Medicine. Canadian Journal of. Canadian Journal of. La Revue e Canadienne nne De Médecine Interne Générale

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1 Volume 8, Supplement Volume 8, Supplement Canadian Journal of Canadian Journal of General General Internal Internal nal nal Medicine Medicine La Revue e Canadienne nne De Médecine Interne Générale La Revue e Canadienne nne De Médecine Interne Générale Publications Agreement Number Publications Agreement Number Issues in Thromboembolism Issues in Thromboembolism The Impact of Stroke in Canada The Human The Impact and Economic of Stroke Burden in Canada of Stroke Management The Human of Atrial and Economic Fibrillation Burden of Stroke Outcomes Management and Management of Atrial of Fibrillation Bleeds with Outcomes the New Oral and Management Anticoagulants of Bleeds with the New Oral Anticoagulants

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3 Canadian Journal of General Internal Medicine Volume 8, Supplement Publications Agreement Number E D I T O R - I N - C H I E F Donald Farquhar E D I T O R E M E R I T U S Hector Baillie EDITO R I AL B O A R D Ranjani Aiyar, Simona Bar, Pat Bergin, Hershl Berman, Peter Brindley, Kaberi Dasgupta, Don Echenberg, Don Farquhar, Bert Govig, Luc Lanthier, Alex Leung, Suzanne Morin, Jock Murray, Kathryn Myers, Glen Pearson, Louise Pilote, Colin Powell, Linda Snell, Matthieu Touchette, Ben Wilson, George Veenhuyzen C S I M O F F I C E APEX Association Management Inc. Ms. Domenica Utano M A N A G I N G E D I T O R Susan Harrison ART DI R E C TOR Andrea Mulholland C O P Y E D I T O R S Scott Bryant, Susan Harrison P R O O F R E A D E R Scott Bryant T R A N S L A T O R Marie Dumont A D V E R T I S I N G John Birkby (905) jbirkby@andrewjohnpublishing.com C I R C U L A T I O N C O O R D I N A T O R Brenda Robinson brobinson@andrewjohnpublishing.com A C C O U N T I NG Susan McClung G R O UP PUB L I S HER John D. Birkby Subscription Rates: Per year: $15.00; per issue: $3.75 Canadian Journal of General Internal Medicine is published four times a year by Andrew John Publishing Inc., with offices located at 115 King Street West, Suite 220, Dundas, ON L9H 1V1. We welcome editorial submissions but cannot assume responsibility or commitment for unsolicited material.any editorial material, including photographs that are accepted from an unsolicited contributor, will become the property of Andrew John Publishing Inc. The publisher and the Canadian Society of Internal Medicine shall not be liable for any of the views expressed by the authors published in Canadian Journal of General Internal Medicine,nor shall these opinions necessarily reflect those of the publisher. Every effort has been made to ensure that the information provided herein is accurate and in accord with standards accepted at the time of printing. However, readers are advised to check the most current product information provided by the manufacturer of each drug to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber to determine the dosages and best treatment for each patient. Neither the publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this publication. C O N T E N T S 5 Guest Editor s Message: The Impact of Stroke in Canada: Important Issues in Preventive Therapy Hector M. Baillie MD 7 Mot du rédacteur invité : Les répercussions de l accident vasculaire cérébral au Canada : aspects importants du traitement préventif Hector M. Baillie MD 9 The Human and Economic Burden of Stroke Mike Sharma MD MSc 14 Management of Atrial Fibrillation Blandine Mondésert MD, Peter G. Guerra MD, Laurent Macle MD, Katia Dyrda MD, Léna Rivard MD, Marc Dubuc MD, Jason G. Andrade MD, Bernard Thibault MD, Denis Roy MD, Paul Khairy MD PhD, Mario Talajic MD ABOUT THE COVER The cover photo was taken by Craig MacIntosh, who was born and raised in Newfoundland and moved to British Columbia in For the past 11 years, he has worked full time as a registered psychiatric nurse. His passions are photography and travelling. This image of Vancouver was captured through a skylight in the Pacific Centre, and shows the Harbour Centre in the background. Volume 8, Supplement Outcomes and Management of Bleeds with the Novel Oral Anticoagulants Calvin H. Yeh BHSc, Peter L. Gross MD MSc, Jeffrey I. Weitz MD Return undeliverable Canadian Addresses to: 115 King St W., Suite 220, Dundas, ON L9H 1V1 For Instructions to Authors, please visit C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

4 CSIM HAS MOVED! The CSIM Office has moved to a new location, effective April 1, CSIM is now managed by APEX Association Management Inc., under the leadership of Ms. Domenica Utano. The new coordinates are as follows: 421 Gilmour Street, Suite 300, Ottawa, ON K2P 0R5 Tel: Toll Free: CSIM (2746) Fax: info@csim.ca CSIM HAS A NEW WEBSITE! Be sure to visit You can also pay your dues online, update your membership information, and register for the CSIM Annual Meeting!

5 The Impact of Stroke in Canada: Important Issues in Preventive Therapy Hector M. Baillie MD G u e s t E d i t o r s M e s s a g e About the Author Hector Baillie is a specialist in complex adult medicine, with an interest in cardiovascular disease. He works in Nanaimo, British Columbia. Correspondence may be directed to hbaillie@telus.net. The focus of this CJGIM supplement is stroke, which for many was given less attention than its cousin, ischemic heart disease. In the old days, treatment of stroke was limited to acetylsalicylic acid (ASA) and rehabilitation. Quite correctly, it was deemed more important to prevent brain damage than to deal with its consequences. Smoking cessation and hypertension management have proved successful in extending the health of the cardiovascular tree. Cardioembolic stroke secondary to atrial fibrillation can be devastating; yet it is potentially more predictable, and amenable to prevention with anticoagulants. In this issue, we have three authors who speak with authority on this important topic. Dr. Mike Sharma ( The Human and Economic Burdens of Stroke ) reminds us that this disease affects more than just the patient, but also families, friends, social networks, and the economy itself. There are hidden costs, difficult to measure, that are particularly prevalent in the stroke community, including depression and dementia. He reminds us that this is a condition increasingly associated with age, is more prevalent in women, and in some areas can be as common as heart attack. We need to recognize the importance of transient ischemic attack (TIA) as a precursor of stroke, just as we do unstable angina for myocardial infarction (MI). Interestingly, Sharma brings attention to asymptomatic stroke, or covert brain infarcts lesions identified on magnetic resonance imaging (MRI) that may herald the development of brain damage later on. Given the economic impact of this malignant disease, we need to invest in our understanding of cerebrovascular disease processes, and prevention strategies. Atrial fibrillation (AF), often a consequence of age, coronary insufficiency, and hypertension, is becoming more and more common in our practices. Over and above its impact on cardiorespiratory function, the diagnosis of AF leads to a discussion of stroke risk. Patients are justifiably concerned about this outcome, maybe even more so than their mortality. To counsel them, we need to be familiar with CHADS 2 and other risk scoring systems and prescribe systemic anticoagulation safely. Dr. Blandine Mondésert et al. ( Management of Atrial Fibrillation ) describe the essential aspects of AF and address risk evaluation. Conventional and novel anticoagulants should be prescribed when bleeding risk is outweighed by benefit: Canadian Cardiovascular Society (CCS) guidelines encourage us to do so more readily. We should be confident in advising our patients of this changing therapeutic landscape: we need to understand when to adjust our therapy for the elderly and renally impaired. This excellent article goes on to review antiarrhythmic therapies, including catheter ablation and more futurist interventions. Most physicians who show reluctance to prescribe anticoagulants cite a fear of patient hemorrhage. This may be based on the tenant first, do no harm, but failure to prevent stroke is harm indeed. Dr. Calvin Yeh et al. ( Outcome and Management of Bleeds with the New Anticoagulants ) put this in perspective. The difficulty in maintaining international normalized ratios (INRs) in the therapeutic range challenges the efficacy of warfarin (Coumadin): new oral anticoagulants (NOACs) will gradually replace the old guard. Even though intracranial and gastrointestinal hemorrhage are less common with NOACs, and the outcome of bleeding is less severe, the lack of specific antidotes is a significant factor in limiting their universal acceptance. Yeh et al. describe an approach to hemorrhage, from supportive care to dialysis (dabigatran), and in severe cases, the use of pro-coagulants (e.g., protein complex concentrates). Stroke prevention is a laudable goal. Health care providers should be more confident in their prescribing after reading these valuable reviews. C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

6 MARK YOUR CALENDARS! Toronto, Ontario Canadian Society of Internal Medicine Annual Meetings October 2 5, 2013 To ronto, Ontario Calgary, Alberta October 1 4, 2014 Calgary, Alberta October 14 17, 2015 Charlottetown, PEI CSIM MEMBERSHIP Ship Wreck Point Lighthouse Prince Edward Island Resident membership is FREE. Please encourage residents (and your colleagues) to join the CSIM. For an application or listing of membership benefits, info@csim.ca or visit Your membership is important and you are encouraged to continue supporting your society. Canadian Society of Internal Medicine 421 Gilmour Street, Suite 300, Ottawa, ON K2P 0R5 Tel: Toll Free: CSIM (2746) Fax: info@csim.ca

7 Les répercussions de l accident vasculaire cérébral au Canada : aspects importants du traitement préventif Hector M Baillie, M.D. M o t d u r é d a c t e u r i n v i t é Au sujet de l auteur Hector Baillie est un médecin spécialiste des maladies de l adulte qui exerce sa profession à Nanaimo en Colombie- Britannique. Prière d adresser la correspondance à hbaillie@telus.net. Le présent supplément de La Revue canadienne de médecine interne générale porte sur l accident vasculaire cérébral (AVC), longtemps laissé pour compte au profit de sa cousine la cardiopathie ischémique. Le traitement passait essentiellement par l acide acétylsalicylique (aspirine) et la réadaptation. À juste titre, l on jugeait alors plus important de prévenir les lésions du cerveau que de s attaquer aux conséquences. L arrêt du tabagisme et la maîtrise de l hypertension se sont avérés des mesures efficaces dans la préservation de la santé de l appareil cardiovasculaire. L AVC cardioembolique dû à la fibrillation auriculaire peut être dévastateur; or, il est prévisible dans une certaine mesure et il est possible de le prévenir par l anticoagulothérapie. Trois experts abordent ici ce sujet important. Le D r Mike Sharma, qui examine les répercussions humaines et économiques de l AVC, nous rappelle que la maladie affecte non seulement le patient, mais touche également sa famille, ses amis, son réseau social et l économie en général. La maladie est lourde de conséquences, parfois difficiles à mesurer, comme la dépression et la démence, particulièrement prévalentes chez les personnes ayant subi un AVC. L auteur souligne le lien entre l affection et le vieillissement, sa prévalence accrue chez la femme et le fait qu elle est aussi courante que l infarctus du myocarde dans certaines régions. Nous devons savoir que l accident ischémique transitoire est un précurseur de l AVC au même titre que l angine instable est annonciatrice de l infarctus du myocarde. L auteur attire notre attention sur «l AVC asymptomatique» ou «infarctus cérébral silencieux», visible à l imagerie par résonance magnétique (IRM), qui peut préfigurer l apparition de lésions cérébrales. Au vu des répercussions économiques de taille de ce trouble malin, nous devons approfondir notre connaissance de la maladie vasculaire cérébrale et de sa prévention. La fibrillation auriculaire (FA), qui accompagne souvent l âge, l insuffisance coronaire et l hypertension, se fait de plus en plus courante. Outre son effet sur la fonction cardiorespiratoire, le diagnostic de FA suppose inévitablement l examen du «risque d AVC». Les patients sont très inquiets à cette perspective, plus inquiets que de leur décès parfois. Pour être en mesure de les conseiller et de les guider, nous devons connaître la classification CHADS 2 et d autres systèmes d évaluation du risque et savoir prescrire l anticoagulothérapie en toute sécurité. La D re Blandine Mondésert et ses collègues, dans leur article sur la prise en charge de la fibrillation auriculaire, décrivent les principaux aspects de la maladie ainsi que l évaluation du risque. Lorsque les avantages l emportent sur le risque de saignement, il convient de prescrire l anticoagulant, classique ou nouveau; d ailleurs, la Société canadienne de cardiologie dans ses lignes directrices sur la FA nous incite à le faire avec plus de promptitude. Pour appliquer cette stratégie thérapeutique avec assurance, et en expliquer le bien-fondé aux patients, nous devons en connaître les tenants et aboutissants, dont la nécessité de l adapter en fonction de l âge et de l état de la fonction rénale. Cet article excellent porte aussi sur le traitement antiarythmisant, notamment l ablation par cathétérisme et de nouvelles interventions qui pointent à l horizon. La plupart des médecins réticents à prescrire un anticoagulant craignent la survenue d une hémorragie. Cela tient peut-être au principe de «ne pas nuire avant toute chose» qui fonde l exercice de la médecine, mais le fait de ne pas C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

8 CSIM Members of Council L e s r é p e r c u s s i o n s d e l a c c i d e n t v a s c u l a i r e c é r é b r a l a u C a n a d a Dr. Maria Bacchus President Western Region Representative Calgary, AB Dr. Benjamin Chen President-Elect Ontario Region Representative Napanee, ON Dr. Stephen Hwang Secretary-Treasurer 2013 Co-chair, Annual Meeting Committee Ontario Region Representative Toronto, ON Dr. Neil Gibson Western Region Representative St. Albert, AB Dr. Patrick Bergin Eastern Region Representative Charlottetown, PEI Dr. Nadine Lahoud Quebec Region Representative LaSalle, QC prévenir l AVC revient à nuire en réalité. Le D r Calvin Yeh et ses collaborateurs, qui étudient les nouveaux anticoagulants, examinent la question en contexte. La warfarine est d usage délicat, car son efficacité relève du maintien du rapport international normalisé (RIN) dans la marge thérapeutique, chose loin d être aisée. Les nouveaux anticoagulants oraux sont en voie de déclasser la vieille garde. Toutefois, l absence d antidote spécifique limite leur adoption universelle même s ils provoquent moins d hémorragie intracrânienne et digestive que la warfarine et que le saignement, le cas échéant, est moins grave. Les auteurs décrivent la prise en charge de l hémorragie, allant du traitement symptomatique à la dialyse (dabigatran) en passant par l utilisation d un procoagulant (concentré de protéines complexes) dans le cas grave. La prévention de l AVC est un objectif louable. Le supplément renferme des articles instructifs qui éclaireront la pratique médicale dans ce domaine. Dr. Donald Echenberg Chair, CPD Subcommittee Quebec Region Representative CMA Representative Sherbrooke, QC Dr. Bert Govig Quebec Region Representative Vice-President, Health Promotion Committee Amos, QC Dr. Tom Maniatis Quebec Region Representative Montreal, QC Dr. William Coke Ontario Region Representative Toronto, ON Dr. Ameen Patel Ontario Region Representative Hamilton, ON Dr. Anne Marie PausJenssen Western Region Representative Saskatoon, SK Dr. Amy Hendricks Western Region Representative Yellowknife, NT Dr. David Simpson Eastern Region Representative Halifax, NS Dr. Pearl Behl Resident Representative Markham, ON Other CSIM Positions Dr. Gary Victor Vice-President, Membership Affairs Kelowna, BC Dr. Bill Ghali Vice-President, Research and Awards Committee Calgary, AB Dr. Jim Nishikawa Vice-President, Education Committee Representative on the RCPSC Specialty Committee in Internal Medicine Ottawa, ON Dr. Don Farquhar CJGIM Editor-in-Chief London, ON Dr. Brian Wong 2013 Co-chair, Annual Meeting Committee Toronto, ON 8 V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

9 O r i g i n a l A r t i c l e The Human and Economic Burden of Stroke Mike Sharma MD MSc About the Author Mike Sharma is associate professor of medicine (neurology) at the McMaster University Population Health Research Institute, in Hamilton, Ontario. Correspondence may be directed to mike.sharma@phri.ca. Summary Stroke is a common condition that is expected to increase in prevalence as the population ages. Comparative studies show a population incidence of acute stroke and transient ischemic attack similar to that for acute myocardial infarction. Women have a lifetime risk of 1:2 of experiencing stroke or cognitive impairment. For men, this risk is 1:3. The average cost for stroke in Canada is more than $74,000 in the first year alone, with costs continuing to accrue due to ongoing disability and care needs. Stroke survivors have significant motor, perceptual, language, and executive function deficits. Estimates of incidence based on acutely symptomatic events systematically undervalue the impact of stroke as they do not account for covert infarcts, which are 5 to 10 times more frequent, result in insidious cognitive and motor impairments, and are linked to symptomatic stroke, depression, disability, and death. Prevention is the key to addressing this problem and reducing the burden on individuals and health care resources. Résumé L accident vasculaire cérébral (AVC) est une affection courante dont la prévalence augmentera fort probablement au fil du vieillissement de la population. Des études comparatives illustrent que l incidence de l AVC aigu et de l accident ischémique transitoire dans la population est la même que celle de l infarctus du myocarde aigu. Le risque à vie de subir un AVC ou un déficit cognitif est d un sur deux chez la femme et d un sur trois chez l homme. Le coût moyen de la prise en charge de l AVC au Canada dépasse les $ la première année seulement, et il ne cesse de grimper en raison de l incapacité qui en découle et des besoins en soins et services de santé. La déficience motrice ou perceptive, le trouble du langage ou de la fonction exécutive sont le lot du survivant d un AVC. L estimation de l incidence fondée sur les manifestations symptomatiques aiguës a le défaut de sous-évaluer systématiquement les répercussions de l AVC, car elle ne tient pas compte des infarctus silencieux ou invisibles, de cinq à dix fois plus fréquents, qui provoquent une altération cognitive et motrice insidieuse et entraînent à terme l AVC symptomatique, la dépression, l incapacité et la mort. La clé de la solution à ce problème réside dans la prévention, seul moyen d en diminuer les répercussions individuelles et systémiques. Stroke is a costly disease in all societies, imposing a significant human, societal, and economic burden. This condition strikes frequently, results in death or disability, and affects individual quality of life, the functioning of families, and social networks. Substantial numbers of individuals require ongoing care, which may be formal or informal, and are further compromised by the depression and cognitive compromise that may ensue. The World Health Organization estimated that, in 2004, 9 million people experienced their first stroke and a further 30.7 million were survivors of stroke. 1 Stroke incidence is strongly age C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

10 Th e H u m a n a n d E c o n o m i c B u r d e n o f S t r o ke dependent, increasing from age 55 and doubling for each decade thereafter. In a study in Oxfordshire, United Kingdom, stroke represented the most common acute vascular event, seen more frequently than myocardial infarction (MI) or acute peripheral vascular disease. This finding, contrary to the most physicians preconception, may be due in part to the population-based design of this study, as opposed to a hospital-based design. 2 At a minimum, stroke rates are similar to those of ischemic heart disease. Stroke burden falls disproportionately on women. In the Oxfordshire data, the age-specific rates of MI and stroke were similar in men; stroke was more common than MI in women after the age of 75, with this difference increasing with age. Worldwide, cerebrovascular diseases are the second cause of death among women over the age of 45. Perhaps more importantly, they are the leading cause of loss of disability adjusted life years, reflecting the frequency of residual impairment in stroke survivors. 3 The lifetime risk of stroke or dementia (frequently related to cerebrovascular disease) is 1 in 2, making this condition very much a disease of women. 4 By comparison, the lifetime risk for stroke and dementia in men is 1 in 3. Women have a longer life expectancy than men and consequently experience stroke at an older age and are more likely than men to be disabled. 5 Stroke has a significant impact on quality of life, with an ongoing need for medication, intervention by health professionals, and modification of lifestyle. Using data from the Canadian Community Health Survey, the Public Health Agency of Canada (PHAC) reported that in 2007, 57.2% of Canadians who were living with the effects of a stroke reported their health as being only fair or poor. Furthermore, 59.5% reported that they needed help with activities and the majority (83.6%) had activity restrictions. 6 Estimates of stroke incidence and prevalence in Canada are limited by the absence of validated community-level screening studies, but reasonable estimates for symptomatic stroke can be obtained from rates of hospital admission. However, it should be recognized that this underestimates the true frequency; an audit undertaken by the Registry of the Canadian Stroke Network (now the Ontario Stroke Registry) showed that 30% of individuals with transient ischemic attack (TIA) and stroke were not admitted to hospital (unpublished data). In addition, the inclusion of covert stroke as noted below substantially increases the impact of cerebrovascular disease on the Canadian population. Accepting these limitations, hospitalization data remain the most readily available data regarding the frequency and impact of stroke. The PHAC report, Tracking Heart Disease and Stroke in Canada, provides the most readily accessible summary of the available data and forms the primary sources for hospitalization, mortality, and risk factor data. The most current version dates from Age standardized rates for acute stroke admission have declined for both men and women over the period 1979 to 2004, with approximately 38,341 admissions in The majority of those admitted are over the age of 65 years, but a substantial minority (27.2%) admitted are younger than 65. Crude rates of admission for acute stroke were higher in women, while the age standardized rates were consistently lower, with the occurrence of stroke at a later age in women. Hospital length of stay was 18.0 days for women and 15.8 days for men. This contrasts with an overall length of stay in acute care hospitals of just over 7 days. 7 Stroke admissions consume a larger proportion of acute care resources than do admissions for other diagnoses. Stroke and dementia are responsible for some of the longest lengths of stay in Canadian hospitals. Mortality due to stroke has declined over the past three decades in Canada, with 11,668 deaths recorded in Canada ranks in the top three jurisdictions for low mortality due to stroke. 6 Stroke mortality is slightly higher in men than in women for all age groups, with the exception of those over 85 years, when the reverse is true. 6 This finding is consistent with the shift in stroke incidence in women to older ages. Stroke outcomes are driven largely by initial stroke severity and risk of recurrence. Paradoxically, those with the mildest initial presentations have the highest risk of early recurrence. TIAs identify individuals with high early risk for stroke and death. Outcome data from the Ontario Stroke Registry on a cohort of patients with TIA seen at stroke centres identified a risk of stroke or death of 9% within 90 days. The subgroup with first-ever TIA fared considerably worse, with a rate of stroke or death in this time frame of 11%. Half of that risk accrued within the first week, with over one third in the first 48 hours after occurrence. 8 These findings are consistent with those from other international studies, which have documented rates of stroke following TIA as high as 20%. 9 Stroke severity varies by subtype of stroke, with cardioembolic strokes having the worst outcomes. One-year mortality in cardioembolic stroke is estimated at 50%. 10 In Canada, the majority (59.7%) of individuals admitted with a stroke in the setting of atrial fibrillation (AF) will be disabled at hospital discharge. An additional 20% will die. Stroke in the setting of AF carries an 80% probability of death or disability. 11 These risks are approximately double the risks of death and disability of stroke as a whole, reflecting the proximal occlusions produced by cardiac emboli and the large volume of brain rendered ischemic. Troublingly, the majority of these strokes are preventable with appropriate anticoagulation. With the frequency and duration of hospitalization accompanied by the issues of disability and the need for ongoing medical care and support, it is no surprise that costs associated 10 V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

11 S h a r m a with stroke are high and likely to increase as the population ages. Costs must be appreciated from the societal perspective, which allows for the inclusion of all costs consequent to a disease. Costs examined from the perspective of a single payer, while valuable for planning and policy development, underestimate the true cost and economic impact. Consider, for instance, the spouse of a stroke survivor who alters his or her pattern of work to participate in the care of the patient. That alteration will result in a loss of economic productivity beyond that of the patient alone. These changes may also influence the pattern of work by a number of family members and others who participate in caregiving and change the trajectory of future careers. All such influences and losses are difficult to measure, but any valid assessment of costs related to disease must take into account losses of productivity and the costs associated with informal caregiving and out-of-pocket costs in addition to the direct medical costs, which are often easier to measure or calculate. In the setting of stroke, the direct medical costs relate to ambulance services, emergency departments (EDs), acute hospital admissions, and rehabilitation, which may take place in a hospital setting or on an outpatient basis. Added to these are the costs of medications administered and personnel costs due to physician, nursing, and allied health interventions. As most individuals survive the initial event, costs are increased for the remaining lifespan of the individual over what would be expected simply due to aging. Mittman and colleagues have published the first national costing study for stroke in Canada. 12 Prospective data were collected on 232 individuals admitted with first-ever ischemic stroke at 12 Canadian centres between 2005 and Unique for studies of this type, participants were followed up with interviews at 3, 6, and 12 months post-discharge. Lost productivity was calculated for patients who reported working prior to hospitalization, and unpaid caregiver time was accounted. The average overall cost of stroke over the first year was $74,353 (range $7,525 to $330,258). The initial 3 months, which included the acute hospitalization, accounted for 54.5% of the overall costs. As expected, there was a significant impact of disability on costs. Interestingly, disability at discharge (largely a reflection of initial stroke severity) did not impact the preadmission costs (ambulance and ED), which averaged $1,882. This is likely due to the standardized rapid transport and ED evaluation protocols at participating centres in the era of acute stroke thrombolysis. Subsequently, however, there was a marked variation in costs based on the level of disability. Over the first year, the costs in the disabled cohort were more than twice those for the nondisabled cohort (disabled $107,883 versus nondisabled $48,339). This difference was most marked in the first 3 months when costs in the disabled cohort were three times those in the nondisabled group, reflecting the intensity of acute medical care and rehabilitation in those with more severe stroke. During the first 3 months, hospitalization and rehabilitation accounted for 80.8% of the costs. Cost drivers shifted to a combination of indirect and rehabilitation costs for the 4- to 6-month period, to indirect costs, home care, and paid caregivers for the bulk of the costs in the remaining 6 months. Lost productivity and unpaid caregivers accounted for 28% of the overall costs and were accounted for only in the proportion who reported working prior to stroke. Individuals who survive stroke have ongoing health problems that influence future costs. In a recent study from the United Kingdom, hospital costs increased by a factor of 4.6 in the first year after TIA or stroke compared with the preceding year. 13 Sixty-four percent of these costs were due to hospitalizations linked to the index stroke, while 10% were for new vascular events. Older data compiled from international sources suggested that, in advanced economies, direct costs for stroke accounted for 3% of health care spending in European countries. This is likely to be a gross underestimate given the high proportion of indirect costs as well as the intensity of treatment attending thrombolysis and acute rehabilitation efforts, which are now the norm in Canadian stroke centres. Depression and cognitive deficits are common after stroke, and the contribution to stroke morbidity has been underestimated in the past as these conditions have not been systematically assessed. Much of the literature on cognition used tests such as the Mini-Mental State Examination (MMSE), which is driven mainly by language and memory and is thus expected to be insensitive to the executive deficits seen commonly in stroke. Cognitive impairment is more common after stroke, and at least 20% of individuals meet the definition of dementia, with a much higher proportion experiencing milder deficits ranging from word finding to planning, sequencing, and shifting mental set. 14 Estimates of the prevalence of depression after stroke range from 20% to over 70%, depending on the setting of the study and definition used. Pooled analyses suggest a prevalence of 37% combining major and minor depression. 15 Depression carries significant implications for survival. Long-term follow-up studies suggest a 10-year mortality of 70% for stroke survivors with depression compared with 40% for those without. 16 Post-stroke dementia increases the risk for recurrent stroke. 17 Our estimates of the impact of stroke are a significant underestimate of the impact of vascular disease on the brain as they are restricted to symptomatic stroke. We now recognize that infarcts seen on imaging studies, principally magnetic resonance imaging (MRI), without attendant symptoms carry significant functional and prognostic implications. These events are five to 10 times more common than symptomatic infarcts, with age being C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

12 Th e H u m a n a n d E c o n o m i c B u r d e n o f S t r o ke the single greatest determinant of prevalence. Prevalence ranges from less than 3 7% of those between 40 and 50 years of age to over 30% by the age of 80, 18 and women have a 30 40% higher prevalence than men. 19 In contrast, the prevalence of symptomatic stroke appears to be higher in men. The reason for this difference is unclear, but might reflect variations in risk factors for symptomatic and asymptomatic stroke. These vary by sex but could also be the result of a decreased probability of stroke diagnosis in women (c.f. cardiac disease). 20 Consequences of Asymptomatic Infarcts The term covert brain infarct has been proposed for asymptomatic strokes as a better reflection of their significance. 21 These infarcts do not produce symptoms of TIA or stroke in the classic sense, but are increasingly associated with neurological dysfunction and an increased risk of overt infarct. Infarcts of this type have been implicated in mild cognitive impairment (MCI). 22 This condition occurs with increasing frequency in the elderly and is associated with an increased risk for Alzheimer s disease. 23 The Cardiovascular Health Study identified an association with MRI-visible infarcts and MCI in older individuals (adjusted odds ratio 1.4). 22 The presence of asymptomatic infarcts doubles the risk of dementia compared with the normal population the Rotterdam Scan Study demonstrated a hazard ratio of 2.26 for the development of dementia in these individuals. 24 These lesions are associated with the precursor of dementia and predict its development. Individuals with asymptomatic infarcts have a stroke incidence that is five times higher than in those without such lesions. When adjusted for other risk factors, the risk of stroke remains, suggesting that silent infarcts are an independent risk factor for stroke. 25 The risk of depression is increased 1.3 to 1.8 times in the presence of MRI lesions. 26 A number of physical limitations have been noted. There is an increase in impairment related to motor tasks such as gait speed, 27 along with mild parkinsonism. 28 Individuals have impairment in speed of movement in the upper and lower extremities along with functional measures of extremity function and gait. 29 As the population ages, the absolute number of Canadians with stroke will likely increase, resulting in additional demand on health services and significant human suffering. In Canadian provinces, health care expenditures are the single largest category of public expenses. As an example, the budget for Ontario includes $48.9 billion in health sector expenses, which form 38.3% of all spending. For comparison, the next largest sector is education at $24.1 billion or 18.9% of total expenses. 30 Over the past few decades, these expenditures have had a rate of growth that overshadows the rate of economic growth. This progression is unsupportable, but fortunately collapse is not inevitable. It is within our personal and professional capacities to direct our efforts at the prevention of diseases such as stroke that have significant human and economic consequences. References 1. World Health Organization. The global burden of disease: Geneva, Switzerland: The Organization, 2004; 2. Rothwell PM, Coull AJ, Silver LE, et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 2005;366: Ribeiro PS. Priorities for women s health from the global burden of disease study. Int J Gynecol Obstet 2008;102: Seshadri S. Lifetime risk of stroke and dementia. Lancet Neurol 2007;6: Wolf PA. Probability of stroke: a risk profile from the Framingham study. Stroke 1991;22: Public Health Agency of Canada. Tracking heart disease and stroke in Canada. Ottawa (ON): The Agency, 2009; 7. Canadian Institute of Health Information. Highlights of inpatient hospitalizations and emergency department visits. Ottawa (ON): The Institute, 2009; 8. Gladstone DJ, Kapral, MK, Fang J, et al. Management and outcomes of transient ischemic attacks in Ontario. CMAJ 2004;170(7): Kennedy J, Hill MD, Eliasziw M, et al. Short-term prognosis following acute cerebral ischemia. Stroke 2002;33: Ezekowitz MD. The increasing need for anticoagulant therapy to prevent stroke in patients with atrial fibrillation. Mayo Clin Proc 2004;79: Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009;40: Mittman N, Seung SJ, Hill MD, et al. Impact of disability status on ischemic stroke costs in Canada in the first year. Can J Neurol Sci 2012;39: Luengo-Fernandez R, Silver LE, Gutnikov SA, et al. Hospitalization resource use and costs before and after TIA and stroke: results from a population-based cohort study (OXVASC). Value Health 2013;16(2): Rockwood K. Vascular cognitive impairment and vascular dementia. J Neurol Sci 2002; : Robinson RG. Poststroke depression: prevalence, diagnosis, treatment, and disease progression. Biol Psychiatr 2003;54: Morris PLP, Robinson RG, Andrzejewski P, et al. Association of depression with 10 year post-stroke mortality. Am J Psychiatr7 1993;150: Yuan HW, Wang CX, Zhang N, et al. Post-stroke depression and risk of recurrent stroke at 1 year in a Chinese cohort study. PloS One 2012;7(10):e doi: /journal.pone Vermeer SE, Longstreth WT, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007;6: Vermeer SE, Koudstaal PJ, Oudkerk M, et al. Prevalence and risk factors of silent brain infarcts in the population based Rotterdam Scan Study. Stroke 2002;33: Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke 2000;31: Longstreth WT Jr., Dulberg C, Manolio TA, et al. Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2002;33: Lopez OL, Jagust WJ, Becker JT, et al. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study, part 2. Arch Neurol 2003;60: V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

13 S h a r m a 23. Breteler MM. Vascular risk factors for Alzheimer s disease: an epidemiologic perspective. Neurbiol Aging 2000;21: Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline: the Rotterdam Scan Study. N Engl J Med 2003;348: Vermeer SE, Hollander M, Van Dijk EJ, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34: Steffens DC, Helms MJ, Krishnan KRR, Burke GL. Cerebrovascular disease and depression symptoms in the Cardiovascular Health Study. Stroke 1999;30: Rosano C, Kuller LH, Chung H, et al. Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning adults. J Am Geriatr Soc 2005;53: Reitz C, Trenkwalder C, Kretzschmar K, et al. Relation of cerebral small vessel disease and brain atrophy to mild Parkinsonism in the elderly. Mov Disord 2006;21: Longstreth WT Jr., Bernick C, Manolio TA, et al. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 1998;55: Ontario Ministry of Finance Ontario budget. Toronto (ON): The Ministry, 2013; /ch2g.html#ch2_t2-27. C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

14 O r i g i n a l A r t i c l e Management of Atrial Fibrillation Blandine Mondésert MD, Peter G. Guerra MD, Laurent Macle MD, Katia Dyrda MD, Léna Rivard MD, Marc Dubuc MD, Jason G. Andrade MD, Bernard Thibault MD, Denis Roy MD, Paul Khairy MD PhD, Mario Talajic MD About the Authors Blandine Mondésert (far left), Peter Guerra, Laurent Macle, Katia Dyrda, Léna Rivard, Marc Dubuc, Jason Andrade, Bernard Thibault, Denis Roy, Paul Khairy, and Mario Talajic (left) are with the Electrophysiology Service, Montreal Heart Institute, and the Department of Medicine, Université de Montréal, in Montreal, Quebec. Correspondence may be directed to blandinemondesert@gmail.com. Summary Atrial fibrillation (AF) is the most common sustained arrhythmia and represents a growing public health burden. It is a complex condition, involving a number of etiological factors and arrhythmia mechanisms associated with atrial remodelling, leading to a dramatic complication: stroke. Treatment decisions can be divided into three major areas: the evaluation and treatment of underlying conditions, rhythm management, and the prevention of thromboembolic complications. Therapeutic options have increased dramatically in recent years and include a variety of novel anticoagulants, emerging antiarrhythmic drugs, new techniques for catheter ablation, and innovative invasive alternatives for stroke prevention. This article reviews these options available for treatment of patients with atrial fibrillation. Résumé La fibrillation auriculaire, trouble du rythme cardiaque tenace le plus courant, représente un problème de santé publique à l ampleur croissante. L affection, complexe, a une étiologie multifactorielle et pour conséquence un remodelage auriculaire à l origine d une complication dévastatrice : l accident vasculaire cérébral (AVC). La prise de décisions d ordre thérapeutique comporte trois volets : l évaluation et le traitement des affections sous-jacentes, le rétablissement du rythme cardiaque et la prévention des complications thromboemboliques. Les options thérapeutiques se sont multipliées ces dernières années : de nouveaux anticoagulants et antiarythmisants, de nouvelles techniques d ablation par cathétérisme et des interventions effractives novatrices destinées à prévenir l AVC. L article passe en revue les options thérapeutiques indiquées dans le traitement de la fibrillation auriculaire. Introduction and Definitions Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence of approximately 1.5 2% in the developed world. AF is associated with a five times greater risk of stroke, a threefold risk of congestive heart failure, and a doubling of mortality. 1,2 AF is the most common arrhythmia managed by emergency physicians, 3 with a hospital rate that has increased by 66% over the past 20 years. 4,5 Increased recognition of AF as a major contributor to the burden of stroke has led to advances in the detection and treatment of AF and the development of strategies to prevent AF-related stroke. Therapeutic options have increased dramatically in recent years and form the basis of this review. In general, treatment decisions can be divided into three major areas: the evaluation and treatment of underlying conditions, rhythm management, and the prevention of thromboembolic complications. Clinical Types of AF Paroxysmal AF is an intermittent episode resolving spontaneously within a week (usually within 48 hours). Persistent AF is an episode persisting more than 7 days or requiring termination by pharmacological or electrical cardioversion. Permanent AF is AF 14 V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

15 M o n d é s e r t e t a l. for which a decision has been made by the patient/physician not to attempt rhythm conversion. Epidemiology and Etiology Approximately 350,000 Canadians live with AF. Approximately 15 20% of patients with ischemic stroke have AF. 6 8 Stroke severity and in-hospital mortality are also significantly greater in those with AF. 9 AF is a disease of advancing age, whose prevalence increases dramatically from 0.1% in patients under age 50, to 10 15% in those >80 years. 10 The prevalence of AF triples between the ages of 65 and 85-plus years. 11 This increase is consistent across ethnic and gender groups. Underlying conditions associated with AF should be determined. Particular effort should be given to identifying and treating potentially reversible causes, such as hyperthyroidism (in 3.1% of AF patients) and Wolff-Parkinson-White syndrome AF is commonly associated with hypertension, heart failure, left ventricular systolic dysfunction, prior myocardial infarction, and valvular heart disease There is also increased awareness of other risk factors including obesity, obstructive sleep apnea, and excess alcohol intake Identification of structural heart disease is important as it influences prognosis and therapeutic choices. Finally, there are approximately 15 20% of AF patients who do not have identifiable comorbidities. 25 While these patients would be classified as having lone (idiopathic) AF, some may have a genetic predisposition, an underlying supraventricular tachycardia that degenerates into AF, or experience AF as a result of high vagal tone secondary to intensive aerobic exercise. 26,27 Symptoms and Scales Decisions about rhythm management should be guided by symptoms, including palpitations, dyspnea, presyncope, syncope, and fatigue. To characterize symptom severity, several scoring systems have been devised The Canadian Cardiovascular Society (CCS) recommends the assessment of quality of life using the validated CCS Severity in Atrial Fibrillation (CCS-SAF) scale (Table 1). 28 This score quantifies Table 1. The Canadian Cardiovascular Society Severity of Atrial Fibrillation Scale (CCS-SAF) a. The three steps of the CCS-SAF scale: Step 1. Symptoms Step 2. Association Step 3. Functionality A. Palpitations B. Dyspnea C. Dizziness, presyncope, or syncope D. Chest pain E. Weakness or fatigue Is AF, when present, associated with the symptoms listed above (A E)? Determine if the symptoms associated with AF or the treatment affect the patient s functionality (subjective quality of life). b. Class definitions of the CCS-SAF scale, ranging from 0 to 4: Class 0 Asymptomatic with respect to AF Class 1 Symptoms attributable to AF have minimal effect on patient s general quality of life: Minimal and/or infrequent symptoms, or Single episode of AF without syncope or heart failure Class 2 Symptoms attributable to AF have a minor effect on patient s general quality of life: Mild awareness of symptoms in patients with persistent/permanent AF, or Rare episodes (e.g., less than a few per year) in patients with paroxysmal or intermittent AF Class 3 Symptoms attributable to AF have a moderate effect on patient s quality of life: Moderate awareness of symptoms on most days in patients with persistent/permanent AF, or More common episodes (e.g., more than every few months) or more severe symptoms, or both, in patients with paroxysmal or intermittent AF Class 4 Symptoms attributable to AF have a severe effect on patient s quality of life: Very unpleasant symptoms in patient with persistent/paroxysmal AF and/or Frequent and highly symptomatic episodes in patients with paroxysmal or intermittent AF and/or Syncope thought to be due to AF and/or Congestive heart failure secondary to AF AF = atrial fibrillation. Source: Adapted from Dorian et al. 28 C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

16 M a n a g e m e n t o f A t r i a l Fi b r i l l a t i o n Table 2. CHADS 2 Score Condition Points Congestive heart failure 1 Hypertension 1 Age 75 years old 1 Diabetes mellitus 1 Prior stroke or TIA or thromboembolism 2 TIA = transient ischemic accident. symptoms attributable to AF and its impact on quality of life. Many patients with AF, especially those of older age and with permanent AF, have no or few symptoms. 29,30 Consequently, AF is often diagnosed when patients present with stroke, or is incidentally detected during routine electrocardiography. Since asymptomatic AF harbours the same stroke risk as symptomatic AF, 31 establishing the diagnosis before a catastrophic complication is paramount. 32 Recent data collected in patients with implanted devices 33 or Holter monitors 34 reinforce the notion that even brief episodes of silent AF convey an increased risk for stroke. Risk Stratification for Stroke Quantifying stroke risk is an integral component of patient management. Several scores have been recommended for use and are outlined below. CHADS 2 Score The most widely adopted tool for stroke risk assessment is the CHADS 2 score (Table 2) CHADS 2 stands for congestive heart failure, hypertension, age 75 years, diabetes, and stroke. A single point is assigned for each risk factor except stroke, which carries 2 points. On the basis of the score, patients may be classified into three-risk categories: low (0), moderate (1), and high ( 2). The annual incidence of stroke increases by about 2.0% for each 1- point increase in CHADS 2 score (from 1.9% to 18.2% with scores of 0 and 6). 35,38 Its simplicity, extensive validation, and ease of applicability render it the risk score of choice by most guidelines. CHA 2 DS 2 -VASC Score One of the limitations of the CHADS 2 score is that patients with a score of 0 represent a heterogeneous population in whom some may be at higher risk and benefit from anticoagulation The CHA 2 DS 2 -VASc score incorporates additional risk factors, namely age between 65 and 74 years (1 point) and age 75 years (2 points), female gender (1 point), and vascular disease (1 point) (Table 3). 41 All three new risk-score components appear to Table 3. CHA 2 DS 2 -VASC Score Condition Points Congestive heart failure 1 Hypertension 1 Age 75 years old 2 Diabetes mellitus 1 Prior stroke or TIA or thromboembolism 2 Vascular disease 1 Age years 1 Sex category (female) 1 TIA = transient ischemic accident contribute significantly to risk prediction in univariate analysis, though female sex is not retained in a multivariate model. 39 The value of assigning a point for female sex continues to be debated. 42 Whereas about 20% of AF patients have a CHADS 2 score (CHADS 2 = 0), 8.5% also qualify as having a CHA 2 DS 2 - VASc score of 0, which is associated with a mean stroke risk of 0.5% per year. 39,40 Most patients with a score of 0 on CHA 2 DS 2 - VASc do not require antithrombotic therapy. Patients with a CHADS 2 1 or CHA 2 DS 2 -VASc 2 have an estimated stroke risk over 2% per year, and for them oral anticoagulant (OAC) therapy is recommended. Although most patients with a CHA 2 DS 2 -VASc score of 1 may benefit from an OAC, a single CHA 2 DS 2 -VASc point based on vascular disease or female sex implies a stroke risk <1.5% per year, such that acetylsalicylic acid (ASA) may be considered instead. The 2010 CCS guidelines recommend that the CHADS 2 schema be used for stroke risk prediction and that further stratification be performed in patients with a CHADS 2 score of 0. As a result, anticoagulation is recommended in most patients over the age of 65 years and in younger women with vascular disease 43 (Figure 1). ASA is an option in patients with one risk factor, but anticoagulation is clearly preferred. For patients with a very low risk (or a CHA 2 DS 2 -VASc score of 0), CCS and European Society of Cardiology (ESC) guidelines also provide the option of no embolic prophylaxis at all HAS-BLED Score The efficacy of antithrombotic therapy must be balanced against the risk of major bleeds, particularly intracerebral hemorrhage, which is often fatal. For vitamin K antagonists (VKAs), bleeding risk depends upon the international normalized ratio (INR), quality of monitoring, duration of therapy (higher risk during initial few weeks), and stability of dietary and other factors that alter VKA potency. The CCS and 2010 ESC guidelines recommended using the HAS-BLED score to assess the risk of hemorrhage in anticoagulated patients. 46,47 Single points are assigned for 16 V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

17 M o n d é s e r t e t a l. Figure 1. Summary of recommendations for antithrombotic agent use based on CHADS 2 score. Additional risk factors of age 65, vascular disease, and female sex are integrated to increase granularity at low CHADS 2 score (CHADS 2 = 0). ASA = acetylsalicylic acid; OAC = oral anticoagulant. Source: Reprinted from Canadian Journal of Cardiology, 28(2), Skanes AC, Healey JS, Cairns JA, et al., Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control, , Copyright (2012), with permission from Elsevier. 48 hypertension (defined as systolic blood pressure >160 mm Hg), abnormal renal and liver functions, stroke, bleeding history or predisposition, labile INRs, elderly (age >65 years), drugs or alcohol. 45,48 Annual bleeding rates vary from 1% (score 0 1) to 12.5% (score 5). A patient with 3 risk factors is considered high risk. Treatment Vitamin K Antagonists A meta-analysis of five major primary prevention trials showed that warfarin reduced stroke by 60% with an absolute risk reduction (ARR) for stroke of 2.7% per year, and a number needed to treat (NNT) of 37 to avoid one stroke during 1 year of treatment. 49 All-cause mortality was significantly reduced (26%) by adjusted-dose VKAs, with a low risk of intracranial hemorrhage (0.3 1%/year). 50 In patients over the age of 75 years, VKA (target INR 2 3) was superior to ASA 75 mg daily in reducing the primary end point of fatal or disabling stroke, intracranial hemorrhage, or clinically significant arterial embolism by 52%, with no difference in the risk of major hemorrhage between warfarin and ASA. 51 However, limitations of warfarin are well known: unpredictable INR levels, the need for monthly measurements, and a major bleeding rate of about 3.0% per year. 52 Up to 50% of patients (particularly the elderly) do not receive anticoagulation, 53 and a substantial proportion remain under-anticoagulated. 54 Novel Oral Anticoagulants Novel oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban have undergone extensive clinical evaluation and been found to be safe and efficacious They fall into two classes: the oral direct thrombin inhibitors (e.g., dabigatran) and the oral direct factor Xa inhibitors (e.g., rivaroxaban and apixaban). 58 Other oral factor Xa inhibitors (edoxaban 59 and betrixaban 60 ) are undergoing evaluation. Major advantages over warfarin include similar or improved stroke prevention, similar or safer bleeding profiles, and non-necessity for anticoagulation monitoring. Compliance is crucial since these drugs have a relatively short half-life. Clinical trials have found that dabigatran 150 mg bid and apixaban are more efficacious than warfarin for stroke prevention, whereas rivaroxaban is non-inferior to warfarin. Apixaban and dabigatran 110 mg bid cause less major bleeding than warfarin, whereas major bleeding rates with dabigatran 150 mg bid and rivaroxaban are comparable to those with warfarin. 57,61 There is significantly less intracranial bleeding with each of the new agents than with warfarin. Dabigatran appears cost-effective for most patients, except for those with very well controlled INRs. The characteristics and outcomes of different NOACs are compared in Table 4. Practical Considerations with NOACs BRIDGING When transitioning from a VKA, the INR should fall below 2.0 before starting a NOAC. When changing from a NOAC to a VKA, the VKA should be started 3 5 days before discontinuing the NOAC, since VKA therapy typically requires 3 5 days to achieve therapeutic levels. C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

18 M a n a g e m e n t o f A t r i a l Fi b r i l l a t i o n Table 4. Summary of the Clinical Trials Involving Novel Anticoagulants versus Warfarin for Stroke Prevention in Non-valvular AF Details Dabigatran (RE-LY) 59,65 Rivaroxaban (Rocket-AF) 60 Apixaban (Aristotle) 61 Name in Canada Pradaxa Xarelto Eliquis Indication Stroke and STE prevention in AF and AFL Stroke and STE prevention in AF and AFL Stroke prevention in AF Drug characteristics Mechanism Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor Bioavailability, % Time to peak levels, h Half-life, h Excretion 80% renal 2/3 liver, 1/3 renal 25% renal, 75% fecal Dose 150 mg bid 20 mg od 5 mg bid Dose in renal impairment 110 mg bid 15 mg od when ClCr ml/min 2.5 mg bid Special considerations Intestinal absorption reduced in Higher levels expected in pts pts taking PPI (ph dependant) with renal or hepatic failure Increase risk of bleeding with verapamil, Activity lower in fasted pts so should be amiodaron, quinidine, ketoconazole taken after food Study characteristics Design Randomized, open-label Randomized, double-blind Randomized, double-blind Number of pts 18,111 14,264 18,201 FU periods, y Randomized groups Dose-adjusted warfarin vs. blinded doses Dose-adjusted warfarin vs. rivaroxaban Dose-adjusted warfarin of dabigatran (110 mg bid, 150 mg bid) 20 mg od vs. apixaban 5 mg od Baseline pt characteristics Mean ± SD Median (interquartile range) Median (interquartile range) Age, y 71.5 ± (65 78) 70 (63 76) Male sex, % CHADS 2 (mean) Outcomes Warfarin D150 D110 Warfarin Rivaroxaban Warfarin Apixaban (% per year) N = 6,022 N = 6,076 N = 6,015 N = 7,133 N = 7,131 N = 9,081 N = 9,120 RR, 95% CI, RR, 95% CI, HR, 95% CI, HR, 95% CI, p value p value p value p value Stroke/systemic embolism 0.66, , 0.91, , , 0.79, , p for superiority p for non-inferiority p for non-inferiority p<.001 for non-inferiority, <.001 <.001 <.001, p for p=.01 for superiority superiority =.12, ITT Ischemic stroke , , 1.11, , 0.94, , 0.92, , p=.03 p=.35 p=.58 p=.42 Hemorrhagic stroke 0.26, , 0.31, , 0.59, , 0.51, , p<.001 p<.001 p=.024 p<.001 p<.001 Major bleeding , , 0.80, , p= , , p=.31 p=.003 p<.001 Intracranial bleeding 0.3, , 0.31, , 0.67, , 0.42, , p<.001 p<.001 p=.02 p<.001 Gastrointestinal bleeding 1.50, , 1.10, , p< , , p<.001 p=.43 p=.37 Myocardial infarction 1.27, , 1.29, , 0.81, , 0.88, , p=.12 p=.09 p=.12 p=.37 Death from any cause 0.88, , 0.91, , 0.85, , 0.89, , p=.051 p=.13 p=.07 p=.047 % Discontinuation at the end of FU % Discontinuation /year AF = atrial fibrillation; AFL = atrial flutter; bid = twice a day; CI = confidence interval; CrCl = creatinine clearance; FU = follow-up; HR = hazard ratio; ITT = intention to treat; od = once daily; PPI = proton pump inhibitor; pt = patient; RR = relative risk; SD = standard deviation; STE = systemic thromboembolism. Source: Adapted from Camm et al V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e

19 M o n d é s e r t e t a l. SURGERY Given their rapid onset and offset of action, no bridging therapy with low molecular weight heparin is required for most interventions. 66 NOACs should be stopped hours before surgery in patients with normal or near-normal renal function. This delay should be doubled in patients with moderate renal dysfunction (creatinine clearance [CrCl] <50 ml/min) or undergoing surgery with a high hemorrhagic risk. Following surgery, NOACs can be restarted as soon as effective hemostasis has been achieved. RENAL FUNCTION All NOACs are eliminated partially by the kidneys (Table 4). Renal function should be assessed at least annually in patients with no or mild renal impairment (CrCl 50 ml/min) and more frequently in patients with moderate renal impairment (such as creatinine clearance ml/min). 32,48 The NOAC dose should generally be reduced in patients with moderate renal impairment. NOACs are contraindicated in patients with severe renal impairment. ANTICOAGULATION TESTING AND ANTIDOTE The NOACs do not require dose adjustment on the basis of coagulation tests. For dabigatran, the ecarin clotting time and thrombin clotting time directly reflect thrombin inhibition 67 ; an activated partial thromboplastin time (aptt) can also be used (especially in an emergency setting) to indicate the presence or absence of an anticoagulant effect, although the correlation between aptt and plasma concentration levels is not linear, particularly at higher concentrations. 67,68 Rivaroxaban prolongs the prothrombin time (PT), and this might be used as a rough estimate of an anticoagulation effect. 69 An anti-xa assay provides a better estimate of anticoagulant effects for oral factor Xa inhibitors. 69,70 These novel drugs do not currently have specific antidotes (under development), and management of bleeding is largely supportive given their relatively short half-life (5 17 hours). 68,71 Animal models suggest that the lack of normalization of coagulation tests does not necessarily correlate with the absence of an anti-hemorrhagic effect. 67 CARDIOVERSION Available data suggest that elective cardioversion can be safely performed on dabigatran 72 and other NOACs with 3 weeks anticoagulation pre-cardioversion and a minimum of 4 weeks anticoagulation post-cardioversion. ACUTE CORONARY SYNDROME AND CORONARY ARTERY DISEASE Concomitant use of antiplatelet therapy with any anticoagulant significantly increases bleeding risk. 73 NOACs should be stopped in patients admitted with acute coronary syndrome treated with heparin. If dual antiplatelet therapy is indicated, anticoagulants (such as triple therapy) should be restricted to patients at the highest risk of stroke (CHADS 2 2). Patients with AF and stable vascular disease (such as no acute event or revascularization within 12 months) can be managed with an oral anticoagulant alone. Thrombolysis is contraindicated in patients on NOACs. 74 ELDERLY Among patients >75 years and certainly those >80 years, dose reduction of the NOACs, especially dabigatran, should be considered. Antiarrhythmic Therapy Rate- versus Rhythm-Control Strategy One of the fundamental therapeutic decisions in a patient with AF is whether to pursue a rate-control strategy (where treatment is directed at adequately controlling the ventricular rate during AF without attempting to restore and maintain sinus rhythm [SR]) or a rhythm-control strategy (where AF conversion is performed and pharmacological or ablation therapy is used to maintain SR). Several large multicentre trials have shown that rhythm control is not superior to rate control with respect to mortality, hospitalization, or quality of life The clinical decision to pursue rhythm control is often based on symptoms while on adequate rate control and the feasibility of maintaining SR. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 80 and Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trials 75 used rate-control targets of <80 beats per minute (bpm) at rest and 110 bpm during exercise. 75,80 Recently, the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation: a comparison between Lenient and Strict Rate Control II) study randomized patients to a strict (resting heart rate [HR] <80 bpm and <110 bpm with exercise) rate-control strategy versus a lenient strategy (resting HR <110 bpm) and reported comparable clinical outcomes. 81 A target resting HR <100 bpm is recommended in most patients. 44 β-blockers or calcium channel blockers alone or in combination should be used to achieve adequate rate control. Digoxin may be used in selected elderly or sedentary patients. Atrioventricular junction ablation with the implantation of a pacemaker is recommended for symptomatic patients with uncontrolled ventricular rates during AF despite a maximally tolerated combination of pharmacological therapy. Rhythm Control The strategy of maintaining SR has never been shown to decrease C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 8, S u p p l e m e n t

20 M a n a g e m e n t o f A t r i a l Fi b r i l l a t i o n mortality or reduce the incidence of thromboembolic complications in AF patients compared to rate control alone. 75,80 83 Improvement in patient quality of life and function, and not the total elimination of AF, should always be the goals of rhythm control. Benefits of antiarrhythmic drug (AAD) therapy must also be balanced against side effects and toxicities. If drug therapy fails to achieve a meaningful improvement in patient quality of life, alternatives should be considered, including catheter ablation of AF or rate control alone. DRUG THERAPY Currently available AADs include propafenone, sotalol, flecainide, dronedarone, dofetilide, and amiodarone. Patients with no structural heart disease or hypertension may be treated initially with dronedarone, sotalol, propafenone, or flecainide. Amiodarone is reserved for refractory cases. Patients with coronary artery disease should not receive flecainide or propafenone. In patients with congestive heart failure or left ventricular dysfunction, drug choices are limited to sotalol (if the ejection fraction>35%) or amiodarone. AF recurs within the first year in approximately 50% of patients treated with an AAD (30% in amiodarone-treated patients) Due to its side effects, amiodarone is generally reserved for patients in whom other agents failed, were not well tolerated, or are contraindicated. PILL IN THE POCKET In some patients, such as those with infrequent highly symptomatic recurrences of AF, intermittent AAD therapy can be a useful treatment option. The efficacy and safety of this approach should first be tested in hospital. Flecainide ( mg) or propafenone ( mg) combined with an atrioventricular-nodal blocking agent (metoprolol mg) to prevent 1:1 conducting atrial flutter are commonly used. 87 Ablation Catheter Patient Selection Catheter ablation is indicated for patients with drug-refractory symptomatic AF that is adversely affecting their quality of life. 44 Recent clinical trials have demonstrated the superiority of ablation over AAD to maintain SR in patients with paroxysmal AF for whom one or more antiarrhythmic drugs have failed Patients with symptomatic persistent AF may also be considered for ablation. 92 Catheter ablation may also be considered as a firstline treatment in highly selected patients with symptomatic paroxysmal AF and minimal or no structural heart disease. 48,93 95 It may also benefit some patients with tachycardia-bradycardia syndrome who are unable to tolerate drug therapy because of bradyarrhythmic complications in the absence of a permanent pacemaker. 96,97 While there is no absolute age limit for ablation, patients enrolled in clinical trials have predominantly been <75 years of age. Finally, if the left atrium (LA) is too enlarged (typically >55 mm), the success rate of catheter ablation is poor. Efficacy of Catheter Ablation for AF Since AF ablation was first described >10 years ago, the technique and technology have evolved dramatically. 90 The initial success rate of maintaining SR off ADD is 60 75% after one procedure and 75 90% after two procedures, 98 with an associated significant reduction in cardiovascular hospitalizations and an improved quality of life. 99,100 Such results were achieved with a repeat ablation rate of 17%. 88,101 Failures most commonly occur as a result of electrical reconnection between pulmonary veins (PVs) and the LA. 102 Improved outcomes have been demonstrated with repeat procedures to isolate electrically reconnected PVs. In patients with persistent AF, the success rates are 10 15% lower than those described for paroxysmal AF with a greater need for repeat procedures. 103 The optimal lesion set to target the substrate has yet to be fully determined, but data suggest that hybrid techniques targeting more than just PV isolation may be required, 104 and this is currently being studied in the large-scale multicentre Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial (STAR-AF-2) trial. 105 Lower success rates (by 5 10% compared with paroxysmal AF) have also been reported in patients with structural heart disease, such as cardiomyopathy, 106 although the benefit in this population may still be significant. The PABA-CHF (Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure) trial reported improvements in ejection fraction in a small number of patients with congestive heart failure despite the lower overall procedural success rate. 107 In patients who do not have a successful outcome post-ablation, some may become responsive to AAD therapy that was previously ineffective. Risks of Catheter Ablation of AF Current estimates indicate a procedural complication rate for AF catheter ablation of 4 5% The most common complication is related to vascular access, such as groin hematoma, pseudoaneurysm, and arteriovenous fistula (1 2% of cases). Less common but more serious complications include cardiac perforation (1%) and thromboembolism (0.5 1%). Cardiac perforation can often be managed by percutaneous pericardiocentesis, with surgical repair rarely required. Acute thromboembolic stroke results in transient deficits in most affected patients. Pulmonary vein stenosis is quite uncommon today (<0.5%) since energy is delivered outside of the PVs. Atrio- 20 V o l u m e 8, S u p p l e m e n t C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e