Author's Accepted Manuscript
The Metabolic Syndrome, Atrial Fibrillation and Stroke: Tackling An Emerging Epidemic Reza Hajhosseiny MBBS BSc, Gareth K. Matthews MBBS PhD, Gregory YH Lip MD FRCP DFM FACC FESC
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)00812-7 http://dx.doi.org/10.1016/j.hrthm.2015.06.038 HRTHM6337
To appear in:
Heart Rhythm
Cite this article as: Reza Hajhosseiny MBBS BSc, Gareth K. Matthews MBBS PhD, Gregory YH Lip MD FRCP DFM FACC FESC, The Metabolic Syndrome, Atrial Fibrillation and Stroke: Tackling An Emerging Epidemic, Heart Rhythm, http://dx.doi. org/10.1016/j.hrthm.2015.06.038 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 galley proof before it is published in its final citable 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.
The metabolic syndrome, atrial fibrillation and stroke: tackling an emerging epidemic Short/Running Title: Metabolic syndrome, Atrial Fibrillation and Stroke
Reza Hajhosseiny MBBS BSc1*, Gareth K. Matthews MBBS PhD2 and Gregory YH Lip MD FRCP DFM FACC FESC3,4
1
BHF Centre of Cardiovascular Excellence, St. Thomas’ Hospital, Westminster Bridge Road,
London, SE1 7EH, UK 2
Department of Physiology, Development and Neuroscience, University of Cambridge,
Downing Site, Cambridge, CB2 3EG, UK 3
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham,
B18 7QH, UK 4
Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health,
Aalborg University, Aalborg, Denmark
* Corresponding author (email [email protected]) Keywords Metabolic syndrome, Atrial fibrillation, Stroke, NOACs, Warfarin, Anticoagulation Abbreviations AF-Atrial Fibrillation, NOAC(s)-Non vitamin K antagonist Oral Anticoagulation drugs, BMI-Body Mass Index, WHO-World Health Organisation, VKA-Vitamin K Antagonists, TTR-Time in Therapeutic Range
Conflicts of interest G.Y.H.L. declares the following: Speaker’s Bureau – Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Sanofi Aventis; Consultant/Advisory Boards – Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi Sankyo, Biotronik, Medtronic, Portola, Boehringer Ingelheim. 1
Abstract
The prevalence of atrial fibrillation (AF) and AF-related stroke is set to increase dramatically in coming decades, with developing regions such as Latin America experiencing the greatest impact. These trends are primarily driven by aging populations and by the increasing prevalence of metabolic syndrome. Metabolic syndrome describes an association between diabetes, hypertension, obesity, dyslipidaemia and an increased risk of cardiovascular disease. It is in large part the result of unbalanced diet and sedentary lifestyle. These essentially modifiable risk factors are becoming more prevalent with the widespread adoption of so-called Western lifestyles.
This review examines the physiology underlying the link between metabolic syndrome and AF. Next it highlights the importance of addressing lifestyle-related risk factors to mitigate the trend towards increasing AF prevalence. It then goes on to discuss the importance of stroke prevention therapy in patients with established AF, focusing on the relative merits of the various available options for anticoagulation. Given the recent availability of comprehensive data around the four currently available non-vitamin K antagonist oral anticoagulant drugs (NOACs), it concludes by discussing the relative merits of specific agents in individual patient groups. Key words atrial fibrillation, stroke, metabolic syndrome
Introduction – the growing impact of atrial fibrillation
Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major cause of morbidity and mortality.1 By predisposing to thromboembolism originating in the left atrial
2
appendage, AF gives rise to up to one fifth of all ischaemic strokes.2-6 AF is becoming increasingly common, posing a major challenge to healthcare systems worldwide: the United States (US), for example, has seen a 60% increase in AF-related hospitalisations over the last 20 years.7, 8 AF is expected to become five times more common over the coming decades, affecting some 12 million Americans by 2050.6, 9
The prevalence of AF will become an increasingly significant burden in developing countries. For example, the number of patients with AF in Venezuela is expected to increase from 230,000 today to more than 1 million by 2050.10 In China, the prevalence of AF in those over the age of 60 is estimated to rise from 3.9 million to 9 million by 2050, while in India; AF is expected to increase from 5 million to 7.5 million by 2050. 11 In a US privately insured population, the excess annual total cost of AF was $14,875 (p < 0.01), with AF five times as costly as non-AF individuals ($18,454 versus $3,579, respectively).12 Indeed, in a study of five European countries (Greece, Spain, Netherlands, Italy and Poland), the total annual cost of AF was €6.2 billion.13
At the same time, the risk of stroke associated with AF is increasing.14 Globally, deaths from stroke are expected to rise from just under 6 million per year in 2005 to over 8 million per year by 2030.15 Increases in the prevalence of, and stroke risk associated with, AF are driven by two main factors.
First, global populations are aging. Changes are particularly striking in the developing world. In Brazil, the population aged over 60 is expected to double from 15 million in 2002 to 30 million in 2020.16Advanced age is a clear risk factor for both the development of AF and for AF-associated stroke. According to the United Nations, a substantial increase in the
3
population of men and women over the age of 60 by 2050 is predicted to result in 5.2 million men and 3.1 million women with AF over the age of 60.17 There is a near-continuous relationship between age and AF prevalence: less than 1% of 55 – 59 year olds and more than 11% of over-85 year olds have AF.18 Age is also among the main determinants of stroke risk in this setting, with those aged over 75 being at a five-fold increased risk compared to those aged less than 65 (hazard ratio (HR) 5.28, 95% confidence interval (CI) 4.57 - 6.09).19 Second, the prevalence of lifestyle-related risk factors is increasing. Diabetes, hypertension, obesity and hyperlipidaemia are foremost among these. These risk factors are collectively referred to as the metabolic syndrome.20 The International Diabetes Federation has outlined a worldwide consensus definition of the metabolic syndrome: 21
1. Central obesity (defined as waist circumference ≥ 94cm for European men and ≥ 80cm for European women) 2. Plus any two of the following four factors: ·
raised TG level: ≥ 150 mg/dL (1.7 mmol/L)
·
reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males and < 50 mg/dL (1.29 mmol/L) in females
·
raised blood pressure: systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg
·
raised fasting plasma glucose (FPG) ≥ 100 mg/dL (5.6 mmol/L)
In the eight years between 1994 and 2002 the prevalence of metabolic syndrome among US adults increased from 24% to 35%, representing an additional 22 million individuals affected.22 As the trend towards populations in the developing world adopting Western lifestyles continues, a metabolic syndrome epidemic is steadily taking hold. Studies in
4
countries spanning Europe, Asia, and Latin America demonstrate the same concerning trends.23
This advancing epidemic will have a major public health impact. If expected trends continue, rates of death from cardiovascular disease and stroke in Latin America will triple by 2024.24 A recent systematic review in China showed stroke prevalence had increased from 5.54 per 1000 (95% CI 3.88–7.20) prior to 2000 to 8.34 per 1000 (95% CI 5.98–10.69) after 2000, with a current incidence of 2.5 million new strokes per year.25 South Asia constitutes approximately 22% of the world population but is estimated to account for up to 40% of worldwide stroke mortality, which will only increase with an ageing population combined with rising AF prevalence.26 It is important that the world takes notice of these emerging trends before they overwhelm healthcare systems, especially in those countries that can least afford it.
In this article we review the evidence for a mechanistic link between the metabolic syndrome and AF. We highlight the need to address lifestyle-related risk factors, which are modifiable, to reduce the risk of AF and stroke. Pragmatically, we stress the importance of providing individualised, patient-focused anticoagulation therapy to those individuals who develop AF in order to minimise their risk of stroke.
Pathophysiology and clinical epidemiology
The metabolic syndrome describes an association between diabetes, hypertension, obesity, dyslipidaemia (high triglyceride and low high-density lipoprotein levels) and an elevated risk
5
of cardiovascular disease in general.20, 27 The presence of metabolic syndrome increases a patient’s risk of developing AF and, for patients in AF, increases stroke risk (Figure 1).
>
Metabolic syndrome is a global phenomenon. In the United States and Latin America, it currently affects at least one in four adults. 28 Similarly, the prevalence among Indian adults is between 18% and 41% 28 Two key factors underlying an on going global rise in metabolic syndrome prevalence are an ageing population and increasing prevalence of obesity. 28 Worldwide obesity rates have nearly doubled since 1980, with the latest World Health Organisation (WHO) estimates suggesting over 1.4 billion adults 20 years of age and older are overweight, and approximately 500 million are obese. 29 In Europe, the prevalence of obesity has increased almost threefold over the last two decades to between 20 and 30% of the adult population today, with rates higher still in the USA at approximately 31%. 30 Worldwide, over 40 million children under the age of 5 are either overweight or obese 29 and, with childhood obesity a predictor of adult obesity, 31 current trends in the prevalence of obesity and subsequent metabolic syndrome are set to continue. A recent study showed the average annual total costs between patients with metabolic syndrome versus no metabolic syndrome differed by a magnitude of 1.6 ($5,732 vs. $3,581), increasing by an average of 24% per additional risk factor (P < 0.001).32 Increases in obesity rates are principally driven by worldwide increases in the intake of high calorie diet, processed carbohydrate and sugars in conjunction with sedentary lifestyle, as the world population shifts towards urbanisation.29, 33
6
Obesity not only contributes directly to the metabolic syndrome, it also increases the likelihood of developing other metabolic syndrome components. Being overweight/obese is associated with hyperlipidaemia, causing hypertriglyceridemia, a high level of low-density lipoprotein cholesterol and a low level of high-density lipoprotein cholesterol. 34, 35 Obesity, and in particular central obesity, is associated with insulin resistance. 36 Adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, proinflammatory cytokines and other factors that are involved in the development of insulin resistance. 36 Obesity is associated with increased urinary sodium retention, activation of the sympathetic nervous system, activation of the renin-angiotensin system and the release of adipokines, which ultimately lead to increased blood pressure and hypertension. 37
The metabolic syndrome and atrial fibrillation In a study of 28449 participants without AF at baseline, the metabolic syndrome was associated with increased risk of new-onset AF, with age adjusted hazard ratios (HR) for each component as follows: obesity-HR 1.64, hypertension-HR 1.69, low LDL-HR 1.52 and impaired fasting glucose-HR 1.35-1.44 (depending on the definition).38
In an electrophysiological study of 236 patients with AF, left atrial low voltage areas (a surrogate marker of left atrial fibrosis) were observed in 46% of patients with the metabolic syndrome vs. 8.2% patients without the metabolic syndrome; p
The Metabolic Syndrome, Atrial Fibrillation and Stroke: Tackling An Emerging Epidemic Reza Hajhosseiny MBBS BSc, Gareth K. Matthews MBBS PhD, Gregory YH Lip MD FRCP DFM FACC FESC
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)00812-7 http://dx.doi.org/10.1016/j.hrthm.2015.06.038 HRTHM6337
To appear in:
Heart Rhythm
Cite this article as: Reza Hajhosseiny MBBS BSc, Gareth K. Matthews MBBS PhD, Gregory YH Lip MD FRCP DFM FACC FESC, The Metabolic Syndrome, Atrial Fibrillation and Stroke: Tackling An Emerging Epidemic, Heart Rhythm, http://dx.doi. org/10.1016/j.hrthm.2015.06.038 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 galley proof before it is published in its final citable 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.
The metabolic syndrome, atrial fibrillation and stroke: tackling an emerging epidemic Short/Running Title: Metabolic syndrome, Atrial Fibrillation and Stroke
Reza Hajhosseiny MBBS BSc1*, Gareth K. Matthews MBBS PhD2 and Gregory YH Lip MD FRCP DFM FACC FESC3,4
1
BHF Centre of Cardiovascular Excellence, St. Thomas’ Hospital, Westminster Bridge Road,
London, SE1 7EH, UK 2
Department of Physiology, Development and Neuroscience, University of Cambridge,
Downing Site, Cambridge, CB2 3EG, UK 3
University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham,
B18 7QH, UK 4
Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health,
Aalborg University, Aalborg, Denmark
* Corresponding author (email [email protected]) Keywords Metabolic syndrome, Atrial fibrillation, Stroke, NOACs, Warfarin, Anticoagulation Abbreviations AF-Atrial Fibrillation, NOAC(s)-Non vitamin K antagonist Oral Anticoagulation drugs, BMI-Body Mass Index, WHO-World Health Organisation, VKA-Vitamin K Antagonists, TTR-Time in Therapeutic Range
Conflicts of interest G.Y.H.L. declares the following: Speaker’s Bureau – Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Sanofi Aventis; Consultant/Advisory Boards – Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi Sankyo, Biotronik, Medtronic, Portola, Boehringer Ingelheim. 1
Abstract
The prevalence of atrial fibrillation (AF) and AF-related stroke is set to increase dramatically in coming decades, with developing regions such as Latin America experiencing the greatest impact. These trends are primarily driven by aging populations and by the increasing prevalence of metabolic syndrome. Metabolic syndrome describes an association between diabetes, hypertension, obesity, dyslipidaemia and an increased risk of cardiovascular disease. It is in large part the result of unbalanced diet and sedentary lifestyle. These essentially modifiable risk factors are becoming more prevalent with the widespread adoption of so-called Western lifestyles.
This review examines the physiology underlying the link between metabolic syndrome and AF. Next it highlights the importance of addressing lifestyle-related risk factors to mitigate the trend towards increasing AF prevalence. It then goes on to discuss the importance of stroke prevention therapy in patients with established AF, focusing on the relative merits of the various available options for anticoagulation. Given the recent availability of comprehensive data around the four currently available non-vitamin K antagonist oral anticoagulant drugs (NOACs), it concludes by discussing the relative merits of specific agents in individual patient groups. Key words atrial fibrillation, stroke, metabolic syndrome
Introduction – the growing impact of atrial fibrillation
Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major cause of morbidity and mortality.1 By predisposing to thromboembolism originating in the left atrial
2
appendage, AF gives rise to up to one fifth of all ischaemic strokes.2-6 AF is becoming increasingly common, posing a major challenge to healthcare systems worldwide: the United States (US), for example, has seen a 60% increase in AF-related hospitalisations over the last 20 years.7, 8 AF is expected to become five times more common over the coming decades, affecting some 12 million Americans by 2050.6, 9
The prevalence of AF will become an increasingly significant burden in developing countries. For example, the number of patients with AF in Venezuela is expected to increase from 230,000 today to more than 1 million by 2050.10 In China, the prevalence of AF in those over the age of 60 is estimated to rise from 3.9 million to 9 million by 2050, while in India; AF is expected to increase from 5 million to 7.5 million by 2050. 11 In a US privately insured population, the excess annual total cost of AF was $14,875 (p < 0.01), with AF five times as costly as non-AF individuals ($18,454 versus $3,579, respectively).12 Indeed, in a study of five European countries (Greece, Spain, Netherlands, Italy and Poland), the total annual cost of AF was €6.2 billion.13
At the same time, the risk of stroke associated with AF is increasing.14 Globally, deaths from stroke are expected to rise from just under 6 million per year in 2005 to over 8 million per year by 2030.15 Increases in the prevalence of, and stroke risk associated with, AF are driven by two main factors.
First, global populations are aging. Changes are particularly striking in the developing world. In Brazil, the population aged over 60 is expected to double from 15 million in 2002 to 30 million in 2020.16Advanced age is a clear risk factor for both the development of AF and for AF-associated stroke. According to the United Nations, a substantial increase in the
3
population of men and women over the age of 60 by 2050 is predicted to result in 5.2 million men and 3.1 million women with AF over the age of 60.17 There is a near-continuous relationship between age and AF prevalence: less than 1% of 55 – 59 year olds and more than 11% of over-85 year olds have AF.18 Age is also among the main determinants of stroke risk in this setting, with those aged over 75 being at a five-fold increased risk compared to those aged less than 65 (hazard ratio (HR) 5.28, 95% confidence interval (CI) 4.57 - 6.09).19 Second, the prevalence of lifestyle-related risk factors is increasing. Diabetes, hypertension, obesity and hyperlipidaemia are foremost among these. These risk factors are collectively referred to as the metabolic syndrome.20 The International Diabetes Federation has outlined a worldwide consensus definition of the metabolic syndrome: 21
1. Central obesity (defined as waist circumference ≥ 94cm for European men and ≥ 80cm for European women) 2. Plus any two of the following four factors: ·
raised TG level: ≥ 150 mg/dL (1.7 mmol/L)
·
reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males and < 50 mg/dL (1.29 mmol/L) in females
·
raised blood pressure: systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg
·
raised fasting plasma glucose (FPG) ≥ 100 mg/dL (5.6 mmol/L)
In the eight years between 1994 and 2002 the prevalence of metabolic syndrome among US adults increased from 24% to 35%, representing an additional 22 million individuals affected.22 As the trend towards populations in the developing world adopting Western lifestyles continues, a metabolic syndrome epidemic is steadily taking hold. Studies in
4
countries spanning Europe, Asia, and Latin America demonstrate the same concerning trends.23
This advancing epidemic will have a major public health impact. If expected trends continue, rates of death from cardiovascular disease and stroke in Latin America will triple by 2024.24 A recent systematic review in China showed stroke prevalence had increased from 5.54 per 1000 (95% CI 3.88–7.20) prior to 2000 to 8.34 per 1000 (95% CI 5.98–10.69) after 2000, with a current incidence of 2.5 million new strokes per year.25 South Asia constitutes approximately 22% of the world population but is estimated to account for up to 40% of worldwide stroke mortality, which will only increase with an ageing population combined with rising AF prevalence.26 It is important that the world takes notice of these emerging trends before they overwhelm healthcare systems, especially in those countries that can least afford it.
In this article we review the evidence for a mechanistic link between the metabolic syndrome and AF. We highlight the need to address lifestyle-related risk factors, which are modifiable, to reduce the risk of AF and stroke. Pragmatically, we stress the importance of providing individualised, patient-focused anticoagulation therapy to those individuals who develop AF in order to minimise their risk of stroke.
Pathophysiology and clinical epidemiology
The metabolic syndrome describes an association between diabetes, hypertension, obesity, dyslipidaemia (high triglyceride and low high-density lipoprotein levels) and an elevated risk
5
of cardiovascular disease in general.20, 27 The presence of metabolic syndrome increases a patient’s risk of developing AF and, for patients in AF, increases stroke risk (Figure 1).
>
Metabolic syndrome is a global phenomenon. In the United States and Latin America, it currently affects at least one in four adults. 28 Similarly, the prevalence among Indian adults is between 18% and 41% 28 Two key factors underlying an on going global rise in metabolic syndrome prevalence are an ageing population and increasing prevalence of obesity. 28 Worldwide obesity rates have nearly doubled since 1980, with the latest World Health Organisation (WHO) estimates suggesting over 1.4 billion adults 20 years of age and older are overweight, and approximately 500 million are obese. 29 In Europe, the prevalence of obesity has increased almost threefold over the last two decades to between 20 and 30% of the adult population today, with rates higher still in the USA at approximately 31%. 30 Worldwide, over 40 million children under the age of 5 are either overweight or obese 29 and, with childhood obesity a predictor of adult obesity, 31 current trends in the prevalence of obesity and subsequent metabolic syndrome are set to continue. A recent study showed the average annual total costs between patients with metabolic syndrome versus no metabolic syndrome differed by a magnitude of 1.6 ($5,732 vs. $3,581), increasing by an average of 24% per additional risk factor (P < 0.001).32 Increases in obesity rates are principally driven by worldwide increases in the intake of high calorie diet, processed carbohydrate and sugars in conjunction with sedentary lifestyle, as the world population shifts towards urbanisation.29, 33
6
Obesity not only contributes directly to the metabolic syndrome, it also increases the likelihood of developing other metabolic syndrome components. Being overweight/obese is associated with hyperlipidaemia, causing hypertriglyceridemia, a high level of low-density lipoprotein cholesterol and a low level of high-density lipoprotein cholesterol. 34, 35 Obesity, and in particular central obesity, is associated with insulin resistance. 36 Adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, proinflammatory cytokines and other factors that are involved in the development of insulin resistance. 36 Obesity is associated with increased urinary sodium retention, activation of the sympathetic nervous system, activation of the renin-angiotensin system and the release of adipokines, which ultimately lead to increased blood pressure and hypertension. 37
The metabolic syndrome and atrial fibrillation In a study of 28449 participants without AF at baseline, the metabolic syndrome was associated with increased risk of new-onset AF, with age adjusted hazard ratios (HR) for each component as follows: obesity-HR 1.64, hypertension-HR 1.69, low LDL-HR 1.52 and impaired fasting glucose-HR 1.35-1.44 (depending on the definition).38
In an electrophysiological study of 236 patients with AF, left atrial low voltage areas (a surrogate marker of left atrial fibrosis) were observed in 46% of patients with the metabolic syndrome vs. 8.2% patients without the metabolic syndrome; p
