Special Issue Article
Recent advances in atrial fibrillation and stroke J. David Spence Robarts Research Institute, Western University, London, ON, Canada
Among patients who have experienced an ischaemic stroke or transient ischaemic attack (TIA), it is possible to reduce the risk of recurrent stroke by 80% or more.1 However, in order to accomplish this, it is necessary to identify the underlying cause of the event, so that the appropriate therapy can be identified to maximally reduce risk of recurrence. Antiplatelet agents are not anticoagulants; they reduce the risk of stroke from embolisation of platelet aggregates, sometimes called ‘white thrombus’ (Fig. 1) in the setting of fast flow along the arterial wall or heart valves, but to prevent thrombus in the setting of stasis (‘red thrombus’, a fibrin polymer with entrapped red cells), it is necessary to use anticoagulants. With recent improvements in blood pressure control and lipid-lowering therapy, the proportion of lacunar strokes due to small vessel disease and strokes due to large artery disease has declined significantly in the past 10 years, and in consequence the proportion of cardioembolic strokes has risen; our group found2 that between 2002 and 2012, cardioembolic stroke increased from 26 to 56% of ischaemic stroke, among patients attending an ambulatory Urgent TIA Clinic. It is thus increasingly important for physicians to have a high index of suspicion for cardioembolic stroke, and to investigate patients intensively if they have no other apparent cause of stroke (‘cryptogenic stroke’). In the diagnosis of cardioembolic stroke, there are two sides to the coin: (1) negative evidence: the absence of other causes of stroke such as hypertension, large artery disease, dissection, or vasculitis; and (2) positive evidence such as the presence of cortical infarctions and/or TIA in multiple vascular territories, cardiac abnormalities such cardiomyopathy, a prosthetic or stenosed valve, a right-to-left shunt, evidence of atrial fibrillation, or clinical clues
Correspondence to: J. David Spence, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON N6G 2V2, Canada. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000026
to paradoxical embolism. The latter includes a previous history of deep vein thrombosis (DVT), pulmonary embolism, the presence of venous insufficiency or varicose veins, a history of prolonged sitting (such as a long flight or sitting at a computer for many hours), dyspnoea or a Valsalva manoeuvre at the onset of the stroke, a history of sleep apnoea, or waking up with stroke.3 A special case is atrial fibrillation (AF). This condition is particularly important because it is associated with larger strokes that are more disabling, is increasing in frequency because of the ageing of the population, is frequently missed by routine Holter recordings, and there is a serious problem of under-use of anticoagulants,4 particularly in the elderly, who are disproportionately more likely to benefit from anticoagulants.5 In the Framingham study, AF accounted for 1.5% of strokes at age 50–59, and 23.5% at age 80–89.6 With the ageing of the population, the number of adults in the US with AF is expected to more than double by 2050.7 Intermittent AF carries the same risk of stroke as does continuous AF, but it is often missed. Two recent studies showed that longer-term monitoring increase the detection of AF among patients with cryptogenic stroke. The CRYSTAL AF study included 441 patients with cryptogenic stroke: 63% male, age 61.5 years; an implantable device detected AF in nearly 10% of patients within 6 months and 30% after 3 years. A multicenter Canadian study8 randomised 527 patients with cryptogenic stroke, age 73 years; 54% male to an automated recorder belt versus repeat Holter recording. At 3 months, 16.1% were found to have AF with the long-term recording versus 3.2% with the repeat Holter recording (Pv0.001). Under-anticoagulation of AF patients is in large part due to problems with warfarin: it is very difficult (perhaps impossible) to use well, because of fluctuations in the International Normalized Ratio (INR), interactions with food and drugs, and changes in intestinal flora that cause the INR to be in the target range
Neurological Research
2015
VOL .
37
NO .
5
381
Spence
Recent advances in atrial fibrillation and stroke
Figure 1 White thrombus in the retinal artery of a patient with amaurosis fugax. Platelet aggregates that embolise from a carotid stenosis to the retinal artery cause transient monocular loss of vision. They ooze gradually through the retina arteries, with vision returning to quadrants or hemispheres of vision as the retinal artery branches are reperfused. (Reproduced by permission of Vanderbilt University Press from: Spence JD. How to Prevent Your Stroke, 2006.)
only 60% of the time even in carefully controlled trials, and much less of the time in real world practice.9 Patients are reluctant to take warfarin because of the requirement for frequent blood testing and the widespread tendency to regard it as ‘rat poison’. Physicians are reluctant to prescribe warfarin because of a misplaced reluctance to cause harm in the face of strong evidence that not prescribing warfarin in AF causes more harm; in part, this is due to traumatic experiences with haemorrhages, which tend to occur early after initiation of warfarin.10 One misplaced concern is the fear of falls; it has been calculated that elderly patients on warfarin would need to fall 295 times for the risk to exceed the benefit of warfarin.9 One mistaken approach to this problem is the use of antiplatelet agents, which are only about a third as effective as anticoagulation in AF. Even dual antiplatelet therapy adds nearly nothing – addition of clopidogrel to aspirin reduced stroke by only 0.67%.9 Fortunately, there are now a number of oral anticoagulants that are safer than warfarin, and at least effective. Table 1 summarises the characteristics of
the ones that are currently in use. These anticoagulants represent an important advance over warfarin, and should markedly reduce the problem of under-anticoagulation. However, they cannot be used in patients with renal failure, nor yet in patients with prosthetic valves. Although they are promoted as not requiring blood testing to adjust the dose, this may not be true for dabigatran. Reilly et al.11 reported an important relationship between dabigatran levels and outcomes. This may be a particular problem with dabigatran for at least two reasons, illustrated in Table 1: dabigatran has the lowed bioavailability, meaning that drug interactions have the potential to increase blood levels of dabigatran proportionally more, and it is the most renally excreted of the new oral anticoagulants available to date.12 A little-recognised problem that should not be overlooked is metabolic B12 deficiency, leading to elevated levels of plasma total homocysteine (tHcy). Among patients attending a stroke prevention clinic, metabolic B12 deficiency was present in 12% below age 50, and 30% above age 70.13 A ‘normal’ serum B12 level does not exclude B12 deficiency; a functional test such as methylmalonic acid, holotranscobalamin, or in folate-replete patients, tHcy is necessary to make the diagnosis. To exclude B12 deficiency on the basis of a total serum B12, the level needs to be above 400 pmol/L.14 Elevated levels of tHcy increase thrombosis, including DVT, retinal vein thrombosis, and cerebral sinus thrombosis, and quadruple the risk ofAF.15 Figure 2 shows the prevalence of hyperhomocysteinemia among patients attending a secondary stroke prevention clinic; just as AF increases steeply with age, so does the prevalence of hyperhomocysteinemia. Because B12 deficiency and hyperhomocysteinemia are so common in patients withAF, and are easily treated, they should always be considered in the management of coagulation in AF. The widespread belief that B vitamins do not reduce the risk of stroke is mistaken; it is based on failure to understand the key roles of B12 and renal function in the interpretation of the clinical
Table 1 Characteristics of new oral anticoagulants (reproduced by permission of Elsevier from: Goette A. Novel oral anticoagulants for stroke prevention in atrial fibrillation: key trial findings and clinical implications. Trends Cardiovasc Med. 2013;23(4):128–34.)
382
Characteristics
Rivaroxaban
Dabigatran
Apixaban
Target Prodrug Dosing Bioavailability, % Half-life Renal clearance, % CMax Drug interactions
Factor Xa No Daily 80–100 5–13 hours *33 2–4 hours Strong inhibitors of both CYP3A4 and P-glycoprotein
Factor IIa Yes Twice daily 6.5 12–14 hours 85 1–2 hours P-glycoprotein inhibitors
Factor Xa No Twice daily 50 8–15 hours *27% 3–4 hours Strong inhibitors of both CYP3A4 and P-glycoprotein
Neurological Research
2015
VOL .
37
NO .
5
Spence
Recent advances in atrial fibrillation and stroke
Figure 2 Prevalence of hyperhomocysteinemia by age group among patients attending a secondary stroke prevention clinic. The prevalence of a total homocysteine level >14 mmol/L rises from ,10– 15% at age 35– 49, to 40% by age 80. Higher levels among patients below age 35 may reflect higher proportions with stroke due to dissection or cardioembolic sources such as paradoxical embolism. In older patients, metabolic B12 deficiency and impaired renal function account for most cases of hyperhomocysteinemia. (Permission requested from Elsevier to reproduce from: Spence D. Mechanisms of thrombogenesis in atrial fibrillation. Lancet. 2009; 373 (9668): 1006).
trials.16,17 B vitamins to lower tHcy do reduce the risk of stroke, but we probably should be using methylcobalamin instead of cyanocobalamin, particularly in patients with impaired renal function.
Conclusions Atrial fibrillation is common, frequently missed, and frequently under-treated with anticoagulation. It can be better diagnosed with prolonged monitoring, and new oral anticoagulants offer advantages that may improve the appropriateness of anticoagulation for this disorder. Vitamin B12 deficiency is a common easily treated factor that should not be overlooked in patients with cardioembolic stroke, particularly AF.
Disclaimer Statements Contributors J. David Spence wrote this update. Funding N/A. Conflicts of interest Dr Spence has received grants from the Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada (HSF), and the National Institute of Health/National Institute of Neurological Disorders and Stroke. Lecture honoraria/travel support/consulting fees were provided by Sanofi-Synthelabo, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of study medication to support HSF grant for clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of the above pharma companies and Takeda Pharmaceuticals, Bristol-Myers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT, AGA, Gore, and AstraZeneca. He is a shareholder and officer of Vascularis.com.
Dr Spence is a member of the Editorial Boards of Hypertension, Stroke, and Arteriosclerosis, Thrombosis, and Vascular Biology. He receives royalties on books from Vanderbilt University Press and McGraw-Hill Medical. Ethics approval N/A.
References 1 Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38(6):1881–5. 2 Bogiatzi C, Wannarong T, McLeod AI, Heisel MJ, Hackam DG, Spence JD. SubtyPes of ischAemic stRoKe cLassification systEm (SPARKLE) incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes. Neuroepidemiology. 2014;42:243–51. 3 Ozdemir AO, Tamayo A, Munoz C, Dias B, Spence JD. Cryptogenic stroke and patent foramen ovale: clinical clues to paradoxical embolism. J Neurol Sci. 2008;275(1–2):121–7. 4 Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009;40(1):235–40. 5 Spence JD. Stroke: atrial fibrillation, stroke prevention therapy and aging. Nat Rev Cardiol. 2009;6(7):448–50. 6 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983–8. 7 Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18): 2370–5. 8 Gladstone DJ, Spring M, Dorian P, Thorpe K, Panzov V, Hall J, et al. Atrial fibrillation detection in patients with cryptogenic stroke: the EMBRACE randomized trial. N Engl J Med. 2014;370(26):2467–77. 9 Spence JD. Atrial fibrillation and stroke prevention: is warfarin still an option? Yes: debate at the controversies in neurology congress, Beijing October 2011. J Neural Transm. 2013; 120(10):1447–51. 10 Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121–7. 11 Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma
Neurological Research
2015
VOL .
37
NO .
5
383
Spence
Recent advances in atrial fibrillation and stroke
concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (randomized evaluation of longterm anticoagulation therapy). J Am Coll Cardiol. 2014; 63(4):321–8. 12 Goette A. Novel oral anticoagulants for stroke prevention in atrial fibrillation: key trial findings and clinical implications. Trends Cardiovasc Med. 2013;23(4):128–34. 13 Spence JD. Nutrition and stroke prevention. Stroke. 2006; 37(9):2430–5.
384
Neurological Research
2015
VOL .
37
NO .
5
14 Spence JD. Nutrition in stroke prevention. US Neurol. 2013;9(1):45–51. 15 Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol. 2007;6(9):830–8. 16 Spence JD, Stampfer MJ. Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses. JAMA. 2011;306(23):2610–1. 17 Spence JD. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes. Clin Chem Lab Med. 2013;51(3):633–7.
Recent advances in atrial fibrillation and stroke J. David Spence Robarts Research Institute, Western University, London, ON, Canada
Among patients who have experienced an ischaemic stroke or transient ischaemic attack (TIA), it is possible to reduce the risk of recurrent stroke by 80% or more.1 However, in order to accomplish this, it is necessary to identify the underlying cause of the event, so that the appropriate therapy can be identified to maximally reduce risk of recurrence. Antiplatelet agents are not anticoagulants; they reduce the risk of stroke from embolisation of platelet aggregates, sometimes called ‘white thrombus’ (Fig. 1) in the setting of fast flow along the arterial wall or heart valves, but to prevent thrombus in the setting of stasis (‘red thrombus’, a fibrin polymer with entrapped red cells), it is necessary to use anticoagulants. With recent improvements in blood pressure control and lipid-lowering therapy, the proportion of lacunar strokes due to small vessel disease and strokes due to large artery disease has declined significantly in the past 10 years, and in consequence the proportion of cardioembolic strokes has risen; our group found2 that between 2002 and 2012, cardioembolic stroke increased from 26 to 56% of ischaemic stroke, among patients attending an ambulatory Urgent TIA Clinic. It is thus increasingly important for physicians to have a high index of suspicion for cardioembolic stroke, and to investigate patients intensively if they have no other apparent cause of stroke (‘cryptogenic stroke’). In the diagnosis of cardioembolic stroke, there are two sides to the coin: (1) negative evidence: the absence of other causes of stroke such as hypertension, large artery disease, dissection, or vasculitis; and (2) positive evidence such as the presence of cortical infarctions and/or TIA in multiple vascular territories, cardiac abnormalities such cardiomyopathy, a prosthetic or stenosed valve, a right-to-left shunt, evidence of atrial fibrillation, or clinical clues
Correspondence to: J. David Spence, Stroke Prevention and Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON N6G 2V2, Canada. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000026
to paradoxical embolism. The latter includes a previous history of deep vein thrombosis (DVT), pulmonary embolism, the presence of venous insufficiency or varicose veins, a history of prolonged sitting (such as a long flight or sitting at a computer for many hours), dyspnoea or a Valsalva manoeuvre at the onset of the stroke, a history of sleep apnoea, or waking up with stroke.3 A special case is atrial fibrillation (AF). This condition is particularly important because it is associated with larger strokes that are more disabling, is increasing in frequency because of the ageing of the population, is frequently missed by routine Holter recordings, and there is a serious problem of under-use of anticoagulants,4 particularly in the elderly, who are disproportionately more likely to benefit from anticoagulants.5 In the Framingham study, AF accounted for 1.5% of strokes at age 50–59, and 23.5% at age 80–89.6 With the ageing of the population, the number of adults in the US with AF is expected to more than double by 2050.7 Intermittent AF carries the same risk of stroke as does continuous AF, but it is often missed. Two recent studies showed that longer-term monitoring increase the detection of AF among patients with cryptogenic stroke. The CRYSTAL AF study included 441 patients with cryptogenic stroke: 63% male, age 61.5 years; an implantable device detected AF in nearly 10% of patients within 6 months and 30% after 3 years. A multicenter Canadian study8 randomised 527 patients with cryptogenic stroke, age 73 years; 54% male to an automated recorder belt versus repeat Holter recording. At 3 months, 16.1% were found to have AF with the long-term recording versus 3.2% with the repeat Holter recording (Pv0.001). Under-anticoagulation of AF patients is in large part due to problems with warfarin: it is very difficult (perhaps impossible) to use well, because of fluctuations in the International Normalized Ratio (INR), interactions with food and drugs, and changes in intestinal flora that cause the INR to be in the target range
Neurological Research
2015
VOL .
37
NO .
5
381
Spence
Recent advances in atrial fibrillation and stroke
Figure 1 White thrombus in the retinal artery of a patient with amaurosis fugax. Platelet aggregates that embolise from a carotid stenosis to the retinal artery cause transient monocular loss of vision. They ooze gradually through the retina arteries, with vision returning to quadrants or hemispheres of vision as the retinal artery branches are reperfused. (Reproduced by permission of Vanderbilt University Press from: Spence JD. How to Prevent Your Stroke, 2006.)
only 60% of the time even in carefully controlled trials, and much less of the time in real world practice.9 Patients are reluctant to take warfarin because of the requirement for frequent blood testing and the widespread tendency to regard it as ‘rat poison’. Physicians are reluctant to prescribe warfarin because of a misplaced reluctance to cause harm in the face of strong evidence that not prescribing warfarin in AF causes more harm; in part, this is due to traumatic experiences with haemorrhages, which tend to occur early after initiation of warfarin.10 One misplaced concern is the fear of falls; it has been calculated that elderly patients on warfarin would need to fall 295 times for the risk to exceed the benefit of warfarin.9 One mistaken approach to this problem is the use of antiplatelet agents, which are only about a third as effective as anticoagulation in AF. Even dual antiplatelet therapy adds nearly nothing – addition of clopidogrel to aspirin reduced stroke by only 0.67%.9 Fortunately, there are now a number of oral anticoagulants that are safer than warfarin, and at least effective. Table 1 summarises the characteristics of
the ones that are currently in use. These anticoagulants represent an important advance over warfarin, and should markedly reduce the problem of under-anticoagulation. However, they cannot be used in patients with renal failure, nor yet in patients with prosthetic valves. Although they are promoted as not requiring blood testing to adjust the dose, this may not be true for dabigatran. Reilly et al.11 reported an important relationship between dabigatran levels and outcomes. This may be a particular problem with dabigatran for at least two reasons, illustrated in Table 1: dabigatran has the lowed bioavailability, meaning that drug interactions have the potential to increase blood levels of dabigatran proportionally more, and it is the most renally excreted of the new oral anticoagulants available to date.12 A little-recognised problem that should not be overlooked is metabolic B12 deficiency, leading to elevated levels of plasma total homocysteine (tHcy). Among patients attending a stroke prevention clinic, metabolic B12 deficiency was present in 12% below age 50, and 30% above age 70.13 A ‘normal’ serum B12 level does not exclude B12 deficiency; a functional test such as methylmalonic acid, holotranscobalamin, or in folate-replete patients, tHcy is necessary to make the diagnosis. To exclude B12 deficiency on the basis of a total serum B12, the level needs to be above 400 pmol/L.14 Elevated levels of tHcy increase thrombosis, including DVT, retinal vein thrombosis, and cerebral sinus thrombosis, and quadruple the risk ofAF.15 Figure 2 shows the prevalence of hyperhomocysteinemia among patients attending a secondary stroke prevention clinic; just as AF increases steeply with age, so does the prevalence of hyperhomocysteinemia. Because B12 deficiency and hyperhomocysteinemia are so common in patients withAF, and are easily treated, they should always be considered in the management of coagulation in AF. The widespread belief that B vitamins do not reduce the risk of stroke is mistaken; it is based on failure to understand the key roles of B12 and renal function in the interpretation of the clinical
Table 1 Characteristics of new oral anticoagulants (reproduced by permission of Elsevier from: Goette A. Novel oral anticoagulants for stroke prevention in atrial fibrillation: key trial findings and clinical implications. Trends Cardiovasc Med. 2013;23(4):128–34.)
382
Characteristics
Rivaroxaban
Dabigatran
Apixaban
Target Prodrug Dosing Bioavailability, % Half-life Renal clearance, % CMax Drug interactions
Factor Xa No Daily 80–100 5–13 hours *33 2–4 hours Strong inhibitors of both CYP3A4 and P-glycoprotein
Factor IIa Yes Twice daily 6.5 12–14 hours 85 1–2 hours P-glycoprotein inhibitors
Factor Xa No Twice daily 50 8–15 hours *27% 3–4 hours Strong inhibitors of both CYP3A4 and P-glycoprotein
Neurological Research
2015
VOL .
37
NO .
5
Spence
Recent advances in atrial fibrillation and stroke
Figure 2 Prevalence of hyperhomocysteinemia by age group among patients attending a secondary stroke prevention clinic. The prevalence of a total homocysteine level >14 mmol/L rises from ,10– 15% at age 35– 49, to 40% by age 80. Higher levels among patients below age 35 may reflect higher proportions with stroke due to dissection or cardioembolic sources such as paradoxical embolism. In older patients, metabolic B12 deficiency and impaired renal function account for most cases of hyperhomocysteinemia. (Permission requested from Elsevier to reproduce from: Spence D. Mechanisms of thrombogenesis in atrial fibrillation. Lancet. 2009; 373 (9668): 1006).
trials.16,17 B vitamins to lower tHcy do reduce the risk of stroke, but we probably should be using methylcobalamin instead of cyanocobalamin, particularly in patients with impaired renal function.
Conclusions Atrial fibrillation is common, frequently missed, and frequently under-treated with anticoagulation. It can be better diagnosed with prolonged monitoring, and new oral anticoagulants offer advantages that may improve the appropriateness of anticoagulation for this disorder. Vitamin B12 deficiency is a common easily treated factor that should not be overlooked in patients with cardioembolic stroke, particularly AF.
Disclaimer Statements Contributors J. David Spence wrote this update. Funding N/A. Conflicts of interest Dr Spence has received grants from the Canadian Institutes for Health Research, Heart and Stroke Foundation of Canada (HSF), and the National Institute of Health/National Institute of Neurological Disorders and Stroke. Lecture honoraria/travel support/consulting fees were provided by Sanofi-Synthelabo, Bayer, Merck, and Boehringer-Ingelheim. Research support for investigator-initiated projects was provided by Pfizer Inc (substantial donation in kind of study medication to support HSF grant for clinical trial) and Merck (small funds to support a summer research student). Contract research was conducted with all of the above pharma companies and Takeda Pharmaceuticals, Bristol-Myers Squibb, Servier, Wyeth, Miles, Roussel-Uclaf, NMT, AGA, Gore, and AstraZeneca. He is a shareholder and officer of Vascularis.com.
Dr Spence is a member of the Editorial Boards of Hypertension, Stroke, and Arteriosclerosis, Thrombosis, and Vascular Biology. He receives royalties on books from Vanderbilt University Press and McGraw-Hill Medical. Ethics approval N/A.
References 1 Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38(6):1881–5. 2 Bogiatzi C, Wannarong T, McLeod AI, Heisel MJ, Hackam DG, Spence JD. SubtyPes of ischAemic stRoKe cLassification systEm (SPARKLE) incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes. Neuroepidemiology. 2014;42:243–51. 3 Ozdemir AO, Tamayo A, Munoz C, Dias B, Spence JD. Cryptogenic stroke and patent foramen ovale: clinical clues to paradoxical embolism. J Neurol Sci. 2008;275(1–2):121–7. 4 Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009;40(1):235–40. 5 Spence JD. Stroke: atrial fibrillation, stroke prevention therapy and aging. Nat Rev Cardiol. 2009;6(7):448–50. 6 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983–8. 7 Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18): 2370–5. 8 Gladstone DJ, Spring M, Dorian P, Thorpe K, Panzov V, Hall J, et al. Atrial fibrillation detection in patients with cryptogenic stroke: the EMBRACE randomized trial. N Engl J Med. 2014;370(26):2467–77. 9 Spence JD. Atrial fibrillation and stroke prevention: is warfarin still an option? Yes: debate at the controversies in neurology congress, Beijing October 2011. J Neural Transm. 2013; 120(10):1447–51. 10 Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121–7. 11 Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma
Neurological Research
2015
VOL .
37
NO .
5
383
Spence
Recent advances in atrial fibrillation and stroke
concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (randomized evaluation of longterm anticoagulation therapy). J Am Coll Cardiol. 2014; 63(4):321–8. 12 Goette A. Novel oral anticoagulants for stroke prevention in atrial fibrillation: key trial findings and clinical implications. Trends Cardiovasc Med. 2013;23(4):128–34. 13 Spence JD. Nutrition and stroke prevention. Stroke. 2006; 37(9):2430–5.
384
Neurological Research
2015
VOL .
37
NO .
5
14 Spence JD. Nutrition in stroke prevention. US Neurol. 2013;9(1):45–51. 15 Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol. 2007;6(9):830–8. 16 Spence JD, Stampfer MJ. Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses. JAMA. 2011;306(23):2610–1. 17 Spence JD. B vitamin therapy for homocysteine: renal function and vitamin B12 determine cardiovascular outcomes. Clin Chem Lab Med. 2013;51(3):633–7.
