REVIEW For reprint orders, please contact: [email protected]
Atrial fibrillation in the elderly: a review
Fayaz A Hakim1 & Win-Kuang Shen*,2 ABSTRACT Atrial fibrillation (AF) is common in the elderly population. Elderly patients with AF are often asymptomatic, may have atypical presentation or may present with heart failure or thromboembolic complications. The optimal management strategy of AF in the elderly population is challenging. We present an overview of AF in elderly patients, in particular addressing the pros and cons of various management strategies, and provide a practical approach within the guidelines. Atrial fibrillation (AF) is a common cardiac arrhythmia affecting 2.2–5 million people in the USA [1,2] . AF accounts for significant morbidity and mortality and consumes a large portion of healthcare expenditures. Age is the most important predictor of the development of AF and progression from paroxysmal AF to permanent AF. The risk of AF, even in the absence of other cardiovascular disease, progressively increases after age of 40 years with steeper increases above 65 years [3] . The prevalence of AF is 2.3% in people above 40 years, 5.9% after 65 years and 10% in those above 80 years of age (ATRIA study) [4] . Approximately 70% of individuals with AF are between 65 and 85 years of age. As the patients are living longer, it is projected that by 2050 the majority of the patients with AF will be above 80 years [4] . Age-adjusted prevalence is higher for men than women. Elderly patients with AF tend to be asymptomatic (silent or subclinical AF) as their ventricular rates are better controlled for being less active and/or having concurrent atrioventricular (AV) nodal disease. They are less likely to report palpitations for the same reasons. The diagnosis is often made incidentally during an evaluation for other reasons. Elderly patients with AF often present with fatigue, stroke, worsening heart failure and/or angina. Those presenting with syncope often have concurrent sinus and AV nodal disease. Due to a high burden of AF and associated morbidity and mortality, screening programs for detecting AF in patients above 65 years of age has been started in many European countries. A mass-screening strategy in 6000 adults in the Swedish population aged 75–76 years showed 3% of participants had previously unidentified silent AF [5] . The cost-effective benefits of systematic screening of this target population by pulse check for irregularity during a physician visit followed by an electrocardiogram if an irregular pulse was detected were demonstrated in a randomized clinical trial (the SAFE study) [6] . Management of AF in elderly patients is challenging due to the fact that AF tends to be more persistent or permanent, age-related physiological changes predispose them to exaggerated pharmacological effects of antiarrhythmic agents (AAAs) and the efficacy and safety of catheter-based ablation is not well represented in clinical studies as highlighted in the Heart Rhythm Society, European Heart Rhythm Association, European Society of Cardiology and the European Cardiac Arrhythmia 2012 consensus statement [7] . An effective management strategy emphasizing older population is needed to halt the impact of AF on public health, which is growing at an exponential rate. The primary goal of this review is to address the pros and cons of various management strategies for AF in the elderly population and provide a practical approach within the ambient guidelines.
KEYWORDS
• ablations • anticoagulation • atrial fibrillation • drug therapy • elderly • practical
approach
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA Clinic Cardiac Electrophysiology, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA *Author for correspondence: Tel.: +480 791 7626; Fax: +480 301 8018; [email protected] 1 2
10.2217/FCA.14.32 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(6), 745–758
part of
ISSN 1479-6678
745
Review Hakim & Shen ●●Age-related cardiovascular changes
Before addressing management of AF in the elderly population, it is imperative to understand the age-related changes in cardiovascular systems that predispose them to the development of AF and altered drug pharmacokinetics and pharmacodynamics that have an impact in selecting AAAs and anticoagulants in these patients. Pathophysiology of AF Pathogenesis of AF is complex and not precisely understood. Age-related changes in the left atrium occur at structural, cellular and molecular levels, which are translated into electrophysiological abnormalities and predisposition to the development of AF. The anatomical and physiological changes in the aging atria have been demonstrated on electroanatomical mapping [8] . With advancing age, there is fatty infiltration and collagen and amyloid deposition in the left atrium. The number and size of atrial myocytes, pacemaker cells in sinoatrial and AV nodes and conduction tissue decrease and are subsequently replaced by fibrosis. These changes were first investigated in rodents [9] and later in human subjects [10] . The left atrial size, pressure and volume increases. These structural and anatomical changes result in loss of excitable tissue and conduction blocks that create a milieu for multiple re-entrant wavelets and hence AF [11] . Dilatation and remodeling of the left atrium causes increased dispersion of effective refractory period and activation of stretch-sensitive ion channels that trigger AF. Calcium plays an important role in normal electrical and mechanical functions of cardiac myocytes. Aging is associated with enhanced sodium/calcium (Na/Ca) exchanger function that results in cytosolic Ca 2+ overload. This causes shortening of action potential duration and decreased conduction velocity and predisposition to arrhythmias [12] . Oscillatory release of Ca 2+ from the sarcoplasmic reticulum between the normal beats generates spontaneous action potentials, which can trigger AF. Aging atria are more susceptible to AF by the other known mechanisms including upregulation of atrial-specific ultra-rapid delayed rectifier potassium (IK UR) currents that decrease the effective refractory period and promote microwavelets [13] , enhanced sympathetic drive and vagal tone, generation of free radical and altered gene expression. The pathophysiology of AF is summarized in Figure 1.
746
Future Cardiol. (2014) 10(6)
Aging & risk factors for AF A number of risk factors have been shown to be associated with the development of AF. In the Framingham Heart Study, age, diabetes mellitus, hypertension, congestive heart failure, coronary artery disease and valve disease were shown to be independent risk factors for AF in both sexes [14] . The risk factors for AF are summarized in Table 1. Medical comorbidities associated with AF are common in elderly patients. The prevalence of obesity is increasing among the elderly population. Obesity was linked to increasing incidence and prevalence of AF in the Olmsted County population and shown to be an independent predictor of AF [15] . Lack of physical activity in the elderly is common and may contribute to the development of obesity, hypertension and coronary artery disease. Obesity is a proinflammatory state, as evident by elevated levels of C-reactive protein and inflammation promoting atrial remodeling [16,17] . Age and obesity are independent risk factors for obstructive sleep apnea, which predisposes to the development and/ or recurrence of AF [18] . Altered adrenergic and vagal discharges, hypoxemia surges and activation of stretch-sensitive channels have been proposed mechanisms triggering AF in obstructive sleep apnea [19] . Diastolic dysfunction and heart failure with preserved ejection fraction is an independent predictor of AF in elderly patients. Other medical conditions that predispose to AF include impaired renal function, subclinical hyperthyroidism and chronic obstructive pulmonary disease, which are common in advanced age. Pharmacokinetics & pharmacodynamics of antiarrhythmia agents in elderly In general, the metabolism of drugs in the elderly population is slow due to altered pharmacokinetics. The metabolism of various AAAs used in the management of AF bears no exception. Absorption
Despite decreases in gastrointestinal motility, splanchnic blood flow and mucosal surface area, the absorption of antiarrhythmic drugs is not significantly affected with aging. However, due to decreased first-pass effect, the bioavailability of certain drugs, for example, propranolol, is increased resulting in systemic toxicity necessitating dose reduction [20] . Distribution
Due to change in body fat and water, the distribution of AAA may be significantly affected. With
future science group
Atrial fibrillation in elderly: a review
Structural heart disease • Hypertension • Heart failure • Coronary artery disease
Advanced age
Review
Modulating factors • Obesity • Diabetes • OSA
Left atrial dilatation and inflammation
• ↑ Interstitial fibrosis • ↓ Myocyte number
Left atrial remodeling
Local triggers • Pulmonary vein
• ↑ Dispersion of refractoriness • ↓ Conduction velocity
∆ lonic channel expression
Increased vulnerability to atrial fibrillation
Figure 1. Pathophysiology of atrial fibrillation. ↑: Increase; ↓: Decrease; OSA: Obstructive sleep apnea.
aging, total body fat increases and the volume of distribution of amiodarone is increased [21] . Similarly, due to decreases in total body water, volume of distribution of digoxin is reduced [22] . Since plasma proteins decrease with aging, free warfarin levels may increase and hence predispose to bleeding [23] .
hence, renally eliminated drugs like digoxin, procainamide, sotalol and dofetilide accumulate in elderly patients at conventional doses and dose reductions based on calculated GFR are needed [25] . The major metabolic pathways of AAA and oral anticoagulants are summarized in Box 1.
Metabolism
●●Age & ionic channels & AAA-targeted
Due to reduction in the liver mass and functions, the metabolism of propafenone, amiodarone and propranolol is reduced [24] . Reduction in the activity of CYP450 monooxygenases decreases the metabolism of flecainide, propafenone, amiodarone, disopyramide, metoprolol and verapramil [24] .
proteins
Elimination
Aging is associated with progressive loss of renal mass and glomerular filtration rate (GFR);
future science group
With advancing age, the properties and the functions of specific ion channels are altered and are associated with various electrophysiological abnormalities and arrhythmias. These are summarized in Table 2. Atria-specific IK UR currents are upregulated and as a result, their enhanced activity predisposes to the development of AF [26] . Decreased activity of L-type Ca 2+ currents (ICaL) in the aging atrial myocardium results in conduction abnormality with
www.futuremedicine.com
747
Review Hakim & Shen Table 1. Risk factors and their odds ratio for predisposing to atrial fibrillation. Risk factors
Published HR range
Validated Age Male gender Hypertension Valve disease Diabetes CHF MI Genetic factors
1.03–5.9 (per year) 1.5–2.7 1.1–2.7 1.8–3.2 1.4–2.2 1.4–7.7 1.4–2.6 1.1–1.9
Less well validated Obesity OSA Subclinical hyperthyroidism COPD CKD Endurance sports Smoking Alcohol B-type natriuretic peptide CRP, IL and TNF-α Troponin-T
1.03–2.0 (per BMI) 2.2–3.0 1.9–3.1 1.5–2.0 1.4–1.9 – 1.3–1.5 1.3–1.5 1.2–4.0 0.9–2.2 1.2
CHF: Congestive heart failure; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; HR: Hazard ratio; IL: Interleukin; MI: Myocardial infarction; OSA: Obstructive sleep apnea. Adapted with permission from the European Heart Association and the European Society of Cardiology.
resulting microreentry [27] . Dysfunction of the ryanodine receptor in a senescent heart has been shown to promote enhanced Ca 2+ activity and predisposition to AF [27] . Age-related changes in the ion channels also alter their responsiveness to various AAAs with predisposition to the drug toxicities. Class I antiarrhythmic drugs, β-blockers and calcium channel blockers can precipitate or worsen sinus node dysfunction or AV conduction blocks. Class Ia and III agents are potassium channel blockers and may precipitate arrhythmia by worsening age-related QT interval prolongation. Age & associated comorbid conditions The presence of medical comorbidities in aging patients may have a negative impact on organ functions following administration of antiarrhythmic drugs (Table 3) . Individuals with depressed ventricular function may experience decompensation of heart failure following administration of β-blockers, calcium channel blockers and class I agents. Similarly, β-blockers and propafenone may precipitate acute exacerbation of obstructive lung diseases. Elderly patients have blunted baroreceptor reflexes and may
748
Future Cardiol. (2014) 10(6)
experience orthostatic symptoms, falls or even syncope following administration of sotalol and disopyramide due to their vasodilating properties. Polypharmacy is common in older patients, and drug interactions associated with various antiarrhythmic medications pose a challenge in selecting the best agent. Medications with anticholinergic properties, for example, disopyramide, can precipitate glaucoma, constipation and urinary retention. Coronary artery disease is common in the aging population and use of Class Ic agents in such situations may precipitate malignant ventricular arrhythmia due to their proarrhythmic properties. Many elderly patients with heart failure and hypertension are on diuretics and are at risk of hypokalemia. Concurrent use of digitalis in such patients predisposes them to digitalis toxicity. Elderly patients, due to high risk of stroke, may be on dipyridamole and may develop complete heart block when exposed to adenosine. Many AAAs are metabolized by the cytochrome oxidase system, the function of which decreases with aging. Concurrent use of medications that are metabolized by cytochrome oxidase isoenzymes, may have a profound effect on the metabolism of antiarrhythmic drugs necessitating dose adjustments. Clinically relevant issues regarding drug therapy in elderly patients with AF are outlined in Box 2. Anticoagulation for stroke prevention in the aging population The risk of stroke in AF increases fivefold with every decade of life after age 59 years, reaching 36.2% for ages 80–89 years [28] . Patients older than 75 years are eligible for anticoagulation even in the absence of other risk factors based on CHADS2 or CHA2DS2-Vasc score. Warfarin has been demonstrated to be significantly superior to aspirin in these patients (relative risk: 0.48; 95% CI: 0.28–20.80; p = 0.003) [29] . However, elderly patients have a tendency to bleed, are sensitive to warfarin, are more likely to be on antiplatelet agents and are at risk for falls. These factors predispose them to a higher risk of bleeding. The cumulative incidence of major hemorrhage during anticoagulation with warfarin for patients ≥80 years of age is 13.1 per 100 person-years versus 4.7 for those 65 years, drugs [aspirin/nonsteroidal anti-inflammatory drug or alcohol]) is a useful clinical tool to identify patients at risk of bleeding with anticoagulation. Patients with a score ≥3 are considered to be at a higher risk of bleeding while on anticoagulants. Nevertheless, the score should not be used alone to include or exclude patients from oral anticoagulation therapy but rather allows clinicians to make an informed judgment as to the risk of bleeding and to identify modifiable bleeding risk factors that need to be addressed. A recent survey from Europe showed that using CHADS2 and HAS-BLED score that anticoagulants were given to >80% of eligible patients including elderly patients [31] . ●●Warfarin
Long-term warfarin use reduces the risk of stroke by 64% versus placebo and by 40% versus antiplatelet agents in patients with nonvalvular AF [32] . However, maintaining adequate anticoagulation could be challenging due to multiple drug–drug interactions, drug–food interactions and genotype variation affecting drug metabolism. Dietary restriction, routine anticoagulation monitoring and frequent dose adjustments may be frustrating from a patient’s perspective resulting in poor compliance. Compliance may further be compromised by inability of elderly patients to take medication due to physical and cognitive impairment. Due to concerns of fatal bleeding in the elderly population [30] , less than 50% of elderly patients with AF are anticoagulated and are less likely to remain on medication during follow-up visits [33] . ●●New oral anticoagulant
Due to favorable efficacy and safety profiles, new oral anticoagulants (NOAC), including direct thrombin inhibitors (dabigatran) [34] and factor-X inhibitors (rivaroxaban, apixaban and endoxaban) [35–37] , are now being prescribed more often. The results of the major trials addressing the efficacy and safety of NOAC are summarized in Table 4. The major caveat to their use is the lack of a reversal agent in case a serious bleeding occurs while on these agents. In the RE-LY trial, 40% of patients were aged 75 years or more and there was no interaction between age and primary efficacy outcome between dabigatran and warfarin (p = 0.81 for interaction in patients aged
Atrial fibrillation in the elderly: a review
Fayaz A Hakim1 & Win-Kuang Shen*,2 ABSTRACT Atrial fibrillation (AF) is common in the elderly population. Elderly patients with AF are often asymptomatic, may have atypical presentation or may present with heart failure or thromboembolic complications. The optimal management strategy of AF in the elderly population is challenging. We present an overview of AF in elderly patients, in particular addressing the pros and cons of various management strategies, and provide a practical approach within the guidelines. Atrial fibrillation (AF) is a common cardiac arrhythmia affecting 2.2–5 million people in the USA [1,2] . AF accounts for significant morbidity and mortality and consumes a large portion of healthcare expenditures. Age is the most important predictor of the development of AF and progression from paroxysmal AF to permanent AF. The risk of AF, even in the absence of other cardiovascular disease, progressively increases after age of 40 years with steeper increases above 65 years [3] . The prevalence of AF is 2.3% in people above 40 years, 5.9% after 65 years and 10% in those above 80 years of age (ATRIA study) [4] . Approximately 70% of individuals with AF are between 65 and 85 years of age. As the patients are living longer, it is projected that by 2050 the majority of the patients with AF will be above 80 years [4] . Age-adjusted prevalence is higher for men than women. Elderly patients with AF tend to be asymptomatic (silent or subclinical AF) as their ventricular rates are better controlled for being less active and/or having concurrent atrioventricular (AV) nodal disease. They are less likely to report palpitations for the same reasons. The diagnosis is often made incidentally during an evaluation for other reasons. Elderly patients with AF often present with fatigue, stroke, worsening heart failure and/or angina. Those presenting with syncope often have concurrent sinus and AV nodal disease. Due to a high burden of AF and associated morbidity and mortality, screening programs for detecting AF in patients above 65 years of age has been started in many European countries. A mass-screening strategy in 6000 adults in the Swedish population aged 75–76 years showed 3% of participants had previously unidentified silent AF [5] . The cost-effective benefits of systematic screening of this target population by pulse check for irregularity during a physician visit followed by an electrocardiogram if an irregular pulse was detected were demonstrated in a randomized clinical trial (the SAFE study) [6] . Management of AF in elderly patients is challenging due to the fact that AF tends to be more persistent or permanent, age-related physiological changes predispose them to exaggerated pharmacological effects of antiarrhythmic agents (AAAs) and the efficacy and safety of catheter-based ablation is not well represented in clinical studies as highlighted in the Heart Rhythm Society, European Heart Rhythm Association, European Society of Cardiology and the European Cardiac Arrhythmia 2012 consensus statement [7] . An effective management strategy emphasizing older population is needed to halt the impact of AF on public health, which is growing at an exponential rate. The primary goal of this review is to address the pros and cons of various management strategies for AF in the elderly population and provide a practical approach within the ambient guidelines.
KEYWORDS
• ablations • anticoagulation • atrial fibrillation • drug therapy • elderly • practical
approach
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA Clinic Cardiac Electrophysiology, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA *Author for correspondence: Tel.: +480 791 7626; Fax: +480 301 8018; [email protected] 1 2
10.2217/FCA.14.32 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(6), 745–758
part of
ISSN 1479-6678
745
Review Hakim & Shen ●●Age-related cardiovascular changes
Before addressing management of AF in the elderly population, it is imperative to understand the age-related changes in cardiovascular systems that predispose them to the development of AF and altered drug pharmacokinetics and pharmacodynamics that have an impact in selecting AAAs and anticoagulants in these patients. Pathophysiology of AF Pathogenesis of AF is complex and not precisely understood. Age-related changes in the left atrium occur at structural, cellular and molecular levels, which are translated into electrophysiological abnormalities and predisposition to the development of AF. The anatomical and physiological changes in the aging atria have been demonstrated on electroanatomical mapping [8] . With advancing age, there is fatty infiltration and collagen and amyloid deposition in the left atrium. The number and size of atrial myocytes, pacemaker cells in sinoatrial and AV nodes and conduction tissue decrease and are subsequently replaced by fibrosis. These changes were first investigated in rodents [9] and later in human subjects [10] . The left atrial size, pressure and volume increases. These structural and anatomical changes result in loss of excitable tissue and conduction blocks that create a milieu for multiple re-entrant wavelets and hence AF [11] . Dilatation and remodeling of the left atrium causes increased dispersion of effective refractory period and activation of stretch-sensitive ion channels that trigger AF. Calcium plays an important role in normal electrical and mechanical functions of cardiac myocytes. Aging is associated with enhanced sodium/calcium (Na/Ca) exchanger function that results in cytosolic Ca 2+ overload. This causes shortening of action potential duration and decreased conduction velocity and predisposition to arrhythmias [12] . Oscillatory release of Ca 2+ from the sarcoplasmic reticulum between the normal beats generates spontaneous action potentials, which can trigger AF. Aging atria are more susceptible to AF by the other known mechanisms including upregulation of atrial-specific ultra-rapid delayed rectifier potassium (IK UR) currents that decrease the effective refractory period and promote microwavelets [13] , enhanced sympathetic drive and vagal tone, generation of free radical and altered gene expression. The pathophysiology of AF is summarized in Figure 1.
746
Future Cardiol. (2014) 10(6)
Aging & risk factors for AF A number of risk factors have been shown to be associated with the development of AF. In the Framingham Heart Study, age, diabetes mellitus, hypertension, congestive heart failure, coronary artery disease and valve disease were shown to be independent risk factors for AF in both sexes [14] . The risk factors for AF are summarized in Table 1. Medical comorbidities associated with AF are common in elderly patients. The prevalence of obesity is increasing among the elderly population. Obesity was linked to increasing incidence and prevalence of AF in the Olmsted County population and shown to be an independent predictor of AF [15] . Lack of physical activity in the elderly is common and may contribute to the development of obesity, hypertension and coronary artery disease. Obesity is a proinflammatory state, as evident by elevated levels of C-reactive protein and inflammation promoting atrial remodeling [16,17] . Age and obesity are independent risk factors for obstructive sleep apnea, which predisposes to the development and/ or recurrence of AF [18] . Altered adrenergic and vagal discharges, hypoxemia surges and activation of stretch-sensitive channels have been proposed mechanisms triggering AF in obstructive sleep apnea [19] . Diastolic dysfunction and heart failure with preserved ejection fraction is an independent predictor of AF in elderly patients. Other medical conditions that predispose to AF include impaired renal function, subclinical hyperthyroidism and chronic obstructive pulmonary disease, which are common in advanced age. Pharmacokinetics & pharmacodynamics of antiarrhythmia agents in elderly In general, the metabolism of drugs in the elderly population is slow due to altered pharmacokinetics. The metabolism of various AAAs used in the management of AF bears no exception. Absorption
Despite decreases in gastrointestinal motility, splanchnic blood flow and mucosal surface area, the absorption of antiarrhythmic drugs is not significantly affected with aging. However, due to decreased first-pass effect, the bioavailability of certain drugs, for example, propranolol, is increased resulting in systemic toxicity necessitating dose reduction [20] . Distribution
Due to change in body fat and water, the distribution of AAA may be significantly affected. With
future science group
Atrial fibrillation in elderly: a review
Structural heart disease • Hypertension • Heart failure • Coronary artery disease
Advanced age
Review
Modulating factors • Obesity • Diabetes • OSA
Left atrial dilatation and inflammation
• ↑ Interstitial fibrosis • ↓ Myocyte number
Left atrial remodeling
Local triggers • Pulmonary vein
• ↑ Dispersion of refractoriness • ↓ Conduction velocity
∆ lonic channel expression
Increased vulnerability to atrial fibrillation
Figure 1. Pathophysiology of atrial fibrillation. ↑: Increase; ↓: Decrease; OSA: Obstructive sleep apnea.
aging, total body fat increases and the volume of distribution of amiodarone is increased [21] . Similarly, due to decreases in total body water, volume of distribution of digoxin is reduced [22] . Since plasma proteins decrease with aging, free warfarin levels may increase and hence predispose to bleeding [23] .
hence, renally eliminated drugs like digoxin, procainamide, sotalol and dofetilide accumulate in elderly patients at conventional doses and dose reductions based on calculated GFR are needed [25] . The major metabolic pathways of AAA and oral anticoagulants are summarized in Box 1.
Metabolism
●●Age & ionic channels & AAA-targeted
Due to reduction in the liver mass and functions, the metabolism of propafenone, amiodarone and propranolol is reduced [24] . Reduction in the activity of CYP450 monooxygenases decreases the metabolism of flecainide, propafenone, amiodarone, disopyramide, metoprolol and verapramil [24] .
proteins
Elimination
Aging is associated with progressive loss of renal mass and glomerular filtration rate (GFR);
future science group
With advancing age, the properties and the functions of specific ion channels are altered and are associated with various electrophysiological abnormalities and arrhythmias. These are summarized in Table 2. Atria-specific IK UR currents are upregulated and as a result, their enhanced activity predisposes to the development of AF [26] . Decreased activity of L-type Ca 2+ currents (ICaL) in the aging atrial myocardium results in conduction abnormality with
www.futuremedicine.com
747
Review Hakim & Shen Table 1. Risk factors and their odds ratio for predisposing to atrial fibrillation. Risk factors
Published HR range
Validated Age Male gender Hypertension Valve disease Diabetes CHF MI Genetic factors
1.03–5.9 (per year) 1.5–2.7 1.1–2.7 1.8–3.2 1.4–2.2 1.4–7.7 1.4–2.6 1.1–1.9
Less well validated Obesity OSA Subclinical hyperthyroidism COPD CKD Endurance sports Smoking Alcohol B-type natriuretic peptide CRP, IL and TNF-α Troponin-T
1.03–2.0 (per BMI) 2.2–3.0 1.9–3.1 1.5–2.0 1.4–1.9 – 1.3–1.5 1.3–1.5 1.2–4.0 0.9–2.2 1.2
CHF: Congestive heart failure; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; HR: Hazard ratio; IL: Interleukin; MI: Myocardial infarction; OSA: Obstructive sleep apnea. Adapted with permission from the European Heart Association and the European Society of Cardiology.
resulting microreentry [27] . Dysfunction of the ryanodine receptor in a senescent heart has been shown to promote enhanced Ca 2+ activity and predisposition to AF [27] . Age-related changes in the ion channels also alter their responsiveness to various AAAs with predisposition to the drug toxicities. Class I antiarrhythmic drugs, β-blockers and calcium channel blockers can precipitate or worsen sinus node dysfunction or AV conduction blocks. Class Ia and III agents are potassium channel blockers and may precipitate arrhythmia by worsening age-related QT interval prolongation. Age & associated comorbid conditions The presence of medical comorbidities in aging patients may have a negative impact on organ functions following administration of antiarrhythmic drugs (Table 3) . Individuals with depressed ventricular function may experience decompensation of heart failure following administration of β-blockers, calcium channel blockers and class I agents. Similarly, β-blockers and propafenone may precipitate acute exacerbation of obstructive lung diseases. Elderly patients have blunted baroreceptor reflexes and may
748
Future Cardiol. (2014) 10(6)
experience orthostatic symptoms, falls or even syncope following administration of sotalol and disopyramide due to their vasodilating properties. Polypharmacy is common in older patients, and drug interactions associated with various antiarrhythmic medications pose a challenge in selecting the best agent. Medications with anticholinergic properties, for example, disopyramide, can precipitate glaucoma, constipation and urinary retention. Coronary artery disease is common in the aging population and use of Class Ic agents in such situations may precipitate malignant ventricular arrhythmia due to their proarrhythmic properties. Many elderly patients with heart failure and hypertension are on diuretics and are at risk of hypokalemia. Concurrent use of digitalis in such patients predisposes them to digitalis toxicity. Elderly patients, due to high risk of stroke, may be on dipyridamole and may develop complete heart block when exposed to adenosine. Many AAAs are metabolized by the cytochrome oxidase system, the function of which decreases with aging. Concurrent use of medications that are metabolized by cytochrome oxidase isoenzymes, may have a profound effect on the metabolism of antiarrhythmic drugs necessitating dose adjustments. Clinically relevant issues regarding drug therapy in elderly patients with AF are outlined in Box 2. Anticoagulation for stroke prevention in the aging population The risk of stroke in AF increases fivefold with every decade of life after age 59 years, reaching 36.2% for ages 80–89 years [28] . Patients older than 75 years are eligible for anticoagulation even in the absence of other risk factors based on CHADS2 or CHA2DS2-Vasc score. Warfarin has been demonstrated to be significantly superior to aspirin in these patients (relative risk: 0.48; 95% CI: 0.28–20.80; p = 0.003) [29] . However, elderly patients have a tendency to bleed, are sensitive to warfarin, are more likely to be on antiplatelet agents and are at risk for falls. These factors predispose them to a higher risk of bleeding. The cumulative incidence of major hemorrhage during anticoagulation with warfarin for patients ≥80 years of age is 13.1 per 100 person-years versus 4.7 for those 65 years, drugs [aspirin/nonsteroidal anti-inflammatory drug or alcohol]) is a useful clinical tool to identify patients at risk of bleeding with anticoagulation. Patients with a score ≥3 are considered to be at a higher risk of bleeding while on anticoagulants. Nevertheless, the score should not be used alone to include or exclude patients from oral anticoagulation therapy but rather allows clinicians to make an informed judgment as to the risk of bleeding and to identify modifiable bleeding risk factors that need to be addressed. A recent survey from Europe showed that using CHADS2 and HAS-BLED score that anticoagulants were given to >80% of eligible patients including elderly patients [31] . ●●Warfarin
Long-term warfarin use reduces the risk of stroke by 64% versus placebo and by 40% versus antiplatelet agents in patients with nonvalvular AF [32] . However, maintaining adequate anticoagulation could be challenging due to multiple drug–drug interactions, drug–food interactions and genotype variation affecting drug metabolism. Dietary restriction, routine anticoagulation monitoring and frequent dose adjustments may be frustrating from a patient’s perspective resulting in poor compliance. Compliance may further be compromised by inability of elderly patients to take medication due to physical and cognitive impairment. Due to concerns of fatal bleeding in the elderly population [30] , less than 50% of elderly patients with AF are anticoagulated and are less likely to remain on medication during follow-up visits [33] . ●●New oral anticoagulant
Due to favorable efficacy and safety profiles, new oral anticoagulants (NOAC), including direct thrombin inhibitors (dabigatran) [34] and factor-X inhibitors (rivaroxaban, apixaban and endoxaban) [35–37] , are now being prescribed more often. The results of the major trials addressing the efficacy and safety of NOAC are summarized in Table 4. The major caveat to their use is the lack of a reversal agent in case a serious bleeding occurs while on these agents. In the RE-LY trial, 40% of patients were aged 75 years or more and there was no interaction between age and primary efficacy outcome between dabigatran and warfarin (p = 0.81 for interaction in patients aged
