Every year hundreds of thousands of people in Latin How ...Instituto Dante Pazzanese de Cardiologia,...

How Can We Avoid a Stroke Crisisin Latin America?

Working Group Report:Stroke Prevention in Patients with Atrial Fibrillation

August 2011

Every year hundreds of thousands of people in LatinAmerica experience a stroke, and the number of strokesper year is predicted to rise dramatically as the populationages. This is an epidemic already beginning to happen,and prompt action is required to avoid a crisis.

Many of these patients die from stroke; others are leftwith severe disabilities, which devastate not only theirlives but also the lives of their families and caregivers.Unsurprisingly, the economic implications of stroke arehuge for both individuals and healthcare systems.

Atrial fibrillation (AF) – the most common sustained abnormality of heartrhythm – affects millions of people in Latin America. For example, inBrazil, it has been estimated that there are approximately 1.5 millionpatients living with AF. Individuals with AF are at a fivefold increased riskof stroke compared with the general population. Furthermore, strokesrelated to AF are more severe, have poorer outcomes, and are more costlythan strokes in patients without AF. Patients with AF are therefore animportant target population for reducing the overall burden of stroke.

This report aims to raise awareness among policy makers and healthcareprofessionals that better knowledge and management of AF, and betterprevention of stroke are possible. However, greater investment inpreventing stroke is needed, particularly in patients with AF. Coordinatedaction by national governments of Latin American countries is urgentlyrequired to achieve earlier diagnosis and better management of AF, and toreduce the risk of stroke in patients with AF. Implementation of therecommendations detailed in this report, at regional and national level,will be crucial.

How Can

We A

void a Stro

ke Crisis in

Latin America?

August 2011

Dr. Álvaro AvezumInstituto Dante Pazzanese de Cardiologia, São Paulo, Brazil

Dr. Carlos CantúNational Institute of Medical Sciences and Nutrition, Salvador Zubirán, Mexico

Dr. Jorge Gonzalez-ZuelgaraySanatorio de la Trinidad San Isidro, Buenos Aires, Argentina

Mellanie True HillsStopAfib.org; American Foundation for Women’s Health

Trudie Lobban MBEArrhythmia Alliance; Atrial Fibrillation Association

Dr. Ayrton MassaroIbero-American Stroke Society, Brazil

Dr. Susana MeschengieserAcademia Nacional de Medicina, Buenos Aires, Argentina

Professor Bo NorrvingLund University, Sweden

Dr. Walter Reyes-CaorsiSanatorio Casa de Galicia, Montevideo, Uruguay

This report was made possible by a sponsorship from Bayer HealthCare Pharmaceuticals. See reverse oftitle page and acknowledgements for further information.



The recommendations in this document are endorsed by the organizations shown below.

ISBN 978-0-9568536-1-5

The content of this report has been determined by the authors independently of Bayer HealthCare in order toensure the independence of the report and outputs of the group. The views expressed in this publication arenot necessarily those of the sponsor.

Bayer sponsored members of Action for Stroke Prevention to support the development of their report.Honoraria were made available; however, it should be noted that the majority of the working group havereceived no payment.

1

Authors

Writing group

Dr. Álvaro AvezumDirector, Research Division, DantePazzanese Institute of Cardiology;Professor, PhD Program, DantePazzanese Institute of Cardiology/SãoPaulo University; International ResearchAssociate, Population Health ResearchInstitute, McMaster University, Canada

Dr. Carlos CantúProfessor of Stroke Program at theUniversidad Nacional Autónoma deMéxico; Chairman of the Department of Neurology, National Institute ofMedical Sciences and Nutrition, Salvador Zubirán, Mexico; FoundingMember of the Mexican StrokeAssociation

Dr. Jorge Gonzalez-ZuelgarayChief of Service of Arrhythmias andElectrophysiology (Sanatorio de laTrinidad San Isidro, Buenos Aires,Argentina); Director of ArrhythmiaCenter (University of Buenos Aires);President of Arrhythmia Alliance andAtrial Fibrillation Association inArgentina; Director, Career of Specialistsin Electrophysiology (University ofBuenos Aires)

Mellanie True HillsFounder and CEO, StopAfib.org and the American Foundation for Women’sHealth

Trudie Lobban MBEFounder and Trustee, ArrhythmiaAlliance; Founder and CEO, AtrialFibrillation Association

Dr. Ayrton Massaro Past-President of Ibero-American StrokeSociety and Co-chair of the 2012 WorldStroke Conference, Brazil

Dr. Susana Meschengieser Head of the Hemostasis and ThrombosisDepartment, Instituto de InvestigacionesHematológicas, Academia Nacional deMedicina, Buenos Aires, Argentina

Professor Bo Norrving Professor in Neurology, Department ofNeurosciences, Section of Neurology,Lund University, Sweden; President,World Stroke Organization

Dr. Walter Reyes-CaorsiAssociate Professor of Cardiology;Director, Electrophysiology Service, Sanatorio Casa de Galicia, Montevideo,Uruguay; Director, Arrhythmia CouncilSouth American Society of Cardiology

Authors

2

Avoid a stroke crisis in Latin America

Working group

Dr. Felicita Andreotti Aggregated Professor, Department ofCardiovascular Medicine, CatholicUniversity, Rome, Italy; 2008–2010 Chair of the ESC Working Group onThrombosis

Dr. Alastair BenbowExecutive Director, European BrainCouncil

Professor John Camm Professor of Clinical Cardiology, St George’s University, London, UK

Professor László Csiba Professor, Department of Neurology,University of Debrecen, Hungary

Professor Antoni Dávalos Director, Department of Neurosciences,Hospital Universitari Germans Trias i Pujol,Barcelona; Associated Professor ofNeurology, Universitat Autònoma deBarcelona, Spain

Professor Shinya GotoProfessor of Medicine, Department ofMedicine (Cardiology) and the MetabolicDisease Center of Tokai UniversityGraduate School of Medicine, and theDepartment of Metabolic SystemsMedicine, Institute of Medical Science,Tokai University, Kanagawa, Japan

Professor Dr. Werner Hacke Professor and Chairman, Department of Neurology, University of Heidelberg,Germany; Past-President, EuropeanStroke Organisation

Professor Graeme J HankeyHead of Stroke Unit, Royal PerthHospital, Perth, Western Australia;Clinical Professor, School of Medicineand Pharmacology, University of WesternAustralia, Nedlands, Western Australia

Professor Dr. Karl-Heinz Ladwig Clinical Psychologist and Professor of Psychosomatic Medicine, Institute of Epidemiology, Helmholtz ZentrumMünchen, German Research Center for Environmental Health, Neuherberg,Germany

Professor Michael G Hennerici Professor and Chairman of Neurology,Department of Neurology, University of Heidelberg, UniversitätsklinikumMannheim, Germany; Chairman,European Stroke Conference

Professor Richard Hobbs Professor and Head of Department ofPrimary Care Health Services, Universityof Oxford, UK; Chairman, EuropeanPrimary Care Cardiovascular Society

Dr. Torsten Hoppe-Tichy Chief Pharmacist, Pharmacy Department,University Hospital of Heidelberg,Germany; Vice-President of ADKA (TheGerman Society of Hospital Pharmacists)

Professor Dayi HuChief of the Cardiology Division ofPeking University’s People’s Hospital,Dean of the Medical College of Shanghaiat Tongji University, and Dean of theCardiology Department of CapitalUniversity of Medical Science, Beijing,China; President of Chinese Society ofCardiology; President of the ChineseCollege of Cardiovascular Physicians

Professor Han Hwa Hu Professor of Neurology, National Yang-Ming University, Taipei, Taiwan; EmeritusChief of the Neurovascular Section,Neurological Institute, Taipei VeteransGeneral Hospital, Taipei, Taiwan;President of the Taiwan StrokeAssociation

Professor Dr. Paulus Kirchhof Senior Consultant, Department ofCardiology and Angiology, UniversityHospital Münster; Associate Professor ofMedicine, Westfälische Wilhelms-Universität Münster, Germany

Eve Knight Chief Executive, AntiCoagulation Europe

Professor Antoine Leenhardt Professor of Cardiology, Paris 7University; Head of the CardiologyDepartment, Lariboisière Hospital, Paris, France

3

Dr. Maddalena Lettino Staff Physician, CCU-CardiologyDepartment, S Matteo Hospital, Pavia,Italy; Past-Chairman, ItalianAtherosclerosis, Thrombosis and VascularBiology (ATBV) Working Group;Chairman of the Italian Working Groupon Acute Cardiac Care

Professor Gregory YH LipConsultant Cardiologist and Professor of Cardiovascular Medicine, University of Birmingham Centre for CardiovascularSciences, City Hospital, Birmingham,United Kingdom

Rod MitchellPatient Advocate, Board Member,European Platform for Patients’Organisations, Science and Industry andEuropean Genetics Alliance Network;Past Board member, InternationalAlliance of Patients’ Organizations

Professor Gérard de Pouvourville Chair, Health Economics, ESSEC BusinessSchool, Paris, France

Dr. David KL QuekConsultant Cardiologist, Pantai HospitalKuala Lumpur, Kuala Lumpur, Malaysia;President of the Malaysia MedicalAssociation and Elected Member of theMalaysian Medical Council

Professor Dr. Kui-Hian SimHead of the Department of Cardiology,Clinical Research Centre, Sarawak GeneralHospital, Sarawak, Malaysia; AdjunctProfessor, Faculty of Medicine and HealthSciences, University of Malaysia, Sarawak,Malaysia; President of the National HeartAssociation of Malaysia

Professor Norio TanahashiProfessor of Neurology, SaitamaInternational Medical Center, SaitamaMedical University, Hidaka City, Japan

Professor Hung-Fat TseProfessor of Medicine, CardiologyDivision, Department of Medicine, The University of Hong Kong, Hong Kong, China

Professor Panos Vardas Professor, Department of Cardiology,Heraklion University Hospital, Crete;President, European Heart RhythmAssociation

Dr. Xavier Viñolas Director, Arrhythmia Unit, Hospital SantPau, Barcelona, Spain

Professor Byung-Woo YoonDepartment of Neurology, Seoul NationalUniversity Hospital; Director of ClinicalResearch Center for Stroke, Korea;Current President of the Korean Societyof Stroke

Professor Shu ZhangProfessor of Medicine, Chief ofDepartment of Cardiology, Director ofArrhythmia Center; National Center forCardiovascular Disease, Fu WaiCardiovascular Hospital, ChineseAcademy of Medical Sciences and PekingUnion Medical College, Beijing, China;President of Chinese Society of Pacingand Electrophysiology, Beijing, China

AcknowledgementsSupport for the writing and editing of this report was provided by ChameleonCommunications International Ltd. We acknowledge with thanks the contribution of Oxford PharmaGenesis™ Ltd who provided editorial support for a previous reporton the European Union: How Can We Avoid a Stroke Crisis? (2009).

The content of this report has been determined by the authors independently of BayerHealthCare in order to ensure the independence of the report and outputs of thegroup. The views expressed in this publication are not necessarily those of the sponsor.

Costs are in US dollars (US$). Where original cost was not in US$, conversion to US$was performed using the website www.xe.com. All exchange rates correct as of May 27, 2011.

Authors

Endorsements

Academia Brasileira de Neurologia (Brazil Academy ofNeurology) – www.abneuro.org

Academia Nacional de Medicina Uruguay (NationalAcademy of Medicine Uruguay) – www.anm.org.uy

ADKA (The German Society of Hospital Pharmacists) –www.adka.de

Anticoagulation Europe – www.anticoagulationeurope.org

Arrhythmia Alliance – www.heartrhythmcharity.org.uk

Arrhythmia Alliance International – www.aa-international.org

Arrhythmia Alliance Argentina – www.arritmias.org.ar

Arrhythmia Alliance Chile – website to be launched

Arrhythmia Alliance Uruguay – www.aa-international.org/uy

Asociación Médica Argentina (Argentina MedicalAssociation) – www.ama-med.org.ar

Asociación Mexicana de Enfermedad Vascular Cerebral, A.C.(Mexican Stroke Association) – www.amevasc.org

Atrial Fibrillation Association – www.atrialfibrillation.org.uk

Atrial Fibrillation Association International – www.afa-international.org

Atrial Fibrillation Association Argentina – website to belaunched

Atrial Fibrillation Association Brazil – website to be launched

Atrial Fibrillation Association Canada – website to belaunched

Atrial Fibrillation Association Mexico – website to belaunched

Atrial Fibrillation Association Peru – website to be launched

Atrial Fibrillation Association US – website to be launched

Atrial Fibrillation Association Venezuela – website to belaunched

Comisión Honoraria para la Salud Cardiovascular (HonoraryCommission for Cardiovascular Health) –www.cardiosalud.org

European Heart Rhythm Association –www.escardio.org/EHRA

European Primary Care Cardiovascular Society –www.epccs.eu

European Stroke Conference – www.eurostroke.eu

European Stroke Organisation – www.eso-stroke.org

Federación Argentina de Cardiología (Argentina Federationof Cardiology) – www.fac.org.ar

German Competence Network on Atrial Fibrillation (AFNET)– www.kompetenznetz-vorhofflimmern.de

InterAmerican Heart Foundation (Fundación InterAméricanadel Corazón; Funação InterAmericana do Coração) –www.interamericanheart.org

Sociedade Brasileira de Cardiologia (Brazilian Society ofCardiology) – www.cardiol.br

Sociedade de Cardiologia do Estado de São Paulo (São Paulo Cardiology Society) – www.socesp.org.br

Sociedad Chilena de Neurología, Psiquiatría y Neurocirugía(Chilean Society for Neurology, Psychiatry andNeurosurgery) – www.sonepsyn.cl

Sociedad Iberoamericana de Enfermedad Cerebrovascular(Iberoamerican Society of Cerebrovascular Disease) –www.siecv.net

Sociedad Neurológica Argentina (Argentina NeurologicalSociety) – www.sna.org.ar

Sociedad Peruana de Neurologia (Peruvian NeurologicalSociety) – www.spneurologia.org.pe

Sociedad Uruguaya de Cardiología (Uruguayan Society ofCardiology) – www.suc.org.uy

Sociedad Uruguaya de Medicina Intensiva (UruguayanSociety of Intensive Care Medicine) – www.sumi.org.uy

StopAfib.org – www.stopafib.org

World Stroke Organization – www.world-stroke.org


4

The organizations listed below endorse the recommendations contained in this report.

Foreword 7

Executive summary 9

Call to action 11

Stroke: a significant cause of poor health and death 17

Atrial fibrillation: a major risk factor for stroke 22

Detecting atrial fibrillation and stratifying stroke risk 27

Features of stroke in patients with atrial fibrillation 32

High cost of stroke in atrial fibrillation to individuals and society 35

Stroke prevention in patients with atrial fibrillation 39

Guidelines for stroke prevention in patients with atrial fibrillation 47

Current challenges for stroke prevention in patients with atrial fibrillation 53

New developments for stroke prevention in patients with atrial fibrillation 62

References 68

Appendix 1 79

Appendix 2 82

Glossary 83

Abbreviations 85

Table of contents

Table of contents

5

A. John Camm, M.D.British Heart FoundationProfessor of ClinicalCardiologySt George’s University ofLondon London, UK

August 2011

Albert L. Waldo, M.D.The Walter H. PritchardProfessor of Cardiologyand Professor of Medicine Case Western ReserveUniversityCleveland, OH, USA

Foreword

Foreword

Stroke affects millions of people in the Latin Americanregion. In 2004 alone, 437000 people in Latin Americasuffered a first-ever stroke, and over a quarter of amillion people died from a stroke. For many sufferers,death is often the first and last manifestation of stroke.For those who survive a stroke, the impact on their livescan be catastrophic – stroke survivors can be left severelydisabled, with the condition having a drastic impact ontheir health and wellbeing. Stroke also places asubstantial emotional and physical burden uponcaregivers, who are often close family members, ofstroke survivors. Unsurprisingly, the economic burden of stroke is huge. For example, total aggregate nationalhealthcare expenditure of initial hospitalization for strokein Brazil and Argentina alone has been calculated atalmost US$900 million. It is likely that the socioeconomiccost of stroke in the Latin American region will risedramatically in the coming years as the population agesand many more people suffer the consequences ofstroke. This is an epidemic already beginning to happen,and prompt action is required to avoid a crisis.

There are simple actions, which if taken now, couldprevent a substantial number of deaths, disabilities, and costs resulting from stroke. If we do nothing, then the Latin American region faces a stroke crisis.Recommendations made in this report are of particularsignificance for patients with atrial fibrillation (AF) – themost common sustained abnormality of the heartrhythm. AF increases the risk of stroke fivefold, and is responsible for 15–20% of all strokes. Theconsequences of AF-related stroke are devastating –patients with AF are significantly more likely to have a severe stroke than those who do not have AF.Furthermore, AF increases the risk of remaining disabledafter a stroke by almost 50%, and patients with AF whohave a stroke have a 50% risk of death within 1 year.Therefore, patients with AF are an important targetpopulation for reducing the overall burden of stroke.

Despite being a common condition, AF is often under-diagnosed, and, consequently, undertreated, resultingin inadequate stroke prevention. In the Latin Americanregion there is a clear lack of information regardingthe burden of AF that needs to be urgently addressed.The recommendations made in this report drawattention to the poor understanding of AF, and aim tohelp policy makers and healthcare professionals gain a greater understanding of AF, including its causes and

management. This report is a positive step forward inraising awareness of the need for greater investmentin the prevention of AF-related stroke in all countriesof the Latin American region. It contains a clear Call to Action – we urge that you give it your full attention.

So how can we avoid a stroke crisis in the LatinAmerican region? Stroke prevention in AF requiresimproved delivery of existing therapies, new strategiesto understand and manage AF, and better therapies to prevent stroke. In addition, improved patienteducation on the risk of AF-related stroke and thesymptoms of AF, as well as equal access to therapyand information for all patients across the region, is paramount. The countries of the Latin Americanregion need a clear strategy now to help coordinatethe various domains of policy development, raisingawareness, research, and educational activities tofocus them on the improvement of AF managementand effective stroke prevention.

As cardiologists with a global interest in the preventionand management of AF-related stroke, it is a privilegefor us to participate actively in an initiative that willhelp to push forward this important issue in the LatinAmerican region. We firmly believe that only throughthe coordinated actions of all participants – both at a country and regional level – will we see the highestnumber of strokes avoided, and the greatestimprovements in patient quality of life achieved. In the future, we would like to see the best preventionstrategies and treatments for AF-related stroke madeavailable to all patients in all countries of the LatinAmerican region irrespective of their socioeconomicbackground. The steps outlined in this report willhopefully put us on the right path to achieving thisgoal. In closing, we hope for the support of all policymakers, healthcare professionals, and medical societiesacross the region in driving forward this vital initiative.

7

9

Every year, 15 million people worldwideexperience a stroke.1 In 2004, strokeaccounted for 5.7 million deathsannually worldwide (9.7% of alldeaths).2 Among Latin Americancountries, Brazil and Mexico have thelargest populations and the highestnumber of deaths from stroke, with 129200 and 33000, respectively.3 Thenumber of strokes per year is predictedto rise dramatically as the populationages2 and it has been predicted thatdeaths due to ischemic heart disease andstroke in Latin America will almost tripleby 2024.4 This is an epidemic alreadybeginning to happen, and prompt actionis required to avoid a crisis.

Surviving a stroke can often be worsethan dying from one. Patients can be leftimmobile, incontinent, and unable tospeak.5 The consequences of stroke candevastate not only the patient’s quality oflife,6 but also the lives of their family whoare most often their caregivers.7 In LatinAmerica, 437000 people suffered a first-ever stroke in 2004.8 The economicburden of stroke is huge. Aggregatenational healthcare expenditures of initialhospitalization for stroke in Brazil andArgentina on their own have beencalculated at US$449.3million andUS$434.1million, respectively.9,10

Atrial fibrillation (AF) is the most commonsustained abnormality of heart rhythm.Compared with the general population,people with AF have a fivefold increasedrisk of stroke.11,12 An important riskfactor for stroke, AF is responsible for20% of ischemic strokes (strokes causedby a blood clot blocking a blood vesselin the brain).13 It is also possible that manystrokes of unknown origin (so-called‘cryptogenic’ strokes) are caused byundiagnosed AF. The risk of stroke in

patients with AF increases with age andwith the addition of other risk factors(e.g. high blood pressure, previousstroke, and diabetes).14

Among the factors that place a patientwith AF at highest risk of stroke are:congestive heart failure, high bloodpressure, age over 75 years, diabetes,and previous stroke or transientischemic attack. More recently,additional risk factors have beenincluded – such as, vascular disease,age 65–74 years, and female gender.15

Furthermore, AF-related strokes aremore severe, cause greater disability,and have a worse outcome thanstrokes in people without AF.13,16–18

In an analysis from a Mexican study, the case death rate at 30 days after an acute stroke event was 22.0% inpatients with a history of AF comparedwith 13.7% without AF.19 Furthermore,the rate of severe disability in thosepatients who survived was significantlyhigher in the AF patient cohort (69% vs 52% in the non-AF patient cohort).

Although data regarding the prevalenceof AF in Latin America are scarce, it isthought that there are a large number of people in the region living with thecondition. In Brazil, it has been estimatedthat there are around 1.5 million patientsliving with AF;20 in Venezuela, it isthought there are 230000 AF sufferers,with this figure predicted to rise to 1million by 2050.21

It is clear that patients with AF representa vast population at high risk of stroke,and in particular severe stroke. AFpatients are therefore an importanttarget population for reducing theoverall burden of stroke.

In 2004, strokeaccounted for

5.7 million deathsannually worldwide (9.7% of all deaths)

Stroke risk isincreased fivefold

in patients with AF

Strokes in peoplewith AF are more

severe, causegreater disability,and have worseoutcomes than

strokes in peoplewithout AF

Executive summary

Executive summary

10

To prevent AF-related stroke, the idealwould be to prevent or reverse AFitself; however, current techniques canonly prevent AF in some patients.Hence, there is a clear need to improvenot only detection but also therapy ofAF in Latin American countries.

Anticlotting therapy reduces stroke riskin patients with AF. When appropriatelyused and properly monitored, it lowersstroke risk by about two-thirds.22 Despitethe existence of guidelines for its use andmanagement, however, such therapy isboth underused and misused in clinicalpractice, largely owing to the significantdrawbacks16,23,24 associated with bothvitamin K antagonists25,26 and aspirin.27–30

Stroke prevention in patients with AFtherefore requires improved delivery of existing therapies, new strategies tounderstand and manage AF, and bettertherapies to prevent stroke.

Furthermore, the symptoms of AF maybe vague or non-specific, so it is oftennot detected in time to administertreatment that could prevent astroke.31,32 Thus, many potentiallypreventable strokes occur every year,leading to thousands of early deathsand a devastating burden onindividuals, families, and society interms of disability, and medical andsocial care costs. The financial burdenof stroke in patients with AF is likely tobe even greater for those patients inLatin American countries where there

is a high level of out-of-pocketexpenditure on healthcare.33

Currently, the incidence and prevalenceof AF and AF-related stroke is unknownin many countries of Latin America.Further studies are urgently needed toprovide data on the present and futureimpact of AF and AF-related stroke in the region. Continued research is alsorecommended to improve the preventionof stroke in patients with AF. In addition,improved patient education on the riskof AF-related stroke and the earlydetection of AF is required.

In conclusion, there is a pressing needfor Latin American countries to promotethe recommendation for earlier diagnosisand better management of AF, therebyreducing the risk of stroke in patientswith AF. These recommendations shouldinclude:

� Educational and awareness initiativesundertaken in each country toimprove early detection of AF

� Better use of interventions for themanagement of AF and strategies toprevent stroke in patients with AF

� Equal and adequate administrationof therapy for patients with AF

� Development of, and greaterimplementation of and adherenceto, guideline recommendations forAF management

� Ongoing research into all aspects of the epidemiology, causes,prevention, and management ofAF


Stroke related to AF can be

prevented, butcurrent therapiesoften have poor

outcomes

Earlier detectionand improved

treatment of AF can help to

prevent stroke

The incidence and prevalence ofAF and AF-related

stroke in manycountries of Latin

America is notknown and furtherresearch is required

11

Latin America needs a clearpolicy on stroke prevention in patients with atrial fibrillation

Latin America is vast and diverse,encompassing both small and largecountries. From a socioeconomicperspective, wide variations also exist in the region. In 2006, 38.5% ofthe population of Latin America andthe Caribbean lived in poverty, and the region has been shown to have the greatest inequality in incomedistribution in the world, with theexception of Sub-Saharan Africa.34

Overall, the gap between the richestand poorest in Latin America iswidening, with the greatest povertyfound in Paraguay and Bolivia.

Although each nation faces uniquehealth challenges, they share a commonneed to turn the tide on the growingburden of cardiovascular diseases. Withcancers and chronic respiratory diseases,cardiovascular diseases are one of themajor group of non-communicablediseases and account for 60% of deathsglobally.35 In response to the burden ofchronic disease in the region, andrecognizing that a strategy to tackle thisissue was needed, the Pan AmericanHealth Organization (PAHO) developed a regional strategy and plan of action.36

The report highlighted four main areasof action: (i) recognize that chronicdiseases need to be prioritized in the

political and public health agendas, (ii) identify surveillance as a keycomponent, (iii) recognize that healthsystems must be reoriented to respondto the needs of people with chronicconditions, and (iv) note the essentialrole of health promotion and diseaseprevention.

The need to tackle this issue was alsohighlighted by the Ministers andSecretaries of Health of the Americas in the 2007 report Health Agenda forthe Americas 2008–2017.37

The PAHO, in collaboration with theWorld Health Organization (WHO), hasalso produced the Stepwise Approach to Risk-Factor (RF) Surveillance (STEPS)instrument to aid the collection ofchronic non-communicable disease riskfactor data for the region.38 Thisinstrument is an adaption of the originalSTEPS methodology, and offers a simple,standardized means for collecting,analyzing, and disseminating data inmember countries. By using this approach,all countries in the region can use STEPSinformation, not only for monitoringcountry-specific trends, but also formaking cross-country comparisons.

Cardiovascular disease makes up thelargest proportion of all deaths fromnon-communicable disease, and is theleading cause of death globally.2,39

Moreover, this disease is on the

Call to action

Call to action

The authors of this report, and all those individuals and societies whoendorse these recommendations, call for national governments of Latin America to ensure better detection and management of atrialfibrillation (AF) and more effective measures to prevent AF-related stroke across all Latin American countries. Through this, we will be ableto reduce the major social and economic burden of a largely preventablecondition: AF-related stroke.

12

increase, and is expected to account for 23.6 million deaths by 2030.40 It has nogeographic, gender, or socioeconomicboundary, and accounts for approximatelyone-third of all deaths in the world; ofthese, 80% of deaths occur in low- andmiddle-income countries.41

In 2004, 896000 patients in LatinAmerica died as a result of cardiovasculardisease.39 The rate of cardiovascularmortality in Latin America varies acrossthe region. In 2004, death rates fromcardiovascular disease, as a proportion of total deaths from all causes, wereapproximately 30% in Mexico, Chile, andVenezuela; 30–35% in Brazil andArgentina; and >35% in Uruguay.3 Therate of cardiovascular mortality for theentire Latin American region is predictedto rise from 28.4% in 2004 to 32.2% in2030, with 1476000 deaths projected in2030.39,42 Latin American countries areundergoing some rapid environmentalchanges, with the rate of urbanization inLatin America and the Caribbean, where77% of the population live in cities, beingthe highest in the developing world.34 It isimportant to monitor the impact of thesechanges on cardiovascular risk factors.

The future rise in cardiovascularmortality in Latin America has beenestimated to exceed that in developedcountries. In Latin America, the deathrates from cardiovascular disease, as a proportion of total deaths from allcauses is predicted to increase by13.4% from 2004 to 2030, comparedwith a 1.0% increase over the sametime period in developed countries.39,42

Cardiovascular disease has an enormousimpact on a country’s economy. Forexample, it is estimated that Brazil willlose US$49 billion in national incomebetween 2005 and 2015 because ofthe combined effects of heart disease,stroke, and diabetes.43

The most prevalent cardiovasculardiseases are coronary heart disease andstroke.44 In 2004, Brazil and Mexico had

the largest populations and the highestnumber of deaths from stroke in theregion, with 129200 and 33000,respectively.3 It has been predicted thatdeaths from ischemic heart disease andstroke in the Latin American region willalmost triple by 2024.4

AF, the most common type of sustainedabnormal heart rhythm, is a majorcause of stroke – in particular, ofsevere, disabling strokes, the majorityof which are preventable. Thus, earlierdetection and treatment of AF, andmore effective prevention of AF-relatedstroke, would help to substantiallyreduce the burden of stroke. Thisconcurs with the aims of the PAHO,which has proactively adapted theWHO’s STEPwise Method to StrokeSurveillance (STEPS Stroke) in LatinAmerican countries as a useful tool to improve data collection, prevention,and treatment of stroke.45

When properly used, therapy that helpsto prevent blood clots has been shown toreduce the risk of stroke in patients withAF by more than 60%.46–48 However,some of the drugs that help to preventunwanted clotting, such as vitamin Kantagonists (VKAs), are underused inclinical practice, or used suboptimally.This may be for several reasons, includingthe complexity of managing such therapywell and a widely held belief that thebleeding risks of therapy may outweighthe benefits.16,23,24

Furthermore, AF is often not diagnoseduntil the patient suffers a first stroke.This increases the size of the problem,meaning that many potentiallypreventable strokes occur every yearbecause of delayed diagnosis of AF as well as underuse of anticlottingtherapy. The result is a devastatingimpact on the health and wellbeing of the individual and an increasedeconomic and social burden to society.

As the age of the population andsurvival from conditions predisposing to


Many potentiallypreventable strokes

occur because ofdelayed diagnosis

of AF and underuseof anticlotting

therapies

AF is a major cause of severe,disabling stroke

It has beenpredicted thatdeaths from

ischemic heartdisease and stroke

in the LatinAmerican region

will almost triple by 2024

13

AF increase, so do the prevalence andincidence of AF.49 Therefore, a clearpolicy on stroke prevention in patientswith AF will give greater prominence tothe management of AF over thecoming decades.

Initiatives for the prevention of strokeand cardiovascular disorders in LatinAmerica should include action atcountry level, which will involvenational government initiatives for:� Adequate diagnosis of AF prior to

the first stroke� Appropriate and effective

management of AF� Effective stroke prevention in

patients who have alreadydeveloped AF

� Continuing research into the causesof AF

Such actions would be in line with oneof the aims of the PAHO: that is, toprevent and reduce the burden ofchronic diseases and related risk factorsin the Americas.36

Principal recommendations

1. Create and raise awarenessamong national governments andthe general public of the impact ofAF and AF-related strokeOnce an individual has AF, their risk ofa stroke is increased fivefold or more

compared with the risk in individualswithout the condition.11,12 There is alack of information regarding theincidence, prevalence, and economicimpact of AF in many Latin Americancountries. It has been estimated that in Brazil in 2005 there were 275000 cases of AF in people aged70–80 years and 200000 cases inpeople aged >80 years.50 Overall, it hasbeen estimated that 1.5 million peoplein Brazil and 230000 in Venezuelasuffer from AF.20,21 Results from a studyin Brazil have shown the prevalence ofAF to increase with age, from around0.8% in those aged 65–69years to 7%in those aged ≥80 years.51 Aggregatenational healthcare expenditures ofinitial hospitalization for stroke in Braziland Argentina have been calculated atUS$449.3 million and US$434.1 million,respectively.9,10 This suggests that,across the region, the economic impactof AF and AF-related stroke is likely tobe considerable.

Despite the high burden of stroke,appropriate management cansubstantially reduce the risk of stroke inpatients with AF. There is a critical needacross Latin America for increasedawareness among national governmentsand the general population of theeconomic and social impact of AF-relatedstroke, for better understanding of AFand its diagnosis/detection, and for

Call to action

Principal recommendations

� Raise awareness of the impact of AF and AF-related stroke� Develop coordinated strategies for early diagnosis of AF� Improve the education of patients and caregivers regarding AF� Encourage new approaches to the management of AF and the

prevention of AF-related stroke� Improve awareness of AF management and the benefits of stroke

prevention among physicians� Promote equality of access to services and information for patients

across countries in the Latin American region� Implement, and advocate adherence to, guidelines for AF

management� Exchange best practice between countries in Latin America� Boost research into the causes, prevention, and management of AF,

and address paucity of information around epidemiology

We call on LatinAmerican

governments todrive policyinitiatives to

improve earlydetection and

management of AF,and to prevent

stroke in patientswith AF

14

improved strategies for AF management.We call on national governments todrive policy initiatives to promoteunderstanding, earlier detection, andimproved management of AF and betterstroke prevention.

2. Develop coordinated strategies forearly and adequate diagnosis of AF AF is often detected only after a stroke,because many patients are unaware oftheir heart condition. However, a simpleprocedure such as routine pulse-taking(which is not always carried out as amatter of routine) followed by electro-cardiographic monitoring, if necessary,can play a crucial role in helping toimprove detection of AF in patients atrisk. This may also be performed duringfollow-up visits when no arrhythmiaswere detected during the first visit.Increased awareness of its early signs,and those of other conditions that arecommonly observed in patients with AF,can improve AF diagnosis in patientswithout symptoms. Opportunisticassessment for AF in the primary caresetting may also be prudent, particularlyamong patients with other risk factorsfor stroke. Among the factors thatplace a patient with AF at highest riskof stroke are: congestive heart failure,high blood pressure, age over 75 years,diabetes, and previous stroke or transientischemic attack (TIA). Campaigns thatraise awareness of the relevance of anirregular pulse as a sign of AF, and ofthe importance of detecting abnormalheart rhythm, would allow timelyinitiation of AF therapy and may help toreduce the need for specific strokeprevention treatment.

3. Improve awareness in patientsand caregivers about AF and itsdetectionPoor understanding of AF and of thedrugs prescribed to prevent AF-relatedstroke is often a barrier to maintaininganticlotting therapy within the effectivetarget range. There is an urgent need toprovide the public with better informationabout the risk of AF-related stroke and



governments toestablish a commonplatform to identifybest practice for themanagement of AF

We call onLatin Americangovernments to

drive educationalinitiatives to

improve patientunderstanding

of AF

the methodology for its prevention.Furthermore, pharmaceutical andtechnological developments – such asnew anticlotting drugs and patient-operated monitoring techniques forexisting drugs – may make it easier infuture to provide appropriate treatmentto protect patients with AF againststroke. Better patient education isneeded to make such innovations widelyknown. We call on national governmentsto fund, drive, and encourageparticipation in such educationalinitiatives to raise awareness of AF,because this could play a significant rolein improving adherence to therapy.

Furthermore, collaboration betweenexisting and newly established patientorganizations in the Latin Americanregion, together with the creation of acommon platform for patients with AF(to exchange and disseminateinformation on AF, its diagnosis andmanagement, and on stroke prevention),would enable the pooling andcomparison of data between differentLatin American countries. Driven bynational governments, such an initiativewould make it possible to identify bestpractice for the successful managementof AF, leading to benchmarks formanagement that would stimulateimprovements across the region.

4. Encourage the development anduse of new approaches to themanagement of AF and theprevention of AF-related strokeIdeally, minimizing risk factors such ashigh blood pressure, structural heartdisease, and diabetes will reduce thelikelihood of AF developing in the firstplace. However, some factors thatcontribute to the emergence of AF, suchas genetics and the natural aging process,are not modifiable, so it will not bepossible to eliminate AF entirely.52

Thus, other important areas of focusare early diagnosis of AF – prior to thefirst stroke – and management of thesigns and symptoms of AF. Effective

We advocate acampaign of

routine pulse-taking across

Latin America, to promote better early

detection of AF

15

use of anticlotting therapy is essentialin most patients who have alreadydeveloped AF, in order to preventcomplications (such as stroke) resultingfrom a circulating blood clot.

The ideal anticlotting drug would beeffective; have a favorable safety profilein a wide range of patients, including theelderly; have a low risk of interactionswith food and other drugs; and have asimple dosing regimen, with no need forroutine monitoring or dose adjustment.Such an agent could eventually increaseadherence to therapy and, potentially,improve outcomes in patients withAF.

5. Improve the awareness of physiciansinvolved in AF managementPhysicians may be so concerned aboutthe bleeding risks associated with anti -clotting therapy that they under estimateits benefits in reducing stroke risk.53–55

Improving awareness of the substantiallyincreased risk of stroke in patients withAF compared with those without AF istherefore important. Physician educationis needed to help in the recognition ofundiagnosed (‘silent’) AF beforecomplications occur. Physicians shouldalso understand fully the managementoptions for patients with AF andrecognize that, when implementedproperly according to guidelines, thebenefits of therapy generally outweighthe risks.

6. Promote equity of access to therapy,monitoring services, and informationfor all patients across Latin AmericaAll patients have a basic right to equalaccess to quality medical treatment forall their health needs, regardless of wherethey live, their status, or their income.Efforts should be consolidated to ensurethat all patients have equal and timelyaccess to diagnostic procedures thatidentify AF, to adequate therapy tomanage the arrhythmia and its underlyingclinical conditions, to anticlotting therapyfor the prevention of stroke, and to betterinformation on AF and its consequences.Resources are needed, throughout Latin

American countries, to ensure clear andrelevant communication with patients sothat they are partners in determiningtheir care.

7. Implement and strongly advocateadherence to guidelines for themanagement of patients with AFSeveral sets of guidelines exist for the management of AF. Theirrecommendations largely overlap, butthe degree to which they are properlyimplemented varies. This can bedemonstrated when the use of anti -clotting therapy is analyzed in largecohorts of AF patients. In Brazil, theproportion of patients with AF at risk of stroke and who received oralanticoagulation has been shown torange from 24% to 61.7%.56,57

Furthermore, in a study in Mexico, only35.9% of patients with a history of AFand a recurrent TIA/ischemic stroke, and 24% of patients with a history ofAF and a first-ever TIA/ischemic strokewere receiving oral anticoagulationtherapy (VKAs).58 Moreover, theproportion of patients receivingguideline-adherent anticlotting therapyvaries. In a Brazilian study, theproportion of patients with AF receivingwarfarin within the optimalinternational normalized ratio (INR)range of 2.0–3.0 was as low as 15.6%,59

and in another study only 55% ofpatients with AF were receiving warfarinat the correctly indicated dose accordingto Brazilian Society of Cardiology and American College of Cardiology,the American Heart Association and the European Society of Cardiologyguidelines (ACC/AHA/ESC).56 It hasbeen shown that non-adherence toguidelines is associated with pooroutcomes.60 There is therefore a needacross much of Latin America to improvethe implementation of, and adherenceto, guidelines for the prevention ofstroke in patients with AF. Initiativesaimed at improving the implementationof existing guidelines for stroke intoclinical practice have been carried out bythe American Heart/Stroke Associations.61

Call to action

We call for acoordinated LatinAmerican effort toinitiate appropriatephysician education

and awarenessstrategies,

supported byadequate resources


governments topromote equal

access to alldiagnostic,

treatment, andmonitoring servicesfor AF, supported

by clearinformation

16

Mechanisms to implement a similarprogram for guidelines in AF for LatinAmerican countries should be explored.

All governments in Latin America canencourage guideline adherence bycalling for better implementation of theexisting guidelines such as the 2006ACC/AHA/ESC guidelines,31 the 2010ESC guidelines,62 and the 2011 ACCFoundation (ACCF)/AHA/Heart RhythmSociety (HRS) guidelines.63 Alongside theseguidelines, country-specific ones areavailable, such as the Brazilian, Mexican,and Argentinian guidelines.20,64,65 We callon national governments in Latin Americato raise awareness of the existingguidelines – improved implementationand adherence to these will help toincrease the number of eligible patientsin the region who receive adequateanticlotting therapy and ensure that suchtherapy is optimally delivered. This inturn would help to reduce the numberof new cases of AF-related stroke.Improved guideline implementation andadherence, and the timely updating ofguidelines as appropriate, would alsoenhance patient safety.

8. Facilitate exchange of best practicebetween Latin American countriesA Latin American initiative to harmonizeexisting national guidelines into one setof unified Latin American guidelineswould help to further the goal of stroke prevention. As a second stage,coordination would be neededbetween the professional bodiesoverseeing the guidelines. An approachsuch as this would help directly in thesharing of best practice and thedevelopment of a focused policy onstroke prevention in patients with AFextending to all countries in the region.It would also ensure that the principleof healthcare equality across LatinAmerican countries is implemented andindividual patients receive similar care.It would also be beneficial if betteralignment between countries in theregion occurred to identify key areaswhere the guidance is being

overlooked or where agreement isrequired on divergent advice.

9. Boost research into theepidemiology, prevention, andmanagement of AFThe ideal would be to prevent AF-relatedstrokes by preventing AF itself. To achievethis requires an increased understandingof the causes of AF, and the developmentof strategies for its prevention andtreatment through research.

Latin American countries could providefunding to boost research into theseareas via a coordinated researchstrategy. Research topics that LatinAmerican countries could stimulate andhelp to coordinate include:� Systematic analysis of the

epidemiology of AF (that is, the factorsthat determine the frequency anddistribution of AF, including ‘silent’ AF)and its relationship to stroke

� Assessment of the burden andseverity of disease for all patientswith stroke, based on patientexperience in the region and quality-adjusted life-years (QALYs)

� Research to identify patients at riskof AF and AF-related stroke, andnew therapeutic approaches to themanagement of AF

� Latin American studies monitoringthe effect of interventions to manageAF and prevent AF-related stroke

The PAHO already acknowledges theimportance of stimulating cardiovasculardisease research activities at the regionallevel, for example through thedevelopment and use of the PanAmerican STEPS and STEPS Strokeinstruments.38,45 To augment andcomplement these efforts, a coordinatedresearch initiative encompassing all theLatin American countries is urgentlyneeded, aimed at improving themanagement of AF, at understandingmore fully its causes and epidemiology,and at preventing AF-related stroke.



governments tosupport initiativesto raise awarenessof existing relevantguidelines for the

management of AF

We advocate aLatin American

initiative todevelop a unified

regional set ofguidelines for the

management of AF,and to share and

promote bestpractice among

all countries in the region

We call onLatin Americangovernments to

support acoordinated

research initiativeto increase

understanding of AF and improvethe prevention ofAF-related stroke

17

within the first 24 hours, when the risk isaround 4–5%.66,67 Studies have shownthat in the 90 days after a TIA, the risk ofstroke exceeds 10%.66

Prevalence and incidence of stroke in Latin America

Every year, 15 million people worldwideexperience a stroke. Approximately 5 million of these suffer permanentdisabilities and over 5 million more die.68

In 2004, stroke accounted for 9.7% ofall deaths worldwide.2

In 2004, the WHO estimated that theprevalence (i.e. total number of cases)of patients surviving a stroke in LatinAmerica was 1.9million.8

In the same year, the incidence (i.e. number of new cases) of first-everstroke was 437000 in Latin America.8

There are no data from the WHO forthe incidence and prevalence of strokeby country in 2004; however, individualstudies have assessed the prevalenceand incidence of stroke in Latin

Stroke: a significant cause of poor health and death


What is stroke?

A stroke occurs when interruption ofblood supply or leakage of blood from ablood vessel causes damage to the brain.There are two main types of stroke:hemorrhagic and ischemic. Ahemorrhagic stroke is caused bybleeding from a blood vessel in thebrain. Ischemic strokes are morecommon, accounting for approximately85% of all strokes,5 and are caused by ablood clot in the brain. This blood clotmay have developed in the brain, or itmay have formed somewhere else in thebody and traveled to the brain (in thiscase, the blood clot is said to have‘embolized’). For example, an ischemicstroke caused by a blood clot thatformed in the heart is known as acardioembolic stroke.

A TIA occurs when the blood supply tothe brain is briefly interrupted. Thesymptoms of a TIA are very similar tothose of a full stroke but last less than 24 hours. Individuals who have had a TIAare at increased risk of stroke comparedwith the general population – particularly

Key points

� Worldwide, 15 million people suffer a stroke each year. Of these, morethan 5 million die and another 5 million are left permanently disabled

� In 2004, there were approximately 1.9 million people in LatinAmerica who had survived an episode of stroke at some time intheir life

� In 2004, 437000 people in Latin America suffered a first-ever stroke,and the number of strokes per year is predicted to rise dramaticallyas the population ages

� Stroke has a huge impact on the health and wellbeing of anindividual and is an economic and social burden to society

� Aggregate national healthcare expenditures of initialhospitalization for stroke in Brazil and Argentina were calculated tobe US$449.3million and US$434.1million, respectively

85% of all strokesare ischemic –

caused by a bloodclot in the brain

In 2004, 1.9 millionpeople in Latin

America survived astroke, and about

437 000 had a first-ever stroke

55–64 65–74 ≥75

45–54

Incidence of �rst-ever stroke per 100 000 women

*For Mexico, annual �rst-ever stroke hospitalization rate data are presented.

0 200 400 600 800 1000 1200 1400 1600 1800

Incidence of �rst-ever stroke per 100 000 men

0 200 400 600 800 1000 1200 1400 1600 1800

Bra

zil

Ch

ileM

exic

o*

Bra

zil

Ch

ileM

exic

o*

Figure 1. Estimates of stroke incidence (a) per 100 000 women and (b) per 100 000 men atselected ages in studies from Brazil, Chile, and Mexico. The number of individualsexperiencing stroke increases substantially with age. Data taken from Cantú-Brito et al.2010,70 Lavados et al. 2005,71 and Minelli et al. 2007.72

American populations. Strokeprevalence studies have been carriedout in both rural and urban settings(Table 1). Crude prevalence ratesranged from 1.7 per 1000 in ruralBolivia to 7.7 per 1000 in Mexico. Inpeople older than 60years, the rangeincreased from 18.2 per 1000 inMexico to 46.7 per 1000 in Columbia.69

The incidence of stroke in individualcountries of Latin America has also


been estimated (Figure 1).70–72

The number of men and womenexperiencing stroke increasessubstantially with age. For example, in Chile the incidence of stroke in men aged ≥75 years is 10 times that inmen aged 45–54 years; in women aged≥75 years, it is nearly 13 times that inwomen aged 45–54 years.71

Furthermore, these data show thatstroke incidence is higher in men thanin women irrespective of age.70–72

18

Study

Table 1. Door-to-door prevalence studies of stroke in Latin America. Adapted from Cantú-Brito et al. 2011 with permission.69

Population screened Number ofstrokes

Strokeprevalence

per 1000

Stroke prevalence

in the elderly (>60 years)

per 1000

Peru, 1995 (Cuzco)

3246 older than 15 years from an urban population of 210 000

21 6.2 NR

Colombia, 1997 (Sabaneta)

13 588 people (all ages) from an urban population of 17 670

76 5.6 46.7

Bolivia, 2000 (Cordillera)

9995 people (all ages) from a rural population of 55 675

16 1.7 19.3

Honduras, 2003 (Tegucigalpa)

1553 people (all ages) from an urban population of 1 180 676

9 5.7 NR

Ecuador, 2004 (Atahualpa)

1568 people older than 15 years from a rural population of 1671

10 6.4 36.1

Honduras, 2007 (Salama)

5608 people (all ages) from a rural population of 6289

20 3.6 32.7

Mexico, 2010 (Durango)

2437 older than 35 years from an urban and rural population of 168 859

20 7.7 18.2


completed cerebrovascular events was168 per 10000 in Mexican Americansand 136 per 10000 in non-HispanicWhites. Specifically, Mexican Americanshad a higher cumulative incidence offirst-ever and recurrent ischemic stroke,intracerebral hemorrhage, andsubarachnoid hemorrhage (bleedingbetween the surface of the brain andthe skull) compared with non-HispanicWhites.78 This increased risk of stroke in Mexican Americans has also recentlybeen shown to extend to patients withatrial fibrillation (AF). In a follow-up tothe BASIC study, patients with ischemicstroke or TIA, and who were found tohave either a chart history of AF or ahistory of AF noted on the admissionelectrocardiogram (ECG) were assessed.In total, 236 patients (88 MexicanAmericans and 148 non-HispanicWhites) with ischemic stroke/TIA andAF were included in the study. The riskof stroke recurrence was significantlyhigher in Mexican Americans comparedwith non-Hispanic Whites. The severityof the recurrent stroke was alsosignificantly higher in Mexican Americansthan non-Hispanic Whites, althoughthere was no difference in survival afterstroke in the two populations.79

Death and poor health in patients with stroke

Stroke accounts for nearly 10% of alldeaths worldwide.2,5 Although stroke isgenerally considered a healthcare issuefor elderly people, its impact onyounger individuals should not beunderestimated. In 2004, the deathrate from stroke in people under 60 years was calculated as 11.3 per100000 for Latin America.39 This figurerises substantially in individuals aged 60 years or over: the death rate fromstroke in Latin America in patients aged60–79 years was 301.3 per 100000.39

Stroke death rates vary betweencountries of the Latin American region.For example, in 2004, stroke deathrates ranged from 31.6 per 100000 in

The world population is aging rapidlyand as a result it has been predictedthat stroke incidence will increase inthe future.2 In Brazil, the proportion of people aged 60years and over isexpected to rise from 7.8% in 2000 to 23.6% in 2050.73 An increase in theproportion of older people (≥60years)globally is being accompanied by adecline in the proportion of the young(<15years).74 It is expected that by2050, the number of older people inthe world will exceed the number ofyoung for the first time in history.74 Theexpected rise in the aging population ofLatin America will further increase theincidence and socioeconomic burden of stroke and limit the medical resourcesavailable to provide for the needs ofstroke suffers and their families.

Although strokes in young adults arerelatively uncommon, approximately25% of strokes occur in people agedbelow 65 years,75 and a national surveyof stroke in the US estimated that3.7% of strokes occurred in patientsaged 15–45 years.76 Availability of dataon the prevalence of stroke from agreater number of countries wouldhelp to inform the best policy for strokeprevention across all Latin Americancountries.

Some ethnic differences in strokeepidemiology may exist, reflectingdifferences in the predisposition tosome of the risk factors associated withstroke. A comparison of analogousstudies suggests that the prevalence ofintracerebral hemorrhage is consistentlyhigher in LatinAmerican compared withwhite populations, but is similar to that among Asians.77 The results ofthe BASIC (The Brain Attack Surveillancein Corpus Christi) study clearlydemonstrated an increased strokeincidence amongst Mexican Americanscompared with non-Hispanic Whites ina representative South East Texascommunity where approximately halfof the population is Mexican American.The crude cumulative incidence of total

19

0

10

20

30

40

50

60

Mexico* Chile

Cas

e d

eath

rat

e (%

)

Brazil

IS

ICH

SAH

*For Mexico, in-hospital case death rate data are presented.

Figure 2. 30-day case death rate by stroke type of first-ever stroke in Latin America (IS, ischemic stroke; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage). Data taken from Cabral et al. 2009,80 Cantú-Brito et al. 2010,70 and Lavados et al. 2005.71

20

Venezuela to 115.3 per 100000 inUruguay.3 Population-based studieshave also shown 30-day case deathrates for stroke to vary in countries inLatin America; rates were reported as19.1% in Brazil,80 23.3% in Chile,71

and 39% in Mexico.70 Case death ratesalso varied according to stroke type –exceeding 50% for subarachnoidhemorrhage in Mexico (Figure 2).

Additionally, stroke is a major cause oflong-term disability worldwide; eachyear, 5million stroke sufferers are leftpermanently disabled.5 The young arenot exempt from the devastatingeffects of stroke. A long-term studyassessing outcomes after stroke inyoung adults aged 15–45 years foundthat after 6 years only 49% were stillalive, not disabled, had not sufferedfrom recurrent vascular events, and hadnot undergone major vascular surgery;a majority of survivors reportedemotional, social, or physical effectsthat lessened their quality of life.81

Stroke can affect virtually all humanfunctions, making it difficult for manypatients to get out of bed, walk shortdistances, and perform basic activities ofdaily living. As well as impairing speechand physical functioning,5 stroke canalso adversely affect mental health.82

Because its onset is sudden, affectedindividuals and their families are oftenpoorly prepared to deal with theconsequences of stroke.82 Thedevelopment of chronic disability canseverely affect quality of life of both thepatient and their relatives, who are oftenthe caregivers.6,7 It is also important toconsider the role of caregivers and thesubsequent impact stroke can have onthem and their families’ lives. In addition,the impact of stroke on society, in termsof morbidity (ill health) and healthburden, is substantial.

Financial cost of stroke in Latin America

Although data are not available on thefinancial cost of stroke for the whole ofLatin America, information is availablefrom individual countries. In twoseparate studies, aggregate nationalhealthcare expenditures of initialhospitalization for stroke in Brazil andArgentina were calculated to beUS$449.3million and US$434.1million,respectively.9,10 Aggregate nationalhealthcare expenditures were found tobe higher for ischemic stroke than forintracerebral hemorrhage (Brazil,US$326.9million vs US$122.4million;Argentina, US$239.9million vs US$194.2million). However, the mean


Each year, 5 millionstroke sufferersworldwide are

left permanentlydisabled

Case study: the impact of stroke

José Luis was a 62-year-old man who lived in Mexico City and had 8 children and 16 grandchildren. Previously, he worked for himself selling electrical domestic appliances. For the past 20 years, José Luis has been living with diabetes mellitus and hypertension, and 5 years ago he was diagnosed with non-valvular AF. Although he was advised to take oral anticoagulation therapy (warfarin), he found it difficult to adhere with the medication. This was mainly due to the monitoring that was required to adequately control his anticoagulation levels. In June 2010, José Luis suffered a sudden large ischemic stroke that left him with weakness down the left-hand side of his body, an inability to speak, and severe communication problems. As a result of the stroke, José Luis is now confined to a wheelchair. He is completely dependent on his family to take care of his needs, fulfilled principally by his wife who is almost always at his side. As José Luis has no social security, he has to pay for his own medication, diapers, any laboratory tests required, doctors, and any treatment for any other medical complications that arise. One of his sons now runs the electrical domestic appliances business solely to pay for his father’s needs. The majority of the family’s income is being used for José Luis’s medical care. Unfortunately, José Luis recently suffered several generalized convulsive seizures that required hospitalization. This has complicated his medical management because he currently receives antiepileptic drugs that interact with the warfarin that José Luis takes to prevent stroke recurrence.


Stroke places a burden on

patients; theirfamilies, caregivers,

and friends; and society

It is therefore evident that stroke is acostly health problem in Latin Americancountries, although further research isrequired to provide a more comprehensivepicture of the burden of the cost ofstroke across a wider selection ofcountries. Stroke places a burden onpatients; their caregivers, families, andfriends; and society. This burden fallsdisproportionately on the elderly, as theyare most at risk. Early diagnosis andeffective management of AF would helpto reduce the burden of stroke in LatinAmerica. Furthermore, the prevention of stroke with pharmacologic or non-pharmacologic therapies in patients athigh risk has the potential to reduce thiseconomic burden significantly.85 Thecost-effectiveness of anticlottingtreatments in patients with AF is discussedfurther in the section ‘Cost of vitamin Kantagonist therapy in stroke preventionin atrial fibrillation’ (page 45).

total costs of initial hospitalization werehigher for intracerebral hemorrhage thanfor ischemic stroke (Brazil, US$4101 vsUS$1902; Argentina, US$12285 vsUS$3888).9,10 The mean length of hospitalstay for ischemic stroke was similar in thetwo studies (Brazil, 13.3 days vs Argentina,13.0 days).9,10 In contrast, mean length ofhospital stay for intracranial hemorrhagewas 12.0 days in Brazil and 35.4 days in Argentina.9,10 In a study from Chile, 530 patients who had suffered a stroke(ischemic stroke, 84% of the population)and who were admitted to a generalhospital or stroke unit, were evaluated.83

The mean costs of hospitalization perpatient at the stroke unit and hospitalwere US$5550 (mean length of stay, 6.6days) and US$4815 (mean length of stay, 9.9 days), respectively.83 Theestimated cost of acute stroke care inMexico in 1994 was US$7700 per patientin private hospitals and US$6600 inhealth sector institutions.84

21

22


Key points

� AF is the most common sustained heart rhythm abnormality

� AF increases the risk of stroke fivefold and is responsible forapproximately 15–20% of all strokes

� The number of people affected by AF in Latin America is currentlyunknown

� The five major modifiable risk factors for stroke are high bloodpressure, smoking, lack of physical exercise, diabetes, and AF

� Common underlying causes of AF include high blood pressure, heartvalve defects, rheumatic heart disease, ischemic heart disease, anddiabetes

� The likelihood of developing AF increases with advancing age

� Data from the US show that people over the age of 40 years have a1 in4 risk of developing AF over their remaining lifetime. Similardata for Latin American populations are unavailable

� The present and future impact of AF on Latin American populationsis currently unknown; further studies are urgently needed in orderto provide these data

The risk of stroke is higher in an

individual with AFthan in someonewith high blood

pressure

Atrial fibrillation: a major risk factor for stroke

AF has been shownto be responsiblefor approximately15–20% of stroke

occurrences

responsible for approximately 15–20%of all strokes,90 and patients with AFhave a 3–4% risk per year of developingstroke.91 High blood pressure is thereforeresponsible for a greater proportion ofthe global burden of stroke than AF, butthe risk of having a stroke is higher inan individual with AF, whatever the type(lone, paroxysmal, persistent, orpermanent) than in an individual withhigh blood pressure: AF confers afivefold increase in the risk of stroke,compared with an approximatelythreefold increase in risk with highblood pressure (Figure 3).11,12 Moreover,many patients with AF also have highblood pressure, so a multi disciplinaryapproach to management is required(see section on ‘Management of otherconditions that increase stroke risk: a multidisciplinary approach’, page 46).In a study of 215 patients with ischemicstroke admitted to a hospital in São Paulo,Brazil, a diagnosis of AF was made in

AF is the most common sustained heartrhythm abnormality,86 and is a majorrisk factor for ischemic stroke anddeath in the general population.13,86

Other established risk factors for strokeinclude high blood pressure, diabetes,heart disease, and lifestyle factors suchas smoking, alcohol consumption, poordiet, and insufficient physical activity.87

The five major modifiable risk factors –the ‘big five’ – that merit targeting inthe prevention of stroke have beenidentified as:88

� High blood pressure � Smoking� Lack of physical exercise � Diabetes � AF

Owing to its high prevalence, highblood pressure is the leading modifiablerisk factor for stroke,68 accounting forapproximately 40% of all strokes.5,68,89

AF, by comparison, is estimated to be

AF: a major risk factor for stroke

23

CHBP2.43.4

50

40

30

20

10

0

*

*

**

No CV conditionCV condition

Two

-yea

r ag

e-ad

just

edin

cid

ence

of

stro

ke/1

000

Risk ratio

CHD CHF AF4.3 4.8

AF, atrial !brillation; CHD, coronary heart disease; CHF, congestive heart failure; HBP, high blood pressure.

Figure 3. Two-year age-adjusted incidence of stroke in the presence and absence ofcardiovascular (CV) conditions. Atrial fibrillation confers a fivefold increase in the risk ofstroke; in patients with high blood pressure, stroke risk is increased threefold. *p<0.001.Adapted from Wolf et al. 1991 with permission.12

problem with the mitral valve in theheart;31 the majority of studies discussedin the following sections involve patientswith non-valvular, rather than valvular,AF. In a study of 840 patients withchronic AF in Argentina, underlyingheart disease was detected in 84.7% of patients. Furthermore, 30.2% ofpatients had a previous history of heartfailure, 59.0% had arterial hypertension,and 12.3% had diabetes.95

The likelihood of developing AFincreases with advancing age. In thepreviously described study involving840 patients with AF from Argentina,the average patient age was 71 years.95

However, some patients seem to havegenetic abnormalities that predisposeto AF, and these abnormalities are mostoften seen in young patients whodevelop AF.52,96 In addition, there arelimited data suggesting that theincidence of AF is higher than normal in athletes.97,98 Furthermore, anincreased frequency of vigorousexercise (i.e. above-average levels of 5–7 days per week) has beenassociated with an increased risk ofdeveloping AF in joggers and men agedbelow 50years.97 Therefore, AF is notjust a condition of the elderly.

16.3% of patients. The prevalence of AFwas significantly higher in those patientsover the age of 80 years (26%).92

Development of atrial fibrillation:causes and contributing factors

AF occurs when the upper chambers ofthe heart (known as the atria) trembleirregularly rather than beating regularlyand effectively. The junction of theupper and lower chambers of the heartreceives more electrical impulses than it can conduct, resulting in irregularsqueezing of the lower chambers(known as the ventricles) and an erraticpulse rate. Because the atria do notempty completely when in fibrillation,blood does not flow properly. Thismeans that blood clots can develop,break up, travel to vessels in the brain,and cause an ischemic stroke.93

Among the most common underlyingcauses of AF are high blood pressure,mitral stenosis (narrowing of a valve inthe heart), rheumatic heart disease,and, to a lesser extent, ischemic heartdisease (reduced blood supply to theheart muscle) and diabetes.17,94 Theterm ‘non-valvular AF’ is used todescribe cases where rhythmdisturbance is not associated with a

High bloodpressure anddiabetes are

among the commoncauses of AF

There is an average delay of 2.6 years

between the onset of symptoms and

the diagnosis of AF

The prevalence and incidence of AF in many Latin

American countriesis currentlyunknown


24

Holter monitoring, echocardiography,and laboratory analysis).65 The MexicanMinistry of Health recommends that anECG, chest X-ray and laboratory testsare performed in adults with a clinicalsuspicion of AF. An echocardiogramshould then be carried out when a finaldiagnosis of AF is made.64 Managementof AF is discussed in more detail in thechapter ‘Stroke prevention in patientswith atrial fibrillation’, page 39.

It should be noted that AF may occur inisolation, or in association with otherdisturbances of normal heart rhythm,most commonly atrial flutter. Atrialflutter can precede or co-exist with AF,but there are differences in themechanisms of the two rhythmdisturbances.31 Atrial flutter will not be discussed further in this report.

Prevalence and incidence of atrial fibrillation

Although data regarding the prevalenceof AF in Latin America are scarce, it hasbeen estimated that a large number ofpeople in the region suffer from thecondition. In Brazil, it has beenestimated that there are around 1.5 million patients living with AF.20

In a population-based study thatassessed electrocardiographic findingsin 1524 participants aged ≥65 years inSão Paulo, Brazil, the age-adjustedprevalence of AF was 2.4%.51 Usingdata extrapolated from the US, it wasestimated that 230000 people inVenezuela suffer from AF, with thisfigure predicted to rise to 1millioncases by 2050.21 The actual incidenceof AF in Latin American countries iscurrently unknown; however, it hasbeen estimated that there were 275000 cases of AF in people aged70–80 years in Brazil in 2005, and 200000 in people aged >80 years.50

Further research is urgently needed in order to assess the prevalence and incidence of AF in many LatinAmerican countries.

Signs and symptoms of atrial fibrillation

A simple and easily identifiable sign ofAF is an irregular pulse, and thesymptoms may include palpitations,chest pain or discomfort, shortness ofbreath, dizziness, and fainting.99

However, many people with AF have no symptoms, or vague, non-specificsymptoms.31 Physicians may encounterAF when patients consult them aboutother conditions, related or unrelatedto the heart. Often, AF is not apparentuntil a person presents to their doctorwith a complication such as ischemicstroke, a blood clot in the leg, or heartfailure. In AF-related emergencyadmissions to hospital, AF most oftenpresents as difficulty with breathing,chest pain, and palpitations.100 Patientswho do experience symptoms of AF arenot always diagnosed immediately. In arecent international survey, there wasan average delay of 2.6 years betweenthe onset of symptoms and thediagnosis of AF.101 This indicates thatmany patients with AF are not beingmanaged effectively and are at risk ofserious long-term consequences, suchas stroke.

Guidelines often give useful advice forthe assessment of conditions as well astheir management. Guidelines coveringthe pharmacologic management of AFare available in Brazil, Argentina, andMexico.20,64,65 The Brazilian Society ofCardiology has recently publishedupdated guidelines on the managementof AF. In a patient with proven AF, aninitial examination would include anassessment of the pattern of occurrenceof the arrhythmia, the tolerability of theepisodes, a determination of the cause,and evaluation of any associated factors.An ECG would be required to confirmthe diagnosis of AF.20 In guidelinesproduced by the Argentine Society ofCardiology, a clinical evaluation for AFshould include in all cases: (1) a clinicalhistory, (2) a physical examination, and (3) complementary tests (ECG, chest X-ray,

25

Increase over timeThe prevalence of AF worldwide appearsto be increasing over time. In one cross-sectional study of almost 18000 adultswith AF diagnosed between July 1996and December 1997 in California, US, it was estimated that approximately 2.1 million people in the US had AF.102

By 2001, this number was thought tohave risen to 2.3 million, and it isprojected to increase approximately 2.5-fold – to more than 5.6 million – by2050 (Figure 4).102 The prevalence andincidence of AF are thought to be risingbecause population age is increasing andsurvival from conditions predisposing toAF (such as heart attack) is improving.49

Increase with age The prevalence of AF has also beenshown to increase with advancing age.In the previously described population-based study from São Paulo, Brazil, theprevalence of AF increased from around0.8% at the age of 65–69 years to 7%in those aged ≥80 years.51 At present,information regarding the incidence ofAF for Latin American countries isscarce; however, data from European

studies are indicative of the increasedincidence of AF with advancing age. Ina population-based cohort study inRotterdam, the incidence of AF wasinvestigated during a mean follow-upperiod of almost 7 years in 6432 individuals. This revealed anincidence of 1.1 per 1000 person-yearsin those aged 55–59 years, rising to20.7 per 1000 person-years in thoseaged 80–84 years.103 The incidence washigher in men than in women.

Lifetime risk of atrial fibrillation

The Framingham Heart Study, a large,long-term US-based study initiated inthe early 1950s, investigated thelifetime risk of AF in individuals whowere free of the condition at firstexamination. The study sample involved3999 men and 4726 women who werefollowed from 1968 to 1999.104 Formen and women aged 40 years andolder, the remaining lifetime risk of AFdeveloping was found to be 1 in 4.Unfortunately, similar data are not yetavailable for Latin Americanpopulations.

AF: a major risk factor for stroke

The prevalence andincidence of AF arerising as population

age increases

7.0

6.0

5.0

4.0

1.0

2.0

3.0

02020

Year

1990 1995

2.662.44

2.94

3.33

4.34

2000 2005 2010 2015 2025 2030 2035 2040 2045 2050

2.08

3.80

2.26

4.78

5.165.42

5.61

Ad

ult

s w

ith

atr

ial �

bri

llati

on

(m

illio

ns)

Figure 4. The number of people with atrial fibrillation is expected to continue to rise:projected number of adults with the condition in the US between 1995 and 2050. Upper,middle, and lower curves represent upper, middle, and lower boundaries of estimate.Adapted from Go et al. 2001 with permission from the American Medical Association.102

People aged 40 years and older have a

1 in 4 remaininglifetime risk ofdeveloping AF

26

The remaining lifetime risk of AFdeveloping underscores the importantpublic health burden posed by thiscondition – particularly when comparedwith the lifetime risk of other majorconditions and morbidities. Forexample, in the US Framingham Studythe remaining lifetime risk of dementiain middle-aged individuals wasapproximately 1 in 6;105 for breastcancer, the remaining lifetime risk was1 in 8 for women aged 40years.104

This chapter has set the scene forunderstanding some of the causes ofAF, its signs and symptoms, and who ismost at risk of developing thecondition. It also highlights themagnitude of the growing problem ofAF and the risk it poses to publichealth. Research is needed in theindividual Latin American countries togain a better understanding of thepatterns of incidence and prevalence ofAF throughout the region. Thefollowing chapters will discuss AF as arisk factor for stroke.


27

Detecting AF and stratifying stroke risk

Atrial fibrillation is often present without symptoms

Although AF may be recognized by a sensation of palpitations or otherpresenting symptoms (see section on ‘Signs and symptoms of atrialfibrillation’, page 24), it is commonlywithout symptoms and may have been so for an unknown period.31

Ambulatory ECG recordings (i.e. ECGrecordings taken using a device that isworn during normal daily activities) anddevice-based monitoring have shownthat an individual may experienceperiods of both symptomatic andasymptomatic AF.31 Often, though, AF is not detected until an individualpresents with a serious complicationsuch as stroke or heart failure.100

Detection and diagnosis of atrial fibrillation

Increased detection and diagnosis ofsilent AF are therefore imperative fortimely initiation of effective treatment,thus preventing many of thecomplications related to AF, includingAF-related stroke. Indeed, the Brazilian,Mexican, and Argentinian guidelines all

recommend that an ECG should beperformed in all patients in whom AF is suspected.20,64,65 Given that somepatients with other risk factors forstroke, such as high blood pressure,diabetes, and ischemic heart disease,frequently undergo check-ups in theprimary care setting, opportunisticassessment for AF during consultationsmay be beneficial where possible.

Systematic versus opportunisticscreeningA multicenter study – the Screening forAF in the Elderly (SAFE) study – wasinitiated in primary care in the UK. Its aimwas to determine the rate of detection of new cases of AF in the populationaged 65years and over, based on avariety of screening strategies.106 TheSAFE study involved 50primary carepractices and almost 15000 patients,identified randomly from computerizedlists of patients in the target study group.Of these, 5000 were assigned to thecontrol group (who received routineclinical care) and 10000 to systematic oropportunistic screening for 12 months:� All patients in the systematic

screening arm were invited by letterto attend a screening clinic

Detecting atrial fibrillation and stratifying stroke risk

Key points

� AF is often not detected until a serious complication such as strokeor heart failure develops

� Routine pulse-taking plays an important role in the detection of AFin at-risk patients

� A history of stroke in patients with AF increases the likelihood ofanother stroke threefold

� Female gender, advanced age, high blood pressure, heart disease,diabetes, and vascular disease also increase the risk of stroke inpatients with AF

� Patients in Latin American countries may currently be receivinginconsistent advice and therapy because of a lack of consensus onAF risk stratification

Increased detectionand treatment ofAF are needed to

prevent stroke


28

� Patients in the opportunistic screeningarm had their notes flagged to remindpractice staff to record the patient’spulse during routine consultation.Those with an irregular pulse weregiven an information sheet andinvited to attend a furtherappointment, where pulse rate and a12-lead ECG were recorded

Overall, both systematic and opportunisticscreening identified substantially morecases of AF than routine care (meanincidence: 1.52% and 1.71% comparedwith 0.99%, respectively). The cost percase detected by systematic screeningwas £1787 (US$2936) compared with£363 (US$597) per patient identifiedopportunistically. Pre-screening by takingthe pulse reduces the number of ECGsto be performed, thus makingopportunistic screening more cost-effective than systematic screening.106

In Latin America’s developing and ruralcountries, systematic screening isunlikely to take place, thereforeopportunistic screening would bemore suitable and cost-effective.

The SAFE study highlights theimportant role of a simple procedure,such as routine pulse-taking, in helpingto improve detection of AF in at-riskpatients. The policy implications arisingfrom the results of this study are thatan opportunistic approach using pulse-taking followed by ECG is probably themost cost-effective option for anyscreening program implementedthrough primary care.106 Severalrecommendations are made for futureresearch that could help define furtherthe optimum patient pathway (Table 2)

Additional risk factors for stroke in patients with atrial fibrillation

Factors reported to further increase therisk of stroke in patients with AFinclude:31,49,107

� Female gender� Advanced age

� Prior stroke or TIA� High blood pressure� Heart disease, for example, heart

failure and valvular heart disease� Diabetes� Vascular disease

Although stroke and AF are both moreprevalent in men than in women,108–110

the literature shows that death rate fromstroke is increased fourfold in womenwith AF compared with twofold in menwith AF.111 However, not all studies havedemonstrated such a significantdifference between the genders.18,111

A history of stroke or TIA is the strongestindependent predictor of stroke inpatients with AF, increasing the risk ofanother stroke approximately threefold.31

Increasing age also has a marked effecton the risk of stroke. Among patientswith AF, the incidence of stroke hasbeen shown to be sevenfold higher inpatients in their 80s compared withthose in their 40s.112 High blood pressureincreases the risk of stroke approximatelythreefold in patients with AF.12 However,it should be borne in mind that neitherof these studies report data specific toparticular countries within the LatinAmerican region.

Screening canidentify more newcases of AF than

routine clinical care

Table 2. Some of the recommendations for further research, based on the findings of the Screening for AF in the Elderly (SAFE) study.106

How the implementation of a screeningprogram for atrial fibrillation (AF)influences the uptake and maintenanceof anticoagulation therapy in patientsaged 65 years and over

The role of computerized software inassisting with the diagnosis of cardiacarrhythmias

How best to improve the performanceof healthcare professionals in interpretingelectrocardiograms

Development of a robust economic modelto incorporate data on new drugs toprevent the development of blood clotsin patients with AF

Previous stroke orTIA increases therisk of another

stroke threefold inpatients with AF


29

Risk stratification schemes for patientswith AF, incorporating the availableevidence on these additional risk factors,have been developed and are discussedin more detail in the next section.

Approaches to risk stratification

To guide the choice of the mostappropriate preventive therapy, somemeans of classifying the level of strokerisk is needed. Several different modelshave attempted to grade the risk ofstroke among patients with non-valvular AF, according to the presenceof coexisting conditions (e.g.previousstroke, TIA, or blood clot; impaired leftventricular function; high blood

pressure; diabetes) and other factors,such as age and gender.15 Riskstratification systems currently used aresummarized in Table 3.

Among patients not receivinganticoagulation therapy, the CHADS2

scheme has been found to be a moreaccurate stroke predictor than AFI114 andSPAF115 – two preexisting schemes.14 Inpatients receiving therapy, three schemeshave predicted stroke significantly betterthan chance: Framingham, CHADS2, andSPAF.116 However, several patientsclassified as being at moderate riskaccording to CHADS2 were at high riskaccording to other schemes (Figure 5)and at low risk according to Framingham

Several modelshave graded the

likelihood of strokeaccording to widelyaccepted risk factors

Stroke risk strata

High Intermediate Low

CHADS2-Revised15

ACC/AHA/ESC31

Score 2–6 Score 1 Score 0

Previous stroke, TIA or thromboembolism; or ≥2 moderate risk factors (age ≥75 years, hypertension, heart failure, LVEF ≤35%; or diabetes)

Age ≥75 years; hypertension; heart failure; LVEF ≤35%; or diabetes

AF (no other risk factors)

ACCF/AHA/HRS63 Previous stroke, TIA or thromboembolism; or ≥2 moderate risk factors (age ≥75 years, hypertension, heart failure,LVEF ≤35%, or diabetes)

Age ≥75 years, hypertension, heartfailure, LVEF ≤35%, or diabetes

AF (no risk factors)

CHA2DS2-VASc15 One ’major‘ risk factor (previous stroke, TIA or thromboembolism, or age ≥75 years), or ≥2 ‘clinicallyrelevant non-major’ risk factors (heart failure/LVEF≤40, hypertension, diabetes, vascular disease [myocardial infarction, peripheral artery disease or aortic plaque], female gender, age 65–74 years)

One ’clinically relevant non-major’ risk factor: heart failure/LVEF ≤40, hypertension, diabetes, vascular disease (myocardial infarction, peripheral artery disease or aortic plaque), female gender, age 65–74 years

No risk factors

Reference

CHADS2-Classical*14 Score 3–6 Score 1–2 Score 0

Table 3. Risk stratification schemes used to predict thromboembolism in atrial fibrillation. Adapted from Lip et al. 2010b with permission.113

*Secondary prevention study. CHADS2 score is a sum of numerical scores assigned to five risk factors: Congestive heart failure (1 point); Hypertension (1 point); Age ≥75 years (1 point); Diabetes (1 point); and Stroke or transient ischemic attack (2 points). For definition of CHA2DS2-VASc see below.ACCF, American College of Cardiology Foundation; AF, atrial fibrillation; AHA, American Heart Association; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack.

30


AFI SPAF CHADS2 FRAM vanWalraven2001

ACCP2004ACCP

100

80

60

40

20

0

LowModerateHigh

Pati

ents

(%

)

ACCP, American College of Chest Physicians; AFI, Atrial Fibrillation Investigators; SPAF, Stroke Prevention in Atrial Fibrillation; SPORTIF, Stroke Prevention using a ORal Thrombin Inhibitor in atrial Fibrillation; FRAM, Framingham.

Figure 5. Percentage of patients with atrial fibrillation (enrolled in the SPORTIF III and V trials)classified as being at low, moderate, and high risk of stroke, based on the individual riskstratification schemes. The results show that different models predict stroke risk differently.Adapted from Baruch et al. 2007 with permission.116

the CHADS2 scheme has been expandedand clarified.15 The CHADS2 score hasbeen refined by including additional riskfactors such as vascular disease, sex, andage 65–74 years. This risk factor-basedscheme can be expressed as theacronym, CHA2DS2-VASc, and has beenvalidated in an analysis from the EuroHeart Survey15 and in several otherstudies.113,119,120 CHA2DS2-VASc denotes:� Congestive heart failure/left

ventricular dysfunction: 1 point� Hypertension: 1 point� Age ≥75 years: 2 points� Diabetes: 1 point� Stroke, TIA or thromboembolism:

2 points� Vascular disease: 1 point

and SPAF.116,117 Few models haveaddressed the cumulative nature of riskfactors, whereby a combination offactors would confer a greater risk thanany factor alone.111

In real-world clinical practice forpatients who have, or are at a high riskof, atherothrombosis, and who maynot have been prescribed anticoagulanttherapy, CHADS2 can predict not onlythe risk of non-fatal stroke, but alsovarious other cardiovascular outcomessuch as cardiovascular death andcombined events (Figure 6).118

In light of the variable understandingand use of risk stratification schemes,

1

Non-fatal strokeNon-fatal MI

CV death/MI/stroke

CV death

0 2 3 4 5 60

5

10

15

An

nu

al e

ven

t ra

te (

%)

CHADS2 score

Figure 6. Annual cardiovascular (CV) event risk in patients with atrial fibrillation with variousCHADS2 scores. Annual event rate of CV death, non-fatal stroke, and combined cardiovascularoutcomes of CV death/non-fatal myocardial infarction (MI)/non-fatal stroke are increased forpatients with higher CHADS2 scoring, whereas the rate of non-fatal MI was not influenced byCHADS2 scoring. Reprinted from Goto et al. 2008 with permission from Elsevier.118

31


� Age 65–74 years: 1 point� Sex category female: 1 point

When tested with a point-basedscoring system (0 = low risk, 1 =intermediate risk, and ≥2 = high risk),CHA2DS2-VASc provided someimprovement in the predictive value forthromboembolism over the CHADS2

score, with low event rates in the ‘low-risk’ group and the classification of onlya small proportion of subjects into the‘intermediate-risk’ group.15

In patients with a low-risk CHADS2 score(0 or 1), or when a more comprehensiverisk assessment is needed, CHA2DS2-VASc may be helpful and complementthe use of the CHADS2 score (Figure7).62

Using data on risk factors for majorbleeding from the Euro Heart Survey aswell as those found in the literaturefrom systematic reviews, a new simplebleeding risk score – HAS-BLED – hasbeen derived for patients with AF:121

� Hypertension (uncontrolled, >160 mmHg systolic): 1 point

� Abnormal renal/liver function: 1 point each – maximum 2 points

� Stroke (previous history, particularlylacunar): 1 point

� Bleeding history or predisposition(e.g. anemia): 1 point

� Labile INR (unstable/high INRs or intherapeutic range <60% of time): 1 point

� Elderly (>65 years): 1 point� Drugs/alcohol (concomitant use of

drugs such as antiplatelet agentsand non-steroidal anti-inflammatorydrugs or alcohol): 1 point for drugsplus 1 point for alcohol excess –maximum 2 points

Although the HAS-BLED score stillneeds to be validated in at least oneother large contemporary cohort of AFpatients before it can be widelyimplemented into daily practice,121 therecent ESC guidelines stated that itwould seem reasonable to use the HAS-BLED score to assess bleeding risk in AFpatients on the basis that a score of ≥3indicates ‘high risk’.62 In addition, somecaution and regular review of thepatient would be needed after theinitiation of anticlotting therapy.62

It therefore appears that different riskstratification schemes predict the risk ofstroke in patients with AF differently,which means that selection of patientsfor therapy may depend on the schemechosen to assess risk. As a result,patients in Latin America may receiveinconsistent advice and therapy,depending on local choices.

*Congestive heart failure, Hypertension, Age ≥75 years, Diabetes, Stroke/TIA/thromboembolism (doubled)

†Other clinically relevant non-major risk factors: age 65–74 years, female sex, vascular disease

Consider other risk factors†

NO

YES

YES

Age ≥75 years

≥2 other risk factors†

NO

NO

OAC

OAC (or aspirin)

Nothing (or aspirin)

1 other risk factor†

NO

YES

YES

OAC, oral anticoagulant; TIA, transient ischemic attack.

CHADS2 score ≥2*

Figure 7. Clinical flow chart for the use of oral anticoagulation for stroke prevention in atrialfibrillation. Adapted from Camm et al. 2010 with permission from Oxford University Press.62

Predictions fromrisk stratification

models may be inconsistent,

which could resultin inequality of

advice and therapy

Key points

� Strokes in people with AF are more severe and have worse outcomesthan strokes in people without AF

� AF almost doubles the death rate from stroke

� AF increases the risk of remaining disabled or handicapped followingstroke by almost 50%

Rheumatic heart diseaseVentricular thrombus

Acute myocardial infarction

Non-valvular atrial !brillation

Prosthetic valves Other, less common sources

15%

5%

10%

10%

10% 50%

Figure 8. The main cause of cardioembolicstroke is non-valvular atrial fibrillation.122

Image reprinted with permission frome.Medicine.com, 2011. Available at:http://emedicine.medscape.com/article/1160370-overview.

Strokes in peoplewith AF are more

severe than strokes in people

without AF

strokes were associated with higherseverity scores (NIHSS [National Institutesof Health Stroke Scale] score >18 pointsin 31.5% of patients) and a worse short-term outcome as measured by themodified Rankin scale (mRs) at day 30:mRs 2–3 in 27.7% of patients, mRs 4–5 in 29.3% of patients, and death in23.4% of patients. The modified Rankinscale is a commonly used scale formeasuring the degree of disability ordependence in the daily activities ofpeople who have suffered a stroke.

Increased severity of stroke

In addition to a high risk of stroke,patients with AF suffer from more severestrokes and have a poorer prognosisafter the event than patients withoutAF.18 The increased severity of strokes inpatients with AF is thought to bebecause such strokes are predominantlycardioembolic.18 A cardioembolic strokeis caused by a blood clot in the heart,part of which breaks away and becomestrapped in large arteries in the brain.18

Blockage of the larger arteries in thebrain, compared with blockage ofsmaller arteries characteristic of othertypes of stroke, results in greaterdamage and therefore more severestroke. Half of all cardioembolic strokesare caused by AF (Figure 8).122

In a Chilean study of 239 patients withischemic stroke, AF was the mostcommon cause of cardioembolic stroke(46%).123 The case death rate at 30 days was highest in cardioembolicstrokes (28%) and lowest in small-vessel infarction (0%). Dependency ordeath at 6 months was also highest incardioembolic strokes (62%) and lowestin small-vessel infarction (21%).123

In the Mexican PREMIER study, which wasa multicenter stroke registry study of1040 patients with first-ever ischemicstroke, 188 patients had cardioembolicstroke.124 Patients with cardioembolic

Features of stroke in patients with atrial fibrillation


32

Features of stroke in AF

33

Annual death rate (%)

Year With AF Without AF

1 50 27

2 14 8

3 14 6

4 10 6

5 11 6

6 4 3

7 5 4

8 4 3

Table 4. Annual death rates from first stroke (rounded to nearest whole number) in patients with and without atrial fibrillation (AF). Adapted from Marini et al. 2005 with permission.13

subjects aged 55 to 94 years whodeveloped AF during 40 years of follow-up of the original US Framingham study,AF was associated with a doubling inmortality in men and women.129 In alarge-scale Italian study of patients whohad suffered a first stroke, AF was foundto increase the 5-year death rate fromstroke almost twofold (Table 4) and to bean independent predictor of death rateeven after adjusting for other outcomepredictors, such as age, sex, and vascularrisk factors.13

A trend towards an increase in the overallearly death rate in patients with AF overthe past 20years has been reported,130

which may reflect the increasing age ofthe population. With both itsprevalence102 and the associated deathrate increasing, there is an urgent needto improve the management of AF, inparticular to prevent the most commonfatal consequences, such as stroke.

Data from the REduction ofAtherothrombosis for Continued Health(REACH) Registry showed that thepresence of AF in patients withatherothrombosis was associated with ahigher rate of all-cause mortality (4.3%)than in those patients without AF (2.3%).This higher mortality in patients with AFwas observed across all subgroups withestablished atherothrombosis or at riskfor atherothrombosis.118

The original scale was introduced by J Rankin in 1957 and modified to itscurrently accepted form by ProfessorWarlow in the late 1980s. At the 1-yearfollow-up, ~40% of patients withcardioembolic stroke had died.

Although mean cost data forcardioembolic stroke in patients in LatinAmerican countries are scarce, cost datafrom Europe may offer an indication ofthe cost spread across the countries ofthe Latin American region. The meancosts of acute hospital care were shownto be higher for cardioembolic stroke(€4890 per patient; US$6948) than fornon-cardioembolic stroke (€3550;US$5044) in a study of more than 500 patients in Germany.125 In addition tobeing more severe, cardioembolic strokesare associated with a higher risk ofrecurrence than other types of stroke.126

The increased severity of strokes inpatients with AF compared with otherstrokes suggests that these patients willexperience a greater impairment inquality of life than patients without AF.A systematic review has shown thatpost-stroke quality of life is significantlypoorer in patients with AF comparedwith healthy controls, the generalpopulation, and other patients withcoronary heart disease.127 Patients withAF are therefore a key targetpopulation for reducing the overallburden of stroke on society.

Increased death rate

The death rate from stroke is significantlyhigher in patients with AF than in thosewithout AF. In the Argentinian NationalStroke Registry (ReNACer), a countrywidehospital-based stroke registry acrossArgentina, 1991 patients with acuteischemic stroke were admitted to the 74 participating institutions betweenNovember 2004 and October 2006.128

Patient demographics from the studyshowed that a history of AF in strokepatients was significantly associated within-hospital mortality.128 In an analysis of

Death rate fromstroke is higher

in patients with AFthan in thosewithout AF

Patients with AFare a key targetpopulation for

reducing the overallburden of stroke

AF increases therisk of remaining

disabled orhandicapped

following stroke by almost 50%

in patients with AF than in thosewithout AF, both immediately after thestroke and after rehabilitation.18 Inaddition, AF was associated with a20% increase in the length of hospitalstay and a 40% decrease in thelikelihood of discharge to home.

At present, there are no data for theentire Latin American region to indicatethe increased risk of disability that thepresence of AF confers on strokepatients; however, data from aEuropean-wide study are indicative ofthe increased risk and levels of disabilityassociated with AF-related stroke.

In a European study involving sevencountries and 4462 patientshospitalized for first-in-a-lifetime stroke,the presence of AF increased the risk ofremaining disabled or handicappedafter a stroke by almost 50%.16

While data regarding the impact of AF-related stroke exist in a limited numberof countries in Latin America, furtherstudies are required in the rest of theregion to provide a completeperspective of the effect of AF-relatedstroke in Latin America.

Increased disability and poor health

AF-related stroke is more severe and isassociated with more ill health thanstroke unrelated to AF.13,16–18

Data from the previously describedPREMIER study were used to assess theseverity of stroke in patients with andwithout a history of AF. In total, 1246 patients with ischemic stroke wereincluded in the registry; 159 patientshad history of AF and in 64 others AFwas diagnosed during the acute strokeevent. The case death rate at 30 dayswas 22.0% in patients with AFcompared with 13.7% in those withoutAF. In patients who survived, the rate ofsevere disability (as measured by a scoreof 3–5 on the Rankin scale) wassignificantly higher in the AF patientcohort compared with the non-AFpatient cohort (69% vs 52%,respectively, Figure 9) (Dr. Cantú-Brito,personal communication).

Data from the US has shown utilizationrates for hospital in-patient, emergencyand outpatient/physician visits to behigher for patients with AF comparedwith patients without the condition.131

Overall, per-patient medical costs havebeen shown to be fivefold higher in AFvs non-AF patient populations.131 Intotal, AF-attributable costs in the UShave been estimated at US$6.65billion.132 This was split between directpatient costs of US$2.93 billion (44%),indirect patient costs of US$1.95 billion(29%), outpatient costs of US$1.53billion (23%), and drug treatment costsof US$235 million (4%).

Data from the Copenhagen StrokeStudy were used to investigate theimpact of stroke on morbidity. Loss ofability to perform normal daily activitiesafter stroke, and decline in neurologicfunction – including level ofconsciousness; partial paralysis of thearm, hand, and/or leg; and difficulty inswallowing – were significantly greater


34

Without AF

With AF

0

10

20

30

40

50 48

31

52

69

60

70

80

Good recovery Severe disability

Pati

ents

(%

)

Figure 9. Patient outcomes after an acutestroke event in patients with and without a history of atrial fibrillation (AF). (Dr. Cantú-Brito, personal communication.)

35

High cost of stroke in AF

High cost of stroke in atrial fibrillation to individuals and society

Significant impact on quality of life

The impact of a stroke on an individual’shealth can be expressed as a utility score.These scores are used to express theimpact of a state of health on health-related quality of life on a scale of 0 to 10,where 10 represents perfect health and 0represents death. Murphy et al. foundthat mild stroke yielded a higher utilityscore (9/10) than severe stroke (4/10).133

This indicates that AF-related strokes,which are more severe than strokes inpatients without AF, result in lower utilityscores (i.e.poorer health-related quality oflife) than other types of stroke. In a study

of the impact of stroke on quality of life inpatients with AF, the average utility scorewas 9/10 for a mild stroke, 1/10 for amoderate stroke and 0/10 for a severestroke; 83% of patients rated their qualityof life after a severe stroke as equal to, orworse than, death.134

In addition to general utility scores,other scores assess the impact of astate of health on a specific aspect ofquality of life (such as neurologicfunction). Some quality of life scores forpatients with and without AF whoexperience stroke are shown in Table 5.Like the utility scores discussed above,the scores given in the table indicate

Key points

� AF-related stroke impairs stroke survivors’ quality of life more thannon-AF-related stroke

� Permanent disability and other consequences of AF-related strokeplace a heavy burden on caregivers, family members, and health andsocial services

� Studies in European populations have shown that healthcare costsassociated with stroke are higher for patients with AF than for patientswithout AF. Similar studies are required in Latin American populations

Table 5. Outcome of stroke in patients with and without atrial fibrillation (AF). Adapted from Jørgensen et al. 1996 with permission.18

Patients with AF Patients without AF30 38

46 50

35 52

67 78

50 40

72 (33) 171 (17)

41 (19) 135 (14)

104 (48) 662 (69)

Initial stroke severity (SSS* score; lower score = greater neurologic impairment)

Neurologic outcome (SSS score at discharge)

Initial disability (BI† score; lower score = decreased ability to perform normal daily activities)

Functional outcome (BI score at discharge)

Length of hospital stay (days)

In-hospital death, n (%)

Discharged to nursing home, n (%)

Discharged to own home, n (%)

Data are presented as mean, rounded to nearest decimal place.*Scandinavian Stroke Scale.125

†Barthel Index.126

AF-related strokehas a more

negative impact on quality of life

than strokeunrelated to AF

that AF-related stroke has a morenegative impact on quality of life thannon-AF-related stroke.

AF also increases the risk of medicalcomplications following stroke. Patientswith AF suffer more frequently frompneumonia, pulmonary edema(accumulation of fluid in the lungs),and bleeding in the brain after strokethan those without AF.135

Heavy burden on carers,families and society

More than one-third of patients whoexperience a stroke return to theirhome with some level of permanentdisability.5 They then rely on informalcaregivers, typically family members, tohelp with their normal daily activitiesand to arrange the required additionalassistance from healthcare services. Inaddition to giving practical help,caregivers have to manage the oftenconsiderable cognitive, behavioral, and

emotional changes in the patient.These changes include mood swings,personality changes, irritability, anxiety,memory loss, and depression.5,136

Caregivers can therefore experience aloss of identity, independence, andsocial life, and extreme tiredness anddepression. They also report fearsregarding the safety of the patient anddistress at not having time to attend toall of the patient’s needs.5,136 In aBrazilian cross-sectional study, theburden and perceived health statusamong 200 caregivers of strokesurvivors was assessed. All of thecaregivers in the study were closerelatives of the stroke patients, withover three-quarters of the caregiversbeing female. Overall, more than aquarter of caregivers found their roleemotionally exhausting. Femalecaregivers reported significantly highertest scores for anxiety and hadsignificantly worse caregiver burdenscores than their male counterparts.Caregiver burden significantlyworsened as stroke severity increased.Patient’s disability and caregiver factors(female sex and levels of depression)were significant independent predictorsof caregiver burden.7

Stroke can have a devastating impactnot only on the individual and theircaregivers but also on the wider family,particularly children.

AF increases therisk of medicalcomplications

following stroke

36


More than one-third of patientswho experience a stroke return

home with somepermanentdisability

Illustrative example:a caregiver’s perspective

�“It is now three years since my father’s stroke. He found it very difficult to cope at first. Straight after the stroke, his power of speech and understanding were badly affected and he was very frustrated. He also had visual disturbances, loss of balance and emotional problems, and required full-time care. I wanted the best for him and it made me sad to see him like that. I felt totally exhausted, yet could not get any rest because I was constantly up and down looking after him. Nowadays, he’s better in himself, but sometimes staggers when he walks and his coordination and speech are poor especially when he is tired. He says I tend to wrap him up in cotton wool but I constantly worry about him and that it could happen again”

Illustrative example:a child’s perspective

�“When my mother had her stroke, I couldn’t wait to go and see her in the hospital. As I got to her room, I could tell straight away that something was wrong. She couldn’t move her left arm and leg and was speaking funny. I was a bit afraid of her, but then she hugged me and my father said she would be alright. I still couldn’t understand what she said. They kept her in the hospital eight days until it was safe for her to come home to us.”

37

High cost of stroke in AF

a proportion of the gross domesticproduct is unequally distributedamongst the income quintiles of thepopulation. For example, in Paraguay,healthcare costs accounted for 14.0%of the expenditure for the poorestquintile versus 8.8% for the richestquintile.33 The more socioeconomicallydisadvantaged individuals are those withdisproportionately higher health risks.140

National health expenditure as aproportion of the gross domesticproduct also influences the healthcarefor populations in Latin America. Theshare of public health expenditure as apercentage of gross domestic product,which serves as an indicator of thehealth provision provided bygovernments, is lower for Latin America(3.3%) compared with a high-incomecountry such as the US (7.2%).33

Overall, national health expenditure forall countries in Latin America and theCaribbean was 6.8% of the region’sgross domestic product.33 Thispercentage varied for each country inthe region; e.g. 5.5% in Mexico, 7.0%in Brazil, and 8.6% in Argentina.33

In Latin America and the Caribbean,48% of national healthcare expenditureis for public health, and 52% for privatehealth (including direct out-of-pocketexpenditure for health goods andservices and to cover health servicesconsumed through private healthinsurance plans).33 Individuals on higherincomes are more likely to be coveredby private health insurance, therebyreducing levels of out-of-pocketexpenditure on health care.33 In poorcountries, where public health sectorexpenditure is low, it is the poorestindividuals who are most affected.140

Because stroke in patients with AF ismore severe than stroke in those withoutAF,18 it is likely to incur greater costs.Data comparing the cost of AF-relatedstroke and stroke not related to AF arenot available for Latin Americancountries. However, data are available

The rehabilitation and long-term careof stroke survivors also place asignificant demand on health and socialservices, often involving nursing, socialcare, and speech, occupational, andphysical therapy.5,137 Together with lossof time in employment andcontribution to the community of thepatient, and most probably also thecaregiver, this amounts to a significantoverall burden on society.

High economic cost

The total cost of stroke for the wholeLatin American region is unknown.However, data from individual countriesattest to the high cost of stroke in theregion. In Brazil and Argentina,aggregate national healthcareexpenditures of initial hospitalizationfor stroke for acute treatment ofincident stroke (ischemic stroke andintracerebral hemorrhage) werecalculated to be US$449.3million andUS$434.1million, respectively.9,10

Data from Western countries also serveto indicate the high cost of stroke.According to a review of data fromeight Western countries, strokeaccounts for approximately 3% ofnational healthcare expenditure and0.3% of gross domestic product.138 Thetotal economic cost of stroke isprobably even greater than this, asthese calculations largely omit costsincurred by the patient and caregivers,because they may be difficult tocapture. In 2006, the total cost ofstroke in the whole of Europe, includinghealthcare costs, productivity costs, andinformal costs, was calculated to beover €38 billion (US$54 billion).139

Government healthcare expenditure inLatin American countries can have animpact on the financial burden of strokeimposed on patients and their families.Inequalities in access to health servicesand resources have constantly beenpresent in the Latin American region.The percentage of health expenditure as

Healthcare costsassociated with

stroke are higher for patientswith AF than for

patients without AF


38

Strong rationale for stroke prevention in patients with atrial fibrillation

In conclusion, patients with AF have ahigher risk of stroke and suffer frommore severe strokes than patientswithout AF. Thus, AF-related strokeimposes an even greater burden onindividuals, caregivers, families, society,and healthcare resources than stroke inpatients without AF, providing a strongrationale for effective management ofAF and prevention of stroke in thishigh-risk population.

from European countries. In the BerlinAcute Stroke Study, the average directcosts of stroke per patient weresignificantly higher in patients with AF(€11799 [US$16770]) than in patientswithout AF (€8817 [US$12532]).141 Theeffect of AF on stroke-related inpatientcosts was also analyzed over a 3-yearperiod in Sweden.142 Among strokesurvivors, the inpatient costs over thisperiod were on average €818 (US$1163)higher in patients with AF comparedwith patients without AF (€10192[US$14487] vs €9374 [US$13325]) aftercontrolling for additional risk factors anddeath rates. Studies are required in LatinAmerican countries to confirm the higheconomic cost of stroke in patients withAF across the region.

39

Stroke prevention in AF

Key points

� Direct treatment of AF can help to prevent strokes. Drugs and non-pharmacologic methods are used to control heart rate and rhythm

� It is recommended that patients receiving treatment for AF alsoreceive therapy to reduce the risk of blood clots

� Maintaining the INR within the target range for patients on VKAtherapy is a universal problem that is compounded in Latin Americancountries for a number of reasons. These include the lack of access to,and the cost of attending, INR monitoring facilities, problemsassociated with INR blood testing in remote/rural areas, and lack ofphysician knowledge in this area

� Currently available anticlotting therapies, such as VKAs and aspirin,are effective in the prevention of AF-related stroke but havedrawbacks

� High blood pressure and diabetes, which commonly affect patientswith AF, also require management to reduce the risk of stroke

Stroke prevention in patients with atrial fibrillation

(a process by which an abnormally fastheart rate or abnormal heart rhythm isterminated by the delivery of atherapeutic dose of electric current tothe heart), catheter ablation (aninvasive procedure used to remove afaulty electrical pathway from theheart), and surgical maze procedures(open-heart surgical ablation using anenergy source to scar the tissue withthe faulty electrical pathway).

Anticlotting therapies forpreventing stroke

AF predisposes to the formation of ablood clot, or thrombus, in the heart.Part of the blood clot can break away,forming what is known as an embolus,which can then become trapped inblood vessels in the brain, causing astroke. Thus, strategies for theprevention of stroke in patients with AFinvolve the use of anticlotting drugtherapy. It is recommended that patientsreceiving treatment for AF to stabilizeheart rhythm also receive some form of

The ultimate aim of AF management isto reduce the risk that a patient willsuffer serious long-term consequencesof the condition, particularly stroke. Thisobjective may be achieved by directmanagement of AF through control ofheart rate and control of heart rhythm,and by use of drugs to reduce the riskof blood clots and hence stroke. Thesestrategies are discussed in this chapter.

Strategies for stabilizing heart rhythm

Effective management of AF will initself prevent stroke. AF is mostcommonly managed using ‘rhythmcontrol’ or ‘rate control’ strategies.17 Inrhythm control, drugs are used tomaintain the heart’s rhythm (these areknown as antiarrhythmic drugs); in ratecontrol, the drugs are used to maintaina steady heart rate.17 Examples of drugsused for rhythm or rate control includeamiodarone, digoxin, and �-blockers.Non-pharmacologic methods used totreat AF include electrical cardioversion

The aim of AFmanagement is to reduce the

risk of long-termconsequences, such

as stroke

AF is commonlymanaged using

‘rhythm control’ or‘rate control’

strategies

anticlotting therapy (see ‘Guidelines forstroke prevention in patients with atrialfibrillation’, page 47).31

There are three main classes of ‘blood-thinning’ drugs currently used in theprevention of stroke in patients with AF: � Anticoagulants, which interrupt the

series of chemical reactions thatresult in the formation of a bloodclot (the coagulation pathway;Figure 10)

� Antiplatelet drugs, which limit theaggregation (clumping together) ofplatelets (components of the bloodthat form a significant part of theblood clot, particularly in the arteries)

� Thrombolytics (in the acute setting),which break up blood clots oncethey are formed

VKAs, which are oral anticoagulants,and acetylsalicylic acid (or aspirin), an

antiplatelet agent, are currently themost widely used drugs in theprevention of stroke in patients with AF.

Vitamin K antagonists VKAs, which include the coumarinswarfarin, phenprocoumon, andacenocoumarol, are widely usedanticoagulant agents that have beenavailable for many years. Acenocoumaroland phenprocoumon are widelyprescribed in Latin America as well as incontinental Europe, whereas warfarin ismore commonly used in the US, UK, andScandinavian countries.143

VKAs exert their anticoagulant effectsby inhibiting the production of fourvitamin K-dependent factors that playkey roles in the coagulationpathway.13,25 By inhibiting the enzymevitamin K epoxide reductase, VKAsprevent the regeneration of the

40


VKAs and aspirinare currently themost widely useddrugs for stroke

prevention inpatients with AF

Patients receivingtreatment for AF

should also receiveanticlotting therapy

Initiation

Propagation

Clot formation

Inactive factor Active factor

Transformation Catalysis

Thrombin

FibrinFibrinogen

Prothrombin

Xa

IXa

IX

VII

XTF VIIa

II

IIa

AT, antithrombin; TF, tissue factor.

AT

Figure 10. Simplified diagram of the coagulation pathway – a series of enzyme reactionsinvolved in the formation of a blood clot. Different enzymes are involved at different steps inthe pathway. The end product of the pathway is fibrin, an insoluble protein that combineswith platelets to form a blood clot.

41


reduced form of vitamin K, an essentialcofactor in the synthesis of a number offactors in the coagulation cascade,including Factor II (prothrombin), FactorVII, Factor IX, and Factor XI. Depletionof the reduced form of vitamin Kultimately impairs the ability to formthrombin, which subsequently inhibitsthe conversion of fibrinogen to fibrin.

Although effective in preventing strokein patients with AF, oral VKAs haveseveral limitations that make the routine,and acute, medical care of patientsreceiving long-term VKA therapyrelatively complicated. The effects ofVKAs can be significantly modified bygenetic factors144 and by interactionsbetween other foods and drugs,including amiodarone, an antiarrhythmicdrug used in the treatment of AF.26,145

Furthermore, there is a narrow windowbetween the dose of VKA that achievestherapeutic efficacy and the dose thatconfers an increased bleeding risk (i.e. thetherapeutic range of the drug is small).

The management of patients receivingVKAs can therefore be challenging, andfrequent monitoring is required. Formonitoring, the patient’s prothrombintime (a measure of clotting time) isdivided by a reference prothrombin time;the resulting value is then converted toan INR. Using INRs standardizes resultsby removing differences betweenlaboratories. A target INR range of 2.0–3.0 is typically recommended forpatients receiving VKA therapy.31,87

If the INR is too high, a patient is atincreased risk of bleeding; too low, and the risk of a blood clot is high. If a patient’s INR is found to be outsidethe target range, the dose of the VKAshould be adjusted accordingly.

Maintenance of the INR within a targetrange requires not only frequentmonitoring but constant doseadjustment, and represents a significantbarrier to effective anticoagulation ineveryday practice. This is especiallydifficult in some Latin American countries

where some patients have limited accessto healthcare resources, including to INRmonitoring facilities. In addition, the costof attending INR monitoring clinics maybe prohibitive for some patients. Theregularity of INR monitoring may also be less stringent than is optimal in moreremote/rural areas because of thedifficulties in transport or cold chainprocesses required in INR testing. Theissue of INR control has also beenstrongly linked to physician knowledge in this area. In a study that assessed the use of anticlotting therapy among AF patients in a Brazilian hospital, the proportion of patients receiving oralanticoagulant therapy (warfarin) withinthe optimal INR range of 2.0–3.0 was as low as 15.6%.59

Efficacy of vitamin K antagonists inclinicial trialsSystematic reviews of clinical trials inpatients with AF have shown that,compared with no therapy, warfarin(with close monitoring and doseadjustment if necessary) provides a 62–68% reduction in the risk of stroke(Figure 11) and a 26–33% reduction indeath rate46–48,114 without significantlyincreasing the risk of major bleeding. Theimplication is that for every 1000 patientstreated with warfarin, 31 ischemicstrokes will be prevented each year.48

There are few studies of the effect ofVKA therapy in Hispanic populations –this could be addressed by carrying outsubset analyses in existing studiesinvolving Hispanic populations whereVKA therapy has been administered.

Importantly for patients with AF, it hasbeen shown that when the dose ismonitored and – where necessary –adjusted, VKAs are effective in preventingboth mild and severe strokes.151,152

Clinical use of vitamin KantagonistsVKAs are currently recommended asfirst-line therapy in patients with AFand a moderate or high risk ofdeveloping stroke.31,87 This is despite

Patients on VKAsneed frequent

monitoring anddose adjustment to

keep INRs withinthe target range

VKAs are currentlyrecommended as

first-line therapy inpatients with AF atmoderate or high

risk of stroke


42

concern that the efficacy and the lowrisk of bleeding observed with VKAs inthe controlled clinical trial setting arenot reflective of, and cannot beachieved in, clinical practice.154 Not onlyare highly motivated patientsmonitored closely in clinical trials, butrelatively few elderly patients arerecruited, and patients at high risk ofbleeding are frequently excluded.48,154

Retrospective cohort studies with anobservational design have providedsome evidence on this matter. In alarge-scale cohort of more than 11500 patients with non-valvular AFtreated in a clinical practice setting,warfarin provided a 51% reduction inthe risk of thromboembolism(formation of a blood clot and thencirculation of part of the blood clot inthe bloodstream) and a 31% reductionin the risk of death compared witheither no therapy or aspirin, afteradjusting for potentially confoundingfactors.155 Overall, there were 148 casesof ischemic stroke or otherthromboembolic event among patients receiving warfarin therapy (1.17 per 100 person-years) and 249 events in patients not receiving

the major drawbacks associated withVKA therapy, including unpredictableinteractions with food and other drugs,which often necessitate significantlifestyle changes; the inconvenienceand burden of INR monitoring; theneed for dose adjustment, which oftendoes not happen; and the perceivedrisk of bleeding, particularly in theelderly. As a result of these drawbacks,which may cause patients to discontinuetaking VKAs, guidelines are not alwaysfollowed, despite the fact thatguideline-adherent management isassociated with improved outcomes.125

Thus, many patients with AF and amoderate to high risk of stroke do notreceive anticoagulant therapy andtherefore remain unprotected.60,153

Current guidelines and adherence tothese guidelines are discussed in moredetail in the chapter ‘Guidelines forstroke prevention in patients with atrialfibrillation’ (page 47).

Vitamin K antagonists: clinicalpractice versus controlled clinicaltrialsOwing to the considerable practicaldifficulties in maintaining the INRwithin the target range, there is often

Relative risk reduction(95%CI)

Adjusted-dose warfarin compared with placebo or control

AFASAK I, 1989SPAF I, 1991BAATAF, 1990CAFA, 1991SPINAF, 1992EAFT, 1993

All trials (n=6)

Favors warfarin Favors placeboor control

100% 50% –100%–50%0

AFASAK I, Atrial Fibrillation, Aspirin, and Anticoagulation study;146 SPAF I, Stroke Prevention in Atrial Fibrillation Study;115 BAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation;147 CAFA, Canadian Atrial Fibrillation Anticoagulation Study;148 SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation;149 EAFT, European Atrial Fibrillation Trial.150

Figure 11. Results from a meta-analysis of six randomized studies, showing that warfarin providesa greater reduction in the risk of stroke in patients with atrial fibrillation than does placebo.Adapted from Hart et al. 2007 with permission from the American College of Physicians.47

Patient populations in clinical trials maynot reflect normal

clinical practice


43

warfarin (2.03 per 100 person-years).The incidence of cerebral bleeding wasalmost doubled with warfarin, but stillremained low. The authors concludedthat the study adds further support forthe routine use of anticoagulation ineligible patients with AF who are atmoderate to high risk of stroke.

An investigation in the clinical practicesetting in Argentina demonstrated a reduction of approximately 44% inthe risk of stroke in patients with AFreceiving VKA therapy compared withthose not receiving VKA therapy.Mortality rate and the combined eventsof death and/or stroke were alsosignificantly lower in the VKA therapycompared with non-VKA therapy patientgroup (mortality 17.6% vs 29.4%;combined events 21.2% vs 34.0%,respectively).156 However, the reductionin the risk of stroke observed in thisstudy was lower than that in clinicaltrials that assessed VKA therapy.47,156

An analysis of the process and qualityof oral anticoagulation use in clinicalpractice has highlighted majormanagement differences betweenanticoagulation clinic care and routinemedical care, with less time within thetherapeutic INR range being achieved inroutine medical care.157,158 Two studiescarried out in Brazil have indicated thatthere are a high percentage of patientswho do not comply with VKA treatment.In the first study, patients takingwarfarin and phenprocoumon werewithin their therapeutic INR range foronly 45.6% and 60.7% of clinic visits,respectively.159 In the second study, only38% and 62% of patients again takingwarfarin and phenprocoumon,respectively, were within their targetINR. Moreover, 50.6% of the patientsprescribed oral anticoagulation for AFwere outside their therapeutic INRrange.160 Thus, patient outcomes afterVKA therapy do appear to be lessfavorable in clinical practice than inclinical trials. Overall, however, thebenefits still outweigh the risks in themajority of patients with AF.

Acetylsalicylic acid (aspirin) Aspirin reduces platelet aggregation andblood vessel constriction, which in turnreduces the risk of a blood clot formingand helps to prevent a stroke.161 It ismost effective in the prevention ofblood clots that are rich in platelets,such as those that form in arteries.

In patients with AF, aspirin reduces therisk of all strokes by approximately 22%compared with placebo; for severe,disabling strokes, the reduction in riskwith aspirin compared with placebo issmaller (13%).47 In addition, aspirin wasassociated with a non-significant 19%reduction in stroke compared with notreatment.47 Clinical trials directlycomparing aspirin with VKA therapy inthe prevention of stroke in AF haveshown VKAs to be significantly superior,providing a risk reduction ofapproximately 50% compared withaspirin.162,163 Despite the perception thatit may be safer than warfarin, a majordrawback of aspirin is that it increasesthe risk of bleeding, particularly in thegastrointestinal tract.27–30

The current ESC guidelines recommendthat patients with one clinically relevantnon-major risk factor, includinghypertension, age 64–75 years, andfemale sex, should receive an oralanticoagulant in preference to aspirin.62

In addition, no treatment with anyanticlotting therapy should beconsidered over aspirin in patientswithout any stroke risk factors.62 Itshould be noted that there is somedoubt as to the real benefit of aspirin in patients at low risk of stroke.164,165

Similar advice is given in local LatinAmerican guidelines such as theArgentinian, Brazilian, and Mexicanguidelines.20,64,65 Summaries of theseguidelines are given in Appendix 1.

Recent studies underline the use ofalternative strategies to aspirin in somepatients with AF. In a contemporarystudy of patients with AF, the oralanticoagulant apixaban was shown to

Patient outcomesafter VKA therapy

may be lessfavorable in routine

medical practicethan in clinical trials

Studies support the use of

anticoagulation inpatients with AF atmoderate to high

risk of stroke

there was a need for other treatmentsthat may interact with the VKA; thepatient was unlikely to adhere torestrictions on alcohol, diet, or non-prescription medications; the risk of VKAtherapy was considered to outweigh therisk of stroke or systemic embolism; orthe patient was unwilling to take VKA.Reasons for discontinuation of VKAtherapy included poor anticoagulant

44


be superior to aspirin for the preventionof stroke in patients with AF for whomVKA therapy was unsuitable and hadbeen discontinued, or for patients whohad not previously been prescribed VKAtherapy but in whom it would beexpected to be unsuitable.166,167 VKAtherapy was considered unsuitable if thepatient was unlikely to comply withdosing or monitoring requirements;

A B C

Figure 12. Various CT images of a patient (Mrs. M) taken at different time pointsshowing the presence of a cerebral infarction in different locations. Permission for usegranted by Dr. Cantú-Brito.

�Case study: an elderly woman receiving warfarin

Mrs. M, a 76-year-old Mexican woman with a history of smoking and arterial hypertension, was diagnosed in 1998 with AF after an episode of acute dyspnea (shortness of breath) and palpitations. She was given aspirin until December 2004 when she had weakness down the left-hand side of her body. A Computed Tomography (CT) scan showed a right frontal infarction (Figure 12A) and she was started on oral anticoagulation with warfarin. During warfarin monitoring in October 2006, her INR rose to 5.2 and, because of the risk of bleeding, warfarin was stopped. On the fourth day after stopping warfarin, Mrs. M developed acute aphasia (impairment of speech and writing) and weakness down the right-hand side of her body. A CT scan revealed a recurrent cerebral infarction, now in the left frontal region (Figure 12B). Her INR was 1.3. The patient recovered from this second infarction with only mild disability, and warfarin was restarted. Again during warfarin monitoring in September 2007, her INR rose to 3.9 and warfarin was once again stopped. On the third day after stopping warfarin, she had a further episode of acute aphasia and weakness down the right-hand side of her body. A CT scan showed a new cerebral infarction, now in the left parietal region (Figure 12C). Her INR was 1.2. Unfortunately, the issues with maintaining Mrs. M’s INR within the correct range caused immediate life-threatening problems. After the third recurrent cerebral infarction, Mrs. M was severely disabled, unable to walk, and she died 2 months later from pneumonia. Therefore, it would be ideal if an oral anticoagulant existed that did not require frequent monitoring, could be given at a fixed daily dose, and was also unaffected by changes in diet or other medications.

45


stroke prophylaxis in Latin America,despite its relevance for some countries.Nevertheless, for other countries, therelevance of assessing cost-effectivenessof VKA is less clear, given the unbalanceddistribution of health care in LatinAmerica.34 Despite this, similar country-specific studies are needed in LatinAmerica, particularly because of thegrowing burden of stroke in the region.

The cost-effectiveness of VKA therapy isdependent on achieving a significantreduction in the risk of thromboembolism.Practical difficulties in maintaining INRvalues within the therapeutic range mayresult in VKA therapy being less cost-effective in clinical practice than incontrolled clinical trials. Monitoring INRin clinical practice may also incuradditional costs, to the patient, caregiver,and society, not captured in the cost-effectiveness studies. Data on the cost ofattending anticoagulation clinics in LatinAmerican countries are not available.However, there are European studies thatprovide costs related to anticoagulationclinics. One study of the cost associatedwith accompanying patients to clinicvisits has shown that caregiversexperience a cost of €17 (US$24) per visitin Portugal and €10 (US$14) per visit inthe UK.171 In addition, in the UK – wherethe frequency of clinic visits is typically 8–12 per year – this figure would equateto an annual cost to the caregiver of upto €120 (US$171). As mentionedpreviously, access to INR monitoringfacilities is unequal in some countries of Latin America and this needs to beaddressed before the relevance ofassessing the cost-effectiveness ofattending anticoagulation clinics can be discussed for the whole of the LatinAmerican region.

Thus, it is important that strokeprevention in clinical practice isimproved so that it is as cost-effectiveas in clinical trials. Ways in which thiscan be achieved include optimizing themanagement of patients receivingVKAs and developing novel therapies

control, adverse events, the need forother treatments that may interact withVKAs, or the patient was unable orunwilling to adhere to dose or INRmonitoring instructions.

Cost of vitamin K antagonisttherapy in stroke prevention inatrial fibrillation Data comparing the cost of AF-relatedstroke prevention using VKA therapywith the cost of treating stroke are notavailable for Latin American countries.However, data from Europe suggestthat the cost of stroke preventionappears to be favorable compared withthe average direct per capita cost fortreatment after stroke. In a UK study,the cost of preventing one AF-relatedstroke per year using VKA therapy wasestimated to be £5260 (US$8642), withregular INR monitoring and hospitaladmissions for bleeding complicationsbeing the major cost drivers.168 The costof prevention thus appears to befavorable compared with an averagedirect per capita cost of €11799 fortreating stroke in the European Union(US$19386).141 Although VKA therapyimposes an added economic burden onhealthcare resources, the cost remainsconsiderably lower than the cost ofmanaging the consequences of bloodclots, such as stroke. In another studyof patients with AF in the UK, the costof treatment of a stroke over a 10-yearperiod was estimated to be almostfourfold greater than the estimated 10-year direct costs of anticoagulation,169

indicating that prevention is substantiallymore cost-effective than treatment.

Numerous other studies have providedfurther evidence that anticoagulation withVKAs is cost-effective in patients with AF at a moderate or high risk of stroke,compared with no therapy or aspirin.111,170

Management of complications aftersuboptimal anticoagulation is the majordriver of cost.170

Little is known regarding the cost-effectiveness of VKA therapy versus no

Studies assessingthe cost-

effectiveness ofVKA therapy areneeded for Latin

American countries

Clinical trials haveshown VKAs to be

cost-effectivecompared withaspirin in theprevention ofstroke in AF

High bloodpressure and

diabetes in patientswith AF further

increase the risk ofstroke and requiremultidisciplinary

patientmanagement


46

abnormal heart rhythm itself, as well aswith anticlotting therapy to reduce therisk of blood clots and, hence, stroke.VKAs have been shown to reduce therisk of stroke in patients with AF inboth clinical trials and clinical practice.Importantly, VKAs have proven efficacyin reducing the risk of severe, fatal, ordisabling strokes. In addition, theseagents have been demonstrated to becost-effective in patients with AF and a moderate to high risk of stroke.However, studies are required tocalculate the cost-effectiveness of VKAsin Latin American populations. VKAsare, however, associated with major,well-recognized drawbacks.Nevertheless, they remain frontlinetherapy in this indication. Thus, in theimmediate term, improved detection of asymptomatic AF, and increased useand optimization of VKA therapy areimportant to reduce the incidence ofsevere stroke in patients with AF.

In the medium to long term, alternativetherapies that combine conveniencewith a favorable benefit-to-risk profilecould help to further improve theprevention of stroke in patients with AF.

The development of effective, fixed-dose therapies with a good safetyprofile is likely to lead to considerableimprovements in the management ofpatients with AF. Various clinical studiesare ongoing, and early indications arethat new anticoagulants show promiseof providing better stroke prevention inthe foreseeable future.

New and emerging anticlotting agentsand recently published clinical trialresults are discussed in more detail inthe chapter ‘New developments forstroke prevention in patients with atrialfibrillation’ (page 62).

or other strategies that are easier tomanage and offer favorable efficacyand safety profiles.

Management of other conditions that increase stroke risk: a multidisciplinary approach

AF commonly coexists with otherconditions, such as high blood pressureand diabetes, which themselves canpredispose to blood clots and stroke.The risk in patients with several ofthese conditions is accumulative – thatis, the more conditions that predisposeto stroke, the greater the risk. Even inpatients who are receiving antiarrhythmicand anticlotting therapy, theseconditions may need proactivemanagement to reduce stroke risk.

Blood pressure control is particularlyimportant in the management of AF, anduncontrolled blood pressure increasesthe risk of stroke 2–3-fold.12,172 AF inpatients with diabetes is also associatedwith a very high risk of stroke. One studyin patients with diabetes found thatthose who also had AF had a more than60% greater risk of death from allcauses than patients without AF; theyalso had an increased risk of death fromstroke and heart failure.173

It is therefore clear that conditions thatincrease the risk of stroke and thatcoexist with AF must be carefullymanaged. This approach is known asmultidisciplinary patient management.

The outlook for stroke prevention in patients with atrial fibrillation

To summarize, patients with AF shouldbe managed using a multidisciplinaryapproach and treated with drugs orother strategies that control the

Alternativetherapies or

strategies areneeded for theprevention of

stroke in patientswith AF

47

Guidelines for stroke prevention in AF

Key points

� Patients at a high risk of stroke should receive anticlotting therapy,such as a VKA

� Aspirin is only recommended in guidelines for patients at a low ormoderate risk of stroke

� Although several sets of guidelines exist for preventing stroke inpatients with AF, the recommendations are not universally applied

� Studies in Latin America have shown that the percentage of patientswith AF receiving adequate guideline-adherent therapy to preventclots varies greatly

� The drawbacks of current therapies, and a lack of physician andpatient education regarding the benefits of therapy, may contributeto this problem

Guidelines for stroke prevention inpatients with atrial fibrillation

difficult to extrapolate because the riskcategories used are different in each setof guidelines. However, the majority ofthe guidelines recommend that patientsat low risk of stroke should receiveaspirin therapy and those at high riskshould receive therapy with oralanticoagulants. Most of the guidelinesalso agree that patients with AF and atmoderate risk of stroke should receiveaspirin or oral anticoagulant therapy.However, the ESC 2010 guidelines favorthe use of oral anticoagulation ratherthan aspirin in this patient group.62

Guidelines: theory versus practice

Despite the existence of internationaland country-specific guidelines for theprevention of stroke in patients with AF,their application varies greatly, and VKAtherapy is often underused.174 In somecases, patients eligible for VKA therapymay receive aspirin therapy instead, orthe dose of VKA may be outside therecommended range (Figure 13).58

In a study of 53 patients with AF at a private clinic in Brazil, among thepatients with an indication foranticoagulant therapy according to

Summary of guidelines

Latin American guidelines for theprevention of stroke in patients with AF for the region as a whole are notavailable. However, in Latin Americancountries such as Argentina, Brazil,Venezuela, and Uruguay, internationallyendorsed guidelines such as the 2006ACC/AHA/ESC consensus guidelines,31

the 2010 ESC guidelines and the newlyupdated 2011 ACCF/AHA/HRSguidelines63 are followed. All theseguidelines (Table 6) are based on expertconsensus by an international faculty, andhave been endorsed by major societies inboth Europe and North America.

Country-specific guidelines for themanagement of AF do exist for someLatin American countries such asArgentina, Brazil, and Mexico. Theseinclude the Argentinian AF guidelines,the Brazilian guidelines on AF, and theMexican diagnosis and treatment of AFguidelines.20,64,65 Summaries of all theseguidelines are shown in Appendix 1.

Agreement on specific recommendationsbetween the different guidelines onstroke prevention in patients with AF is

Guidelinesendorsed by majorsocieties exist forthe prevention ofstroke in patientswith AF, and theseare used by Latin

American countries

Guideline consensusrecommends VKAs

for patients atmoderate or high

risk of stroke

48


Guideline(Reference)

ACC/AHA/ESC200631

No risk factor orcontraindication to VKAs

One moderate risk factor

Any high risk factor or >1 moderate risk factor

Aspirin, 81–325 mg/day

Aspirin, 81–325 mg/day orwarfarin (INR 2.0–3.0, target 2.5)

Warfarin (INR 2.0–3.0, target 2.5)

Less validated/weaker risk factors:• Female gender• Age 65–74 years• Coronary artery disease

Moderate risk factors:• Age ≥75 years• Hypertension• Heart failure• Diabetes• LV dysfunction

High risk factors:• Previous stroke, TIA, or thromboembolism• Mitral stenosis• Prosthetic heart valve

ACC/AHA/HRS201163

No risk factor orcontraindication to VKAs

One moderate risk factor

Any high risk factor or >1 moderate risk factor

Aspirin, 81–325 mg/day

Aspirin, 81–325 mg/day orwarfarin (INR 2.0–3.0, target 2.5)

Warfarin (INR 2.0–3.0, target 2.5)

Less validated/weaker risk factors:• Female gender• Age 65–74 years• Coronary artery disease

Moderate risk factors:• Age ≥75 years• Hypertension• Heart failure• Diabetes• LV dysfunction

High risk factors:• Previous stroke, TIA, or thromboembolism• Mitral stenosis• Prosthetic heart valve

ESC 201062 One ‘major’ risk factor or≥2 ‘clinically relevant non-major’ risk factorsCHA2DS2-VASc score ≥2

One ‘clinically relevant non-major’ risk factorCHA2DS2-VASc score = 1

No risk factorsCHA2DS2-VASc score = 0

Oral anticoagulation, e.g. VKA(INR 2.0–3.0, target 2.5)

Either oral anticoagulation or aspirin 75–325 mg/dayPreferred: oral anticoagulation rather than aspirin

Either aspirin 75–325 mg/day or no antithrombotic therapyPreferred: no antithrombotic therapy rather than aspirin

Risk factors for stroke and thromboembolism‘Major’ risk factors: • Previous stroke, TIA or systemic embolism• Age ≥75 years ‘Clinically relevant non-major’ risk factors: • Heart failure or moderate to severe LV systolic dysfunction (e.g. LV ejection fraction ≤40%), hypertension, diabetes mellitus, female sex, age 65–74 years, vascular diseaseRisk factor-based approach expressed as a point-based scoring system (CHA2DS2-VASc)• 2 points assigned for a history of stroke or TIA, or age ≥75 years• 1 point assigned for age 65–74 years, a history of hypertension, diabetes, recent cardiac failure, congestive heart failure, LV dysfunction, vascular disease (myocardial infarction, complex aortic plaque, and peripheral artery disease) and female sex

INR, international normalized ratio; LV, left ventricular; TIA, transient ischaemic attack; VKA, vitamin K antagonist.

Risk category Recommendation Definition ofrisk factors

Table 6. Summary of the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) 2006 and the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society (ACCF/AHA/HRS) 2011 guidelines for the prevention of stroke in patients with atrial fibrillation, and the European Society of Cardiology (ESC) 2010 guidelines for the management of atrial fibrillation.


49

Brazilian guidelines, only 61.7% wereusing oral anticoagulants. Furthermore,only 65.9% of patients indicated fororal anticoagulation according toAmerican/European guidelines werereceiving oral anticoagulants.56

In an assessment of 301 patients withAF in a Brazilian University HeartHospital, only 46.5% of patients whowere eligible for anticoagulation werereceiving VKA therapy.59 In anotherstudy of 136 patients with AF at aBrazilian tertiary outpatient clinic, only55% of patients at moderate to highrisk for thromboembolism receiveddose-adjusted VKA therapy. Of the 37 patients who did not receivewarfarin, only 7 patients had acontraindication to the drug.175 Finally,in a Brazilian University Hospital studyof 279 patients with AF and other riskfactors for thromboembolism (49.1%of patients had ≥3 risk factors), only24% received a prescription for oralanticoagulation therapy. In addition,almost half of those patients who didreceive a prescription did not regularlyuse the oral anticoagulation therapy.57

All of these studies highlight thediscrepancy between the guidelinerecommendations and what ishappening in clinical practice.

The magnitude of this problem wasrecently confirmed in a large prospectivestroke registry study in Mexico involving2837 Latin American patients withischemic stroke and 357 with TIA.58

Among these patients, 385 had aknown history of AF with a prevalenceof 12.5% in patients with ischemicstroke and 8.1% in patients with TIA. In patients with a history of AF and a recurrent TIA/ischemic stroke (n=145),only 13.1% were taking VKAs with a therapeutic INR at the time of strokeonset, 22.8% were on VKAs with asubtherapeutic INR (<2), 32.4% weretaking antiplatelets, and 31.7% did notreceive any anticlotting agents. Theanticlotting agents received by patientswith known AF and a first-ever ischemic

stroke or TIA (n=240), before theiradmission to hospital, are shown inFigure 13. In this Hispanic population,most of the patients with AF who wereadmitted with a stroke, and who werecandidates for anticoagulation, were notreceiving anticlotting therapy or werereceiving a subtherapeutic level of oralanticoagulants, or were not taking theiroral anticoagulants.58

It is worth noting that not all studies onthe use of VKAs in patients with AFindicate that they are underused.176–179

Indeed, the degree of adherence toguidelines reported in different studiesvaries; a review of the literature from2000 indicated that, generally, only 15–44% of eligible patients with AFwere receiving warfarin.23

Underuse of anticoagulant therapy inpatients with AF who are at high risk ofstroke is associated with significantlygreater risk of thromboembolism and the combined endpoint of cardiovasculardeath, thromboembolism, or major

Oral anticoagulant (VKA) therapeutic doseDual antiplatelet therapy

Oral anticoagulant (VKA) subtherapeutic dose

Single antiplatelet agent

No antithrombotics

4%

3%

22%

51%

20%

Figure 13. Anticlotting therapies receivedbefore admission to hospital by patients inMexico with known AF who experienced afirst-ever ischemic stroke or transientischemic attack. Only 4% of patients receivedoral anticoagulation (vitamin K antagonists[VKAs]) at the therapeutic dose.58 Figuresupplied by Dr. Cantù-Brito.

There is discrepancybetween guidelinerecommendations

and clinical practice

Adherence toguidelines variesgreatly, and VKAtherapy is often

underused

bleeding.60 This was confirmed in a studyin Argentina that showed that the risk ofdeath significantly increased in patientswith AF who were not receivinganticoagulation therapy. In this study of615 patients with chronic AF, only51.4% of patients were receivinganticoagulants on entry to the study.156

The analysis of the anticoagulated andnot anticoagulated patient populationsshowed a mortality of 17.6% and29.4%, respectively.

Reasons for poor adherence to guidelines

Adherence to guidelines for theprevention of stroke in patients with AFmay be low for several reasons. Theseinclude difficulties in maintaining INRwithin the therapeutic range,26 andphysicians’ concerns about bleedingrisk, particularly in the elderly.53

Difficulties in maintaining dose ofvitamin K antagonist within thetherapeutic rangeA prospective Peruvian study was carriedout in patients with heart disease (AF 38.4%, mechanical valve prostheses58.8%) who were taking warfarin. On arandom day, only 48.2% of patientsmaintained optimal oral anticoagulantINR protection.180 The numbers ofpatients who had under-anticoagulationand over-anticoagulation INR levels were37.9% and 13.9%, respectively.

The problems associated with theutilization of VKAs are universal. Manypatients, both the young and the elderly,find the frequent monitoring andnecessary dose adjustments associatedwith VKAs inconvenient and timeconsuming, and may miss appointments.Elderly patients particularly may beunwell, become confused or forgetful, or have difficulty with transport, thuscausing them to miss appointments. Thiscan be especially true for patients livingin the more remote areas of LatinAmerica. Moreover, in some countriesthere are several formulations of

warfarin and irregular drug qualitycontrol, which results in patients beingswitched from one formulation toanother. Other challenges associatedwith VKA therapy include drug–druginteractions, imposed lifestylerestrictions, the need to discontinuetherapy for various procedures, variabledose responses, the lack of suitablelaboratories to enable adequateanticoagulation monitoring in ruralareas, and the fear of increased bleedingfor patients during daily activities,accidents, and sporting activities.

In a Brazilian study assessing oralanticoagulation use in clinical practice,patients were asked about theirperception of oral anticoagulant use(phenprocoumon 58% of patients,warfarin 42% of patients). Overall,95% of patients questioned wereconcerned about the daily use ofmedication. Furthermore, patientsfound the need for periodic blood tests(21.4%) and the daily limitations causedby the use of oral anticoagulation(12.8%) as disadvantageous totreatment.160 A recent comprehensivereview of the literature has shown thatpatients with AF receiving warfarin whowere monitored infrequently (defined as representative of routine clinicalpractice) were within the target INR fora smaller proportion of the time thanpatients who were monitored frequently,according to strict protocols.181 Thegreater the length of time that apatient’s INR is within the target range,the lower their risk of a blood clot or ofuncontrolled bleeding.

Physicians’ concerns about bleeding risk Some physicians may overestimate therisk of bleeding associated with the useof VKAs and underestimate their benefitsin preventing thromboembolism andstroke; conversely, they mayunderestimate the bleeding risk ofaspirin therapy and overestimate itsbenefits.53,54,182 As a result, some eligiblepatients are not receiving optimum


50

The need forfrequent

monitoring anddose adjustment ofVKAs contributes to poor adherence

to guidelines

51


and who were also treating otherpatients with AF. Patients treated in the 90 days after the physician hadencountered a bleeding event weresignificantly less likely to receive aprescription for VKA therapy thanpatients treated before the event.189

In contrast, patients who experiencedan ischemic stroke while not receivingVKA therapy did not influence aphysician’s prescribing behavior towardssubsequent patients.189 In other words,a bleeding event may make a physicianless likely to prescribe VKAs, but astroke does not increase the likelihoodthat a physician will prescribe VKAs.

It has been postulated that the reasonsfor this phenomenon are twofold. First,Tversky and Kahneman’s ‘availabilityheuristic’ suggests that assessments ofthe probability of an event are influencedby the ease with which instances of theevent can be recalled.190 Major bleedingevents related to anticoagulation are dramatic and therefore easilyremembered and may lead to reductionsin VKA prescribing. Secondly, Feinstein’s‘chagrin factor’ postulates that, whenchoosing between alternatives, physiciansavoid those actions that cause them the most regret.191 In the case ofanticoagulation, physicians may regretacts of commission (i.e. bleeding eventsassociated with the administration ofanticoagulation) more than they regretacts of omission (i.e. stroke eventsassociated with withholdinganticoagulation). This may be in keepingwith one of the principles of theHippocratic oath, to ‘do no harm’.189

Discrepancies between patients’and physicians’ perceptions ofstroke and bleeding riskDevereaux et al. carried out a study ofperceptions of risk among patients withAF at high risk of developing strokeversus those among physicians. Forboth groups, the aim was to identifyhow big the reduction in risk of strokeshould be to justify anticlotting therapy(i.e. VKA or aspirin therapy to reduce

therapy that could prevent strokes.24

For many physicians, bleeding risk is aparticular concern in the elderly, whomay become confused and may takemore than the recommended dose ofwarfarin per day. A Chilean study thataimed to determine the effect of apatient’s age on the quality of oralanticoagulation reported that olderpatients (>80 years) were more likely to have occasional INRs >5 than theiryounger counterparts (patients <60 years).183 Furthermore, as elderlypatients are particularly prone to falls,there is a fear among physicians thatelderly patients who fall may suffer asevere hemorrhage if they are takingVKA therapy.184–186 However, evidencehas shown that, in patients with AF whoare receiving anticoagulant agents, therisk of a cerebral bleed from falling is sosmall that the benefits of treatmentoutweigh the risk.187 Furthermore, theincidence of stroke among patients aged75years or more with AF is lower inthose who are receiving VKA therapythan in those taking aspirin, withoutincreasing the risk of hemorrhage.162

Bleeding risk during VKA therapy inpatients with AF is not homogeneousand a number of clinical factors,including hypertension, older age, andhistory of bleeding have been identifiedthat are associated with incrementalbleeding risk.188 A number of bleedingrisk stratification schemes exist, includinga new simple major bleeding risk scoreknown as HAS-BLED,121 which is usedto predict bleeding risk in the ESCguidelines.62 The HAS-BLED score isdescribed in more detail in the sectionon detecting AF and stratifying strokerisk (page 31).

Major bleeding events associated withVKA therapy can profoundly influencephysicians’ prescribing behavior, evenwhen they have evidence that the riskof major bleeding is low. Choudhry et al.studied 530 physicians who weretreating patients with AF who hadbleeding events while receiving VKAs,

Physicians mayoverestimatebleeding risk

from VKAs andunderestimate

their benefits instroke prevention


52

These results indicate that patientsplace more value than physicians do onthe avoidance of stroke, and less valueon the avoidance of bleeding.192 It isimportant that the views of theindividual patient are taken intoaccount when assessing whether to use anticoagulant therapy, even if thephysician is risk averse.

To summarize, adherence to guidelinesfor the prevention of stroke in patientswith AF is often suboptimal, largelybecause of the drawbacks associatedwith VKA therapy and a lack of physicianand patient education regarding thebenefit-to-risk ratio of therapy. There is a clear need for improvements in theimplementation of, and adherence to,guidelines for AF to improve patientoutcomes in stroke for what is a growingburden in Latin America.

the risk of blood clots) and how muchrisk of excess bleeding from therapywas acceptable.192 In order for VKAtherapy to be justified, physiciansconsidered that it needed to prevent asignificantly higher number of strokesthan patients felt acceptable (Table 7).The number of strokes that needed tobe prevented to justify aspirin therapydid not differ significantly betweenpatients and physicians.

When perceptions of bleeding risk wereevaluated, the maximum number ofbleeding events associated with warfarinor aspirin that patients found acceptablewas significantly higher than thatconsidered acceptable by physicians(Table 7). Moreover, the results suggestthat physicians perceive the risk ofbleeding to be higher with VKAs thanwith aspirin. This perception is at variancewith the findings by Mant et al. that,compared with aspirin, warfarindecreases stroke risk without increasingthe risk of bleeding.162

Patients place more value thanphysicians do onstroke avoidance

and less value on avoidance of bleeding

Scenario

NS, not significant; SD, standard deviation.

Table 7. Hypothetical thresholds among patients with atrial fibrillation at high risk of developing stroke versus those among physicians for how much reduction in risk of stroke is necessary and how much risk of excess bleeding is acceptable over 2 years of anticlotting treatment. Patients place more value than physicians do on stroke avoidance, and less value on avoidance of bleeding.192

Patients’ threshold(mean ± SD)

Physicians’ threshold(mean ± SD)

Statisticalsignificance ofdifference in

thresholds

Minimum number of strokes that need to be prevented in 100 patients

WarfarinAspirin

1.8 ± 1.91.3 ± 1.3

2.5 ± 1.61.6 ± 1.5

p=0.009NS

Maximum number of excess bleeds acceptable to patients

WarfarinAspirin

17.4 ± 7.114.7 ± 8.5

10.3 ± 6.16.7 ± 6.2

p<0.001p<0.001

53

Current challenges for stroke prevention in AF

Key points

A national government-wide commitment within Latin America isneeded to reduce AF-related stroke. This could be achieved by:

� Coordinating strategies for early and adequate diagnosis of AF, andpromoting the development of relevant research programs

� Raising awareness and understanding of AF and AF-related strokeamong patients and caregivers

� ‘Empowering’ patients and caregivers to take more active roles indetermining and evaluating their care

� Encouraging the uptake and use of new therapies and procedures

� Improving knowledge and awareness among physicians involved inAF management

� Optimizing the continuum of care for all patients with AF

� Providing equity of access to AF therapy, and information for allpatients across the Latin American region

� Improving the implementation of, and promoting adherence to,guidelines for the management of AF and a collaborative approachto guideline development

Current challenges for stroke preventionin patients with atrial fibrillation

irregular pulse and abnormal heartrhythm should be investigated. One suchinitiative that hopes to achieve this, the‘Know Your Pulse’ campaign, will soonbe launched by the Arrhythmia Allianceand associated organizations inArgentina, Bolivia, Brazil, Chile, Mexico,and Uruguay.193,194

There may be scope for introducing morewidespread AF screening programs, afterthe positive results of the SAFE study.106

Some of the recommendations forfurther research put forward by the SAFEstudy investigators focus specifically onaspects of screening, such as the role ofcomputerized software in assisting withthe diagnosis, and how best to improvethe performance of healthcareprofessionals in interpreting the results of ECGs.106 These recommendationsneed to be followed up and acted upon.

It is clear that significant improvementsare required in the detection andtreatment of AF, in the implementationof, and adherence to, guidelines on theuse of existing anticlotting therapies,and in the development of better andmore effective strategies to reducestroke risk. The current challenges in theprevention of stroke in patients with AFare discussed in more detail below.

Improved detection and diagnosis of atrial fibrillation

Awareness of the early signs of AF andcommon coexisting conditions is requiredto maximize the opportunity for strokeprevention in patients at risk. Clearstrategies are needed that will lead toimproved detection and diagnosis of AFby physicians. Part of this involvesfostering an increased awareness amongthe general public that signs such as an

More widespreadscreening and

awareness-raisingwould improvedetection and

diagnosis of AF

Increased awareness among patients

Wider access to informationMany patients with AF do not havesufficient access to information abouttheir condition and its treatment. Aninternational quantitative survey wascarried out in 11 countries, includingMexico and Brazil, to analyzeunderstanding, perception, andattitudes towards AF among physicians(cardiologists/electrophysiologists) andpatients with AF.195 Overall, 46% ofphysicians thought that their patient’sability to explain their condition waspoor, and one in four patients surveyedfelt unable to explain their condition toanother person. Physicians thought thatover 50% of their patients with AF hadan important need for more andimproved information about theircondition. In terms of the quality andlevel of AF information provided topatients, only 35% of physicians foundit easy to understand, and only 20% of physicians thought that there wasenough of it. From a patient perspective,almost a quarter (23%) did not knowwhere to seek, and who to contact, toget additional information on AF.Results from another recent survey ofAF involving over 3700 patients with AF and physicians in 12 countriesworldwide, also including Mexico andBrazil, found that people with AF werelikely to turn to family and friends(29%), pharmacists (26%), andwebsites (18%) for information abouttheir condition.196 Over time, fewerpatients with AF were worried as theybecame more informed. Similarly, in astudy of 119 patients with AF in theUK, 37% were unaware of theirspecific heart condition and 48% didnot know the reasons for commencingVKA therapy.197 Approximately two-thirds of patients were unaware thatVKAs had a role in preventing bloodclots and stroke, and over 60% feltthat their underlying illness (i.e. AF) was not severe.

A number of organizations are workingto improve access to information on AFin Latin America. The ArrhythmiaAlliance, a charity set up in the UK topromote greater understanding,diagnosis, treatment, and quality of lifefor people with cardiac arrhythmias, isnow established in Argentina, and willsoon extend to Bolivia, Brazil, Chile,Ecuador, Mexico, and Uruguay.194 Themain tasks of the charity are to createawareness about arrhythmias andsudden death, and to promote thecreation of a legal framework for abetter ‘chain of survival’. A number ofactivities have been undertaken inArgentina including ‘World HeartRhythm Week’, the ‘Know Your Pulse’campaign, and the ‘Campaign for thePrevention of Sudden Death’. ‘WorldHeart Rhythm Week’ is an annualinternational event that aims to raiseawareness of heart rhythm disordersand sudden cardiac death.198 It isorganized by the Arrhythmia Allianceand held in partnership with theInternational Cardiac Pacing andElectrophysiology Society (ICPES).

The ‘Know Your Pulse’ campaign raisesawareness of routine pulse-taking asbeing one of the easiest ways to pickup an irregular pulse and so preventpotentially fatal cardiac arrhythmias.193

The ‘Campaign for the Prevention ofSudden Death’ seeks to address theneed to optimize training incardiopulmonary resuscitation, theavailability of external defibrillators andthe scarce motivation amongwitnesses.199

The Arrhythmia Alliance in Argentinaalso aims to interact with individuals andgroups involved in this area, provideeducation materials, and promotevolunteering to help disseminateknowledge effectively.200 In addition tothe Arrhythmia Alliance in Argentina,Bolivia, Brazil, Chile, Ecuador, Mexico,and Uruguay, a partnership of theArrhythmia Alliance and Atrial FibrillationAssociation will soon be launched in a

54


Many patients donot understand the

role of VKAs inpreventing bloodclots and stroke

55


Fibrillation Guide’ aimed at educatingconsumers, patients, and caregiversabout the condition.206 To servepatients and caregivers in Latin Americaand around the globe, the site isavailable in a number of languages,including Spanish and Portuguese, andfeatures an International AF ServicesLocator to help patients find help withtheir AF. Advice from the StopAfib.orgGlobal Medical Advisory Board ensuresthat patient and caregiver content isculturally appropriate.

Better adherence to therapyAccording to AntiCoagulation Europe,adherence to therapy is reliant on thepatients understanding of theircondition. AntiCoagulation Europe is aregistered charity committed to theprevention of thrombosis and theprovision of information and support forpeople already receiving anticoagulantand antiplatelet therapy.207 Althoughsome patients fully appreciate the needto stay within the therapeutic range –but fail to do so for reasons outside theircontrol (e.g. genetic or metabolicfactors) – not all patients have thisunderstanding. Without the properinformation or guidance, adherence canbe poor, leaving patients at risk ofbleeding or stroke. The need forimproved understanding isdemonstrated by the ‘It’s About Time’survey. This found that, although justbelow three-quarters of patients knewtheir target INR reading, over one-thirdof patients believed that being outsidetheir target range had no major effecton their health. Only 30% of patientshad been in their target INR range intheir last 5–10 monitoring sessions, and7% had not been in their target INRrange in any of their last 5–10 sessions.208

Although there are no similar surveys forLatin American countries, patients dounderstand the relevance of their INR ingeneral (Dr. Meschengieser, Dr. Reyes, Dr Avezum, personal communications2011). Patients who do not understandare not good candidates for warfarintherapy and, consequently, may not

number of other Latin Americancountries. The Atrial FibrillationAssociation is a UK registered charitywhich focuses on raising awareness ofAF by providing information and supportmaterials for patients and medicalprofessionals involved in detecting,diagnosing and managing AF.201

International patient information oncardiac arrhythmias, prepared withguidance from the International MedicalAdvisory Committee of the ArrhythmiaAlliance, has been translated into manydifferent languages, including Spanishand Portuguese.202

StopAfib.org is a worldwide patient-to-patient resource to help patients withAF treat and manage their illness. Themission of the organization is to raiseawareness of AF to ensure it getsdiagnosed and treated, improve qualityof life for those living with AF, supportthe patient-healthcare providerrelationship, and decrease AF-relatedstrokes. Information for patients withAF and their caregivers is accessiblefrom anywhere in the world and thesite provides up-to-date content onwhat AF is, why it is a problem, andhow to manage and treat it. It alsoshares patient stories and providesvaluable resources.203 The patient andcaregiver resources section of the siteprovides general information on AF, aswell as information about patientdiscussion forums, social media,guidelines, medications, and physicianresources.204 StopAfib.org is the mostvisited arrhythmia site worldwide, withsignificant traffic from Latin America,and is also HONcode certified by theHealth on the Net Foundation.

Recent global campaigns to raiseawareness of AF from StopAfib.orghave included the ‘Take A StandAgainst Atrial Fibrillation’ campaign,held in conjunction with AtrialFibrillation Awareness Month inSeptember 2010,205 and thesimultaneous release of an online ‘Get Started Learning About Atrial

Without clearinformation or

guidance, patientadherence can be

poor, leavingpatients at risk ofbleeding or stroke

Patient‘empowerment’ is

associated withimproved clinical

outcomes


56

stroke. Furthermore, the disadvantages –and resulting poor use – of currentanticoagulant therapy have led to thesearch for new therapies and otherstrategies that can be used in theprevention of stroke in patients with AF.For example, new anticoagulant drugsthat are easier to use and moreconvenient than VKAs are becomingavailable. These drugs have morepredictable effects and a better safetyprofile, and thereby have the potential toincrease adherence to therapy andimprove outcomes for patients. A largemultinational survey in collaboration withthe patient organization AntiCoagulationEurope found that 68% of patients withchronic AF would be interested in newanticoagulation drugs for which routinemonitoring was not needed.211

Unfortunately, similar data for LatinAmerican populations do not exist.

Improved knowledge and awareness among healthcare professionals

Benefits of current treatments toprevent strokePoor adherence to guidelines may resultfrom underestimation of the efficacyand/or overestimation of the risks ofanticoagulation therapy. This highlightsthe urgent need for improvedawareness among physicians of theefficacy of VKAs in preventing stroke inpatients with AF. Physicians also need tobe reassured that the risk of bleeding isusually small compared with the greatbenefits that therapy can bring.

Healthcare professionals should beconvinced of the importance ofcommunicating the benefits and risks ofpotential therapy to patients. Patientshave a significant amount of informationto absorb in one consultation with thephysician. Therefore, written informationneeds to be provided, critical facts andadvice repeated and the patient’s fullunderstanding confirmed during futureconsultations. In addition,communication between different

receive such medication. The provisionof education and guidance has beenshown to help patients achievetherapeutic targets of anticoagulation,as demonstrated in a study of 188 patients attending an anticoagulationclinic in Chile. After the implementationof guidance and a patient educationprogram, the number of patients withan INR >5.0 and <1.5 in all age groupsstudied decreased significantly.183

Greater patient ‘empowerment’Educating patients and encouragingthem to take a more active role indecision-making, setting goals, andevaluating outcomes is often describedas patient ‘empowerment’, and isassociated with improved clinicaloutcomes.209 Indeed, patient educationand involvement in the management ofVKA therapy has been shown to reducethe risk of major bleeding.210 Thus,patient information should help toempower patients by being consistentand available in formats appropriate forall affected, including people withdifferent native languages and differentlevels of literacy. However,inconsistencies in the level ofeducation, socioeconomic factors, andlocal/national provision of services inLatin American countries, as well asother factors such as age and cognitiveproblems, may lead to inequalities inthe uptake of patient informationoutputs. In Argentina, there are nodifferences in the uptake of patientinformation between males andfemales; however, for older patients,access to the Internet may be limited ornon-existent, although printed materialis still available to them. Moreover,patients from poorer backgrounds areless informed about their illness andhealthcare options.

Provision of new therapeutic options

New strategies for AF treatment mayalso be helpful in reducing theprevalence of AF and, hence, AF-related

New anticoagulantdrugs are becoming

available thatshould increaseadherence totherapy and

improve clinicaloutcomes


57

Healthcareprofessionals needto communicate, so as to provide

consistentinformation and

advice for patients

Increased trainingand advice on

managinganticoagulants

would increase thewillingness ofphysicians to

prescribe VKAs

professionals and patients.157,215

Anticoagulation clinics are widespread inAmerica and Western Europe. Althoughanticoagulation clinics are available insome Latin American countries, accessto them is variable. Anticoagulationclinics in Mexico are mainly found in thelarge academic hospitals in the big cities.In Argentina, there are manyanticoagulation clinics, private andpublic. Similarly to Mexico, these clinicsalso tend to be found in the large cities.Anticoagulation clinics are uncommon inBrazil; however, access to these clinics isavailable through some academicinstitutions. Patients in these clinicsoften have the best INR monitoringavailable to them, and time withintherapeutic range values can reacharound 80%. In Uruguay, the majorityof public and private hospitals haveanticoagulation clinics. Whereanticoagulation clinics are unavailable,alternatives have been made in order toprovide anticoagulation monitoringservices. For example, patients in Brazilwho do not have access toanticoagulation clinics have their INRcontrol monitored by their doctor.Where anticoagulation clinics are notavailable in Mexico, INR monitoring isoften carried out by a qualifiedphysician, usually a cardiologist.However, in rural areas in Mexico,anticoagulation therapy tends to beavoided because monitoring is notavailable. In smaller towns in Argentina,patients who were previously connectedto a clinic can have their INR monitoringperformed near to their home, withtheir results and details of their newdose available by phone or fax. Overall,the lack of availability of anticoagulationmonitoring facilities for some patients inLatin America means that INRmonitoring may be suboptimal, whichcan lead to reduced levels ofanticoagulation control.

If patients are referred to ananticoagulation clinic, communicationbetween all the healthcare professionalsinvolved is crucial: delegation of one

healthcare professionals interacting withthe patient needs to be improved toensure that consistent information andadvice is provided. If the patient isoverwhelmed by too much informationand/or contradictory opinions, they areunlikely to agree to, and subsequentlyadhere to, therapy.

Management of patients receivingvitamin K antagonistsThere is a clear need for a properinfrastructure for the delivery andmonitoring of VKAs across all thecountries of the Latin American regionas well as for better education andsupport for physicians who managepatients receiving VKAs. Such patientsmay be managed by the physician whoprescribed the therapy, a primary careprovider or a dedicated anticoagulationservice.212 In surveys, physicians havereported that increased training andavailability of consultant advice orguidelines specifically on managinganticoagulation therapy would increasetheir willingness to prescribe VKAs.213

There is general agreement amongboth primary care physicians andspecialists that anticoagulation therapyis best managed in primary rather thansecondary care to ensure optimalaccess and continuity of care.213 Thismay prove difficult in some LatinAmerican countries because of theinconsistency in access to healthcareservices, which is particularly noticeablein rural and impoverished areas whereadequate infrastructure, drugs supply,and staff are lacking.214

Anticoagulation clinics – a potentialeducational resourceAnticoagulation clinics may be in ahospital or attached to a primary carepractice. At times, they have beenconsidered the gold standard of VKAmanagement,212 helping to increase thetime that a patient’s INR values arewithin the target range, improve theoverall cost-effectiveness of therapy,increase patient adherence and providevaluable information for both healthcare


58

Healthcareproviders may

need education and support in

ensuring a seamlesstransition between

the differentstrands in the

patient pathway

study in Germany has also shown self-management to be cost-effective.219

However, this approach may not beappropriate for all patients as shown in the Cochrane analysis in which self-testing could not be used for up to half of the patients requiring oralanticoagulation therapy.218 Therefore,support from adequately trainedphysicians will be needed for self-management to be successful.220

Computer programs that analyzeseveral variables and recommend thelevel of adjustment of the VKA dose, if required, have been developed toassist in management. Such computerprograms have been shown to performas well as staff in anticoagulationclinics, and may therefore be a usefultool for optimizing care.221,222 Here too,healthcare professionals will needspecific training to enable them toadjust to these changes in practice,while still retaining an essentialsupervisory role.

Moves towards patient-centered careManagement of patients with AF is alsolikely to be greatly improved by a moveto more patient-centered care. Variousdefinitions of patient-centered careexist, but common elements includeconsideration of patients’ needs,preferences, and concerns relating tooverall health, rather than just to thespecific condition in focus.223 Althougha patient-centered approach is widelyadvocated, it is not alwaysimplemented.223 Instead, health care istypically centered on treating thedisorder, rather than consideringpatients’ individual needs.223,224 There isevidence that anticlotting therapytailored to patients’ preferences is morecost-effective in terms of QALYs thangiving the same therapy to everypatient.225 There is therefore a need to provide physicians with furthereducation on the benefits of patient-centered care, with support inimplementing this approach locally.

part of the integrated care of a patientto an external clinic can weaken therelationship between the primary carephysician and patient, and may lead todisruption of care if communicationbreaks down.212 Therefore, healthcareproviders may need education andsupport in ensuring a seamless transitionbetween the different strands in thepatient pathway. As management ofpatients receiving anticoagulantsevolves, anticoagulation clinics willchange and adapt.212 The staff that runclinics may have an increasing role aseducators and coordinators ofanticoagulation therapy, providingsupport for other healthcare providers.

Awareness of treatment innovationsNovel anticoagulants currently inadvanced stages of development maysimplify the management of patientswith AF. As with any chronicintervention, however, high-qualityguidance and education for doctors,patients and their caregivers will beessential. Healthcare professionals willneed to identify and manage eligiblepatients and know how to deal withemergency situations. Increasedresources for education and rapiddissemination of information will allow faster introduction and uptake of new therapies.

Patient self-management andcomputer programsPatient self-management, or self-testing, has been proposed to reducethe burden of regular INR monitoring.Increased involvement of the patientshould improve adherence, and severalstudies have shown self-monitoring tobe an effective and acceptablealternative to management at ananticoagulation clinic.216,217 A Cochraneanalysis of 18 clinical trials highlightedthe benefits of patient self-monitoringand self-management in improving thequality of their oral anticoagulationtherapy compared with standardmonitoring.218 Although no such dataexist for Latin American populations, a

Patient self-management of INR

monitoring willneed the initial

support ofadequately trained

physicians


59

Educatingphysicians on

the benefits ofpatient-centeredcare will improve

the management ofpatients with AF

that the primary care practice has all itneeds for appropriate follow-up care.Insufficient discharge information cancontribute to hospital readmission.230

Education of caregivers also plays a keyrole in the success of therapy, and theavailability of a healthcare provider toanswer questions and address concernsis likely to improve continuity of care.

The implications of a breakdown incontinuity of care are illustrated in thecase study on the next page.

Equity of access to health care and information

Exchange of information – abenchmark for managementAn example from another area ofmedicine illustrates how best practicecan be exchanged between countries ina given region. For patients withmultiple sclerosis (MS), the EuropeanMultiple Sclerosis Platform (EMSP) hasbeen set up with the mission ofexchanging and disseminatinginformation on all issues relevant topeople affected by the disease.231 Theway in which MS is managed variesacross Europe; hence, the EMSP has setup an ‘MS barometer’ to record theexperiences of patients with MS withregard to health care and quality of life,and to allow comparisons of theseexperiences across Europe. The aim isto identify which aspects of the diseaseare well managed and in whichcountries, as well as in what areashealthcare providers need to improvetheir policies and practices.

In addition to providing patients withinformation, an equivalent organizationfor AF could serve to collate andcompare data from different countriesin Latin America, potentially identifyingsuccesses and benchmarks formanagement and helping to driveimprovements where necessary. It ishoped that the establishment of theArrhythmia Alliance/Atrial FibrillationAssociation in many Latin American

An optimized continuum of care

Continuity of care, involving continuingcommunication between healthcareproviders, is essential for high-qualitycare. As the provision of health careoften involves several different serviceproviders, continuity of care is defined as‘coherent health care with a seamlesstransition over time between variousproviders in different settings’.226

Biem et al. have described sevencharacteristics (the seven Cs) of optimalcontinuity of care:226

1. Regular contact between patientsand healthcare providers

2. Collaboration between healthcareprofessionals and patients ineducating and “empowering” thepatient

3. Communication between healthcareproviders

4. Coordination of the multidisciplinaryteams involved, with clearidentification of different roles

5. Contingency plans in the form ofaccess to healthcare professionalsout of hours to answer questionsand address concerns

6. Convenience – achieved, forexample, by avoiding the need forpatients to keep repeatinginformation and by consideringhome monitoring

7. Consistency of the advice providedby different professionals andimplementation of, and adherenceto, clinical practice guidelines

The close monitoring required inpatients receiving VKA therapy can beproblematic in ensuring continuity ofcare. When patients are transferred toother healthcare providers or to differentsettings, such as during hospitalizationor at discharge, critical information canbe lost. Indeed, transferring patients atnight time and at weekends has beenreported to increase death rate.227,228

Comprehensive, timely, and appropriatedischarge information is essential –possibly in some portable format229 – so

Comprehensive,timely dischargeinformation isessential forappropriateprimary care

follow-up

Case study: the importance of continuity of care

A 75-year-old man with a history of diabetes, high blood pressure, and osteoarthritis presented with a cough at a rural healthcare center. Pneumonia and AF were subsequently diagnosed. He received oxygen, cefuroxime (for pneumonia), and digoxin (for AF) and was transferred to a regional care hospital.

In hospital, the patient was seen by a resident in the emergency room and by a senior medical student. After 1 day, he was transferred to a medical ward. His condition improved but the AF persisted. Warfarin therapy was initiated and a pharmacist provided information on the drug. The patient’s wife, who managed all of his medications, was unable to travel to visit her husband in this hospital. He was later discharged after an INR measurement of 2.0, with a 1-week course of cefuroxime, and instructed to remain on metformin (for diabetes), enalapril (for high blood pressure), digoxin, and warfarin. He was also told to make an appointment with a physician for INR monitoring the next day.

A weekend locum physician received the discharge letter listing the diagnoses and medications but not the INR measurement. The repeat INR was 2.8. The patient was advised to stay on the same dose and see the family doctor on Monday for repeat INR testing.

At home, the patient took ibuprofen for osteoarthritis and some herbal pills. On Sunday evening, his wife became worried about bleeding after the glucose finger-stick test (used to monitor his diabetes). On Monday, when the patient saw the family doctor, his INR was 4.8. The patient was advised to take acetaminophen instead of ibuprofen, to stop taking the herbal pills and warfarin, and to have his INR tested the next day.

The patient found it difficult to travel to have his INR tested, because of arthritis. His wife thought he was on too many medications. At his next clinic appointment, he refused warfarin but agreed to start taking aspirin.

One year after the initial diagnosis of AF, the patient suffered a stroke which left him with weakness down his right side and speech impairment

Case study adapted from Biem et al. 2003226


60

the poor, those who live in rural areas,mothers, children, the elderly, groups atepidemiologic risk, and those fromindigenous populations, which hasbeen the case in countries such asBrazil, Costa Rica, Honduras, andPanama.33 In a Brazilian study thatsought to determine if healthcare forolder community residents (≥60 years)was based on health-related criteriaand not on other patientcharacteristics, investigators reportedthat the use of healthcare services didnot differ by race, ethnicity, or religion,but that private healthcare insurancefacilitated outpatient access and

countries will lead to the sharing ofbest practices, as well as educating andempowering patients and physicians.

Equal access for allIn addition to possible variations inliteracy, education, income, and careacross countries of the Latin Americanregion, people of different backgroundsmay have different access to healthcare, or their perceptions of the healthcare they receive may differ. Access tohealth care is an issue for manycountries in the region – populationgroups most likely to face inequalitieswhen accessing health care including

An AF patients’platform wouldmake it easier to collate data,

identify successes,and drive

improvements


61

Regular reviews,updates and

endorsement of the guidelines willensure that theyare relevant tocurrent clinical

practice

We call for equaland timely access to quality healthcare and betterinformation for

all patients

the whole of Latin America, as toomany different sets of guidelines cancause confusion and reduce adherence.Guidelines also need to be easy tofollow and readily available to allrelevant healthcare professionals.

Summary of current challenges

In summary, numerous challengesremain in the prevention of stroke inpatients with AF in Latin America. Thelevel and quality of information on AFprovided to physicians and patientsneeds to be improved. Increaseddetection of AF by physicians is vital,and improved education is neededamong patients and healthcareprofessionals on the benefit-to-riskprofile of aspirin and VKAs, and on the optimum management of patientsreceiving VKAs. Healthcare professionalsneed to be aware of new anticoagulantsand other therapeutic strategies thatare emerging, as well as advances inthe treatment of AF. It is also importantto encourage patient empowermentand patient-centered care and ensureequity of access to health care for all.Finally, improved implementation of,and adherence to, guidelines,development of new guidelines, andimplementation of strategies to ensureeffective communication betweenhealthcare professionals will improvepatient management, as will optimizingthe continuum of care. All these factorswill contribute to the prevention ofstroke in patients with AF.

increased education facilitatedhospitalization.232 Differences were alsofound as a function of age, sex, andemployment status. Under any healthsystem based on personal recognitionof a health problem, those witheducation, a higher income, and betterhealth insurance are more likely toaccess health care.

All patients have a basic right to equalaccess to quality medical treatment,regardless of where they live, theirstatus or their income.

Collaborative approach to guideline development

The efficacy and tolerability of VKAs inthe prevention of stroke in patients withAF are well established,31 but severaldrawbacks can lead to poor adherenceto guidelines, as discussed earlier.

Regular reviews, updates, andendorsement of the guidelines willensure that these are relevant to currentclinical practice and may therebyincrease adherence.53,233 Programsaimed at improving the implementationof existing guidelines into clinicalpractice would also be of benefit toLatin American countries. ‘Get With The Guidelines-Stroke’, carried out bythe American Heart/Stroke Association,is an example of an initiative aimed atimproving adherence to the latestscientific guidelines.61 Mechanisms toimplement a similar program forguidelines in AF should be explored.Furthermore, there is a rationale forproviding standardized guidelines for

Key points

� New anticoagulants in development aim to offer reliable efficacy andtolerability, with the benefit of simplified dosing and no need forfrequent monitoring or dose adjustment

� Several new oral anticoagulants directly target key steps in theclotting pathway

� Four oral anticoagulants are in phase III development or have beenrecently licensed for use in the prevention of stroke in AF

� New antiplatelet agents and drugs for stabilizing heart rhythm arealso either in advanced stages of development or have also beenapproved

� Non-pharmacologic methods for managing abnormal heart rhythmexist, and research is ongoing in this area

� Surgical procedures are being developed to reduce the risk of clotsreaching the brain


62

New anticoagulantsare needed that

offer reliableefficacy and

tolerability, withsimplified dosing

and no need for frequent

monitoring or dose adjustment

VKAs are taken orally but interact withmany foods and drugs, have a narrowtherapeutic window and requirefrequent dose adjustment andmonitoring, which is often not carriedout in practice. They therefore meet fewof the criteria for an ideal therapy forstroke prevention in patients with AF.

The search for new anticoagulants hastherefore focused on compounds thatmeet more of the criteria for an idealanticoagulant. Several new oralanticoagulants are in development:relevant phase III trials (large, late-stagestudies) of these drugs – eitherpublished or listed on the global clinicaltrials registry, www.clinicaltrials.gov –are shown in Appendix 2 (page 82). Inthe coagulation pathway (Figure 10,page 40) there are many potentialtargets for new anticoagulant agents.The agents that are currently mostadvanced in their development targetsingle proteins in the coagulationpathway (Factor Xa and thrombin).234

Those agents that are in phase IIIdevelopment or have been recentlylicensed are discussed in this chapter.

Limitations of VKAs and aspirin restricttheir use and effectiveness in theprevention of stroke in patients with AF(see chapter on ‘Stroke prevention inpatients with atrial fibrillation’, page 39).These limitations have led to anongoing search for alternative effectiveand convenient therapies. In addition,there have been developments inantiarrhythmic drugs used to treat AF.These developments are discussed inmore detail in this chapter.

Anticoagulant agents

The characteristics of an idealanticoagulant for long-term use in achronic condition such as AF include:234

� Effectiveness� A good safety profile in a wide

range of patients, including theelderly

� A low tendency to interact with foodand other drugs

� No requirement for regular monitoring� Oral administration� Administration of fixed doses

without the need for doseadjustment

New oralanticoagulants are in advancedstages of clinical

development

New developments for stroke prevention in patients with atrial fibrillation

63

New developments for stroke prevention in AF

Oral direct Factor Xa inhibitors

act at a pivotalpoint in thecoagulation

pathway to inhibitthrombin

generation

population (1.7% vs 2.2%, respectively,p=0.015). Additionally, in the intent-to-treat population, which followed allpatients randomized in the trial until itscompletion, whether or not theycompleted the full course of therapy orswitched to other options, rivaroxabanshowed comparable benefits to warfarin(2.1% vs 2.4%, p<0.001 for non-inferiority). This result indicates that thetreatment benefits compared withwarfarin were sustained as long as thepatients received rivaroxaban.

For the principal safety measure,rivaroxaban showed similar rates ofmajor and non-major clinically relevantbleeding events, compared with warfarin(14.9% vs 14.5%, p=0.442). Rates ofmajor bleeding were also comparablebetween rivaroxaban and warfarin(3.6% vs 3.5%, p=0.576). Patientstreated with rivaroxaban had fewerintracranial hemorrhages (0.5% vs0.7%, p=0.019), critical organ bleedingevents (0.8% vs 1.2%, p=0.007), andbleeding-related deaths (0.2% vs 0.5%,p=0.003) compared with those treatedwith warfarin, but showed increasedrates of hemoglobin/hematocrit drop(2.8% vs 2.3%, p=0.019) andtransfusions (1.7% vs 1.3%, p=0.044),compared with warfarin.

Rivaroxaban-treated patients also hadnumerically fewer myocardialinfarctions (0.9% vs 1.1%, p=0.121),and an observed reduction in rates ofall-cause mortality compared withwarfarin (1.9% vs 2.2%, p=0.073),though these results were notstatistically significantly different.

ApixabanPhase II studies of apixaban for theprevention of VTE and treatment ofsymptomatic deep vein thrombosis havebeen completed,238,239 and help serve asdose-finding studies for phase III trials ofstroke prevention in patients with AF.ARISTOTLE, a randomized, double-blindphase III study, is evaluating the efficacyand safety of apixaban 5 mg twice daily

Oral direct Factor Xa inhibitorsFactor Xa is the primary site foramplification in the coagulationpathway.235 Inhibition of Factor Xaachieves effective anticoagulation byinhibiting thrombin generation, whileallowing the vital functions of existingthrombin to continue, thus potentiallymaintaining hemostasis at sites ofhemostatic challenge.235 Oral directinhibitors of Factor Xa includerivaroxaban, apixaban, and edoxaban.Rivaroxaban and apixaban are bothlicensed for the prevention of venousthromboembolism (VTE) in adult patientsundergoing elective hip or kneereplacement surgery. Rivaroxaban isapproved for this indication in more than100 countries worldwide. Edoxaban isapproved in Japan for the prevention ofVTE in patients undergoing total kneearthroplasty, total hip arthroplasty, andhip fracture surgery. A press releasestated that rivaroxaban has beensubmitted for EU marketingauthorization in stroke prevention inpatients with AF, as well as for thetreatment of deep vein thrombosis andthe prevention of recurrent deep veinthrombosis and pulmonary embolism.236

Unlike VKAs, rivaroxaban does notrequire routine coagulation monitoring.Studies of other oral direct Factor Xainhibitors are underway in differentindications, including stroke preventionin patients with AF.

Rivaroxaban ROCKET AF was a randomized, double-blind phase III study that compared theefficacy and safety of once-dailyrivaroxaban (20 mg, or 15 mg for patientswith moderate renal impairment) withdose-adjusted warfarin for theprevention of stroke in 14264 patientswith AF. Results from this trial wererecently reported at AHA.237

Rivaroxaban was superior to warfarin forthe primary efficacy endpoint, showinga 21% relative risk reduction (RRR) forstroke and non-CNS systemic embolismin the prespecified on-treatment

64


Several otheranticoagulants are

in development

of VTEs in adults who have undergoneelective total hip or elective total kneereplacement surgery. Dabigatran isapproved in at least 14 countries,including the US, Canada, and Japanfor stroke risk reduction in patientswith AF. Approval was based on RE-LY,a phase III randomized, non-inferioritystudy, which compared the efficacy andsafety of dabigatran at doses of 110mgor 150mg twice daily with dose-adjusted warfarin (INR 2.0–3.0) for theprevention of stroke in patients with AF.RE-LY was a blinded study with regardsto the dabigatran dose given, and openlabel with regards to warfarin.Approximately 18000 patients with AFand at risk of stroke were enrolled inthis study and followed up for amedian of 2 years.

At a dose of 110mg twice daily,dabigatran was associated with a similarrate of stroke and systemic embolism todose-adjusted warfarin (1.53% vs1.69%, respectively) and a significantlylower rate of major bleeding thanwarfarin (2.71% vs 3.36%, respectively,p=0.003).245 At the higher dose ofdabigatran (150mg twice daily), the rateof stroke and systemic embolism wassignificantly lower than with warfarin(1.11% vs 1.69%, respectively, p<0.001)but the rate of major bleeding wassimilar to that associated with warfarin(3.11% vs 3.36%, respectively, p=0.31).The rate of intracranial bleeding wassignificantly lower with both dabigatrandoses (110 mg, 0.23%; 150 mg, 0.30%)compared with warfarin (0.74%,p<0.001 for both comparisons).

There were higher rates of myocardialinfarction with dabigatran (110 mg,0.72% [p=0.07 vs warfarin]; 150 mg0.74% [p=0.048 vs warfarin])compared with warfarin (0.53%).245

After the identification of severaladditional primary efficacy and safetyoutcome events during routine clinicalsite closure visits, a post hoc analysis ofthe RE-LY study was carried out.246 Thisinvolved checking all primary and

compared with warfarin for strokeprevention in patients with AF.240 Resultsfrom ARISTOTLE will be presented at theESC 2011 meeting. Another phase IIIstudy (AVERROES) investigated whetherapixaban was more effective than aspirinin preventing stroke in patients with AFwho had failed or were unsuitable forVKA therapy (Appendix 2, page 82).167

Apixaban was shown to reduce the riskof stroke or systemic embolism comparedwith aspirin with no significantlyincreased risk of major hemorrhage.166

Edoxaban (DU-176b) Phase II studies have compared theFactor Xa inhibitor edoxaban withwarfarin in patients with AF; early resultsindicate that patients receiving 30mg or60mg once-daily doses of edoxabanhad a similar incidence of bleeding tothose assigned to warfarin.241 A phase IIIstudy (ENGAGE-AF TIMI48) has alsobeen initiated to demonstrate the safetyand efficacy profile of two doses ofedoxaban vs warfarin.242 Results areexpected in March 2012.243

Indirect Factor Xa inhibitorsBiotinylated idraparinux is an indirectinhibitor of Factor Xa that acts viaantithrombin. Unlike the direct Factor Xainhibitors in development, biotinylatedidraparinux must be administered bysubcutaneous injection.234 A phase IIIstudy (BOREALIS-AF) was evaluatingwhether biotinylated idraparinux,administered subcutaneously once aweek, was at least as effective aswarfarin for the prevention of strokeand systemic thromboembolic events inpatients with AF; however, the trial wasdiscontinued early because of a strategicdecision by the sponsor rather than dueto any safety concern.244

Oral direct thrombin inhibitorsDabigatran etexilate is an oral directthrombin inhibitor. This class of drugblocks the conversion of fibrinogen tofibrin in the coagulation pathway.Dabigatran has been approved in 83 countries for the primary prevention

Antiplatelet agentsreduce the risk of

blood clots forming by inhibiting

aggregation ofplatelets

65


New drugs to treatAF by stabilizingheart rhythm orheart rate are inadvanced stages of development

unsuitable.253 This study showed that,compared with aspirin and placebo,clopidogrel in combination with aspirinsignificantly reduced the risk of strokein patients with AF but was alsoassociated with a significantly greaterrate of major bleeding.

Other antiplatelet agents are in phase IIIclinical trials (ticagrelor) or have recentlybeen approved for clinical use(prasugrel).254 However, there are nodata on the use of these drugs for theprevention of stroke in patients with AF.

Other pharmaceutical agents

The efficacy and safety of agents inother classes, such as thromboxanereceptor antagonists (e.g. NCX-4016and S18886), platelet adhesionantagonists, and thrombin receptorantagonists (e.g. vorapaxar), are beingevaluated in phase I and II trials.254

Alternative strategies in development

Current strategies are focused onreducing thromboembolic risk withdrugs that target the process of clotformation. However, other strategiesare emerging for stroke prevention inpatients with AF. These include:management of AF itself through theuse of drugs to control heart rhythmand/or rate; non-pharmacologicmethods that control rhythm and/orrate or prevent blood clots reaching thebrain; and surgical interventions toreduce thromboembolic risk.17

New pharmacological methods forrestoring normal heart rhythmAF itself can be managed using ‘rhythmcontrol’ or ‘rate control’ strategies. Inrhythm control, drugs are used tomaintain the sinus rhythm of the heart;in rate control, drugs are used tomaintain a steady heart rate. Examplesof drugs used for rhythm or ratecontrol include amiodarone, digoxin,and �-blockers.

secondary efficacy and safety data forconsistency and re-evaluating the studydatabase for possible underreporting ofevents. This analysis led to theidentification of 32 new myocardialinfarction events (4 clinical and 28 silentmyocardial infarctions). Althoughobserved myocardial infarction rateswere higher with both dabigatrandoses, the statistical significancepreviously seen with the higher dosewas no longer evident.

Rates of dyspepsia were significantlyhigher with both dabigatran doses (110mg, 11.8%; 150 mg, 11.3%)compared with warfarin (5.8%, p<0.001for both comparisons).245 Further studiesof dabigatran and other direct thrombininhibitors are ongoing.247,248

Other anticoagulantsThere are several other oralanticoagulants in earlier stages ofdevelopment for stroke prevention inAF. Agents that have been studied inphase II trials include the directthrombin inhibitor AZD0837, theindirect thrombin inhibitor odiparcil,and the direct Factor Xa inhibitorsYM150 and betrixaban.248–252

Antiplatelet agents

Clopidogrel is an inhibitor of plateletaggregation. Reduced plateletaggregation reduces the risk of a bloodclot forming and helps to preventanother heart attack or stroke.Clopidogrel is currently indicated forthe prevention of atherothromboticevents in patients suffering from heartattack, ischemic stroke, or establishedperipheral arterial disease and inpatients suffering from acute coronarysyndrome. Studies have assessed theefficacy and safety of clopidogrel forstroke prevention in patients with AF.The ACTIVE-A trial investigated theeffects of clopidogrel in combinationwith aspirin for the prevention of strokein patients who had an increased risk ofstroke and for whom VKA therapy was

66


Surgical proceduresare being

developed toreduce the risk of

blood clotstraveling from theheart to the brain

Existing data suggest that catheterablation is more effective thanantiarrhythmic drug therapy inmaintaining normal heart rhythm.258

Whether this intervention results infewer AF-related strokes requirestesting in clinical trials. The efficacy of surgery versus antiarrhythmic drugtherapy has yet to be assessed inclinical trials.

Surgical interventions to reducethromboembolic riskIn patients with non-valvular AF, morethan 90% of blood clots form in theleft atrial appendage (part of the leftatrium).17 Closing the left atrialappendage may therefore be aneffective way to reduce the risk ofblood clots and stroke. Several newocclusion devices have been developedthat allow the left atrial appendage tobe blocked off. Such devices aredesigned to be placed permanently justbehind, or at the opening of, the leftatrial appendage. Once in place, theyshould prevent any blood clots of aharmful size from entering thebloodstream and ultimately causingstroke.259,260 In Latin America, occlusiondevices are used in Argentina, Brazil,Chile, and Venezuela. The results of arecently published trial showed that theefficacy of percutaneous closure of theleft atrial appendage with an occlusiondevice was non-inferior to that ofwarfarin therapy. Although there was ahigher rate of adverse events in theintervention group compared withwarfarin, the authors concluded thatclosure of the left atrial appendagemight provide an alternative strategy tochronic warfarin therapy for strokeprophylaxis in patients with AF.261

Next steps

To summarize, there are severalpharmacologic agents that have beendeveloped for use in patients with AF,including the new oral anticoagulantsrivaroxaban, dabigatran, apixaban, andedoxaban. Non-pharmacologic

Dronedarone is a new antiarrhythmicdrug that is licensed for maintainingnormal heart rhythms in patients with a history of AF or atrial flutter in the US,and for use in clinically stable adultpatients with a history of, or current,non-permanent AF to prevent recurrenceof AF, or to lower ventricular rate in theUK. In a phase III study of 4628 patientswith AF (the ATHENA study), dronedaronewas shown to reduce the incidence ofdeath or hospitalization due tocardiovascular events compared withplacebo.255 In a post hoc analysis of theATHENA data, dronedarone administeredover a follow-up period averaging 21months was also associated with areduced risk of stroke compared withplacebo, particularly in patients withmultiple risk factors for stroke.256 Rare butsevere cases of hepatic injury have beenreported with the use of dronedarone.257

Non-pharmacologic methodsNon-pharmacologic interventions forstroke prevention in AF concentrate oneliminating the AF itself or stoppingpotentially harmful blood clots reachingthe brain.

Non-pharmacologic management ofabnormal heart rhythmThere are numerous non-pharmacologicmethods for the management ofabnormal heart rhythm.17 These include:� Electrical cardioversion (the process

by which an abnormally fast heartrate or disturbance in heart rhythmis terminated by the delivery of anelectric current to the heart at aspecific moment in the heart cycle)

� Catheter ablation (an invasiveprocedure used to remove a faultyelectrical pathway from the heart)

� Surgical procedures (open-heartsurgery or minimally invasiveprocedures that also serve to removethe faulty electrical pathways fromthe heart)

� Installation of a device into the wallof the left atrial appendage of theheart (a procedure aimed at closing/occluding the left atrial appendage)

Research into non-pharmacologic

methods formanaging

abnormal heartrhythm is also

ongoing

67


A new global registry of a differentmagnitude has now been establishedwith a truly international reach. TheGlobal Anticoagulant Registry in theFIELD (GARFIELD) is prospectivelyfollowing 50000 patients newlydiagnosed with AF and 5000 patientswith previously diagnosed AF – all eligiblefor long-term anticoagulant therapy –over 6 years.263 Patients are beingincluded and followed, regardless ofwhether or not they receive appropriatetherapy. The GARFIELD registry isdocumenting details such as the riskfactors, treatment patterns and clinicalevents associated with AF, and willprovide a picture of the real-life globalburden of the condition. In addition, itwill show how the new advances intherapy, particularly new anticoagulants,can contribute to the prevention ofstroke in patients with AF.264

In addition, a number of hospital-basedstroke registries exist.265 The LuisVernaza Hospital Stroke registry inEcuador included 500 Hispanic patientswith a first stroke. Results from theregistry suggest that the pattern ofstroke is different in Hispanics comparedwith other ethnic groups; the prevalenceof cerebral hemorrhage is 2–3 timeshigher in Hispanics than in whites but issimilar to that observed in Chinese.266

It is hoped that the availability of newtherapy options, together with a greaterunderstanding of their impact on theburden of stroke, will pave the way forbetter management of patients with AF.

approaches to the management ofarrhythmia and surgical interventions toreduce thromboembolic risk are alsobeing developed.

Valuable insights into the impact ofthese new therapies on the preventionof stroke in patients with AF can begained from registries. A number ofregistries of AF patients are in existencein Latin America, some of which arecountry specific.

The Board of Electrophysiology andArrhythmias of the South AmericanSociety of Cardiology is currentlyconducting a registry on the prevalenceof AF in the cardiology consultation inSouth America (REFASUD).262 TheREFASUD is an online-based registry thatconsists of a questionnaire thatphysicians complete over a given period(2–4 weeks) for each patient with AFthat they encounter. The questionnaireconsists of demographic data, types offibrillation, underlying heart disease, andtreatment strategies undertaken.262 Thestudy will offer a valuable insight intothe epidemiology of AF in SouthAmerica in order to improve interventionstrategies for patients with AF.

The First National Registry of ChronicAtrial Fibrillation of Argentina included945 consecutive patients with chronicAF; of these, 615 were followed up at2 years.156 The mortality rate was high,and the lowest survival rate wasassociated with older age, leftventricular dysfunction, and lack ofanticoagulation at admission.

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79

Appendix 1

Summary of guidelines for the prevention of stroke in patients with atrial fibrillation

Appendix 1

Risk category Recommendation

Internationally used AF guidelines

European Society of Cardiology (ESC) – Management of atrial �brillation guideline 201062

All patients with AF • Administration of antithrombotic therapy should be based on the presence (or absence) of risk factors for stroke and thromboembolism

Patients with AF and one major risk factora or • Administer an oral anticoagulant, such as a VKA≥2 clinically relevant non-major risk factorsb (target INR 2.5; range 2.0–3.0)

Patients with AF and one clinically relevant • Administer either an oral anticoagulant, such as a VKA non-major risk factorb (target INR 2.5; range 2.0–3.0) or aspirin (75–325 mg/day). However, an oral anticoagulant is preferred over aspirin

Patients with AF and no risk factors • Administer either aspirin (75–325 mg/day) or no antithrombotic therapy. However, no antithrombotic therapy is preferred over aspirin

Patients with AF in whom oral anticoagulation • Dabigatran may be considered as an alternative to dose-adjusted is appropriate therapy: VKA therapy:• Patients at low risk of bleeding – Dabigatran 150 mg twice daily (HAS-BLED score 0–2) • Patients with a measureable risk of bleeding – Dabigatran 110 mg twice daily (HAS-BLED score ≥3) • Patients with one clinically relevant non-major – Dabigatran 110 mg twice daily risk factorb

American College of Cardiology Foundation, American Heart Association, and Heart Rhythm Society (ACCF/AHA/HRS) – Focused update on the management of patients with atrial �brillation (updating the 2006 guideline), 201163

All patients with AF or atrial flutter, except • Antithrombotic therapy is recommended to prevent thromboembolismthose with lone AF or contraindications • Selection of antithrombotic agent should be based on absolute risks of stroke and bleeding and the relative risk and benefit for a given patient

Patients without mechanical heart valves at high • Chronic oral anticoagulant therapy with a dose-adjusted VKA risk of stroke (i.e. prior thromboembolism (INR 2.0–3.0) unless contraindicated. INR should be determined [stroke, TIA, or systemic embolism] and at least weekly during initiation of therapy and monthly when rheumatic mitral stenosis) anticoagulation is stable Patients with >1 moderate risk factor (age ≥75 years, • VKA is recommended hypertension, heart failure, impaired left ventricular systolic function [ejection fraction ≤35% or fractional shortening <25%], or diabetes mellitus)

Low-risk patients or in those with contraindications • Aspirin 81–325 mg/day is recommended as an alternative to VKAsto oral anticoagulation

Patients with AF who have mechanical heart valves • Target intensity of anticoagulation should be based on the type of prosthesis, maintaining an INR of at least 2.5

For primary prevention of thromboembolism in • Antithrombotic therapy with either aspirin or a VKA is reasonable, patients with non-valvular AF who have just one based upon an assessment of the risk of bleeding complications, validated risk factor (age ≥75 years ability to safely sustain adjusted chronic anticoagulation, and [especially in female patients], hypertension, patient preferences heart failure, impaired left ventricular function, or diabetes mellitus)

For patients with non-valvular AF who have Antithrombotic therapy with either aspirin or a VKA is reasonable. ≥1 less-well-validated risk factor (age 65–74 years, The choice of agent should be based upon the risk of bleedingfemale gender, or coronary artery disease) complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences continued

80



Latin American country-specific AF guidelines

Argentine Society of Cardiology (Sociedad Argentina De Cardiología [SAC]) – consensus on atrial �brillation, 200565

All patients with AF • Administration of antithrombotic agent should be based on the absolute risks of cerebrovascular accident or hemorrhage and the relative risk and benefit for each patient

Patients with non-valvular AF who are aged • Administer oral anticoagulation or aspirin <60 years (except for lone AF)

Patients with a high risk of cerebrovascular accident • Administer dose-adjusted warfarin (INR 2.0–3.0) unless contraindicated. Assess the need for oral anticoagulation regularly

Patients with a low risk of stroke or strong • Aspirin 325 mg/day suggested as an alternativecontraindications for oral anticoagulants

Patients with AF with mitral valve disease or • Administer oral anticoagulant (INR 2.0–3.0) mechanical or biologic heart valve prosthesis

Patients with persistent, permanent, • Administer antithrombotic therapy with the same criteria or paroxysmal AF for each type of AF

Patients with atrial flutter • Give the same anticoagulation therapy as for patients with AF with similar risk factors

Patients with AF who are aged >75 years with • Maintain INR close to 2.0 for prevention of thromboembolism a high risk of hemorrhage and without a clear contraindication for oral anticoagulation

Patients with AF and without a prosthetic • Interrupt oral anticoagulation for a week for surgery or diagnosticheart valve procedures, because of the risk of bleeding, without substituting with heparin

• In high-risk elective patients for whom oral anticoagulation is to be discontinued, or discontinued for more than 1 week, administer unfractionated heparin or low molecular weight heparin

Patients with AF who are aged <60 years without • Administration of aspirin is optionalheart disease or embolic risk factors

Patients with AF duration >48 hours or unknown: Before cardioversion • Maintain on oral anticoagulation for 3 weeks After successful cardioversion • Maintain on oral anticoagulation (INR >2.0) for 4 weeks Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia [SBC]) – Brazilian guidelines on atrial �brillation, 200920

Patients with AF but no contraindications • Antithrombotic therapy (INR 2.0–3.0) for an unspecified period of time

Patients requiring secondary stroke prevention • Administration of VKA (INR >2.5)for cerebrovascular accident, TIA, prior systemic embolization

Patients with rheumatic mitral stenosis or metallic • Administration of VKA (INR >2.5) prosthetic valve

Patients with AF and ≥2 risk factors (age ≥75 years, • Give VKA, or aspirin (81–325 mg/day) when this is contraindicated hypertension, cardiac insufficiency, LVEF ≤35%, or diabetes mellitus)

Patients with AF who have anticoagulation • Administer heparin, preferentially of low molecular weight interruption due, for example, to surgical procedures with a high risk of hemorrhaging

Patients with AF, no valvulopathy, and only one • Give VKA or aspirin (81–325 mg/day)risk factor (age ≥75 years, hypertension, cardiac insufficiency, LVEF ≤35%, or diabetes mellitus)

Patients with AF, no valvulopathy and ≥1 risk • Give VKA or aspirin (81–325 mg/day)factor (age 60–74 years, female, or coronary artery disease)

continued

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Appendix 1


Patients with AF who are aged <60 years • Give aspirin (81–325 mg/day) and have no heart disease or risk of thromboembolic events

Patients with AF duration ≥48 hours or unknown: Before cardioversion • Maintain on oral anticoagulation (INR 2.0–3.0) for 3 weeks

After successful cardioversion • Maintain on oral anticoagulation (INR 2.0–3.0) for 4 weeks

Patients with AF with metallic valve prosthetics • Patients must maintain an INR >2.5

Mexican National Center for Health Technology Excellence (Centro Nacional de Excelencia Tecnológica en Salud [CENETEC])– diagnosis and treatment of atrial !brillation, 200964

Patients with AF with a low risk of stroke • Administer aspirin(CHADS2 score 0) with lone AF

Patients with AF who are aged <75 years • Administer aspirin or coumarin-derived agents as anticoagulant with a moderate risk of stroke (CHADS2 score 1) (maintain INR 2.0–3.0)

Patients with AF who are aged >75 years • Administer aspirin or coumarin-derived agents as anticoagulant with a moderate risk of stroke (CHADS2 score 1) (maintain INR 1.6–2.5)

Patients with AF who are aged <75 years • Administer coumarin-derived agents as anticoagulantwith a moderate risk of stroke (CHADS2 score 2) (maintain INR 2.0–3.0)

Patients with AF who are aged >75 years • Administer coumarin-derived agents as anticoagulantwith a moderate risk of stroke (CHADS2 score 2) (maintain INR 1.6–2.5)

Patients with AF at high risk of stroke • Administer coumarin-derived agent as anticoagulant (CHADS2 score >2), patients with valvular (maintain INR 2.5–3.5)heart disease, and patients with hypertrophic cardiomyopathy

Patients with AF at high risk undergoing • Treat with intravenous unfractionated heparin or low molecularhemodynamic or surgical intervention weight heparin, preoperatively and postoperatively

a Prior stroke, TIA, or thromboembolism, older age (≥75 years), and valvular heart disease, including mitral stenosis.

b Heart failure (LVEF ≤40%), hypertension, diabetes, female sex, age 65–74 years, and vascular disease (specifically myocardial infarction, complex aortic plaque, and peripheral arterial disease).

AF, atrial fibrillation; INR, international normalized ratio; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack; VKA, vitamin K antagonist.

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Oral direct thrombin inhibitor Dabigatranetexilate

Drug orintervention

Studyacronym

Study title(ClinicalTrials.gov identifier)

Estimatedcompletion date

Randomized Evaluation of Long-term anticoagulant therapY (RELY) comparing the efficacy and safety of two blinded doses of dabigatran etexilate with open-label warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: prospective, multicenter, parallel-group, non-inferiority trial (NCT00262600)

RE-LY Completed and published:Connolly SJ et al. N Engl J Med 2009;361:1139–51Update published:Connolly SJ et al. N Engl J Med 2010;363:1875–6

Direct Factor Xa inhibitors Apixaban

Rivaroxaban

A phase III, active (warfarin) controlled, randomized, double-blind, parallel arm study to evaluate efficacy and safety of apixaban in preventing stroke and systemic embolism in subjects with non-valvular atrial fibrillation(NCT00412984)

ARISTOTLE April 2011http://clinicaltrials.gov/ct2/show/NCT00412984

Antiplatelet agentsClopidogrel A parallel randomized controlled evaluation of clopidogrel

plus aspirin, with factorial evaluation of irbesartan, for the prevention of vascular events, in patients with atrial fibrillation (NCT00249873)

ACTIVE A Published:Connolly SJ et al. N Engl J Med 2009;360:2066–78

A parallel randomized controlled evaluation of clopidogrel plus aspirin, with factorial evaluation of irbesartan, for the prevention of vascular events, in patients with atrial fibrillation (NCT00249795)

ACTIVE I Published:Yusuf S et al. N Engl J Med 2011;364:928–38

A parallel randomized controlled evaluation of clopidogrel plus aspirin, with factorial evaluation of irbesartan, for the prevention of vascular events, in patients with atrial fibrillation (NCT00243178)

ACTIVE W Published:Connolly S et al. Lancet 2006;367:1903–12

Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment: a randomized double-blind trial (NCT00496769)

AVERROES Published:Connolly SJ et al. N Engl J Med 2011;364:806–17

Edoxaban A phase III, randomized, double-blind, double-dummy, parallel-group, multicenter, multinational study for evaluation of efficacy and safety of edoxaban versus warfarin in subjects with atrial fibrillation – effective anticoagulation with Factor Xa next generation in atrial fibrillation (ENGAGE-AF TIMI-48) (NCT00781391)

ENGAGE-AF TIMI-48

March 2012http://www.clinicaltrials.gov/ct2/show/NCT00781391

A prospective, randomized, double-blind, double-dummy, parallel-group, multicenter, event-driven, non-inferiority study comparing the efficacy and safety of once-daily oral rivaroxaban with dose-adjusted warfarin for the prevention of stroke and non-central nervous systemsystemic embolism in subjects with non-valvular atrial fibrillation (NCT00403767)

ROCKET AF Completed:Results presented at the AHA scientific sessions: 12–16 November 2010

Phase III studies of new pharmaceutical agents for stroke prevention in atrial fibrillation

Data obtained from searching www.clinicaltrials.gov using the term ‘stroke prevention atrial fibrillation’ (last accessed June 2011). In total, 72 studies were obtained with this search term; 26of these are phase IIIstudies, and those relevant to new agents or methods of stroke prevention in patients with AF are listed.

Appendix 2

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Glossary

Glossary

1 billion 1000 million

Anticoagulant A type of drug that reduces the ability of the blood to clot by inhibiting any step in thecoagulation pathway, thereby resulting in impaired formation of fibrin (the end result of theclotting pathway)

Antiplatelet agent A type of drug that inhibits the formation of blood clots by inhibiting activation of blood platelets

Antithrombotic therapy Any therapy that interferes with the formation of blood clots (thrombi)

Asymptomatic Showing or causing no symptoms

Atherothrombotic event An ischemic event triggered by platelet activation following disruption of plaque or fattydeposits in the arteries

Atrial fibrillation A heart rhythm abnormality, characterized by rapid, disorganized electrical signals, whichcause the atria to contract quickly, irregularly (known as fibrillation), and inefficiently

Cardioembolic stroke A stroke caused by a blood clot originating in the heart

Cardioversion The process by which an abnormally fast heart rate or disturbance in heart rhythm isterminated by the delivery of an electric current to the heart at a specific moment in theheart cycle (electrical cardioversion) or injection of anti-arrhythmic agents (pharmacologiccardioversion)

Coagulation The process by which a blood clot is formed; essential for the arrest of bleeding

Coagulation pathway The pathway of chemical reactions that results in the formation of a blood clot

Direct thrombin inhibitor A class of anticoagulants that act by binding directly to thrombin and blocking interactionwith its substrate fibrinogen, thus inhibiting the generation of fibrin and clot formation

Embolize The process of forming an embolus

Embolus/embolism A blood clot, air bubble, piece of fatty deposit, or other object that has been carried in thebloodstream, which lodges in a vessel and impedes the circulation

Epidemiology The study of the occurrence and distribution of disease

Factor Xa inhibitor A class of anticoagulants that inhibit Factor Xa in the coagulation cascade either by bindingdirectly to Factor Xa, or indirectly through antithrombin. Inhibition of Factor Xa reduces theproduction of thrombin

Fibrinogen A soluble plasma protein. In the final phase of the coagulation process, thrombin convertsfibrinogen to insoluble fibrin, which polymerizes and forms the fibrous network base of a clot

Hemorrhagic stroke A stroke caused by leakage from a blood vessel in the brain

Heart attack An ischemic event in a section of heart after interruption of its blood supply (also known asmyocardial infarction)

Incidence The number of new cases of a disease or condition in a population over a given period of time

International normalized Prothrombin time test results vary according to the activity of the thromboplastin used. Theratio (INR) INR conversion normalizes results for any thromboplastin preparation but is valid only with

vitamin K antagonists

Ischemic stroke Stroke caused by a blood clot or embolus blocking a blood vessel in the brain

84


Morbidity The state of having a disease; ill health

Platelet A very small, disc-shaped component of the blood that forms a significant part of a bloodclot, particularly in the arteries

Prevalence The total number of cases of a disease or condition in a population at any given time

Prothrombin time The prothrombin time measures clotting time in the presence of tissue factor(thromboplastin). It is used to assess the overall functioning of the extrinsic and commonpathways

QALY (quality-adjusted A measure that represents the composite of several outcomes affecting quality of life; life-year) 1 year in perfect health is considered to be equal to 1.0 QALY; 1 year in less than perfect

health would have a QALY <1

Stroke A condition caused by disruption of the blood supply to part of the brain, or leaking ofblood from a blood vessel into the brain, which may result in damage or death of brain cells

Subarachnoid hemorrhage Bleeding between the surface of the brain and the skull

Therapeutic range The interval between the lowest dose of a drug that is sufficient for clinical effectiveness andthe higher dose at which adverse events or toxicity become unacceptable

Thrombin Thrombin (Factor IIa) is the terminal enzyme of the coagulation cascade and convertsfibrinogen into fibrin, which forms clot fibers. Thrombin also activates several othercoagulation factors, in addition to protein C

Thromboembolism The process by which a blood clot becomes detached from its place of formation andcirculates in the blood

Thrombolytic Having the ability to break up a blood clot

Thrombus A blood clot

Transient ischemic attack A brief disruption of the blood supply to part of the brain

Vitamin K antagonist A class of compounds that inhibit the vitamin K-dependent formation of specific coagulationfactors. This results in decreased levels of the affected coagulation factors, leading toanticoagulation

Warfarin A vitamin K antagonist that is currently the most commonly used oral anticoagulant

85

Abbreviations

Abbreviations

ACC American College of Cardiology

ACCF American College of Cardiology Foundation

AF Atrial fibrillation

AHA American Heart Association

CHADS2 Congestive heart failure; Hypertension; Age >75 years; Diabetes; Stroke or transient ischemic attack (a system for scoring risk factors for stroke, assigning 1 point each to C, H, A and D, and 2 points to S)

CHA2DS2-VASc Congestive heart failure or left ventricular dysfunction; Hypertension; Age ≥75 years; Diabetes;Stroke, TIA, or thromboembolism; Vascular disease; Age 65–74 years; Sex category female (a systemfor scoring risk factors for stroke, assigning 1 point each to C, H, D, V, A, Sc, and 2 points to A, S)

CT Computed tomography

CV Cardiovascular

ECG Electrocardiogram

EMSP European Multiple Sclerosis Platform

ESC European Society of Cardiology

HAS-BLED Hypertension (uncontrolled, >160 mmHg systolic); Abnormal renal/liver function; Stroke (previoushistory, particularly lacunar); Bleeding history or predisposition (e.g. anemia); Labile INR(unstable/high INRs or in therapeutic range <60% of time); Elderly (>65 years); Drugs/alcohol(concomitant use of drugs such as antiplatelet agents and non-steroidal anti-inflammatory drugs oralcohol) (a system for scoring risk factors for bleeding, assigning 1 point each)

HRS Heart Rhythm Society

INR International normalized ratio

LV Left ventricular

LVEF Left ventricular ejection fraction

MS Multiple sclerosis

PAHO Pan American Health Organization

QALY Quality-adjusted life-year

STEPS Stepwise Approach to Risk-Factor (RF) Surveillance

TIA Transient ischemic attack

VKA Vitamin K antagonist

VTE Venous thromboembolism

WHO World Health Organization



August 2011

Every year hundreds of thousands of people in LatinAmerica experience a stroke, and the number of strokesper year is predicted to rise dramatically as the populationages. This is an epidemic already beginning to happen,and prompt action is required to avoid a crisis.

Many of these patients die from stroke; others are leftwith severe disabilities, which devastate not only theirlives but also the lives of their families and caregivers.Unsurprisingly, the economic implications of stroke arehuge for both individuals and healthcare systems.

Atrial fibrillation (AF) – the most common sustained abnormality of heartrhythm – affects millions of people in Latin America. For example, inBrazil, it has been estimated that there are approximately 1.5 millionpatients living with AF. Individuals with AF are at a fivefold increased riskof stroke compared with the general population. Furthermore, strokesrelated to AF are more severe, have poorer outcomes, and are more costlythan strokes in patients without AF. Patients with AF are therefore animportant target population for reducing the overall burden of stroke.

This report aims to raise awareness among policy makers and healthcareprofessionals that better knowledge and management of AF, and betterprevention of stroke are possible. However, greater investment inpreventing stroke is needed, particularly in patients with AF. Coordinatedaction by national governments of Latin American countries is urgentlyrequired to achieve earlier diagnosis and better management of AF, and toreduce the risk of stroke in patients with AF. Implementation of therecommendations detailed in this report, at regional and national level,will be crucial.

How Can

We A

void a Stro

ke Crisis in

Latin America?

August 2011

Dr. Álvaro AvezumInstituto Dante Pazzanese de Cardiologia, São Paulo, Brazil

Dr. Carlos CantúNational Institute of Medical Sciences and Nutrition, Salvador Zubirán, Mexico

Dr. Jorge Gonzalez-ZuelgaraySanatorio de la Trinidad San Isidro, Buenos Aires, Argentina

Mellanie True HillsStopAfib.org; American Foundation for Women’s Health

Trudie Lobban MBEArrhythmia Alliance; Atrial Fibrillation Association

Dr. Ayrton MassaroIbero-American Stroke Society, Brazil

Dr. Susana MeschengieserAcademia Nacional de Medicina, Buenos Aires, Argentina

Professor Bo NorrvingLund University, Sweden

Dr. Walter Reyes-CaorsiSanatorio Casa de Galicia, Montevideo, Uruguay

This report was made possible by a sponsorship from Bayer HealthCare Pharmaceuticals. See reverse oftitle page and acknowledgements for further information.

Every year hundreds of thousands of people in Latin How ...Instituto Dante Pazzanese de Cardiologia,...

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