Riesgo/beneficio de la anticoagulación en la insuficiencia renal

Transcripción

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

2 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

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

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

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

6 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

7 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: , DOI: /CIRCULATIONAHA GUIJARRO ACO. IRC

8 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: , DOI: /CIRCULATIONAHA GUIJARRO ACO. IRC

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

10 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

11 Chronic Kidney Disease Increases Risk for Venous Thromboembolism +100% +50% GUIJARRO ACO. IRC J Am Soc Nephrol 19: , doi: /ASN

12 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

13 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

14 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 Manzano-Fernández S et al. Chest 2009;135:

15 To bleed or not to bleed That is the question INR RESULTS GUIJARRO ACO. IRC

16 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 Reinecke H et al. JASN 2009;20:

17 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 Lip GY,., Chest 137, , 2010 Pisters, Chest, Chest :1093

18 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 Condition C Congestive heart failure Points 1 H Hypertension: 1 A Age 75 years 1 D S 2 Diabetes mellitus Prior Stroke or TIA Annual Event Rate GUIJARRO ACO. IRC November 15, 2011 vol. 155 no

19 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 > Cl Creat < 30 0 > Cl Creat < 30 GUIJARRO ACO. IRC WE DO NOT NEED LESS ANTITHROMBOTICS WE DO NEED BETTER ANTITHROMBOTICS Monreal. Am J Medicine (2006) 119,

20 To bleed or not to bleed That is not the question GUIJARRO ACO. IRC

21 Not to bleed & not to die That is the question GUIJARRO ACO. IRC

22 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

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 ~ Twice daily Twice daily Once daily Half-life, h ~ 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

24 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

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

26 ROCKET AF RENAL FAILURE Principal efficacy endpoint (stroke and systemic embolism) 5 Major bleeding R W R W CrCl ml/min CrCl 50 ml/min GUIJARRO ACO. IRC Eur Heart J (2011) 32 (19): doi: /eurheartj/ehr342

27 GUIJARRO ACO. IRC

28 Como a nuestro parescer cualquiera tiempo pasado fue...anterior GUIJARRO ACO. IRC

29 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

30 VITAMINA K: ACTIVACION DE FACTORES DE COAGULACIÓN INHIBICIÓN DE LA CALCIFICACIÓN VASCULAR. GUIJARRO ACO. IRC Danziger J CJASN 2008;3:

31 ANTAGONISTAS DE LA VITAMINA K: INHIBICIÓN DE LA COAGULACIÓN AUMENTO DE LA CALCIFICACIÓN VASCULAR GUIJARRO ACO. IRC Danziger J CJASN 2008;3:

32 Warfarin use and the risk of valvular calcification GUIJARRO ACO. IRC 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 = ( )]. The association still stands after adjustment for confounding risk factors. Journal of Thrombosis and Haemostasis,2009; 7:

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

34 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?

35 GRACIAS POR SU ATENCIÓN

36 GUIJARRO ACO. IRC

37

38 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 Condition C Congestive heart failure Points 1 H Hypertension: 1 A Age 75 years 1 D S 2 Diabetes mellitus Prior Stroke or TIA Annual Event Rate GUIJARRO ACO. IRC November 15, 2011 vol. 155 no

39 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: GUIJARRO ACO. IRC by American Society of Nephrology

40 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): , October 4, DOI: /CIRCULATIONAHA GUIJARRO ACO. IRC

41 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

42 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 Reinecke H et al. JASN 2009;20:

43 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 Reinecke H et al. JASN 2009;20:

44 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 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

45 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 ~ Twice daily Twice daily Once daily Half-life, h ~ Renal clearance, % ~ (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

46 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

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

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

49 ROCKET AF RENAL FAILURE Safety endpoints. GUIJARRO ACO. IRC Eur Heart J (2011) 32 (19): doi: /eurheartj/ehr342

50 ROCKET AF RENAL FAILURE Principal efficacy endpoint (stroke and systemic embolism) 5 Major bleeding R W R W CrCl ml/min CrCl 50 ml/min GUIJARRO ACO. IRC Eur Heart J (2011) 32 (19): doi: /eurheartj/ehr342

51 GUIJARRO ACO. IRC

52 To bleed or not to bleed That is the question INR RESULTS GUIJARRO ACO. IRC

53 To bleed or not to bleed That is the question INR RESULTS GUIJARRO ACO. IRC