Diapositiva 1

Nuevas Estrategias Antitrombticas en la Prevencin del Accidente Cerebro Vascular en la Fibrilacin Auricular

Prof.Dr.Juan R CortsQuiero a gradecer la infitacion a participar en esta reunio ciemtifica en donde se me a pedido que comente mi experiecia con rivaroxaban en el estudio RocketFibrilacin auricular (FA)La FA es el trastorno ms frecuente del ritmo cardaco1Aproximadamente 25% de las personas desarrollan FA a lo largo de la vida 1Afecta a >10% de personas > de 80 aos1En 2007, 6,3 millones de personas en EE.UU., Japn, Alemania, Italia, Espaa, Francia y Reino Unido vivan con una FA diagnosticada2Con el envejecimiento de la poblacin es previsible que esta cifra se duplique en 30 aos31. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046. 2. Decision Resources. Atrial Fibrillation Report. Dec 2008. 3. Go AS, et al. JAMA 2001;285:2370-2375.Incremento global del nmero de pacientes con Fibrilacin Auricular WPA2009-report.pdf. Accessed July 2011.Year2.082.442.265.15.102468101214161990199520002005201020152020202520302035204020452050Pacientes con FA (millones)5.4211.715.24.349.411.73.337.58.92.946.87.78.410.23.804.7810.313.15.1611.114.35.6112.115.95.65.92.666.16.7Olmsted County Data, 2006 (asume incremento en la incidencia de FA)Estudio ATRIA, 2000Olmsted County Data, 2006 (no asume futuros incrementos de la incidencia de FA)Se espera que el nmero de pacientes con FA aumenteEstimaciones recientes sugieren que para el aos 2025 habr 1.2 billones de individuos de ms de 60 aos en todo el mundo.1 Como consecuencia, se espera que aumente el nmero proyectado de personas con FA. Por ejemplo en los EEUU:Como parte del estudio ATRIA , Go y col. (2001) estimaron que habra un incremento en el nmero de adultos con FA de 2.3 millones en el ao 2000, a ms de 5.6 millones para el ao 2050 con ms de 50% de individuos afectados de 80 aos y ms2En un estudio que describi las tendencias de la incidencia de FA ajustadas por edad en una comunidad en Olmsted County, Minnesota, si el incremento en la incidencia de FA de 1980 hasta el 2000 contina hasta el 20503

AbreviacinATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; US, United States

References1. United Nations. Available at: http://www.un.org/esa/population/publications/WPA2009/WPA2009-report.pdf. Accessed July 2011.2.Go AS et al. JAMA 2001;285:23702375.3.Miyasaka Y et al. Circulation 2006;114:119125.Mecanismos principales del ACV isqumico

Enfermedad de pequeos vasos1520%

Enfermedad de grandes vasos1024%

ACV Cardioemblico2030%

Criptognico 2040%*

Otro~5%

1. Adams HP et al. Stroke 1993;24:3541; 2. Camm AJ et al. Eur Heart J 2010;31:23692429; 3. Northwest Geriatric Education Center. http://depts.washington.edu/nwgec/Educational_Resources/stroke_module.pdf. Accessed July 2011*Consistente con estimacin de la prevalencia de FA no diagnosticadaFA paroxsticano detectada?Los principales mecanismos de ACV isqumicoStroke is classified as either ischaemic or haemorrhagic.1,2 Ischaemic stroke, the most common type, has three primary causes:1,3Lacunar infarcts or small vessel disease primarily caused by hypertension and diabetes mellitus and is responsible for ~1520% of ischaemic strokesLarge vessel atherosclerosis or blockage of an extracranial (carotid or vertebral) or large intracerebral artery also responsible for ~1024% of ischaemic strokesThromboembolic stroke, primarily from cardiac emboli responsible for 2030% of allstrokesThe remainder is caused by another known origin (~5%) or is cryptogenic in origin (2040%)

ReferencesAdams HP et al. Stroke 1993;24:3541 Camm AJ et al. Eur Heart J 2010;31:23692429Northwest Geriatric Education Center. Available at: http://depts.washington.edu/nwgec/Educational_Resources/stroke_module.pdf. Accessed July2011Pathophysiology and prognosis of stroke in AF4En los pacientes con FA el riesgo de padecer un ACV aumenta cinco veces Incidencia de ACV/1000 individuos, a 2 aos, ajustada por edad.IndividuosCon FAIndividuosSin FA Tasa de riesgo = 4.8p1 ao)Permanente(aceptado)Paroxstica(usual 48 horas)Primer episodio diagnosticado de FA10Progression of AFThe progression of AF is hypothesized to be driven by structural changes in the atrium including electrical and contractile changes known as atrial remodellingAF is a progressive disease; it tends to progress from paroxysmal (self-terminating, usually within 48 hours) to persistent (non-self-terminating or requiring cardioversion), long-standing persistent (lasting longer than 1 year) and eventually to permanent (accepted) AFFirst-onset AF may be the rst of recurrent attacks or indeed, may already be permanent

ReferenceCamm AJ et al. Eur Heart J 2010;31:23692429Background10Puntaje de CHADS2 y riesgo de ACV en pacientes con FAItemPuntosInsuficiencia Cardaca Congestiva1Hipertensin 1EdAd 75 aos1Diabetes mellitus 1Stroke (ACV/AIT)2Suma de puntosGage BF et al, 2001.CHADS2

Riesgo de ACV (95%CI)*618.2 (10.527.4)512.5 (8.217.5)48.5 (6.311.1)35.9 (4.67.3)24.0 (3.15.1)12.8 (2.03.8)01.9 (1.23.0)*Por 100 pacientes - ao sin terapia antitrombtica.CHADS2 score and stroke risk in patients with AF The ability of the CHADS2 scheme to predict ischaemic stroke rates was examined by using patient data from the National Registry of AF. The subset that was examined contained 1,733 patients, aged 6595 years, with non-rheumatic AF, who were not prescribed warfarin at hospital discharge.1CHADS2 exhibited a c-statistic of 0.82 (95% CI: 0.800.84).Stroke rates (per 100 patient-years), in patients not receiving antithrombotic therapy, increased by a factor of 1.5 (95% CI: 1.31.7) for each 1-point increase in the CHADS2 score.

Reference1.Gage BF et al. JAMA 2001;285:28642870.

Guas para la terapia preventiva segn la estratificacin de riesgo de CHADS2 Categora de riesgoPuntajeTasa de ACV* (% por ao)Terapia antitrombtica#Bajo01.9 ASAIntermedio12.8ASA or VKAModerado a alto24.018.2VKA*Tasa de ACV sin terapia antitrombtica. #de acuerdo con las guas ACC/AHA/ESC 2006 y ACCP 2008.Fuster V et al, 2006.CHADS2 risk stratification for strokepreventionFor primary or secondary prevention of stroke, guidelines currently recommend that patients with AF receive either an anticoagulant (usually a VKA) or an antiplatelet regimen (typically ASA), depending on the perceived risk of stroke and adverse bleeding events.14 CHADS2 risk stratification permits an evidence-based method for deciding what antithrombotic therapy to choose for stroke prophylaxis in patients with AF, and was essentially adopted by the ACC/AHA/ESC2 and ACCP3 in their 2006 and 2008 stroke prevention in AF guidelines, respectively.Both sets of guidelines recommend ASA therapy for patients with a low stroke risk (CHADS2 score of 0): 81325 mg/day in the ACC/AHA/ESC 2006 guidelines2 and 75325 mg/day in the ACCP 2008 Guidelines3Patients at an intermediate risk of stroke (CHADS2 score of 1) were recommended to receive ASA or VKA therapy in these guidelines (target INR range 2.03.0)Patients at a moderate or higher risk of stroke (CHADS2 score of 2) were explicitly recommended VKA therapy, unless contraindications existCHADS2 is still retained in the 2010 ESC guidelines, but as an initial screening method; patients with a CHADS2 score of 1 undergo more detailed stroke risk assessment using the CHA2DS2-VASc scheme.4

AbbreviationINR, international normalized ratio

References1.Gage BF et al. Circulation 2004;110:22872292.2.Fuster V et al. Circulation 2006;114:e257354.3.Singer DE et al. Chest 2008;133(6 Suppl):546S592S.4.Camm AJ et al. Eur Heart J2010;31:2369429.Escala de CHA2DS2-VASc y riesgo de ACV en pacientes con FAItemPuntosACV/AIT o ES previa2Edad 75 2Insuficiencia Cardaca*1Hypertension1Diabetes mellitus1Edad 6574 aos1Femenino1Enfermedad Vascular 1CHA2DS2-VAScTasa de ACV al ao923.64%822.38%721.50%619.74%515.26%49.27%35.92%23.71%12.01%00.78%*O disfuncin sistlica moderada a severa (Fey 40%)Olesen JB et al. BMJ 2011;342:d124; Camm AJ et al. Eur Heart J2010;31:23692429 Suma de puntajesCHA2DS2-VASc score and stroke risk in patients with AF An ideal validation cohort for a thromboembolic risk scheme would be a large real world cohort of patients with atrial fibrillation, without any use of anticoagulation treatment. In Denmark, the national patient registry allows such an analysis in a large cohort of real world patients and was used to evaluate the predictive capability of CHADS2 and CHA2DS2-VASc for thromboembolismThe table (right-hand on slide) shows rates of thromboembolism per 100 person-years according to CHA2DS2-VASc risk scores at one year of follow-upThe high risk categories (score 2) had markedly increased rates of thromboembolism compared with the low or intermediate risk categories

ReferencesOlesen JB et al. BMJ 2011;342 ePublication doi: 10.1136/bmj.d124Camm AJ et al. Eur Heart J2010;31:2369242913Risk stratification for stroke and bleedingGuas ESC 2010: Seleccin de pacientes para ACOCamm AJ et al. Eur Heart J 2010;31:23692429CHADS2 score 2*SiSiOtros factores de riesgo# 2Otro factor de riesgo# (1)NoSiOACOAC (o ASA)Nada (o ASA)*ICC, HTA, edad >75 aos, diabetes mellitus, ACV/AIT/ ES (2 points)

#Otros factores de riesgo no-mayores clinicamente relevantes: Edad 6574, sexo femenino, enfermedades vascularesConsiderar otros factores de riesgo#NoSiEdad 75 aosNoNoTreatment guidelinesESC 2010 guidelines: selection of patients forOACsThe simplest risk assessment scheme is the CHADS2 score. The CHADS2 (cardiac failure, hypertension, age, diabetes mellitus, stroke [doubled]) risk index is based on a point system in which 2points are assigned for a history of stroke or TIA and 1 point each is assigned for age >75years, a history of hypertension, diabetes mellitus or recent cardiacfailureThe CHADS2 stroke risk stratification scheme can be used as a simple initial means of assessing stroke risk, particularly suited to primary care physicians and non-specialistsFor patients with a CHADS2 score of 2, the guidelines recommended OAC therapy (e.g.with a VKA) in a dose adjusted to achieve an INR value in the range of 2.03.0, unless contraindicated1For patients with a CHADS2 score of 01, or when a more detailed stroke risk assessment is indicated, the guidelines recommended to use a more comprehensive risk factor-based approach, incorporating other risk factors for thromboembolism (see next slide on CHA2DS2-VASc score)1

AbbreviationsCHADS2, Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, Stroke or transient ischaemic attack (2 points); OAC, oral anticoagulant

Reference1. Camm AJ et al. Eur Heart J 2010;31:23692429

Treatment guidelines14Guas ESC 2010: HAS-BLED para evaluar el riesgo de sangradoCaractersticas clnicasPuntajeHipertensin (PAS >160 mm Hg)1Insuficiencia heptica o renal1 + 1ACV1Predisposicin o antecedente de hemorragias1RIN Lbil1Edad >65 aos1Drogas o alcohol1 + 1PUNTAJE MXIMO9Pisters R et al. Chest 2010;138:10931100ESC 2010 guidelines: HAS-BLED for evaluation of bleeding risk2Optimum selection of patients with AF for anticoagulation therapy depends not only on assessment of their risk of stroke but also on identification of those at increased risk of developing bleedingcomplicationsUsing a real-world cohort of 3,978 European subjects with AF from the Euro Heart Survey,1a new simple bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly), has beenderived2The maximum possible score is 9, with 1 point for each of the components: Hypertension: systolic BP >160 mm HgAbnormal kidney function: the presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/l. Abnormal liver function: chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangementBleeding: previous bleeding history and/or predisposition to bleeding (e.g.bleeding diathesis, anaemia, etc.)Labile INRs: unstable/high INRs or poor time in therapeutic range (e.g. 60%)Elderly: patients aged >65 yearsDrugs/alcohol: concomitant use of drugs, such as antiplatelet agents, non-steroidal antiinflammatory drugs or alcohol abuse, etc.A score of more than 3 indicates high risk, and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy, whether with VKA or ASA2

AbbreviationsBP, blood pressure; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly

ReferencesPisters R et al. Chest 2010;138:10931100 Camm AJ et al. Eur Heart J2010;31:23692429Treatment guidelines15El riesgo de sangrado mayor aumenta con el puntaje HAS-BLED (p=0.007)

FA - Cohorte de la Euro Heart SurveyHAS-BLED scorePisters R et al, 2010.Nmero de pacientes7981,2867441874682000Nmero de eventos de sangrado913147410000Caractersticas ClnicasPuntosHypertension (SBP >160 mmHg)1Abnormal renal or liver function1 + 1Stroke1Bleeding1Labile INRs1Elderly (age >65years)1Drugs or alcohol1 + 1Cumulative scoreRange 09Risk of major bleeding increases with the HAS-BLED score The predictive accuracy of HAS-BLED in the AF cohort of patients from the Euro Heart Survey was good. The number of bleeds per 100 patient-years increased as the HAS-BLED score increased.The 2010 ESC Guidelines state that it would seem reasonable to use the HAS-BLED score to assess bleeding risk in patients with AF on the basis that a score of 3 indicates high risk. In addition, some caution and regular review of the patient would be needed following the initiation of antithrombotic therapy.2

References1.Pisters R et al. Chest 2010;138:10931100.2.Camm AJ et al. Eur Heart J2010;31:23692429.

Historia del tratamiento

1930s1940s1980s1990s2000sOralParenteralParenteralParenteralOralOralParenteralUFH: antithrombin-dependent inhibition of FXaand thrombin in 1:1 ratioVKAs: indirectly affect synthesisof multiple vitamin K-dependent coagulation factorsLMWH: antithrombin-dependent inhibitionof FXa >thrombinDTIsIndirect FXa inhibitorsDTIsDirect FXa inhibitorsAlban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990 UFH, unfractionated heparin; FXa, Factor Xa; VKAs, vitamins K antagonists; LMWH, low molecular weight heparin; DTIs, direct thrombin inhibitors1717ReferencesAlban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005;35 Suppl1:1220Link KP. The discovery of dicoumarol and its sequels. Circulation 1959;19:97107Maraganore JM et al. Design and characterization of Hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990;29:70957101 Esta vieja droga ha resistido todos los desafios por mas de 60 anosDescubrimiento de la Warfarina

Karl Paul LinkJournal Biologic Chemistry1940Primera descripcin de dicumarol1941Aprobado como rodenticide 1952Anticoagulacin oralLa warfarina como muchas cosas en la medicina fue descubierta por casualidad por un veterrinario.D e la universidad de wisconsin es por eso que la w viene de wisconsin a de alumni r research f foundationAdvantages and Disadvantages of NOACs

VentajasDesventajasAnticoagulacin oralSANGRADOEFECTO TERAPEUTICOToda droga que logre mayor nivel de prevencin (menor tasa de tromboembolismo) ser potencialmente ms hemorrgica (menor seguridad teraputica)Thrombosis backgroundPrevencin de ACV en la FA: AVKs vs placebo. Reduccin del riesgo de tromboembolismo en la FAHart RG et al. Ann Intern Med 2007;146:857867A favor de AVKA favor de placeboAFASAK I, 1989; 1990SPAF I, 1991EAFT, 1993SPINAF, 1992CAFA, 1991BAATAF, 1991All trials (n=6)Reduccin del riesgo relativo (95% IC)Ao del Estudio100%50%050%100%20Stroke prevention in AF: VKAs vs placebo or no treatmentHart and colleagues performed a meta-analysis of clinical trials (n=6) that compared adjusted-dose warfarin with placeboWarfarin reduced the relative risk of stroke by 64% (95% CI 4974), compared with placeboLa mortalidad total fue reducida en un 26% y el ACV isqumico ajustado a la dosis un 67%. El riesgo de HIC fue pequeo.AbbreviationsBAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA, Canadian Atrial Fibrillation Anticoagulation; SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation

ReferenceHart RG et al. Ann Intern Med 2007;146:857867Vitamin K antagonists and antiplatelet therapy for stroke prevention in AFLa Warfarina fue significativamente ms efectiva que la combinacin ASA + clopidogrelNumber at riskClopidogrel + ASA3,3353,1682,419941Warfarin 3,3713,2322,466930Cumulative risk of stroke0.050.040.030.020.01000.051.01.5YearsCumulative hazard ratesClopidogrel + ASARR=1.72 (1.242.37), p=0.001WarfarinAnnual incidence (%) RR 1.44p=0.0003RR 1.10p=0.5310864205.603.932.422.21Primary endpoint*Major bleeding Clopidogrel/ASA Warfarin *Composite of stroke, non-CNS embolism, myocardial infarction and vascular deathACTIVE Writing Group of the ACTIVE Investigators et al. Lancet 2006;367:19031912ACTIVE-W : Los pacientes con FA y 1 factor de riesgo adicional 21Warfarin significantly more effective than clopidogrel + ASA combinedACTIVE-W results: patients with AF and 1 additional risk factor:In ACTIVE-W, patients (n=6,706) with AF and 1 additional risk factor for stroke were randomized to receive warfarin or clopidogrel plus ASAThe additional risk factors for stroke were: age 75 years, previous stroke/TIA or systemicembolism, left ventricular ejection fraction