Tratamiento Anticoagulante oral
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Tratamiento Anticoagulante oral
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Tratamiento Anticoagulante oral
- 1. Julián Vega Adauy , Residente Cardiología UC SEPTIEMBRE+2011 ORAL ANTICOAGULANT TREATMENT OAT Facultad de Medicina Pontificia Universidad Católica de Chile
- 5. Indicación de TACO TAC Red UC 16-17 Otros 10-16 Tromboembolismo venoso 5-14 Tromboembolismo sistémico 14-21 Prótesis mecánicas 39-47 Fibrilación auricular (%) 2154-2439 N: pacientes 2002-2011
- 6. Rangos PTB programa TACO Red UC entre 1-2 y 30-4-2008 INR 1.8-3.2 INR 2.8-4.2 N: 4150 N: 778 En general pacientes están en rango útil 50-60% del tiempo
- 8. Vitamin K-Dependent Clotting Factors Vitamin K Synthesis of Functional Coagulation Factors VII IX X II
- 9. WARFARIN MECHANISM OF ACTION KH2 KH1
- 10. Pharmacodynamic FC dependientes VK Epoxide Reductase -Carboxylase ( GGCX )
- 11. Vida media de las proteínas K-dependientes Proteína Vida-media Factor VII 4–6 horas Factor IX 24 horas Factor II 60 horas Factor X 48–72 horas Proteína C 8 horas Proteína S 30 horas
- 12. $ 16.463 (5mgx30) Acebron 4mgx20, $4.759 Neo-sintrom 4mgx20, $14.948 Precio 36-72 36-48 Efecto máximo (hs) 30-40 4-5 5-9 2 Vida media (hs) Duración efecto (días) 84 68 Efecto terapéutico (hs) 24 8 Inicio del efecto (hs) 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10 4 Presentación (mg) Warfarina Acenocumarol
- 19. C. Van Walraven, Chest 2006
- 21. Riesgos Beneficios REDUCCION EVENTOS TE HEMORRAGIA INR
- 22. UTD 17.3
- 23. RIESGO DE HIC en OAT Hylek EM, Singer DE, Ann Int Med 1996
- 24. Menor INR efectivo en prevención TE Hylek EM, et al. NEJM 1996 INR below 2.0 results in a higher risk of stroke
- 28. Mechanical Prosthetic Heart Valves Patient Characteristics Recommendation Bileaflet mechanical valve in the aortic position, Goal INR 2.5; range, 2.0–3.0 left atrium of normal size, NSR, normal ejection fraction Tilting disk valve or bileaflet mechanical valve in Goal INR 3.0; range, 2.5–3.5* the mitral position Bileaflet mechanical aortic valve and AF Goal INR 3.0; range, 2.5–3.5* Caged ball or caged disk valves Goal INR 3.0; range, 2.5–3.5; and aspirin therapy (80–100 mg/d) Additional risk factors Goal INR 3.0; range, 2.5–3.5; and aspirin therapy (81 mg/d) Systemic embolism, despite adequate therapy Goal INR 3.0; range, 2.5–3.5; with oral anticoagulants and aspirin therapy (81 mg/d) * Alternative: goal INR 2.5; range, 2.0–3.0; and aspirin therapy (80–100 mg/d)
- 30. Add warfarin dose distribution Ave: 5.2 mg/d n = 186 European-American 30x dose variability Distribución de dosis de warfarina
- 31. Drug Interactions with Warfarin: No Effect Level of Evidence No Effect Alcohol, antacids, atenolol, bumetadine, enoxacin, famotidine, fluoxetine, ketorolac metoprolol, naproxen, nizatidine, psyllium, ranitidine ‡ Ibuprofen, ketoconazole Diltiazem, tobacco, vancomycin I II III IV
- 36. CYP2C9 Genotype y OAT (Higashi et al., JAMA 2002) - Según variante y alelos, menor dosis, pero mayor tiempo para INR estables TIME TO STABLE ANTICOAGULATION CYP2C9-WT ~90 days *2 or *3 carriers take longer to reach stable anticoagulation CYP2C9-Variant ~180 days
- 37. Warfarin maintenance dose (mg/day) Inter-Individual Variability in Warfarin Dose: Genetic Liabilities SENSITIVITY CYP2C9 coding SNPs - * 3/*3 RESISTANCE VKORC1 nonsynonymous coding SNPs Frequency Common VKORC1 non-coding SNPs? 0.5 5 15
- 38. Asian Clade Distribution Low dose phenotype A (89%) B (11%) African-American Clade Distribution High dose phenotype A (14%) B (47%) Other (39%) Clade A = Low Clade B = High VKORC1 Haplotype Frequency Differs Between Populations European (CEPH) Clade Distribution B (58%) A (37%)
- 39. Factores predictores independientes de dosis de OAT Variable Change in Warfarin Dose P value Target INR, per 0.5 increase 21% <0.0005 BMI , per SD 14% <0.0001 Ethnicity ( African-American, [Asian] ) 13%, [ 10-15%] 0.003 Age , per decade 13% <0.0001 Gender , Female 12% <0.0001 Drugs (Amiodarone) 24% 0.007 CYP2C9*2 , per allele 19% <0.0001 CYP2C9*3 , per allele 30% <0.0001 Gage et al., Thromb Haemost , 2004 ~ 30% de variabilidad de la dosis se explica por estos factores
- 40. LIMITACIONES DE OAT Inicio retardado, reversibilidad lenta Rango útil 50-60 % tiempo Monitoreo Hemorragias Frecuente ajuste de dosis Interacción con los alimentos Interacción drogas Rango terapéutico estrecho (INR 2-3)
- 41. Limitaciones llevan a Rp inadecuado (warfarina en FA en atención primaria) Samsa GP, et al. Arch Intern Med 2000 Sobre TIR 6% Bajo TIR 13% TIR 15% No warfarin! 65% Solo 35% de los pacientes con FA recibieron warfarina
- 43. OAT Recipes & Management INICIO Warfarina dosis 5-10mg dias 1 al 2, luego según INR (1B) iniciar con 5mg (1C) en pacientes: desnutridos, DHC, ICC, ancianos, Cirugía mayor reciente, utilizan medicamentos incrementan efecto de OAT (Amiodarona), CONTROL INR INR posterior a 2da ó 3era dosis de OAT (2C) INR estable, control no menor a 4 semanas (2C)
- 45. 42% 7% 51% Dose too high Dose too low Dose ok DOSIS DE INICIO
- 48. MANEJO CON INR FUERA DE RANGO Vitamina K, demora 6-8hs corregir hemostasia PFC: 4U (1.0 lt) en 30-45’ – 2hs en corregir hemostasia CPP: (marcas) revierte INR en 15’ CPP + Vitamina K, repetir según INR Objetivo INR <1.4 y Plaquetas >100k Ó Factor RVII (novoseven) Sangrado de riesgo vital (ICH) Reversión rápida >20: OD mayor de OAT VK 3-5mg, INR dentro de 24hs, si no reduce, repetir VK Sangrado severo: reversión rápida VK 10mg ev (15-20’) repetir c/12hs + PFC 10-20 ml/kg (Si problema de volumen: CPP) INR >9.0, sin sangrado clínico significativo
- 49. MANEJO CON INR FUERA DE RANGO, REVERSION aVK M Yasaka, Thrombosis Research, 2002
- 50. M Aguilar. Mayo Clinic Proceedings, 2007
- 55. Fuster et al. JACC 2006
- 56. ACTIVE – W Failure of clopidogrel/ASA to prevent stroke, embolism, MI or vascular death compared to OAC Lancet 2006; 367 :1903-1912
- 57. New antithrombotic treatments in Phase III trials for stroke prevention in atrial fibrillation Tissue Factor Plasma Clotting Cascade Prothrombin Thrombin Fibrinogen Fibrin Thrombus Platelet Aggregation Conformational Activation of GPIIb/IIIa Collagen Thromboxane A 2 ADP AT Aspirin Clopidogrel Prasugrel AZD6140 Dabigatran Ximelagatran Factor Xa Idraparinux Apixaban Rivaroxaban
- 58. CARACTERÍSTICAS DE ANTICOAGULANTES ORALES. Garcia D et al. Blood. 2010 /12hrs /24hrs /12hrs /24 hrs Dosis 10 110 mg 2.5,5 Posología 25% 66% 80% Excrec renal 8-15 9-13 12-14 40 Vida ½ (hrs) Factor Xa Factor Xa DTI Antag vit K Mecanismo Apixaban Rivaroxaban (Xarelto) Dabigatran (Dapraxa) Warfarina
- 61. Nuevos OAT vs Warfarina Features Warfarin New agents Onset Slow Rapid Dosing Variable Fixed Food/drug interactions Many None or very few Monitoring Yes No Half life Long Short Antidote Yes No
- 62. Julián Vega Adauy , Residente Cardiología UC SEPTIEMBRE+2011 Gracias por su atención
Notas del editor
- The four Vitamin K dependent clotting factors are synthesized in the liver.
- Warfarin works by interfering with internal recycling of oxidized Vitamin K to the reduced form. When warfarin is given, the oxidized form of Vitamin K builds up in the blood leading to a deficiency of reduced Vitamin K and a decrease in carboxylation of prothrombin. Warfarin interferes with –carboxylation of terminal glutamic acids on the procoagulant proteins, Factors II, VII, IX, and X. –carboxylation from the Glu to the Gla form of these proteins in a critical step in the biosynthesis of these proteins that is required their normal function in coagulation. – carboxylation is a post-translational step that is Vitamin K dependent and linked to the oxidation of hydroquinone (the active cloting form of Vitamin K) to the Vitamin K epoxide. The reaction uses molecular oxygen for the conversion of hydroquinone to the epoxide, and CO 2 , for the –carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive carboxylation of the glutamic acid residues on the Vitamin K dependent proteins from the inactive Glu to the active Gla form. Under normal physiologic circumstances, Vitamin K is absorbed as the quinone form (Vitamin K 1 ). The quinone is reduced to the hydroquinone (the reduced form), which in turn is oxidized to Vitamin K epoxide (the oxidized form). The active cofactor form of Vitamin K (hydroquinone) is then regenerated through two reduction steps. First the 2–3 epoxide is reduced to the quinone (the dietary source of Vitamin K 1 ). This is then reduced to the hydroquinone which, when recycled to the epoxide, acts as the cofactor for the Glu to Gla conversion of the Vitamin K dependent coagulation factors by blocking both reduction steps, thereby depleting the stores of the hydroquinone form of Vitamin K.
- Page Hemorrhage or bleeding is the main complication of warfarin, and it is influenced by the intensity of anticoagulation. 1-3 Intracranial hemorrhage (ICH) is the most feared bleeding risk because it can result in death or severe neurologic disability 1 On the other hand, the benefits of warfarin therapy include reducing the Risk of stroke and death due to atrial fibrillation (AF) 2 Risk of reinfarction and revascularization after a myocardial infarction (MI) 3 Risk of recurrent venous thromboembolism (VTE) in patients with mechanical heart valves (MHVs) 2 Risk of recurrent VTE, such as deep vein thrombosis and pulmonary embolism 2 Ansell J et al. Chest . 2004;126:204S-233S. Hirsh J et al. J Am Coll Cardiol . 2003;41:1633-1652. Rothberg MB et al. Ann Intern Med . 2005;143:241-250.
- The relationship between the incidence of intracranial bleeding and INR in warfarin-treated patients is shown in this slide. The risk (expressed as an odds ratio) increases dramatically with increasing INR levels.
- The relationship between the risk of stroke anti INR in patients with atrial fibrillation treated with warfarin is shown on this slide. The risk of stroke increases dramatically when the INR falls below 2.0, although there appears to be some protection when the INR is above 1.5.
- These indications and recommended intensities of treatment are derived from the Fifth American College of Chest Physicians Consensus Conference (1998). For most indications a therapeutic range of 2.0 to 3.0 is recommended. A higher INR range of 2.5 to 3.5 is recommended for parents with mechanical prosthetic valves and post myocardial infarction and for some patients with antiphospholipid syndrome and a history of thrombosis.
- This slide lists the venous drugs and foods that have been reported to have no effect on warfarin The strength of the evidence is shown in the left hand column. With excessive consumption, alcohol potentiates the effect (Slide 33), but when limited to two glasses of wine /day, it has been reported not to influence the ant/coagulant effect of warfarin.
- And clear practical implication for the genetic effects of CYP2C9.
- Debido a las limitaciones de los AVK, se ha estimado que hasta el 50% de los pacientes elegibles para ser tratados no reciben tratamiento anticoagulante (Rowan et al. JACC. 2007)
- This slide summarizes the results of two studies demonstrating the inverse relationship between mean warfarin dosage requirements and increasing age. The elderly require a lower dose of warfarin to achieve the same level of therapeutic effectiveness.
- An approach to the management of patients who are excessively over anticoagulated and either have minor bleeding or no obvious bleeding is outlined on this slide. In all cases, warfarin treatment should be interrupted the INR checked and warfarin restarted at a lower dose when the INR returns to the therapeutic range. If the INR is above 5 but below 9, oral Vitamin K, should be considered if the patient is at excessive risk of bleeding.
- If the INR is between 9 and 20; oral Vitamin K 1 should be administered in a dose of 2.5 mg. If the INR is >20 more aggressive measures should be used. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of at least 5 mg, an infusion of fresh frozen plasma and hospitalization should be considered, and the hematocrit checked for hidden bleeding. If the INR is excessively out of range and dose not make sense with the recent trend in INR results in individual patients, the clinician is advised to consider the possibility of laboratory error before a dose adjustment is made. In this case, it is optimal to repeat the INR before a dose change is made to verify the results. If there is serious bleeding, the patient should be hospitalized. Vitamin K should be administered by slow intravenous infusion over 10 minutes in a dose of 5–10 mg, an infusion of fresh frozen plasma should be given Prothrombin concentrate should be considered if bleeding is life-threatening.
- INR values before and after PCC administration according to combination of PCC and vitamin K. VK: vitamin K, m: minutes, h: hour
- Universidad San Sebastián, SCEMUSS www.scemuss.com