Accepted Manuscript Beta-adrenergic receptor blockers in hypertension Sheldon W. Tobe, MD, MSc CH (HPTE), FRCPC, FACP, FASH PII:
S0828-282X(14)00109-3
DOI:
10.1016/j.cjca.2014.02.015
Reference:
CJCA 1125
To appear in:
Canadian Journal of Cardiology
Received Date: 23 February 2014 Revised Date:
24 February 2014
Accepted Date: 24 February 2014
Please cite this article as: Tobe SW, Beta-adrenergic receptor blockers in hypertension, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.02.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Beta-adrenergic receptor blockers in hypertension Sheldon W Tobe, MD, MSc CH (HPTE), FRCPC, FACP, FASH1*, Division of Nephrology, Sunnybrook Health Sciences Centre,Toronto, Ontario, Canada,
RI PT
Complete Word count: 1591
Email: *Sheldon W Tobe: [email protected],
M AN U
Email: *Sheldon W Tobe: [email protected]
SC
*Correspondance: Dr. Sheldon W Tobe, Associate Professor of Medicine, The University of Toronto; Suite A240, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada
Phone: 416-480-6901 Fax: 416-480-694 Dialysis Division of Nephrology, Suite A240, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada Email: *Sheldon W Tobe: [email protected]
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Phone: 416-480-6901 Fax: 416-480-6940
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Key words: Hypertension, beta blocker, clinical practice guidelines
ACCEPTED MANUSCRIPT
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Beta-blockers have been used widely since the 1970s in the treatment of hypertension. In recent years however, the use of beta-blockers as an initial therapy in the treatment of hypertension has been challenged. The reasons for this controversy and the rationale for keeping beta blockers as a recommended treatment for hypertension are covered in the articles in this supplement.
M AN U
SC
Beta blockers are efficacious in the management of hypertension [1], but they are also known for their adverse effects on glucose metabolism and insulin levels. Insulin resistance in hypertension is associated with reduced skeletal muscle blood flow and reduced insulin-mediated glucose utilization[2]. Insulin resistance in obesity is also due in part to lower muscle blood flow and reduced glucose utilization [3]. Non-vasodilating beta blockers reduce muscle blood flow and impair insulin sensitivity [4]. Vasodilating beta blockers may counteract insulin resistance by increasing muscle blood flow, restoring glucose utilization. Improved insulin sensitivity was demonstrated for carvedilol in comparison to metoprolol [5] and nebivolol compared to atenolol [6]. These effects may be important from a hemodynamic perspective, as described by Messerli when comparing carvedilol to non-vasodilating beta blockers: “By shifting the hemodynamic profile from a pattern of normal cardiac output and high vascular resistance to a pattern of low cardiac output and high vascular resistance, traditional beta blockers make the hypertensive patient hemodynamically older and may accelerate the biological clock [7]”. The vasodilating beta blockers may thus offer a potential advantage in the management of hypertension.
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The impact on central hemodynamics, as described by Messerli above for non-vasodilating beta blockers, would be expected to lead to a lack of effect on central blood pressure, particularly in older patients. Lack of improvement in central blood pressure is theorized to be at least in part responsible for the higher risk of stroke found in outcome trials with beta blockers compared to other antihypertensives in older patients [8]. As is pointed out in many of the articles included in this supplement, the role of beta blockers in hypertension has been debated hotly since the publication of a meta-analysis on the subject by Lindholm in 2005 [8]. Following this publication, beta blockers were relegated to fourth line therapy by the National Institute for Health and Clinical Excellence (NICE) on the management of hypertension from the United Kingdom [9] and maintained only as a possible choice for antihypertensive treatment by the European Society of Hypertension [10] and the Eight Joint National Committee (JNC8) for hypertension in the United States [11]. Having chaired the Canadian Hypertension Education Program (CHEP) guidelines process for five years until 2012, I personally felt that there was a need to explain why Canadian hypertension guidelines continue to recommend beta blockers for the initial management of hypertension in patients under the age of 60 years, as well as part of combination therapy in hypertensive patients who require more than one agent. The release in Canada of nebivolol, a new vasodilatory beta blocker, provided the stimulus to review the beta blocker class in antihypertensive therapy. For this supplement, volunteer experts and participants in Canadian clinical practice guidelines groups such as CHEP were invited to write
ACCEPTED MANUSCRIPT
targeted review articles to inform clinicians managing hypertension in understanding how to use this class of antihypertensive confidently and safely.
M AN U
SC
RI PT
In the first article in the series Dr. Pierre Larochelle, who is the immediate past-President of Hypertension Canada, reviews thirty years of beta blocker clinical trials for hypertension, starting with the seminal beta blocker studies and concluding with a description of the major meta-analyses of the hypertension literature. Dr. Ross Feldman, past chair of CHEP and the first-President of Hypertension Canada, has summarized the physiology and pathophysiology of beta blockers, including data from his own research. Dr. Luc Poirier, who is presently Chair of the CHEP, gives a clinical pharmacologist’s review of the mechanism and actions of beta blockers and the heterogeneity within the class. In addition to variability in their durations of action, the various beta blockers have different properties. These properties affect how they will be used by clinicians managing patients with different conditions, including ischemic heart disease, heart failure and hypertension. These properties include water or lipid solubility, the potency and selectivity of blockade of the β1 receptor and other beta receptors, the ability of the molecule to stimulate β-adrenergic receptors (intrinsic sympathomimetic activity) and vasodilatory activity (a table showing the properties of the commonly used beta blockers is found in Larochelle’s paper).
EP
TE D
Dr. Jonathan Howlett, known for his role in heart failure guidelines, reviews nebivolol and the literature describing its use in hypertension and in heart disease. The article by Drs. Kuyper and Khan updates a previous meta-analysis performed by Khan from 2006, which motivated the CHEP position on recommending beta blockers as initial therapy for hypertension therapy in patients under 60 years of age, in response to the Lindholm meta-analysis a year earlier [12]. Their updated meta-analysis was carried out to determine if the efficacy of beta blockers in hypertension could be stratified by atenolol versus non-atenolol agents in patients under age 60 and in older patients. The role of beta blockers in atrial fibrillation and heart failure is discussed by Dr. Paul Dorian, who reviews the role of beta blockers in atrial fibrillation, in the context of comorbidities, including hypertension.
AC C
Beta blockers remain part of our armamentarium for the management of hypertension. The vasodilating beta blockers have a theoretical advantage over the non-vasodilating beta blockers. By preserving muscle blood flow they should improve the surrogate outcomes of insulin resistance and central blood pressure. Unfortunately, clinical outcome studies of vasodilating beta blockers compared to other antihypertensives and to the non-vasodilating beta blockers in the management of hypertension are lacking. Because of this lack of evidence, vasodilating beta blockers are not mentioned specifically as a sub-class in the CHEP hypertension recommendations. The theoretical advantages of vasodilating beta blockers should motivate the organization of prospective clinical trials to determine whether the use of vasodilating beta blockers is associated with hard outcome differences compared to non-vasodilating beta-receptor antagonists.
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
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Reference List
Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C, Chalmers J, Fagard R, Gleason A, Heritier S, Li N, Perkovic V, Woodward M, MacMahon S: Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: metaanalysis of randomised trials. BMJ 2008;336:1121-1123.
2
Baron AD, Brechtel-Hook G, Johnson A, Hardin D: Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 1993;21:129-135.
3
Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. Journal of Clinical Investigation 1990;85:1844.
4
Jacob S, Balletshofer B, Henriksen EJ, Volk A, Mehnert B, Loblein K, Haring HU, Rett K: Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers. Blood Press 1999;8:261-268.
5
Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ: Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. Journal of Hypertension 1996;14:489-494.
6
Poirier L, Cleroux J, Nadeau A, Lacourciere Y: Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. Journal of Hypertension 2001;19:14291435.
7
Messerli FH, Grossman E: beta-Blockers in hypertension: is carvedilol different? Am J Cardiol 2004;93:7B-12B.
8
Lindholm LH, Carlberg B, Samuelsson O: Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis. The Lancet 2005;366:1545-1553.
9
Krause T, Lovibond K, Caulfield M, McCormack T, Williams B: Management of hypertension: summary of NICE guidance. BMJ 2011;343:d4891.
M AN U
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EP
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10
SC
1
Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De BG, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S,
ACCEPTED MANUSCRIPT
RI PT
Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De BM, De GS, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA: 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159-2219. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Jr., Svetkey LP, Taler SJ, Townsend RR, Wright JT, Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-520.
12
Khan N, McAlister FA: Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-1742.
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11
S0828-282X(14)00109-3
DOI:
10.1016/j.cjca.2014.02.015
Reference:
CJCA 1125
To appear in:
Canadian Journal of Cardiology
Received Date: 23 February 2014 Revised Date:
24 February 2014
Accepted Date: 24 February 2014
Please cite this article as: Tobe SW, Beta-adrenergic receptor blockers in hypertension, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.02.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Beta-adrenergic receptor blockers in hypertension Sheldon W Tobe, MD, MSc CH (HPTE), FRCPC, FACP, FASH1*, Division of Nephrology, Sunnybrook Health Sciences Centre,Toronto, Ontario, Canada,
RI PT
Complete Word count: 1591
Email: *Sheldon W Tobe: [email protected],
M AN U
Email: *Sheldon W Tobe: [email protected]
SC
*Correspondance: Dr. Sheldon W Tobe, Associate Professor of Medicine, The University of Toronto; Suite A240, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada
Phone: 416-480-6901 Fax: 416-480-694 Dialysis Division of Nephrology, Suite A240, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada Email: *Sheldon W Tobe: [email protected]
TE D
Phone: 416-480-6901 Fax: 416-480-6940
AC C
EP
Key words: Hypertension, beta blocker, clinical practice guidelines
ACCEPTED MANUSCRIPT
RI PT
Beta-blockers have been used widely since the 1970s in the treatment of hypertension. In recent years however, the use of beta-blockers as an initial therapy in the treatment of hypertension has been challenged. The reasons for this controversy and the rationale for keeping beta blockers as a recommended treatment for hypertension are covered in the articles in this supplement.
M AN U
SC
Beta blockers are efficacious in the management of hypertension [1], but they are also known for their adverse effects on glucose metabolism and insulin levels. Insulin resistance in hypertension is associated with reduced skeletal muscle blood flow and reduced insulin-mediated glucose utilization[2]. Insulin resistance in obesity is also due in part to lower muscle blood flow and reduced glucose utilization [3]. Non-vasodilating beta blockers reduce muscle blood flow and impair insulin sensitivity [4]. Vasodilating beta blockers may counteract insulin resistance by increasing muscle blood flow, restoring glucose utilization. Improved insulin sensitivity was demonstrated for carvedilol in comparison to metoprolol [5] and nebivolol compared to atenolol [6]. These effects may be important from a hemodynamic perspective, as described by Messerli when comparing carvedilol to non-vasodilating beta blockers: “By shifting the hemodynamic profile from a pattern of normal cardiac output and high vascular resistance to a pattern of low cardiac output and high vascular resistance, traditional beta blockers make the hypertensive patient hemodynamically older and may accelerate the biological clock [7]”. The vasodilating beta blockers may thus offer a potential advantage in the management of hypertension.
AC C
EP
TE D
The impact on central hemodynamics, as described by Messerli above for non-vasodilating beta blockers, would be expected to lead to a lack of effect on central blood pressure, particularly in older patients. Lack of improvement in central blood pressure is theorized to be at least in part responsible for the higher risk of stroke found in outcome trials with beta blockers compared to other antihypertensives in older patients [8]. As is pointed out in many of the articles included in this supplement, the role of beta blockers in hypertension has been debated hotly since the publication of a meta-analysis on the subject by Lindholm in 2005 [8]. Following this publication, beta blockers were relegated to fourth line therapy by the National Institute for Health and Clinical Excellence (NICE) on the management of hypertension from the United Kingdom [9] and maintained only as a possible choice for antihypertensive treatment by the European Society of Hypertension [10] and the Eight Joint National Committee (JNC8) for hypertension in the United States [11]. Having chaired the Canadian Hypertension Education Program (CHEP) guidelines process for five years until 2012, I personally felt that there was a need to explain why Canadian hypertension guidelines continue to recommend beta blockers for the initial management of hypertension in patients under the age of 60 years, as well as part of combination therapy in hypertensive patients who require more than one agent. The release in Canada of nebivolol, a new vasodilatory beta blocker, provided the stimulus to review the beta blocker class in antihypertensive therapy. For this supplement, volunteer experts and participants in Canadian clinical practice guidelines groups such as CHEP were invited to write
ACCEPTED MANUSCRIPT
targeted review articles to inform clinicians managing hypertension in understanding how to use this class of antihypertensive confidently and safely.
M AN U
SC
RI PT
In the first article in the series Dr. Pierre Larochelle, who is the immediate past-President of Hypertension Canada, reviews thirty years of beta blocker clinical trials for hypertension, starting with the seminal beta blocker studies and concluding with a description of the major meta-analyses of the hypertension literature. Dr. Ross Feldman, past chair of CHEP and the first-President of Hypertension Canada, has summarized the physiology and pathophysiology of beta blockers, including data from his own research. Dr. Luc Poirier, who is presently Chair of the CHEP, gives a clinical pharmacologist’s review of the mechanism and actions of beta blockers and the heterogeneity within the class. In addition to variability in their durations of action, the various beta blockers have different properties. These properties affect how they will be used by clinicians managing patients with different conditions, including ischemic heart disease, heart failure and hypertension. These properties include water or lipid solubility, the potency and selectivity of blockade of the β1 receptor and other beta receptors, the ability of the molecule to stimulate β-adrenergic receptors (intrinsic sympathomimetic activity) and vasodilatory activity (a table showing the properties of the commonly used beta blockers is found in Larochelle’s paper).
EP
TE D
Dr. Jonathan Howlett, known for his role in heart failure guidelines, reviews nebivolol and the literature describing its use in hypertension and in heart disease. The article by Drs. Kuyper and Khan updates a previous meta-analysis performed by Khan from 2006, which motivated the CHEP position on recommending beta blockers as initial therapy for hypertension therapy in patients under 60 years of age, in response to the Lindholm meta-analysis a year earlier [12]. Their updated meta-analysis was carried out to determine if the efficacy of beta blockers in hypertension could be stratified by atenolol versus non-atenolol agents in patients under age 60 and in older patients. The role of beta blockers in atrial fibrillation and heart failure is discussed by Dr. Paul Dorian, who reviews the role of beta blockers in atrial fibrillation, in the context of comorbidities, including hypertension.
AC C
Beta blockers remain part of our armamentarium for the management of hypertension. The vasodilating beta blockers have a theoretical advantage over the non-vasodilating beta blockers. By preserving muscle blood flow they should improve the surrogate outcomes of insulin resistance and central blood pressure. Unfortunately, clinical outcome studies of vasodilating beta blockers compared to other antihypertensives and to the non-vasodilating beta blockers in the management of hypertension are lacking. Because of this lack of evidence, vasodilating beta blockers are not mentioned specifically as a sub-class in the CHEP hypertension recommendations. The theoretical advantages of vasodilating beta blockers should motivate the organization of prospective clinical trials to determine whether the use of vasodilating beta blockers is associated with hard outcome differences compared to non-vasodilating beta-receptor antagonists.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
RI PT
Reference List
Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C, Chalmers J, Fagard R, Gleason A, Heritier S, Li N, Perkovic V, Woodward M, MacMahon S: Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: metaanalysis of randomised trials. BMJ 2008;336:1121-1123.
2
Baron AD, Brechtel-Hook G, Johnson A, Hardin D: Skeletal muscle blood flow. A possible link between insulin resistance and blood pressure. Hypertension 1993;21:129-135.
3
Laakso M, Edelman SV, Brechtel G, Baron AD: Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. Journal of Clinical Investigation 1990;85:1844.
4
Jacob S, Balletshofer B, Henriksen EJ, Volk A, Mehnert B, Loblein K, Haring HU, Rett K: Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers. Blood Press 1999;8:261-268.
5
Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ: Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. Journal of Hypertension 1996;14:489-494.
6
Poirier L, Cleroux J, Nadeau A, Lacourciere Y: Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. Journal of Hypertension 2001;19:14291435.
7
Messerli FH, Grossman E: beta-Blockers in hypertension: is carvedilol different? Am J Cardiol 2004;93:7B-12B.
8
Lindholm LH, Carlberg B, Samuelsson O: Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis. The Lancet 2005;366:1545-1553.
9
Krause T, Lovibond K, Caulfield M, McCormack T, Williams B: Management of hypertension: summary of NICE guidance. BMJ 2011;343:d4891.
M AN U
TE D
EP
AC C
10
SC
1
Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De BG, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S,
ACCEPTED MANUSCRIPT
RI PT
Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De BM, De GS, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA: 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159-2219. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Jr., Svetkey LP, Taler SJ, Townsend RR, Wright JT, Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-520.
12
Khan N, McAlister FA: Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737-1742.
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