevated the incidence of stroke in patients on beta-blockers. Further research is necessary to evaluate the efficacy of beta-blockers in managing primary hypertension.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for Authors
In the present manuscript, Izadi et al. reviewed the efficacy of beta blockers
in reducing coronary heart diseases, myocardial infarction, heart failure, and sudden death based on the available published data. Overall, it is a very concise review with detailed information. However, some sentences do not carry a precise meaning. It is suggested that authors should review the manuscript carefully and correct all the mistakes. Besides that, the following points need to be clarified.
Minor comments:
1. 1st line of the Abstract may be split into two.
2. “ myocardial infraction” should be “myocardial infarction.” Check throughout the manuscript.
3. “6 randomized controlled trials and 3 meta-analyses were chosen.” It should be placed before “The term words used were”.
4. “Even though, the benefits of treating hypertension in elderly patients via decrease of cardiovascular morbidity and mortality have been well documented in all the prospective intervention studies.” The meaning of this line is not clear to me.
5. “Based on the Eighth Joint National Committee, JNC 8, which is the most recent guide-41 lines published” Please edit to make a meaningful sentence.
6. Line #1101-1112: It is not clear what is “MAPHY Study” and what is “HAPPY study”. Please mention the full form of these.
7. Should “Happy” be in lowercase or uppercase?
8. Line 128: LIFE???
9. Line 145-146: CAPPP and STOP-2 ???
10. Line 172-173: NORDIL, STOP-2 ???
11. Should “Stop-2” be in lowercase or uppercase?
12. Please write a meaningful sentence: “In conclusion, even though all of the sources were peer-reviewed, published articles, more information is needed to find the gaps between the studies.”
Comments on the Quality of English Language
Overall, it is a very concise review with detailed information. However, some sentences do not carry a precise meaning. It is suggested that authors should review the manuscript carefully and correct all the mistakes.
Author Response
Greetings, and thank you for your valuable feedback. I have made an effort to correct all of the issues.
In the present manuscript, Izadi et al. reviewed the efficacy of beta blockers
in reducing coronary heart diseases, myocardial infarction, heart failure, and sudden death based on the available published data. Overall, it is a very concise review with detailed information. However, some sentences do not carry a precise meaning. It is suggested that authors should review the manuscript carefully and correct all the mistakes. Besides that, the following points need to be clarified.
Minor comments:
- 1st line of the Abstract may be split into
Revised and corrected
Even though Beta-blockers had been used as a first-line therapy for hypertension since the late 1960s, the Eighth Joint National Committee, JNC 8. This decision was based on the relatively weak evidence from previous studies, which found that first-line beta-blockers were less effective in reducing stroke and heart failure as the main outcomes.
Despite the general perception, the most common events caused by hypertension are death and MI, not stroke or heart failure. Therefore, this study aimed to clarify beta-blocker efficacy by incorporating the data from all relevant beta-blocker trials, using the composite outcome of major cardiovascular events.
- “Myocardial infraction” should be “myocardial infarction.” Check throughout the
Done
- “6 randomized controlled trials and 3 meta-analyses were chosen.” It should be placed before “The term words used were”.
Done
- “Even though, the benefits of treating hypertension in elderly patients via decrease of cardiovascular morbidity and mortality have been well documented in all the prospective intervention studies.” The meaning of this line is not clear to me
Corrected
Although treating hypertension in elderly patients has been shown to decrease cardiovascular morbidity and mortality in prospective intervention studies, treated hypertensive patients still have significantly higher rates of hypertension-related cardiovascular complications compared to people without hypertension
- “Based on the Eighth Joint National Committee, JNC 8, which is the most recent guide-41 lines published” Please edit to make a meaningful sentence.
Based on the Eighth Joint National Committee (JNC 8), there are currently four groups of medications recommended as the first-line treatment for primary hypertension.
- Line #1101-1112: It is not clear what is “MAPHY Study” and what is “HAPPY study”. Please mention the full form of these.
There are reference number next to these for clarification. MAPHY (16) and HAPPY(21)
- Should “Happy” be in lowercase or uppercase? Upper, and corrected
- Line 128: LIFE??? Name of other study reference (3)
- Line 145-146: CAPPP and STOP-2??? Name of other study
- Line 172-173: NORDIL, STOP-2??? Name of other study
- Should “Stop-2” be in lowercase or uppercase? Upper Case, Corrected
- Please write a meaningful sentence: “In conclusion, even though all of the sources were peer-reviewed, published articles, more information is needed to find the gaps between the ”
Rewrite Conclusion:
Beta-blockers were shown to be more effective than diuretics, which are one of the four recommended first-line medications. However, they were not as effective and safe as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers. More information is needed to fill the gaps between the studies.
At present, this information could potentially lead to the reintroduction of beta blockers as the first-line medications in primary hypertension.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for Authors
The manuscript has been thoroughly executed and is suitable for publication in the journal. The study significantly addresses the importance of beta blockers as first-line therapy for hypertension.
Comments on the Quality of English Language
The grammatical errors in the manuscript need to be checked.
Author Response
Greetings, and thank you for your valuable feedback.
Round 2
Reviewer 1 Report
Comments and Suggestions for Authors
I appreciate the authors’ responses.
Introduction
I can see that the authors improved the introduction section.
I have minor criticisms in this section:
Second paragraph:
…seventh Joint National Committee (JNC 7), but were…
It must show why beta-blockers were removed from the JNC 8 guidelines.
The last sentence is confusing, I think the main message of the paragraph is about beta-blockers.
Major criticisms
I still believe the manuscript lacks clarity. It seems that the results section is also the discussion section. Furthermore, the discussion section lacks references, which is unusual.
You could write only one section: “Results and discussion.”
The discussion section starts concluding, but you have a conclusion section.
I appreciate the authors’ efforts in improving their manuscript. Work is required to improve the clarity and show the manuscript's relevance.
Comments on the Quality of English Language
Moderate editing of English language required.
Author Response
Thank you for your feedback. I corrected it.
A) "Minor: The opening sentence: “ Even though Beta-blockers had been used as a first-line therapy for hypertension since the late 1960s, the Eighth Joint National Committee, JNC 8.” Is incomplete and revising is required. "
Corrected paragraph:
Even though Beta-blockers had been used as first-line therapy for hypertension since the late 1960s, the Eighth Joint National Committee, JNC 8, decided to no longer recommend them. This decision was based on the relatively weak evidence from previous studies, which found that first-line beta-blockers were less effective in reducing stroke and heart failure as the main outcomes.
B)MDPI recommendation:
I attached the Completed PRISMA checklist and PROSPERO registration data to the file. I will Email the PRISMA form one more time.
I appreciate your support and your help to improve this article.
Author Response File: Author Response.docx
