Riesgo/beneficio de la anticoagulación en la insuficiencia renal

Riesgo/beneficio de la anticoagulación en la insuficiencia renal Dr. Carlos Guijarro Unidad de Medicina Interna Universidad Rey Juan Carlos

Riesgo/beneficio de la anticoagulación en la insuficiencia renal Insuficiencia renal Factor de riesgo de Fibrilación Auricular Ictus Factor de riesgo enf. tromboembólica Insuficiencia renal Factor de riesgo de Sangrado Balance riesgo / beneficio Nuevos anticoagulantes e insuficiencia renal Balance riesgo / beneficio Dicumarínicos y calcificación vascular Conclusiones GUIJARRO ACO. IRC-2011 2

Renal function and risk of coronary heart disease. GUIJARRO ACO. IRC-2011 3 Di Angelantonio E et al. BMJ 2010;341:bmj.c4986

Major bleeding events in FRENA ODDS RATIO Univariate 7.7 (2.2 27) Multivariate 6.2; (1.8 22) GUIJARRO ACO. IRC-2011 4 J Thromb Haemost 2009; 7: 1414 6.

To bleed or not to bleed That is the question INR RESULTS GUIJARRO ACO. IRC-2011 5

Riesgo/beneficio de la anticoagulación en la insuficiencia renal Insuficiencia renal Factor de riesgo de Fibrilación Auricular Factor de riesgo enf. tromboembólica Insuficiencia renal Factor de riesgo de Sangrado Nuevos anticoagulantes e insuficiencia renal Balance riesgo / beneficio Dicumarínicos y calcificación vascular Conclusiones GUIJARRO ACO. IRC-2011 6

Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation: ARIC Study. Cumulative incidence of AF by cystatin C-based GFR. Cox model adjusted for age, sex, education, height, hs CRP; BMI, SBP (& tx), CV disease, smoking, alcohol Alonso Circulation 2011; 123:2946-2953, DOI: 10.1161/CIRCULATIONAHA.111.020982 GUIJARRO ACO. IRC-2011 7 4

Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation: ARIC Study. Cumulative incidence of AF by cystatin C-based GFR. x2 Normoalbuminuria x5 Microalbuminuria Proteinuria x10 Alonso Circulation 2011; 123:2946-2953, DOI: 10.1161/CIRCULATIONAHA.111.020982 GUIJARRO ACO. IRC-2011 8 4

ATRIAL FIBRILATION, STROKE & CHRONIC KIDNEY DISEASE GUIJARRO ACO. IRC-2011 9 Reinecke H et al. JASN 2009;20:705-711

Chronic Kidney Disease Increases Risk for Venous Thromboembolism +100% +50% GUIJARRO ACO. IRC-2011 11 J Am Soc Nephrol 19: 135 140, 2008. doi: 10.1681/ASN.2007030308

Table 2. Factors influencing hemostasis in CKD Factors Predisposing for Bleeding Platelet abnormalities including subnormal dense granule content Reduction in intracellular ADP and serotonin Procoagulant Factors Atherosclerosis and diffuse endothelial damage Dysfunctional activated protein C metabolism Impaired release of the platelet α-granule protein and β-thromboglobulin Enhanced intracellular camp and abnormal mobilization of platelet Ca 2+ Abnormal platelet arachidonic acid metabolism Both elevated plasminogen activator inhibitor-1 to tissue-type plasminogen activator ratios and inhibition of plasmin by increased levels of lipoprotein(a) Defects in the expression of glycoprotein GPIb (the receptor for von Willebrand factor) Defective cyclo-oxygenase activity Abnormality of the activation-dependent binding activity of GPIIb/IIIa Increased formation of vascular PGI2 Altered von Willebrand factor Indirectly: Presence of uremic toxins, especially parathyroid hormone Anemia/altered blood rheology Erythropoietin deficiency Specific drug treatment (e.g., nonsteroidal antiinflammatory drugs) GUIJARRO ACO. IRC-2011 13

Bleeding Risk & Mortality in patients treated with antithormbotics and PCI In relation to CKD MAJOR BLEEDING MORTALITY Non CKD CKD Non CKD CKD GUIJARRO ACO. IRC-2011 14 Manzano-Fernández S et al. Chest 2009;135:983-990.

ALTO Algoritmo para anticoagulación oral en fibrilación auricular e insuficiencia renal crónica FIBRILACION AURICULAR E IRC CL CREAT < 60 ML/MIN. FACTORES DE RIESGO DE EMBOLISMO Ictus, valvulopatía Edad, HTA; ICC, diabetes NO SI SI ANTICOAGULACIÓN PREVIA > 3 MESES? NO NO ANTICOAGULACIÓN Valorar AAS 100 mg/d (Si no estaba ya indicada por enf. Aterotrombótica previa) RIESGO DE SANGRADO Hemorragia previa, hepatopatia, Neoplasia, Cl creat < 30, caídas BAJO INICIAR / CONTINUAR ANTICOAGULACIÓN INR 2-3 Valorar AAS 100 mg/d Iniciar a dosis bajas Controles frecuentes GUIJARRO ACO. IRC-2011 16 Reinecke H et al. JASN 2009;20:705-711

score CHA 2 DS 2 VASc vs HASBLED Risk factor Clinical characteristic* Points awarded 1 Congestive heart failure/lv dysfunction C 1 Hypertension H 2 Age 75y A2 1 Diabetes mellitus D 2 Stroke/TIA/TE S2 1 Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) V 1 Age 65-74y A 1 Sex category (ie female gender) 9 Maximum Score Sc H Hypertension 1 A Abnormal renal and liver function (1 point each) 1-2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (age >65) 1 D Drugs or alcohol (1 point each) 1-2 Maximum Score 9 GUIJARRO ACO. IRC-2011 17 Lip GY,., Chest 137, 263-272, 2010 Pisters, Chest, Chest. 2010 138:1093

Risks for Stroke, Bleeding, and Death Relation to the CHADS 2 Score: A Subgroup Analysis of the RE-LY Trial VASCULAR MORTALITY MAJOR BLEEDING THROMBOSIS 3-6 2 0-1 Condition C Congestive heart failure Points 1 H Hypertension: 1 A Age 75 years 1 D S 2 Diabetes mellitus Prior Stroke or TIA 1 2 0 1 2 3 4 5 Annual Event Rate GUIJARRO ACO. IRC-2011 18 November 15, 2011 vol. 155 no. 10 660-667

Venous Thromboembolism in Patients with Renal Insufficiency: Findings from the RIETE Registry 15 day mortality Multivariate Analysis Odds Ratio Fatal Bleeding Fatal PE Absolute Risk Fatal Bleeding Fatal PE 6 6 4 4 2 2 0 > 60 30-60 Cl Creat < 30 0 > 60 30-60 Cl Creat < 30 GUIJARRO ACO. IRC-2011 20 WE DO NOT NEED LESS ANTITHROMBOTICS WE DO NEED BETTER ANTITHROMBOTICS Monreal. Am J Medicine (2006) 119, 1073-1079

To bleed or not to bleed That is not the question GUIJARRO ACO. IRC-2011 22

Not to bleed & not to die That is the question GUIJARRO ACO. IRC-2011 23

Novel Oral Anticoagulants Characteristic Apixaban Dabigatran Rivaroxaban Trial Aristotle RE-LY ROCKET-AF Target Factor Xa Thrombin Factor Xa Oral bioavailability, % Dosing frequency a ~50 3 7 80 Twice daily Twice daily Once daily Half-life, h ~12 12 17 5 9 Renal clearance, % Potential drug interactions ~27 80 Potent inhibitors of CYP3A4 Rifampicin, quinidine, amiodarone, potent P-gp inhibitors 66 (half is inactive drug) Potent inhibitors of CYP3A4 and P- gp GUIJARRO ACO. IRC-2011 25

Renal exclusion criteria for Clinical Trials with new antitrhombotic agents Apixaban Dabigatran Rivaroxaban NV Atrial Fib Aristotle RE-LY ROCKET-AF Exclusion criteria Creat>2.5 mg/dl or cgfr <25 ml/min Cr Cl < 30 ml /min DVT /PE AMPLIFY RE-COVER Cr Cl < 30 ml /min (15 mg) Cr Cl < 50 ml/min (20 mg) EINSTEIN DVT EINSTEIN PE Exclusion criteria Significantly impaired kidney function Cr Cl < 30 ml /min Cr Cl < 30 ml /min GUIJARRO ACO. IRC-2011 26

APIXABAN & DABIGATRAN IN AF & MODERATE RF Apixaban versus Warfarin in AF. ARISTOTLE Dabigatran versus Warfarin in AF. RELY GUIJARRO ACO. IRC-2011 27

ROCKET AF RENAL FAILURE Principal efficacy endpoint (stroke and systemic embolism) 5 Major bleeding 4 3 2 1 0 R W R W CrCl 30 49 ml/min CrCl 50 ml/min GUIJARRO ACO. IRC-2011 28 Eur Heart J (2011) 32 (19): 2387-2394. doi: 10.1093/eurheartj/ehr342

GUIJARRO ACO. IRC-2011 29

Como a nuestro parescer cualquiera tiempo pasado fue...anterior GUIJARRO ACO. IRC-2011 30

VITAMINA K: ACTIVACION DE FACTORES DE COAGULACIÓN INHIBICIÓN DE LA CALCIFICACIÓN VASCULAR. GUIJARRO ACO. IRC-2011 32 Danziger J CJASN 2008;3:1504-1510

ANTAGONISTAS DE LA VITAMINA K: INHIBICIÓN DE LA COAGULACIÓN AUMENTO DE LA CALCIFICACIÓN VASCULAR GUIJARRO ACO. IRC-2011 33 Danziger J CJASN 2008;3:1504-1510

Warfarin use and the risk of valvular calcification GUIJARRO ACO. IRC-2011 34 1155 patients, with AF, 725 (63%) were treated with warfarin 430 (37%) without warfarin. Valvular calcification Valvular calcification was present in 65% on warfarin vs. 52% not on warfarin Association between the use of warfarin and the risk of calcification [unadjusted OR= 1.71, 95% CI = (1.34 2.18)]. The association still stands after adjustment for confounding risk factors. Journal of Thrombosis and Haemostasis,2009; 7: 2023 2027

Nuevos dicumarínicos: Tecarfarin Antagonista oral de vitamina K Metabolismo por esterasas (no CYP450) Menor interacción con Alimentación Fármacos Tecarfarin Acenocumarol Warfarin Circulation 2009; 120:1029 35.

Conclusiones La insuficiencia renal crónica se asocia con Mayor riesgo de f. auricular / ictus Mayor riesgo de Enf tromboembólica Mayor riesgo de sangrado Mortalidad trombo >> sangrado (ETE) Necesitamos mejores antitrombóticos papel de nuevos antitrombóticos en la insuficiencia renal avanzada?

GRACIAS POR SU ATENCIÓN

Risks for Stroke, Bleeding, and Death Relation to the CHADS 2 Score: A Subgroup Analysis of the RE-LY Trial VASCULAR MORTALITY MAJOR BLEEDING THROMBOSIS 3-6 2 0-1 Condition C Congestive heart failure Points 1 H Hypertension: 1 A Age 75 years 1 D S 2 Diabetes mellitus Prior Stroke or TIA 1 2 0 1 2 3 4 5 Annual Event Rate GUIJARRO ACO. IRC-2011 40 November 15, 2011 vol. 155 no. 10 660-667

Synopsis of atrial fibrillation in CKD. Various stages of CKD are displayed by the same colors in all panels (blue, no CKD; green, CKD without hemodialysis; red, hemodialysis; purple, peritoneal dialysis). Reinecke H et al. JASN 2009;20:705-711 GUIJARRO ACO. IRC-2011 41 2009 by American Society of Nephrology

prothrombin time (seconds). Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. placebo P<0.001 for PCC, repeated measures ANOVA. prothrombin complex concentrate (PCC) rivaroxaban Circulation. 124(14):1573-1579, October 4, 2011. DOI: 10.1161/CIRCULATIONAHA.111.029017 GUIJARRO ACO. IRC-2011 44 3

APTT ecarin clotting time Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. thrombin time No effect of Prothrombin Complex Concentrate on Dabigatran changes of clotting times GUIJARRO ACO. IRC-2011 45 4

Algorithm for oral anticoagulation in atrial fibrillation and CKD. All patients with permanent, persistent, and especially paroxysmal atrial fibrillation are at high risk for ischemic stroke. GUIJARRO ACO. IRC-2011 46 Reinecke H et al. JASN 2009;20:705-711

ALTO Algoritmo para anticoagulación oral en fibrilación auricular e insuficiencia renal crónica. FIBRILACION AURICULAR E IRC CL CREAT < 60 ML/MIN FACTORES DE RIESGO DE EMBOLISMO Ictus, valvulopatía Edad, HTA; ICC, diabetes SI ANTICOAGULACIÓN PREVIA > 3 MESES? NO NO NO ANTICOAGULACIÓN Valorar AAS 100 mg/d (Si no estaba ya indicada por enf. Aterotrombótica previa) RIESGO DE SANGRADO Hemorragia previa, hepatopatia, Neoplasia, Cl creat < 30, caídas BAJO INICIAR / CONTINUAR ANTICOAGULACIÓN INR 2-3 Iniciar a dosis bajas Controles frecuentes GUIJARRO ACO. IRC-2011 47 Reinecke H et al. JASN 2009;20:705-711

FIBRILACION AURICULAR E IRC CL CREAT < 30 ML/MIN FACTORES DE RIESGO DE EMBOLISMO ANTICOAGULACIÓN PREVIA > 3 MESES? SI NO RIESGO DE SANGRADO MUY ALTO ACEPTABLE GUIJARRO ACO. IRC-2011 48 NO ANTICOAGULACIÓN Valorar antiagregación SIN ASOCIAR A ANTICOAGULANTES VALORAR ANTICOAGULACION SI MUY ALTO RIESGO (INR 2-2.5) INICIAR / CONTINUAR ANTICOAGULACIÓN INR 2-3 Controles frecuentes JACC 2011; 57, Pages 1339-1348

Pharmacologic Characteristics of Novel Oral Anticoagulnts with Completed Phase 3 Clinical Trials For Stroke Prevention in Atrial Fibrillation Characteristic Apixaban Dabigatran Rivaroxaban Trial Aristotle RE-LY ROCKET-AF DVT AMPLIFY RE-COVER Oral bioavailability, % Dosing frequency a EINSTEIN DVT EINSTEIN PE ~50 3 7 80 Twice daily Twice daily Once daily Half-life, h ~12 12 17 5 9 Renal clearance, % ~27 80 66 (half is inactive drug) Exclusion criteria Creat>2.5 mg/dl or cgfr <25 ml/min Cr Cl < 30 ml /min Cr Cl < 30 ml /min (15 mg) Cr Cl < 50 ml/min (20 mg) GUIJARRO ACO. IRC-2011 50

Renal exclusion criteria for Clinical Trials with new antitrhombotic agents Characteristic Apixaban Dabigatran Rivaroxaban NV Atrial Fib Aristotle RE-LY ROCKET-AF Exclusion criteria Creat>2.5 mg/dl or cgfr <25 ml/min Cr Cl < 30 ml /min DVT /PE AMPLIFY RE-COVER Cr Cl < 30 ml /min (15 mg) Cr Cl < 50 ml/min (20 mg) EINSTEIN DVT EINSTEIN PE Exclusion criteria Significantly impaired kidney function Cr Cl < 30 ml /min Cr Cl < 30 ml /min GUIJARRO ACO. IRC-2011 51

ROCKET AF RENAL FAILURE Efficacy events in the per-protocol (on-treatment) population. GUIJARRO ACO. IRC-2011 52 Eur Heart J (2011) 32 (19): 2387-2394. doi: 10.1093/eurheartj/ehr342

ROCKET AF RENAL FAILURE Efficacy endpoints according to the intention to treat. GUIJARRO ACO. IRC-2011 53 Eur Heart J (2011) 32 (19): 2387-2394. doi: 10.1093/eurheartj/ehr342

ROCKET AF RENAL FAILURE Safety endpoints. GUIJARRO ACO. IRC-2011 54 Eur Heart J (2011) 32 (19): 2387-2394. doi: 10.1093/eurheartj/ehr342

ROCKET AF RENAL FAILURE Principal efficacy endpoint (stroke and systemic embolism) 5 Major bleeding 4 3 2 1 0 R W R W CrCl 30 49 ml/min CrCl 50 ml/min GUIJARRO ACO. IRC-2011 55 Eur Heart J (2011) 32 (19): 2387-2394. doi: 10.1093/eurheartj/ehr342