Del Rely a la práctica clínica

Del Rely a la práctica clínica J Zamorano

Predicted increase in number of patients with AF in the US (ATRIA study) Millions of AF patients projected over time 6 5 4 3 2 1 2.08 2.26 2.44 2.66 2.94 3.33 3.8 4.34 4.78 5.16 5.42 5.61 0 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Go et al. JAMA 2001;285:2370-75

Prevalencia en España de fibrilación auricular: desconocida e infraestimada

Prevalencia de fibrilación auricular: desconocida e infraestimada Incidencia de fibrilación auricular Las probabilidades de desarrollar fibrilación auricular a lo largo de la vida llegan a ser del 25% en varones (más que las mujeres) Lloyd-Jones DM. Circulation 2004; 110: 1042

60% 50% 40% 30% 20% 10% 0% Fibrilación Auricular Mortalidad sujetos 55-74 años Framingham Varones con FA Mujeres con FA Varones sin FA Mujeres sin FA 1 2 3 4 5 6 7 8 9 10 años de seguimiento Benjamin EJ et al, Circulation 1998; 98: 946

Cual es el problema real?

Atrial Fibrillation and Stroke AF responsible for 1/6 of all strokes Warfarin reduces stroke in AF by 64% significant increase in intracranial and other hemorrhage Difficult to use Only 50% of eligible patients receive warfarin An alternative treatment is needed

Comparative study design characteristics of new anticoagulants for AF RELY ROCKET ARISTOTLE ENGAGE-AF Sample size 18,113 14,266 18,201 20,500 New treatment and Dabigatran 110 mg BID Rivaroxaban 20 mg Apixaban 5 mg Edoxaban 30 mg QD dose Dabigatran 150 mg BID QD BID Edoxaban 60 mg QD Dose adjustment No At randomization At randomization During trial Design Non-inferiority Non-inferiority Non-inferiority Non-inferiority PROBE Double-blind Double-blind Double-blind Patients CHADS2 1 CHADS2 2 CHADS2 1 CHADS2 2 Primary outcome Stroke or systemic Stroke or systemic Stroke or systemic Stroke or systemic embolism embolism embolism embolism Safety outcome Major Bleeding Major Bleeding Major Bleeding Major Bleeding Abbreviations: BID, twice daily; QD, once daily; PROBE, prospective randomized open-label with blinded event adjudication 8

New oral anticoagulants in AF pharmacological properties Property Dabigatran Rivaroxaban Apixaban Edoxaban Route of administration Oral Oral Oral Oral Target Thrombin FXa FXa FXa Dosing Twice daily Once daily Twice daily Once daily Monitoring required No No No No Half-life (hrs) 12 17 9 12 8 15 8 11 Mode of elimination Renal 80% Renal ~66% Hepatic ~ 28% Renal ~25% Hepatic ~ 75% Renal ~35% Fxa = Factor Xa Eriksson BI et al. Annu Rev Med 2011;62:41 57; Pradaxa SmPC, 2011

Comparison of Study Designs RELY: Primary Efficacy Evaluation: Stroke or non-cns Embolism Rocket AF: Non-Inferiority: Intention-to-treat Superiority: Intention-to-treat Primary Efficacy Evaluation: Stroke or non-cns Embolism Non-Inferiority: Superiority: Protocol Compliant on treatment On Treatment, then by Intent-to- Treat RE-LY used Intention to treat for both non-inferiority and superiority testing; Rocket AF used on treatment analysis for first tests of non-inferiority and superiority

RE-LY: Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) 2.1 2.2 2.1 32.6 34.7 32.7 32.2 35.2 32.6 30.9 37.0 32.1 Prior stroke/tia (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 32.2 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 Warfarin Naïve (%) 49.9 49.8 51.4 Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

RE LY: Dabigatran (Pradaxa ) Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or open-label warfarin. Patients were followed for a mean of 2 years. %/year 10 5 *Dabigatran 150 mg vs. warfarin; Dabigatran 110 mg vs. warfarin (p <0.001*, p = 0.34 ) (p = 0.31*, p = 0.03 ) %/year 10 1.53 1.69 1.11 2.71 3.11 3.36 0 0 Stroke/systemic embolism Dabigatran 110 mg 5 Major bleeding Dabigatran 150 mg Warfarin Results Dabigatran 150 mg superior to warfarin for stroke/systemic embolism; dabigatran 110 mg was non-inferior Stroke in dabigatran 150 mg arm (p < 0.001) Major bleeding was higher in warfarin arm compared with dabigatran 110 mg, but was similar to dabigatran 150 mg Conclusions Dabigatran 150 mg superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile. The 110 mg dose was non-inferior for efficacy, associated with lower bleeding compared with warfarin Could prove to be alternative to warfarin for chronic anticoagulation; further data are awaited Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub]

Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 <0.001<0.001 <0.001 Dabigatran 150 vs. Warfarin Margin = 1.46 0.50 0.75 1.00 1.25 1.50 Dabigatran better HR (95% CI) Warfarin better

ROCKET AF Rivaroxaban (Xarelto ) Trial design: Patients with atrial fibrillation at increased risk for stroke were randomized to the direct factor Xa inhibitor rivaroxaban 20 mg oral daily (n = 7,131) vs. warfarin with target INR 2-3 (n = 7,133). Results Per 100 patient-years 4 2 0 (p for noninferiority < 0.001) 1.7 primary 2.2 Stroke or non-cns systemic embolism Rivaroxaban, 20 mg daily Warfarin, INR 2-3 Stroke or non-cns systemic embolism (per 100 patient-years): 1.7 with rivaroxaban vs. 2.2 with warfarin (p for noninferiority < 0.001, p for superiority = 0.12 by intention to treat analysis, p for superiority = 0.015 by on-treatment analysis) Major and nonmajor clinically relevant bleeding (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44) Intracranial hemorrhage (per 100 patient-years): 0.5 vs. 0.7 (p = 0.019) Conclusions Among atrial fibrillation patients with high stroke risk, rivaroxaban was noninferior to warfarin Rivaroxaban (on-treatment analysis) was associated with a reduced incidence of the primary outcome without an excess of major bleeding or intracranial hemorrhage Patel MR, et al. N Engl J Med 2011;Aug 10:[Epub]

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.001 21% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66 0.95); P (superiority)=0.011 No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768 Granger CB, NEJM 2011;365:981-92

Bleeding Outcomes Outcome Primary safety outcome: ISTH major bleeding* Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value 2.13 3.09 0.69 (0.60, 0.80) <0.001 Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001 Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding 4.07 6.01 0.68 (0.61, 0.75) <0.001 GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001 TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001 Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001 * Part of sequential testing sequence preserving the overall type I error Granger CB, NEJM 2011;365:981-92

Efficacy Outcomes Outcome Apixaban (N=9120) Event Rate (%/yr) Warfarin (N=9081) Event Rate (%/yr) HR (95% CI) P Value Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011 Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012 Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42 Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001 Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70 All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047 Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019 Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37 * Part of sequential testing sequence preserving the overall type I error Granger CB, NEJM 2011;365:981-92

Phase III AF Trials Results Scorecard Re-LY ROCKET-AF ARISTOTLE Drug Dabigatran Rivaroxaban Apixaban Stroke + SEE 150 mg superior 110 mg non-inferior ITT cohort: non-infer. On Rx cohort: superior superior Bleeding 150 mg: similar 110 mg: lower similar lower Mortality 150 mg: p = 0.051 110 mg: similar similar Superior: p = 0.047 Ischemic stroke 150 mg: lower 110 mg: similar similar similar Mean TTR 62% 55% 62% Stopped drug 21% 23% 23% WD consent 2.3% 8.7% 1.1% TTR = time in therapeutic range, a measure of the quality of warfarin titration WD consent = withdrawal of consent, no further data available

Ictus Bajo INR Sangrado Alto INR

ADJUSTED STROKE RATE CHADS 2 score Patients (n= 1733) Adjusted stroke rate (%/year) 95% confidence interval 0 120 1.9 (1.2 - -3.0) 1 463 2.8 (2.0 3.8) 2 523 4.0 (3.1 5.1) 3 337 5.9 (4.6 7.3) 4 220 8.5 (6.3 11.1) 5 65 12.5 (8.2 17.5) 6 5 18.2 (10.5 27.4) CHA 2 DS 2 -VASc score Patients (n= 7239) Adjusted stroke rate (%/year) 0 1 0% 1 422 1.3% 2 1230 2.2% 3 1730 3.2% 4 1718 4.0% 5 1159 6.7% 6 679 9.8% 7 294 9.6% 8 82 6.7% 9 14 15.2% www.escardio.org/guidelines

Risk factor CHA 2 DS 2 -VASc Risk factors for stroke and thrombo-embolism Score In non-valvular AF Congestive heart failure/lv dysfunction 1 Major Risk factors Clinically revelant non-major Hypertension Risk factors 1 AGE 75 2 Previous stroke, TIA, Heart failure or moderate to Or systematic embolism Severe LV systolic dysfunction Age 75 years (e.g. LV EF 40%) Hypertension Diabetes Mellitus Age 65-74 years Vascular disease Female sex Diabetes Mellitus 1 Stroke/TIA/thrombo-embolism 2 Vascular disease 1 Age 65-74 1 Sex category (i.e. female sex) 1 Maximum score 9 www.escardio.org/guidelines

The HAS-BLED bleeding risk score *Hypertension is defined as systolic blood pressure > 160 mmhg. INR = international normalized ratio.

Fibrilación auricular. ESC 2012 Highlights 1. Presentación clínica y diagnóstico 2. Refinamiento riesgo tromboembolismo y hemorragia 3. Nuevas recomendaciones de tratamiento 4. Ablación como método de tratamiento CHA 2 DS 2 -VASc Score CHF 1 HTA 1 Age 75 2 Diabetes 1 Stroke/AIT/TE 2 Enfermedad Vascular 1 Age 65-75 1 Sexo (i.e. femenino) < 75 1 CHA 2 DS 2 -VASc Tasa ACV Nada/AAS (% año) 0 ACO/AAS 0 1 ACO 1.3 2 2.2 3 3.2 4 4.0 5 6.7 6 9.8 7 9.6 8 6.7 9 15.2 H Hypertension 1 A Abnormal renal/liver 1 ó 2 S Stroke 1 B Bleeding 1 L Labile INR 1 E Elderly (>75) 1 D Drugs/Alcohol 1 ó 2 Clase I nivel evidencia A

. QUÉ HA CAMBIADO RESPECTO A LOS ANTICOAGULANTES ORALES? Antagonistas Vit K Vs Dabigatrán - New OAC drugs, which may be viable alternatives to a VKA,, may be considered. - Recommendations : - CHA 2 DS 2 -VASc 2, Dabigatran may be considered, as an alternative to VKA: - HAS-BLED=0 2: dabigatran 150 mg b.i.d. [in view of the improved efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin)] - HAS-BLED= 3: dabigatran 110 mg b.i.d.. [in[ view of a similar efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and of major bleeding compared with VKA)] - CHA 2 DS 2 -VASc=1: dabigatran 110 mg b.i.d.. may be considered [in view of a similar efficacy with VKA in the prevention of stroke and systemic embolism but lower rates of intracranial haemorrhage and major bleeding compared with the VKA and (probably) AAS.]

y qué piensan los demás?

CCS Atrial Fibrillation Guidelines 2010: Prevention of Stroke and Systemic Thromboembolism in Atrial Fibrillation and Flutter John A Cairns, MD, FRCPC, Stuart Connolly, MD, FRCPC, Sean McMurtry, MD, PhD, FRCPC, Michael Stephenson, MD, FCFP, Mario Talajic, MD, FRCPC

Guías FA Canadienses 2010 Estratificación de riesgo Riesgo embólico / Riesgo hemorrágico En todos los pacientes con FA o flutter debe realizarse una estratificación del riesgo tromboembólico (CHADS 2 ) y hemorrágico (HASBLED) porque la mayoría recibirán tratamiento anticoagulante Strong Recommendati on High Quality Evidence

-We recommend that all patients with AF or AFL should be stratified using a predictive index for stroke(e.g. CHADS 2 ) and for the risk of bleeding(e.g. HAS-BLED), and that most patients should receive antithrombotic therapy. - CHADS 2 =0: AAS(-) patients at very low risk of stroke should receive AAS(75-325 mg/day). We suggest that some young persons with no standard risk factors for stroke may not require anyantithrombotic therapy. -CHADS 2 =1: OAC (AAS) patients at low risk of stroke should receive OAC therapy (either warfarinor dabigatran). We suggest, based on individual risk/benefit considerations, that AASis a reasonable alternative for some. -CHADS 2 2:OAC patients at moderate risk of stroke should receive OAC therapy (either warfarin or dabigatran). We suggest, that when OAC therapy is indicated, most patients should receive dabigatranin preference to warfarin (excluding CAD patients). In general, the dose of dabigatran150 mg pobid is preferable to a dose of 110 mg po (Conditional recommendation. High Quality Evidence).

AHA-ACC-HRS 2011

INDICACIONES ACO EN FA Riesgo trombótico CHADS-VASc CHADSVASc = 0 CHADSVASc = 1 CHADSVASc 2 AAS o nada ACO o AAS ACO Riesgo hemorrágico elevado (HASBLED 3) considerar la indicación o mayores controles