Nuevas Estrategias Antitrombóticas en la Prevención del Accidente Cerebro Vascular en la Fibrilación Auricular Quiero a gradecer la infitacion a participar.

Presentación del tema: "Nuevas Estrategias Antitrombóticas en la Prevención del Accidente Cerebro Vascular en la Fibrilación Auricular Quiero a gradecer la infitacion a participar."— Transcripción de la presentación:

1 Nuevas Estrategias Antitrombóticas en la Prevención del Accidente Cerebro Vascular en la Fibrilación Auricular Quiero 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 Rocket Prof.Dr.Juan R Cortés

2 Fibrilación auricular (FA)
La FA es el trastorno más frecuente del ritmo cardíaco1 Aproximadamente 25% de las personas desarrollan FA a lo largo de la vida 1 Afecta a >10% de personas > de 80 años1 En 2007, 6,3 millones de personas en EE.UU., Japón, Alemania, Italia, España, Francia y Reino Unido vivían con una FA diagnosticada2 Con el envejecimiento de la población es previsible que esta cifra se duplique en 30 años3 1. Lloyd-Jones DM, et al. Circulation 2004;110: Decision Resources. Atrial Fibrillation Report. Dec 2008. 3. Go AS, et al. JAMA 2001;285:

3 Incremento global del número de pacientes con Fibrilación Auricular
Year 2.08 2.44 2.26 5.1 2 4 6 8 10 12 14 16 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Pacientes con FA (millones) 5.42 11.7 15.2 4.34 9.4 3.33 7.5 8.9 2.94 6.8 7.7 8.4 10.2 3.80 4.78 10.3 13.1 5.16 11.1 14.3 5.61 12.1 15.9 5.6 5.9 2.66 6.1 6.7 Olmsted County Data, 2006 (asume incremento en la incidencia de FA) Estudio ATRIA, 2000 Olmsted County Data, 2006 (no asume futuros incrementos de la incidencia de FA) Se espera que el número de pacientes con FA aumente Estimaciones recientes sugieren que para el años 2025 habrá 1.2 billones de individuos de más de 60 años en todo el mundo.1 Como consecuencia, se espera que aumente el número proyectado de personas con FA. Por ejemplo en los EEUU: Como parte del estudio ATRIA , Go y col. (2001) estimaron que habría un incremento en el número de adultos con FA de 2.3 millones en el año 2000, a más de 5.6 millones para el año 2050 – con más de 50% de individuos afectados de 80 años y más2 En un estudio que describió 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 continúa hasta el 20503 Abreviación ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation; US, United States References 1. United Nations. Available at: WPA2009-report.pdf. Accessed July 2011. 2. Go AS et al. JAMA 2001;285:2370–2375. 3. Miyasaka Y et al. Circulation 2006;114:119–125. WPA2009-report.pdf. Accessed July 2011.

4 Mecanismos principales del ACV isquémico
Pathophysiology and prognosis of stroke in AF Mecanismos principales del ACV isquémico Enfermedad de pequeños vasos 15–20% Enfermedad de grandes vasos 10–24% ACV Cardioembólico 20–30% Criptogénico 20–40%* Otro ~5% Los principales mecanismos de ACV isquémico Stroke is classified as either ischaemic or haemorrhagic.1,2 Ischaemic stroke, the most common type, has three primary causes:1,3 Lacunar infarcts or small vessel disease – primarily caused by hypertension and diabetes mellitus – and is responsible for ~15–20% of ischaemic strokes Large vessel atherosclerosis or blockage of an extracranial (carotid or vertebral) or large intracerebral artery – also responsible for ~10–24% of ischaemic strokes Thromboembolic stroke, primarily from cardiac emboli – responsible for 20–30% of all strokes The remainder is caused by another known origin (~5%) or is cryptogenic in origin (20–40%) References Adams HP et al. Stroke 1993;24:35–41 Camm AJ et al. Eur Heart J 2010;31:2369–2429 Northwest Geriatric Education Center. Available at: Accessed July 2011 FA paroxística no detectada? *Consistente con estimación de la prevalencia de FA no diagnosticada 1. Adams HP et al. Stroke 1993;24:35–41; 2. Camm AJ et al. Eur Heart J 2010;31:2369–2429; 3. Northwest Geriatric Education Center. Accessed July 2011 4

5 En los pacientes con FA el riesgo de padecer un ACV aumenta cinco veces
Estudio Framingham (N=5,070) 60 Tasa de riesgo = 4.8 p<0.001 50 40 Incidencia de ACV/1000 individuos, a 2 años, ajustada por edad. 30 Patients with AF have a ~fivefold increased risk of ischaemic stroke AF is shown to substantially increase the risk of experiencing an ischaemic stroke1 The Framingham Heart Study was a landmark study that prospectively followed men and women who were free of cardiovascular disease (including AF) at study enrolment every 2 years for the development of cardiovascular disease2 A 34-year follow-up of this study, involving 5,070 participants, evaluated the impact of various cardiovascular conditions, including AF, on the incidence of stroke1,2 In a comparison of the 2-year age-adjusted incidence of stroke per 1,000 individuals with and without AF, those with AF were almost five times more likely to suffer an ischaemic stroke than those without AF (risk ratio=4.8, p<0.001, 2-year age-adjusted incidence of stroke: ~50/1,000 individuals with AF vs ~10/1,000 individuals without AF)1 Overall, it is estimated that ~15% of all ischaemic strokes are caused by AF2 References Wolf PA et al. Stroke 1991;22:983–988. Wolf PA et al. Arch Intem Med 1987;147:1561–1564. 20 10 Individuos Sin FA Individuos Con FA Wolf PA et al, 1991.

6 El Riesgo de ACV es independente del tipo de Fibrilación Auricular
Risk stratification for stroke and bleeding El Riesgo de ACV es independente del tipo de Fibrilación Auricular Proporción de pacientes con ACV isquémico durante el primer año de seguimiento (%) Ischaemic stroke risk is independent of the type of AF The Euro Heart Survey examined the characteristics and management of all types of AF in cardiology practices in Europe The survey enrolled 5,333 patients during 2003–2004, of which 80% had follow-up data. One of the outcomes examined was the number of patients who experienced ischaemic stroke during the 1-year follow-up period It was observed that the risk of ischaemic stroke was broadly similar across all types of AF Whether there was any difference in stroke rates between the four AF types was tested with the χ2 statistic; the p-value was 0.582, indicating that there was no significant difference in stroke rates between AF types Reference Nieuwlaat R et al. Eur Heart J 2008;29:1181–1189 (n=708) (n=886) (n=1,126) (n=1,170) Nieuwlaat R et al. Eur Heart J 2008;29:1181–1189 6

7 Riesgos de la Fibrilación Auricular
MORBILIDAD 1,2 MORTALIDAD 1,2 Riesgo de ACV x 5 3 Mortalidad x 2 8 ACV por FA mayor severidad y discapacidad 4, 5 ACV asociados a FA mayor mortalidad 5 IC frecuentemente coexiste con FA y empeora el pronóstico 6 Mortalidad al año del 50% 9 Internaciones x 2-3 7 En Framingham aumenta la mortalidad por FA a los 30 días 10 7

8 Costo de salud del ACV producido por Fibrilación Auricular
Se estima que el 44 % del costo del tratamiento de la FA lo generan las hospitalizaciones. “La FA es un factor predictor de mayores costos en los cuidados del ACV, por su influencia en la severidad de las secuelas. “ Los costos de un ACV producido por FA son aproximadamente el doble de los ACVs de otra causa. Es importante tener en cuenta los costos asociados con el cuidado del paciente que padeció un ACV cuando se deciden estrategias para prevenir el mismo. A Pharmacoeconomic Perspective on Stroke Prevention in Atrial Fibrillation Journal of Managed Care 16(10 Suppl. S):S284 S290,01/11/2010

9 Detección El ECG de superficie muestra intervalos R-R absolutamente irregulares No pueden distinguirse ondas P en el ECG de superficie El ciclo auricular (cuando es visible), por ejemplo en el intervalo entre dos activaciones auriculares, es usualmente variable y < 200 ms Esto debe durar al menos 30 segs en una tira de ritmo para ser considerado FA

10 Background La progresión de la FA es secundaria a los cambios estructurales de la aurícula (cambios eléctricos, contráctiles , remodelado atrial) Primer episodio diagnosticado de FA Paroxística (usual ≤48 horas) Persistente (>7 días o requiere cardioversión) Progression of AF The progression of AF is hypothesized to be driven by structural changes in the atrium –including electrical and contractile changes – known as atrial remodelling AF 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) AF First-onset AF may be the first of recurrent attacks – or indeed, may already be permanent Reference Camm AJ et al. Eur Heart J 2010;31:2369–2429 Persistente de larga duración (>1 año) Permanente (aceptado) Camm AJ et al. Eur Heart J 2010;31:2369–2429 10

11 Puntaje de CHADS2 y riesgo de ACV en pacientes con FA
Riesgo de ACV (95%CI)* 6 18.2 (10.5–27.4) 5 12.5 (8.2–17.5) 4 8.5 (6.3–11.1) 3 5.9 (4.6–7.3) 2 4.0 (3.1–5.1) 1 2.8 (2.0–3.8) 1.9 (1.2–3.0) Item Puntos Insuficiencia Cardíaca Congestiva 1 Hipertensión EdAd ≥75 años Diabetes mellitus Stroke (ACV/AIT) 2 Suma de puntos 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 65–95 years, with non-rheumatic AF, who were not prescribed warfarin at hospital discharge.1 CHADS2 exhibited a c-statistic of 0.82 (95% CI: 0.80–0.84). Stroke rates (per 100 patient-years), in patients not receiving antithrombotic therapy, increased by a factor of 1.5 (95% CI: 1.3–1.7) for each 1-point increase in the CHADS2 score. Reference 1. Gage BF et al. JAMA 2001;285:2864–2870. *Por 100 pacientes - año sin terapia antitrombótica. Gage BF et al, 2001.

12 Terapia antitrombótica#
Guías para la terapia preventiva según la estratificación de riesgo de CHADS2 Categoría de riesgo Puntaje Tasa de ACV* (% por año) Terapia antitrombótica# Bajo 1.9 ASA Intermedio 1 2.8 ASA or VKA Moderado a alto ≥2 4.0–18.2 VKA CHADS2 risk stratification for stroke prevention For 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.1–4 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): 81–325 mg/day in the ACC/AHA/ESC 2006 guidelines2 and 75–325 mg/day in the ACCP 2008 Guidelines3 Patients at an intermediate risk of stroke (CHADS2 score of 1) were recommended to receive ASA or VKA therapy in these guidelines (target INR range 2.0–3.0) Patients at a moderate or higher risk of stroke (CHADS2 score of ≥2) were explicitly recommended VKA therapy, unless contraindications exist CHADS2 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 Abbreviation INR, international normalized ratio References 1. Gage BF et al. Circulation 2004;110:2287–2292. 2. Fuster V et al. Circulation 2006;114:e257–354. 3. Singer DE et al. Chest 2008;133(6 Suppl):546S–592S. 4. Camm AJ et al. Eur Heart J 2010;31:2369–429. *Tasa de ACV sin terapia antitrombótica. #de acuerdo con las guías ACC/AHA/ESC 2006 y ACCP 2008. Fuster V et al, 2006.

13 Escala de CHA2DS2-VASc y riesgo de ACV en pacientes con FA
Risk stratification for stroke and bleeding Escala de CHA2DS2-VASc y riesgo de ACV en pacientes con FA CHA2DS2-VASc Tasa de ACV al año 9 23.64% 8 22.38% 7 21.50% 6 19.74% 5 15.26% 4 9.27% 3 5.92% 2 3.71% 1 2.01% 0.78% Item Puntos ACV/AIT o ES previa 2 Edad ≥75 Insuficiencia Cardíaca* 1 Hypertension Diabetes mellitus Edad 65–74 años Femenino Enfermedad Vascular Suma de puntajes CHA2DS2-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 thromboembolism The table (right-hand on slide) shows rates of thromboembolism per 100 person-years according to CHA2DS2-VASc risk scores at one year of follow-up The high risk categories (score ≥2) had markedly increased rates of thromboembolism compared with the low or intermediate risk categories References Olesen JB et al. BMJ 2011;342 ePublication – doi: /bmj.d124 Camm AJ et al. Eur Heart J 2010;31:2369–2429 Olesen JB et al. BMJ 2011;342:d124; Camm AJ et al. Eur Heart J 2010;31:2369–2429 *O disfunción sistólica moderada a severa (Fey ≤40%) 13

14 Guías ESC 2010: Selección de pacientes para ACO
Treatment guidelines Treatment guidelines Guías ESC 2010: Selección de pacientes para ACO CHADS2 score ≥2* *ICC, HTA, edad >75 años, diabetes mellitus, ACV/AIT/ ES (2 points) #Otros factores de riesgo no-mayores clinicamente relevantes: Edad 65–74, sexo femenino, enfermedades vasculares No Si Considerar otros factores de riesgo# Edad ≥75 años No Si Otros factores de riesgo# ≥2 ESC 2010 guidelines: selection of patients for OACs The 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 2 points are assigned for a history of stroke or TIA and 1 point each is assigned for age >75 years, a history of hypertension, diabetes mellitus or recent cardiac failure The 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-specialists For 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 2.0–3.0, unless contraindicated1 For patients with a CHADS2 score of 0–1, 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 Abbreviations CHADS2, Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke or transient ischaemic attack (2 points); OAC, oral anticoagulant Reference 1. Camm AJ et al. Eur Heart J 2010;31:2369–2429 No Si OAC Otro factor de riesgo# (1) OAC (o ASA) Si No Nada (o ASA) Camm AJ et al. Eur Heart J 2010;31:2369–2429 14

15 Guías ESC 2010: HAS-BLED para evaluar el riesgo de sangrado
Treatment guidelines Guías ESC 2010: HAS-BLED para evaluar el riesgo de sangrado Características clínicas Puntaje Hipertensión (PAS >160 mm Hg) 1 Insuficiencia hepática o renal 1 + 1 ACV Predisposición o antecedente de hemorragias RIN Lábil Edad >65 años Drogas o alcohol PUNTAJE MÁXIMO 9 ESC 2010 guidelines: HAS-BLED for evaluation of bleeding risk2 Optimum 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 bleeding complications Using a ‘real-world’ cohort of 3,978 European subjects with AF from the Euro Heart Survey,1 a new simple bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly), has been derived2 The maximum possible score is 9, with 1 point for each of the components: ‘Hypertension’: systolic BP >160 mm Hg ‘Abnormal 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 derangement ‘Bleeding’: 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 years ‘Drugs/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 Abbreviations BP, blood pressure; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly References Pisters R et al. Chest 2010;138:1093–1100 Camm AJ et al. Eur Heart J 2010;31:2369–2429 Pisters R et al. Chest 2010;138:1093–1100 15

16 El riesgo de sangrado mayor aumenta con el puntaje HAS-BLED (p=0.007)
Características Clínicas Puntos Hypertension (SBP >160 mmHg) 1 Abnormal renal or liver function 1 + 1 Stroke Bleeding Labile INRs Elderly (age >65 years) Drugs or alcohol Cumulative score Range 0−9 FA - Cohorte de la Euro Heart Survey Risk 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 References 1. Pisters R et al. Chest 2010;138:1093–1100. 2. Camm AJ et al. Eur Heart J 2010;31:2369–2429. HAS-BLED score Número de pacientes 798 1,286 744 187 46 8 2 Número de eventos de sangrado 9 13 14 7 4 1 Pisters R et al, 2010.

17 Historia del tratamiento
Parenteral UFH: antithrombin-dependent inhibition of FXa and thrombin in 1:1 ratio 1930s Oral VKAs: indirectly affect synthesis of multiple vitamin K-dependent coagulation factors 1940s Parenteral LMWH: antithrombin-dependent inhibition of FXa >thrombin 1980s Parenteral DTIs 1990s References Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005;35 Suppl 1:12–20 Link KP. The discovery of dicoumarol and its sequels. Circulation 1959;19:97–107 Maraganore JM et al. Design and characterization of Hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990;29:7095–7101 Esta vieja droga ha resistido todos los desafios por mas de 60 anos Parenteral Indirect FXa inhibitors DTIs 2000s Oral Direct FXa inhibitors Oral UFH, unfractionated heparin; FXa, Factor Xa; VKAs, vitamins K antagonists; LMWH, low molecular weight heparin; DTIs, direct thrombin inhibitors Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990 17 17

18 Descubrimiento de la Warfarina
Anticoagulación oral Descubrimiento de la Warfarina Karl Paul Link Journal Biologic Chemistry–1940 Primera descripción de dicumarol–1941 Aprobado como rodenticide –1952 La 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 foundation

19 Thrombosis background
Anticoagulación oral Advantages and Disadvantages of NOACs Toda droga que logre mayor nivel de prevención (menor tasa de tromboembolismo) será potencialmente más hemorrágica (menor seguridad terapéutica) SANGRADO EFECTO TERAPEUTICO Ventajas Desventajas

20 Prevención de ACV en la FA: AVKs vs placebo
Prevención de ACV en la FA: AVKs vs placebo. Reducción del riesgo de tromboembolismo en la FA Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF Año del Estudio Reducción del riesgo relativo (95% IC) AFASAK I, 1989; 1990 SPAF I, 1991 BAATAF, 1991 CAFA, 1991 SPINAF, 1992 EAFT, 1993 Stroke prevention in AF: VKAs vs placebo or no treatment Hart and colleagues performed a meta-analysis of clinical trials (n=6) that compared adjusted-dose warfarin with placebo Warfarin reduced the relative risk of stroke by 64% (95% CI 49–74), compared with placebo La mortalidad total fue reducida en un 26% y el ACV isquémico ajustado a la dosis un 67%. El riesgo de HIC fue pequeño. Abbreviations BAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA, Canadian Atrial Fibrillation Anticoagulation; SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation Reference Hart RG et al. Ann Intern Med 2007;146:857–867 All trials (n=6) 100% 50% –50% –100% A favor de AVK A favor de placebo Hart RG et al. Ann Intern Med 2007;146:857–867 20

21 La Warfarina fue significativamente más efectiva que la combinación ASA + clopidogrel
Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF ACTIVE-W : Los pacientes con FA y ≥1 factor de riesgo adicional 10 Cumulative risk of stroke 0.05 RR 1.44 p=0.0003 Clopidogrel/ASA RR=1.72 (1.24–2.37), p=0.001 8 Warfarin 0.04 6 5.60 RR 1.10 p=0.53 0.03 Annual incidence (%) Cumulative hazard rates Clopidogrel + ASA 4 3.93 0.02 2.42 2.21 Warfarin 2 Warfarin significantly more effective than clopidogrel + ASA combined ACTIVE-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 ASA The additional risk factors for stroke were: age ≥75 years, previous stroke/TIA or systemic embolism, left ventricular ejection fraction <45%, peripheral arterial disease, or if aged 55–74 years, patients also had to have diabetes mellitus or previous coronary artery disease The primary endpoint was the first occurrence of stroke, non-CNS systemic embolus, myocardial infarction or vascular death Patients were allocated randomly to receive warfarin therapy (target INR 2.0–3.0) or clopidogrel (75 mg/day) plus ASA (75–100 mg/day) and were intended to be followed for approximately 2 years The trial was stopped early because of clear evidence of the superiority of warfarin therapy Patients on warfarin had 165 primary endpoint events (annual risk 3.93%) and those on clopidogrel plus ASA had 234 (annual risk 5.60%; RR=1.44; 95% CI 1.18–1.76; p=0.0003) Major bleeding rates were similar in both treatment groups It was concluded that warfarin therapy is superior to clopidogrel plus ASA for the prevention of vascular events in patients with AF at high risk of stroke Abbreviations CNS, central nervous system; INR, international normalized ratio; TIA, transient ischaemic attack Reference ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;376:1903–1912 0.01 Primary endpoint* Major bleeding 0.05 1.0 1.5 Years Number at risk Clopidogrel + ASA 3,335 3,168 2, Warfarin 3,371 3,232 2, *Composite of stroke, non-CNS embolism, myocardial infarction and vascular death ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet 2006;367:1903–1912 21

22 Los AVKs se asocian con mayor sangrado, particularmente entre los pacientes más añosos
Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF 0.10 Age 80 years 0.08 Age <80 years Cumulative incidence with major haemorrhage 0.06 0.04 0.02 0.00 VKAs are associated with major bleeding, particularly among the elderly Although VKAs are undoubtedly effective for stroke prevention in patients with AF, the elderly, in particular, face the risk of major haemorrhage during therapy In a study of warfarin in the elderly,1 consecutively admitted patients with AF who started warfarin were identified from January 2001 to June 2003 and followed for 1 year Patients had to be ≥65 years of age, have established care at the study institution and have their warfarin managed on site Outcomes included major haemorrhage, time to termination of warfarin and reason for discontinuation Of 472 patients, 32% were ≥80 years of age and 91% had ≥1 stroke risk factor The risk of major haemorrhage was shown to be particularly high for elderly patients The cumulative incidence of major haemorrhage was: 13.1 per 100 person-years for those ≥80 years of age 4.7 per 100 person-years for those <80 years of age (p=0.009) An increased risk of haemorrhage was associated with: Age ≥80 years An INR of ≥4.0, although only 2% of person-time was spent in this range The first 90 days of warfarin therapy Within the first year, 26% of patients aged ≥80 years stopped taking warfarin. Perceived safety issues accounted for 81% of these discontinuations Rates of major haemorrhage and warfarin termination were highest among patients with CHADS2 scores ≥3 Abbreviation CHADS2, Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke or transient ischaemic attack (2 points) Reference Hylek EM et al. Circulation 2007;115:2689–2696 100 200 300 400 Days on warfarin Consecutive admitted patients with AF who started warfarin were identified from January 2001 to June 2003 and followed for 1 year Patients had to be ≥65 years of age, have established care at the study institution, and have their warfarin managed on site Hylek EM et al. Circulation 2007;115:2689–2696 22

23 VKAs: La relación beneficio/riesgo mejora con la edad
Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF VKAs: La relación beneficio/riesgo mejora con la edad Net clinical benefit: events prevented per 100 person-years 2.34 3.30 1.29 ≥85 1.00 1.40 0.44 75–84 Age, years 0.11 0.40 –0.37 65–74 VKAs: benefit–risk improves with increasing age The net benefit of warfarin anticoagulation was assessed in a retrospective study of patients with AF (n=13,559) who formed part of the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) cohort Net clinical benefit was defined as the annual rate of (ischaemic strokes and systemic emboli prevented by warfarin) minus (intracranial haemorrhages attributable to warfarin multiplied by 1.5 [to reflect the greater clinical impact of intracranial haemorrhage versus thromboembolism]) Of note, the older the patient, the greater the net clinical benefit. The net clinical benefit significantly favoured warfarin in patients aged ≥75 years, suggesting that age should not be perceived as a barrier to anticoagulant prescription Reference Singer DE et al. Ann Intern Med 2009;151:297–305 –0.25 0.08 –0.65 <65 –1 –0.5 0.5 1 1.5 2 2.5 3 3.5 Worse with warfarin Better with warfarin Singer DE et al. Ann Intern Med 2009;151:297–305 23

24 Thrombosis background
Ventajas y desventajas de los VKAs Thrombosis background Advantages and Disadvantages of NOACs Desventajas Ventajas

25 Thrombosis background
Ventajas y desventajas de los VKAs Advantages and Disadvantages of NOACs Estrecha ventana terapeutica Requiere monitoreo de rutina Desventajas Ventajas 1. Ansell J et al. Chest 2008;133:160S–198S; 2. Nieuwlaat R et al. Am Heart J 2007;153:1006–1012; 3. Ogilvie IM et al. Am J Med 2010;123:638–645; 4. Nieuwlaat R et al. Eur Heart J 2005;26:2422–2434; 5. Waldo A et al. J Am Coll Cardiol 2005;46:1729–1736

26 VKAs tienen una estrecha ventana terapéutica
Benefits and limitations of current treatment options VKAs tienen una estrecha ventana terapéutica ACV isquémico1 ACV hemorrágico1 1 2 3 4 5 6 8 10 12 Stroke rate per 100 patient-years 16 Observed Predicted 95% CI 14 VKAs have a narrow therapeutic window Both observed event rates and cerebrovascular event rates predicted as a function of INR1 demonstrate that: INR <2 is associated with an increased risk of ischaemia INR >3 is associated with an increased risk of haemorrhagic stroke Because of its narrow therapeutic window, VKA-related haemorrhage is the leading cause of iatrogenic hospitalization, accounting for 13% of hospitalizations due to drug-related adverse events2 References Amouyel P et al. Eur J Intern Med 2009;20:63–69 Pouyanne P et al. BMJ 2000;320:1036 RIN debajo de 2 se asocia con un incremento del riesgo de ACV isquémico INR por encima de 3 se asocia con un incremento del riesgo de ACV hemorrágico VKA-related haemorrhage is the leading cause of iatrogenic hospitalization, accounting for 13% of hospitalizations due to drug-related adverse events2 1. Amouyel P et al. Eur J Intern Med 2009;20:63–69; 2. Pouyanne P et al. BMJ 2000;320:1036 26

27 Thrombosis background
Ventajas y desventajas de los VKAs Thrombosis background Advantages and Disadvantages of NOACs Elevada interaccion con drogas y alimentos Vida media prolongada Lento comienzo de acción Polimorfismos genéticos (VKORC1 y CYP2C9) Dosis Variables Estrecha ventana terapeutica Requiere monitoreo de rutina Desventajas Ventajas 1. Ansell J et al. Chest 2008;133:160S–198S; 2. Nieuwlaat R et al. Am Heart J 2007;153:1006–1012; 3. Ogilvie IM et al. Am J Med 2010;123:638–645; 4. Nieuwlaat R et al. Eur Heart J 2005;26:2422–2434; 5. Waldo A et al. J Am Coll Cardiol 2005;46:1729–1736

28 Interacciones medicamentosas
Benefits and limitations of current treatment options Interacciones medicamentosas Decreased INR response VKAs have many drug–drug interactions VKAs have a non-selective mode of action and as a result, multiple medications have been found to have an effect on VKA response Increased INR response is associated with an increased risk of bleeding Decreased INR response is associated with an increased risk of stroke and other thromboembolic events Reference Coumadine Package Insert US revised January 2010 Coumadine Package Insert US revised January 2010 28

29 Increased INR response

30 Thrombosis background
Ventajas y desventajas de los AVK Advantages and Disadvantages of NOACs Elevada interaccion con drogas y alimentos Vida media prolongada Lento comienzo de acción Polimorfismos genéticos  (VKORC1 y CYP2C9) Dosis Variables Estrecha ventana terapeutica Requiere monitoreo de rutina Bajo costo Antídoto Eficacia bien establecida Desventajas Ventajas 1. Ansell J et al. Chest 2008;133:160S–198S; 2. Nieuwlaat R et al. Am Heart J 2007;153:1006–1012; 3. Ogilvie IM et al. Am J Med 2010;123:638–645; 4. Nieuwlaat R et al. Eur Heart J 2005;26:2422–2434; 5. Waldo A et al. J Am Coll Cardiol 2005;46:1729–1736

31 El control del RIN en la práctica es subóptimo
Benefits and limitations of current treatment options El control del RIN en la práctica es subóptimo Retrospective, multicentre cohort study (ISAM) 32–50% de los pacientes con FA tienen un excelente control (RIN dentro del objetivo durante >70% del tiempo) 11–36% de los pacientes tienen un control subóptimo (RIN dentro del objetivo durante <50% del tiempo) INR control in routine practice is suboptimal – results from the ISAM study (1) ISAM was a retrospective, multicentre cohort study conducted in the US, Canada, France, Italy and Spain, which assessed 1,511 patients with chronic non-valvular AF from representative practices1 Medical records were used to extract data relating to their OAC care. All patients included in this study received a VKA for at least 60 days A total of 18,148 INR tests with 1,234 patient-years of evaluable treatment were analysed The percentage of all INRs in a range of 2.0–3.0 varied from 50.8% to 60%, while the percentage of time in this range varied from 58.1% to 69.5% Analysis of INR control at a patient level based on 1,384 patients who had INRs covering a minimum of 60 days of treatment showed that the mean percentage of patient time in an INR range of 2.0–3.0 varied from 57.0% to 68.9% At a patient level, there was considerable variability in the degree of INR control achieved, with some patients with 32–50% achieving excellent levels of control (70% or more of time within target range), and 11–36% achieving poor levels of control (<50% time in range) Abbreviations ISAM, International Study of Anticoagulation Management; OAC, oral anticoagulant Reference Ansell J et al. J Thromb Thrombolysis 2007;23:83–91 Ansell J et al. J Thromb Thrombolysis 2007;23:83–91 31

32 El control del RIN en la práctica es subóptimo
Benefits and limitations of current treatment options El control del RIN en la práctica es subóptimo Retrospective, multicentre cohort study (ISAM) % INRs 20 40 60 80 100 US Canada France Italy Spain INR <2 INR 2–3 INR >3 Time in therapeutic range INR control in routine practice is suboptimal – results from the ISAM study (2) The ISAM study found that anticoagulation care varied from country to country and suggested that better INR control may be achieved in the anticoagulation clinic setting compared with routine care1 Patients were treated in routine medical care in the US, Canada and France, and in anticoagulation clinics in Italy and Spain Overall, in the real-life setting, INR control in many patients is far from optimal Reference Ansell J et al. J Thromb Thrombolysis 2007;23:83–91 Ansell J et al. J Thromb Thrombolysis 2007;23:83–91 32

33 La fibrilación auricular en el mundo real
72534 ots 255 hospitales 34% TENIA FA O ANTECEDENTES DE FA 9% TENIA CONTRAINDICACIONES PARA WARFARINA analysis, we found that older patients, women, black patients, Medicaid recipients, and those with a history of coronary artery disease, anemia, and renal insufficiency were less likely to be discharged on warfarin (Table 2). Additionally,HF admissions at smaller hospitals, nonacademic hospitals, and hospitals without house staff or interventional capabilities were less likely to discharge patients on warfarin Tambien es llamativo en caso pero o inusal que los pacientes de mas riesgo son los menos tratados. Aca vemos que los score chads tienen menos terapeutica JACC 2009 ;54: 33

34 Motivos por los cuales los médicos argentinos no indican tratamiento anticoagulante. Registro RENAFA
Debido a la escasa información disponible acerca de datos observacionales en pacientes con fibrilación y aleteo auricular en Argentina, se diseñó el registro nacional de fibrilación auricular (RENAFA) con el objetivo de contar con datos locales. Este es un registro prospectivo multicéntrico que incluyó a todos los distritos de la Sociedad Argentina de Cardiología. Entre agosto 2010 y febrero de 2011 se incluyeron un total de 1052 pacientes con riesgo de fibrilación auricular, 91% de los cuales tenían fibrilación auricular. La población del registro era una población de riesgo moderado, con una edad media de 68 años, mayoría hombres, 56% CHADS mayor o igual a 2. En relación a los factores de riesgo, 43% tenía dislipemia; 16%, diabetes; 74%, hipertensión arterial; sólo 11% tenía antecedentes de stroke o AIT, y 41% tenía antecedentes de insuficiencia cardíaca. Aproximadamente la mitad de los pacientes con FA o AA no presentaba miocardiopatía. Al identificar las etiologías, se encontró que las causas más frecuentes fueron: 15,2% miocardiopatía hipertrófica, y 13,8% miocardiopatía dilatada. En aquellos pacientes en quienes se tenía valoración de la fracción de eyección (58% del total de los pacientes), la mitad tenía fracción de eyección del ventrículo izquierdo conservada. En relación al tratamiento, 56% de los pacientes recibían tratamiento para control de la frecuencia y sólo 44% para control de ritmo. La siguiente diapositiva resume los datos relacionados al tratamiento anticoagulante. Sólo 67,9% de los pacientes con FA y AA recibían anticoagulantes orales y en 21% se registraba contraindicación para recibirlos, según el criterio del médico tratante.

35 Blancos en anticoagulación
TF/VIIa ORALES DIRECTOS PARENTERALES INDIRECTOS X IX Los AVKs iniben la síntesis hepática varios factores de coagulación3 IXa VIIIa AT Va Fondaparinux Rivaroxaban Apixaban Edoxaban Xa Targets for the newer anticoagulants The coagulation cascade ultimately leads to the conversion of soluble fibrinogen to insoluble fibrin by the enzymatic action of thrombin (Factor IIa), leading to the formation of a thrombus VKAs, such as warfarin, produce an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to carboxyglutamates on the N-terminal regions of vitamin K–dependent proteins. These proteins, which include the coagulation factors II, VII, IX and X, require carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, VKAs induce hepatic production of partially decarboxylated proteins with reduced coagulant activity3 The two main targets for the new anticoagulant drugs are thrombin and Factor Xa which, together with Factor Va, cleaves prothrombin (Factor II) to form thrombin (Factor IIa) Among the parenteral anticoagulants: Fondaparinux indirectly inhibits Factor Xa LMWH and UFH indirectly inhibit both Factor Xa and thrombin Fondaparinux, LMWH and UFH each require AT as a cofactor for activity against Factor Xa. They are, therefore, indirect inhibitors Among the OACs: Rivaroxaban, apixaban and edoxaban are direct Factor Xa inhibitors Dabigatran etexilate and AZD 0837 are direct thrombin inhibitors Abbreviations AT, antithrombin; LMWH, low molecular weight heparin; TF, tissue factor; UFH, unfractionated heparin References Weitz et al. J Thromb Haemost 2005;3:1843–1853. Weitz et al. Chest 2008;133:234–256. Ansell et al. Chest 2008;133:160S–198S. AT HBPM II AT HNF Ximelagatran Dabigatran AZD 0837 IIa Fibrinogen Fibrin Adapted from: 1. Weitz et al, 2005 and 2. Weitz et al, 2008; 3. Ansell et al, 2008.

36 Implicancias Clínicas: comparación farmacocinética
Properties of conventional and new OACs: MoA, PK, PD Implicancias Clínicas: comparación farmacocinética Parámetro Dabigatran Rivaroxaban Apixaban Warfarina Objetivo Trombina Factor Xa Factores vitamino k dependientes Biodisponibilidad Oral 6.5% 80–100%* ~66% Alta Unión a proteinas plasmáticas 34–35% 92–95% 87% 99% Dosificación Fija, dos veces al día Fija, una vez al día Variable, una vez al día Prodroga Sí No Vida media 12–14 5–9 (jóvenes) 11–13 (ancianos) 8–13 40 Tmax (h) ~6 2–4 1–3 8-12 Monitoreo de coagulación de rutina Comparison of the pharmacological characteristics of newer oral anticoagulants The four newer OACs in the Phase III stage of development for stroke prevention in patients with AF are: The direct thrombin inhibitor dabigatran The Factor Xa inhibitors: rivaroxaban, apixaban and edoxaban The Factor Xa inhibitors have higher oral bioavailability than the direct thrombin inhibitor dabigatran, which is administered as the prodrug dabigatran etexilate Plasma protein binding for the newer agents ranges from 34% to 95% All the newer OACs can be administered at fixed doses either once or twice daily The half-life of the newer agents ranges from 5 to 14 hours depending on the drug and the patient, and tmax ranges from 1 to 6 hours None of these newer OACs requires routine coagulation monitoring Abbreviation tmax, time to reach maximum plasma concentration References Eriksson BI et al. Annu Rev Med 2011;62:41–57 Frost C et al. J Thromb Haemost 2007;5(Suppl 2):P-M-664 Kubitza D et al. Clin Pharm Ther 2005;78:412–421 Lopes RD et al. Am Heart J 2010;159:331–339 Ogata K et al. J Clin Pharmacol 2010;50:743–753 ROCKET AF Study Investigators. Am Heart J 2010;159:340–347.e1 Ruff CT et al. Am Heart J 2010;160:635–641.e2 Stangier J et al. J Clin Pharmacol 2005;45:555–563 Dabigatran Prescribing information . Available at: /022512s004lbl.pdf. Accessed September 2011 Eliquis Summary of Product Characteristics. Available at: WC pdf. Accessed September 2011 Pradaxa Summary of Product Characteristics. Available at: document_library/EPAR_-_Product_Information/human/000829/ WC pdf. Accessed September 2011 Xarelto Prescribing Information. Available at: Accessed September 2011 Kubitza et al. Eur J Clin Pharmacol ;61:873–880 Raghavan N et al . Drug Metab Dispos 2009;37:74–81 Xarelto Summary of Product Characteristics. Available at: document_library/EPAR_-_Product_Information/human/000944/WC pdf. Accessed September 2011 *15–20mg debe ser administrada con una comida principal Eriksson BI et al. Annu Rev Med 2011;62:41–57; Frost C et al. J Thromb Haemost 2007;5(Suppl 2):P-M-664; Kubitza D et al. Clin Pharm Ther 2005;78:412–421; Lopes RD et al. Am Heart J 2010;159:331–339; Ogata K et al. J Clin Pharmacol 2010; 50:743–753; ROCKET AF Study Investigators. Am Heart J 2010;159:340–347.e1; Ruff CT et al. Am Heart J 2010;160: 635–641.e2; Stangier J et al. J Clin Pharmacol 2005;45:555–563; Dabigatran PI; Eliquis SmPc; Pradaxa SmPc; Xarelto PI 36

37 Implicancias Clínicas: comparación farmacocinética
Properties of conventional and new OACs: MoA, PK, PD Implicancias Clínicas: comparación farmacocinética Parámetro Dabigatran Rivaroxaban Apixaban Warfarina Clearance renal 80% 33% droga activa; 33% metabolizada ~25% Interacciones farmacológicas Rifampicina, quinidina, amiodarona, inhibidores de la bomba de protones Inhibidores potentes del CYP3A4* Citocromo P450 Múltiples drogas y alimentos Comparison of the pharmacological characteristics of newer oral anticoagulants (2) Dabigatran, rivaroxaban, apixaban and edoxaban are all partially cleared via the renal route. However, not all new anticoagulants rely on this route to the same extent with apixaban being 25% renally excreted, for example, and dabigatran being 80% renally excreted All the newer OACs have interactions with P-gp inhibitors and the Factor Xa inhibitors, as they undergo some metabolism in the liver, also have interactions with CYP3A4 inhibitors Abbreviations CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein Reference Eriksson BI et al. Annu Rev Med 2011;62:41–57 Xarelto Summary of Product Characteristics. Available at: document_library/EPAR_-_Product_Information/human/000944/WC pdf. Accessed September 2011 *Inhibidores potentes CYP3A4 antifúngicos (ketoconazole, itraconazole,) macrólidos (claritromicina) e inhibidores de las proteasas del HIV (ritonavir) Eriksson BI et al. Annu Rev Med 2011;62:41–57, Xarelto Summary of Product Characteristics, 4 March 2011 37

38 Thrombosis background
Ventajas y desventajas de los nuevos anticoagulantes orales Advantages and Disadvantages of NOACs Ventajas Desventajas

39 Thrombosis background
Ventajas y desventajas de los nuevos anticoagulantes orales Advantages and Disadvantages of NOACs Amplia ventana terapeutica Mejora la adherencia Sin interacciones alimentarias Baja interaccion con drogas Rapido comienzo y terminacion de la accion No requiere monitoreo de rutina Dosis fijas Comparable eficacia y mejor seguridad Costo Falta de control de adherencia Falta de antídoto Ventajas Desventajas

40 Todos estos trail incluyen mas de 50
Todos estos trail incluyen mas de pacientes estudiados y comparados

41

42 Características Poblacionales ROCKET comparado con RE-LY y ARISTOTLE
Población Edad (mediana) 73 71.6 70 CHADS2 (media) 3.47±0.94 2.1±1.1 CHADS2 >2 87% 32.5% 30% Ictus, ES, AIT previo 54.5% 20% 19.5% AVK previo 62.4% 50% 57% ICC 62.5% 32% 35% Infarto Miocardio 17% 16% 14% Diabetes 40% 23% 25% Discontinuación 23.7% 21% 25.3% INR 2-3 (mediana/media) 58% 64% 66% Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 63 Granger CB et al ES: Embolismo Sistémico; AIT: Accidente Isquémico Transitorio; AVK: Antagonista Vit K

43 RE-LY® - diseño del estudio
Fibrilación auricular no valvular con riesgo moderado o alto de ictus o embolia sistémica (al menos un factor de riesgo adicional) R Warfarina 1 mg, 3 mg, 5 mg (INR 2,0-3,0) N = 6000 Dabigatrán etexilato 110 mg dos veces al día N = 6000 Dabigatrán etexilato 150 mg dos veces al día N = 6000 Objetivo principal: no inferioridad respecto a la warfarina Seguimiento mínimo de 1 año, máximo de 3 años y medio de 2 años Criterio principal de valoración: ictus + embolia sistémica Stuart J. Connolly et al. N Engl J Med 2009; 361: September 17, 2009

44 35%

45 RE-LY® - Resultados Stuart J. Connolly et al. N Engl J Med 2009; 361: September 17, 2009

46 RE-LY® - Resultados Stuart J. Connolly et al. N Engl J Med 2009; 361: September 17, 2009

47 RE-LY® - Efectos no deseados
Stuart J. Connolly et al. N Engl J Med 2009; 361: September 17, 2009

48 Antithrombotic therapy for stroke prevention in AF
Rivaroxaban Once-daily compared with AVKs in the Prevention of Stroke and Embolism Trial in AF - 2 factores: DM, CAD, IC, HTA, Edad > 75 - 1 factor: ACV/o AIT o embolía., FA No-valvular de moderado a alto riesgo de AVE o embolía sistémica ( al menos dos factores de riesgo bajo o 1 alto riesgo ) Rivaroxaban 20mg día (15mg Cl ml/min) N=7131 Doble Ciego Warfarina Objetivo INR 2,5 (INR ) N=7133 Doble Ciego Estudio Clínico doble ciego Objetivo primario: No inferiordad a la warfarina Evento Primario: AVE + Embolía sistemica Mahaffey et al. AHA 2010 48

49 Análisis del estudio Preespecificados Post hoc
No-inferioridad (población por protocolo, en tratamiento) Todos los pacientes que hubiesen recibido ≥1 dosis del fármaco en estudio y sin violaciones graves del protocolo; se incluyeron los eventos hasta dos días tras la última dosis de la fase doble ciego Superioridad (población de seguridad, en tratamiento) Todos los pacientes que hubiesen recibido ≥1 dosis del fármaco en estudio; se incluyeron los eventos hasta dos días tras la última dosis de la fase doble ciego Análisis adicionales: análisis por “intención de tratar” (ITT) Todos los pacientes aleatorizados, incluyendo los eventos hasta el fin del estudio Post hoc Poblaciones ITT: en tratamiento y sin tratamiento En aquellos que completaron el estudio según lo planificado, incluyendo los eventos que ocurrieron durante la transición a la fase abierta de tratamiento al final del estudio Study statistical analyses1 The prespecified number of events to ensure a robust statistical result was 405 in the per-protocol on-treatment population Reference Patel MR et al. N Engl J Med 2011;365:883–891 Patel MR et al. N Engl J Med 2011;365:883-91

50 Resultado de eficacia primaria Stroke and non-CNS Embolism
Rivaroxaban Warfarin Event Rate 1.71 2.16 Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

51 Variable primaria en tratamiento y sin tratamiento
Eventos durante el tratamiento ciego (en tratamiento) Eventos después de la suspensión (sin tratamiento) 10 10 9 9 Rivaroxabán 8 8 7 HR=0.79 (0.66–0.96) p=0.02 (superioridad) 7 HR=1.10 (0.79–1.52) p=0.58 (superioridad) 6 6 Warfarina Tasa acumulada de acontecimientos (%) Tasa acumulada de acontecimientos (%) 5 5 4 4 Warfarina 3 3 Rivaroxabán 2 2 1 1 120 240 360 480 600 720 840 120 240 360 480 600 720 840 Días desde la aleatorización Días desde la suspensión del tratamiento Número de pacientes en riesgo Riva Warf Población ITT; ITT con y sin tratamiento: análisis post hoc Patel MR et al. N Engl J Med 2011;365:883-91

52 Ultima dosis de Rivaroxabán
ROCKET AF – transición a Antagonistas de la Vitamina K en ramas abiertas una vez completado el estudio Primera dosis de la droga en estudio Transición a AVK abierto Seguimiento R Ultima dosis de Rivaroxabán Anticoagulación subóptima Rivaroxabán Inicio Warfarina Difficulties in transitioning to open-label VKA in ROCKET AF study completers The median time to the first therapeutic INR value was 13 days after cessation of rivaroxaban. Warfarin group: INR measurements were discouraged for 3 days1 References Patel MR et al. N Engl J Med 10 Aug 2011 ( /NEJMoa ). Warfarina Warfarina continua Período de Tratamiento Doble Ciego Período de Observación Post-tratamiento R=randomization Duración del Estudio

53 ROCKET-AF Variable primaria en tratamiento y sin tratamiento
Rivaroxabán n/N (% anual) Warfarina n/N (% anual) HR (IC del 95%) Valor de p No inf. Sup. Por protocolo, en tratamiento 188/6.958 (1,7) 241/7.004 (2,2) 0,79 (0,66, 0,96) < 0,001 Seguridad, en tratamiento 189/7.061 (1,7) 243 /7.082 (2,2) 0,79 (0,65, 0,95) 0,02 ITT 269/ (2,1) 306/7.090 (2,4) 0,88 (0,75, 1,03) 0,12 ITT, en tratamiento 188 (1,7) 240 (2,2) ITT, sin tratamiento 81 (4,7) 66 (4,3) 1,10 (0,79, 1,52) 0,58 HR IC del 95% Criterio principal de valoración de la eficacia: ictus o embolia sistémica ITT durante el tratamiento, después de la suspensión: análisis post hoc 0,5 1 2 A favor de rivaroxabán A favor de warfarina Patel MR et al. N Engl J Med 2011;365:883-91 53 53 53

54 ROCKET AF Análisis de variable primaria por Subgrupos
RR, IC 95% 0.1 0.2 0.5 1 2 5 10 Rivaroxabán mejor Warfarina Rivaroxaban Warfarina p- n/N (%) Global 189/7061 2.7 243/7082 3.4 Sexo 0.92 Varón 103/4270 2.4 136/4283 3.2 Mujer 86/2791 3.1 107/2799 3.8 Edad (años) 0.11 <75 107/3988 119/4005 3.0 ≥75 82/3073 124/3077 4.0 Peso (kg) 0.78 ≤70 63/2004 78/2008 3.9 70–≤90 92/3022 129/3133 4.1 >90 34/2033 1.7 36/1940 1.9 CrCl (ml/min) 0.72 <50 50/1485 60/1456 50–80 91/3290 2.8 128/3396 >80 47/2278 2.1 54/2221 Patel MR et al. N Engl J Med 2011;365:883-91

55 Variables Secundarias
Rivaroxaban (N=7061) Warfarina (N=7082) RR, IC 95% n (% por año) Variable combinada de ictus, embolismo sistémico y muerte vascular 346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)* Variable combinada de ictus, embolismo sistémico y muerte vascular e IM 433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)* Componentes de la variable secundaria Ictus por todas las causas 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03) Embolismo sistémico 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* IM 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06) Mortalidad vascular 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10) Mortalidad total 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02) Hazard ratio (95% CI) and P-value from Cox proportional hazard model with treatment group as a covariate. P-values (2-sided for superiority of rivaroxaban versus warfarin): Composite of stroke, non­CNS SE, ans vascular death: p=0.034 Composite of stroke, non-CNS SE, vascular death, and MI : p=0.010 All-cause stroke: p=0.092 Non-CNS SE: p=0.003 MI: p=0.121 Vascular death: p=0.289 All-cause mortality: p=0.073 *estadísticamente significativo Patel MR et al. N Engl J Med 2011;365:883-91

56 Análisis de Seguridad Patel MR et al. N Engl J Med 2011;365:883-91
G w_script.ppt 4/7/2017 1:02:08 PM 2_ MoA update final.ppt G w_script.ppt Análisis de Seguridad 4/7/2017 1:02:08 PM Parámetro Rivaroxaban (N=7111) Warfarina (N=7125) RR (95% CI) n (% por año) Variable principal de seguridad 1475 (14.9) 1449 (14.5) 1.03 (0.96,1.11) Sangrado “grave” 395 (3.6) 386 (3.4) 1.04 (0.90,1.20) Descenso Hb (≥2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusión 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Sangrado orgánico crítico 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Hemorragia intracraneal 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* Sangrado mortal 27 (0.2) 0.50 (0.31,0.79)* Sangrado no grave relevante 1185 (11.8) 1151 (11.4) 1.04 (0.96,1.13) RR , IC 95% The principal safety outcome was defined as the composite of major and non-major clinically relevant bleeding P-values (2-sided for superiority of rivaroxaban versus warfarin in hazard ratio): Principal safety outcome: p=0.44 Major bleeding: p=0.58 Decrease in hemoglobin (≥2 g/dl): p=0.02 Transfusion: p=0.04 Critical bleeding: p=0.007 Fatal bleeding: p=0.003 Intracranial hemorrhage: p=0.02 Non-major clinically relevant bleeding: p=0.35 Major bleeding from a gastrointestinal site was more common with rivaroxaban (224 bleeds [3.2%] compared with warfarin (154 bleeds [2.2%]; p<0.001). 0.2 0.5 1 2 5 Sangrado gastrointestinal: Rivaroxabán = 224 eventos (3.2%); Warfarina = 154 evenots (2.2%); p<0.001* Favorable Rivaroxabán Favorable Warfarina Patel MR et al. N Engl J Med 2011;365:883-91 56 56 56

57 Eventos Adversos Rivaroxabán (N=7111) Warfarina (N=7125) 82,4 82,2
Cualquier evento adverso 82,4 82,2 Cualquier evento adverso grave 37,3 38,2 Evento adverso que lleva a discontinuar tratamiento 15,7 15,2 Epistaxis 10,1 8,6 Edema Periférico 6,1 6,2 Mareos 6,3 Nasofaringitis 5,9 6,4 Insuficiencia cardíaca 5,6 Bronquitis Disnea 5,3 5,5 Diarrea Adverse events Adverse events reported with rivaroxaban in ROCKET-AF were found to be comparable with warfarin.1 Of note: Overall, dabigatran was also found to be well tolerated in RE-LY® and the rate of adverse events was similar across all three treatment arms – dabigatran 150 mg, dabigatran 110 mg and warfarin.2 References Mahaffey KW et al. Presented at AHA 2010; Session LBCT Available at: Connolly SJ, et al. N Engl J Med 2009;361:1139–1151 Patel MR et al. N Engl J Med 2011;365:883-91 57

58 Variable primaria: ictus + embolismo sistémico
ROCKET-AF Cohorte de Prevención secundaria 7 Variable primaria: ictus + embolismo sistémico Ictus/TIA previo, warfarina 6 Ictus/TIA previo rivaroxaban 5 4 Sin ictus/TIA previo, warfarina Eventos acumulados – Ictus o embolismo sistémico (%) 3 2 Sin ictus/TIA previo, rivaroxaban 1 6 12 18 24 30 Meses El uso de Rivaroxaban es eficaz tanto en prevención 1ª como 2ª 20th European Stroke Conference (Hamburg - May 2011)

59 Tratamiento nuevos ACO Pacientes con Insuficiencia Renal
Los nuevos anticoagulantes se eliminan parcialmente por vía renal1 No obstante, no todos los nuevos anticoagulantes se eliminan en la misma medida por esta vía1 Rivaroxaban2 Apixaban3 Edoxaban4 Dabigatran etexilato5 Eliminación en forma activa Via renal ~33%* ~25%# 35% ~80%† Renal elimination of the new OACs and their use in patients with renal impairment Warfarin is almost entirely metabolized and very little unchanged drug is excreted renally6 Renal clearance of the Factor Xa inhibitors as unchanged drug is approximately one-third2–5 This means the Factor Xa inhibitors can potentially be used to treat renally impaired patients if the doses are adjusted accordingly Adjusted doses for renally impaired patients are under evaluation in trials for the Factor Xa inhibitors in AF7–9 Dabigatran has approximately 80% renal clearance5 and is contraindicated in patients with severe renal impairment References Eriksson BI et al. Annu Rev Med 2011;62:41–57. Weinz C et al. Drug Metab Dispos 2009;37:1056–1064. Raghavan N et al. Drug Metab Dispos 2008;37:74–81. Ogata K et al. J Clin Pharmacol 2010;50:743–753. Blech S et al. Drug Metab Dispos 2008;36:386–399. Baker RI et al. Med J Aust 20041;181: Ruff CT et al. Am Heart J 2010;160:635–641. Lopes RD et al. Am Heart J 2010;159:331–339. ROCKET AF Study Investigators. Am Heart J 2010;159:340–347.e1. Manejo potencial mediante ajuste de dosis Contraindicado en Insuf Renal grave *33% adicional excretado por vía renal tras degradación metabólica en forma de fármaco inactivo6 #Porcentaje estimado de la dosis administrada por vía oral †Media tras la administración intravenosa dentro de las primeras 24 horas tras la dosis 1. Eriksson BI et al, 2011; 2. Weinz C et al, 2009; 3. Raghavan N et al, 2008; 4. Ogata K et al, 2010; 5. Blech S et al, 2008; 6. Xarelto Summary of Product Characteristics 2011.

60 Variable primaria Pacientes con IR moderada (CrCl 30-49 ml/min)
G w_script.ppt 4/7/2017 Variable primaria Pacientes con IR moderada (CrCl 30-49 ml/min) Rivaroxabán Warfarina Tasa de eventos 2,32 2,77 Warfarina Rivaroxabán Tasa acumulada de eventos (%) HR (IC 95%): 0.84 (0.57, 1.23) Días desde la aleatorización N.º en riesgo: Rivaroxabán Warfarina Tasas de acontecimientos porcentuales al año Basado en la población por protocolo con cumplimiento terapéutico Fox KAA et al. Eur Heart J 2011;32:

61 HR (IC del 95%) Riva vs Warfarina
Insuficiencia renal Variables clínicas (% anual) Rivaroxabán (n=7.111) Warfarina (n=7.116) HR (IC del 95%) Riva vs Warfarina p (interacción) Variable primaria de eficacia* 1,57 2,32 2,00 2,77 0,78 (0,63–0,98) 0,84 (0,57–1,23) 0,76 EP + muerte vascular 2,76 4,64 3,32 4,83 0,83 (0,70–0,98) 0,96 (0,73–1,27) 0,38 EP + IM, muerte vascular 3,55 5,58 4,16 6,54 0,85 (0,73–0,99) 0,85 (0,67–1,09) 0,98 Ictus Isquémico 1,20 1,98 1,34 1,78 0,90 (0,69–1,16) 1,11 (0,71–1,73) 0,41 Hemorrágico 0,26 0,29 0,42 0,52 0,62 (0,37–1,03) 0,56 (0,21–1,51) 0,88 No determinado 0,07 0,05 0,10 0,09 0,68 (0,24–1,90) 0,51 (0,05–5,67) 0,84 CrCl ≥ 50 ml/min† CrCl ml/min‡ 0,01 0,1 1 10 Basado en población por protocolo en tratamiento *Ictus y embolia sistémica †Rivaroxabán 20 mg od. ‡Rivaroxabán 15 mg od Fox KAA et al. Eur Heart J 2011;32:

62 Sitios de sangrado en pacientes con CrCl 30–49 ml/min
Clinical data Sitios de sangrado en pacientes con CrCl 30–49 ml/min Major bleeding (% per year) CrCl 30–49 ml/min CrCl ≥50 ml/min Rivaroxaban 15 mg (N=1,474) Warfarin (N=1,476) Rivaroxaban 20 mg (N=5,637) Warfarin (N=5,640) Gastrointestinal (upper, lower, and rectal)* 2.88 1.77 1.79 1.12 Intracranial haemorrhage# 0.71 0.88 0.44 Macroscopic haematuria 0.05 0.18 0.28 0.19 Bleeding associated with non-cardiac surgery 0.24 0.42 0.15 Intra-articular 0.00 0.23 0.17 Epistaxis 0.09 0.10 0.13 Reference Fox KA et al. Eur Heart J 2011; 32 (19): *p=0.02 (rivaroxaban vs warfarin in CrCl 30–49 ml/min); p= (rivaroxaban vs warfarin in CrCl ≥50 ml/min) #p=0.02 (rivaroxaban vs warfarin in CrCl ≥50 ml/min) Fox KA et al. Eur Heart J 2011; 32 (19):

63 Conclusiones Clinical data Basado en el objetivo primario pre-especificado de eficacia: Una dosis fija de Rivaroxaban una vez al día fue no inferior a warfarina para prevenir el ACV o la embolia sistémica fuera del SNC Rivaroxaban fue superior a Warfarina mientras los pacientes estaban en la fase de tratamiento activo. Seguridad: La incidencia global de eventos adversos de sangrado fue similar en ambos grupos Hubo un incremento de sangrado gastrointestinal pero una menor incidencia de hemorragia intracraneana así como una menor incidencia de sangrado fatal con rivaroxaban Implicancias: Rivaroxaban, administrado una vez al día, demostró no-inferioridad vs. warfarina en la prevención de ACV y embolismo sistémico, con una tasa global de eventos adversos de sangrado similar y una menor tasa de hemorragias intracraneales Reference Patel MR et al. N Engl J Med 2011;365:883–891 Patel MR et al. N Engl J Med 2011;365:883–891 63

64 Desventajas de Dabigatran en comparación con Rivaroxaban
Administración de dos dosis diarias Intolerancia gástrica Interacción con los inhibidores de la bomba de protones IAM

65 Otras indicaciones de Rivaroxaban
Prevención de ACV en Fibrilación Auricular Tratamiento de TVP Tratamiento de TEP Rivaroxabán Sindrome Coronario Agudo* Prevención de TEV The number and variety of different indications that Xarelto is being investigated in means that the knowledge required is vast Scientific experts such as you are needed to not only comprehend these data but also to put it into context and be able to communicate the broad range of indications – linking the different diseases to the different HCPs and adapting your scientific exchanges and projects accordingly – not an easy task but one I am confident you are and will achieve *Gibson CM, Mega JL, Burton P, et al. Rationale and design of the Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS-ACS 2 - TIMI 51) trial: A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011; 161:

66 Antithrombotic therapy for stroke prevention in AF
Clinical data ARISTOTLE: apixaban vs warfarin Randomized, phase III, double-blind, non-inferiority, event-driven trial Apixaban 5 mg b.i.d 5 mg bid Warfarin target INR 2-3 INR range 2–3 R N=18,201 Apixaban 2.5 mg bid* End of treatment Follow-up AF or atrial flutter And at least 1 additional risk factor: Prior stroke/ TIA or SE Age ≥75 years Symptomatic HF or LVEF ≤40% Diabetes mellitus Hypertension Abbreviation SE, systemic embolism Reference Granger CB et al. N Engl J Med 2011;365:981–992 *Lower dose for patient with any two of the following: Age ≥80 years Body weight ≤60 kg Serum creatinine ≥1.5 mg/dl (133 µmol/l) Granger CB et al. N Engl J Med 2011;365:981–992 66

67 Punto Final Primario Stroke o Embolia sistémica
P (no-inferioridad)<0.001 21% RRR Apixaban 212 pacientes, 1.27% anual Warfarin pacientes, 1.60% anual HR 0.79 (95% CI, 0.66–0.95); P (superioridad)=0.011 No. En Riesgo Apixaban Warfarina Granger CB et al. N Engl J Med 2011;365:981–992

68 Sangrado Mayor SegúnISTH definición
31% RRR Apixaban 327 pacientes, 2.13% anual Warfarin 462 pacientes, 3.09% anual HR 0.69 (IC 95% , 0.60–0.80); P<0.001 No. Apixaban Warfarina Granger CB et al. N Engl J Med 2011;365:981–992

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70 AVERROES: Resultados Conolly et al.NEM:2011

71 AVERROES: Resultados Conolly et al.NEM:2011

72 Aspectos sin resolver…
No hay un método de monitoreo establecido No hay un rango terapéutico conocido No hay antídoto disponible Manejo del sangrado Seguridad a largo plazo No hay comparación entre los agentes

73 Estudio RECOVER II El estudio RECOVER II confirma la no inferioridad del dabigatran,en relación a la warfarina en la prevencion del TEV,y similares episodios de sangrado.Futuro estudios deben compararlo con lo otros nuevos AC apixaban,rivaroxaban,y edoxaban Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysi s. April 11,2014 Schulman S, Kakkar AK, Goldhaber SZ, et al., on behalf of the RE-COVER II Trial Investigators. Circulation 2014;129:

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77 GRACIAS POR LA ATENCIÓN