Os Novos Anticoagulantes não são necessários

Os Novos Anticoagulantes não são necessários H. Luz Rodrigues Serviço de Nefrologia e Transplantação Instituto de Farmacologia e Neurociências

1948 Introdução dum ratícida Warfarin Wisconsin Alumni Research Foundation + coumarin Karl Paul Link (1901 1978) Promovendo a varfarina como raticida

1951 Sobrevivência a uma tentativa de suicídio com ratícida 567 mg de varfarina em 6 dias Tratado com 2 transfusões + 2 injecções Vit. K 100 doentes com EM ou TVP tratados com varfarina Presidente Dwight D. Eisenhower tratado com varfarina pós EM - 1955 What was good for a war hero and the President of the United States must be good for all, despite being a rat poison!

Faster onset of action No antidote

Br J Haematol 2011

Drawbacks of Warfarin Drug and food interactions Follow-up monitoring (INR) Require dosage adjustments Late onset of action: 5-7 days Prolonged effect after suspension after 5 days INR 1.5 Bleeding risk

Dabigatran pharmacokinetic interactions Dabigatran is a substrate for the efflux transporter P-glycoprotein Inhibitors of P -gp efflux transporter: Abiraterone, Alfentanil, Amiodarone, Atorvastatin, Azithromycin, Boceprevir, Carvedilol, Clarithromycin, Cobicistat, Conivaptan, Crizotinib, Cyclosporine, Darunavir, Diltiazem, Dipyridamole, Dronedarone, Duloxetine, Erythromycin, Fenofibrate, Grapefruit, Indinavir, Itraconazole, Ivacaftor, Ketoconazole, Lapatinib, Lomitapide, Lopinavir, Lovastatin, Mefloquine, Mifepristone, Nelfinavir, Nicardipine, Nifedipine, Nilotinib, Posaconazole, Progesterone, Propafenone, Propranolol, Quinidine, Quinine, Ranolazine, Reserpine, Ritonavir, Saquinavir, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telithromycin, Ticagrelor, Tolvaptan, Ulipristal, Vandetanib, Vemurafenib, Verapamil UpTDate April 2014

Dabigatran pharmacokinetic interactions Dabigatran is a substrate for the efflux transporter P-glycoprotein EMA Contraindications Cyclosporine Dronedarone Itraconazole Ketoconazole Not recommended Protease inhibitors Tacrolimus Use caution Amiodarone Ticagrelor Quinidine Posaconazole Verapamil (110 mgx2) FDA Dronedarone or Ketoconazole + CrCl 30 to 50 ml/min, consider a dose reduction to 75 mg x 2 any inhibitor of P-gp, if CrCl <30 ml/min EMA - Pantoprazole 30 % dabigatran levels concomitant PPI treatment did not appear to reduce the efficacy CANADA Dabigatran 2 h before an antacid

Dabigatran pharmacokinetic interactions Dabigatran is a substrate for the efflux transporter P-glycoprotein Inducers of P -gp efflux transporter Carbamazepine Dexamethasone Doxorubicin Nefazodone Pentobarbital Phenobarbital Prazosin Rifampin St. John's wort Tenofovir Tipranavir Trazodone Vinblastine EMA, FDA, CANADA Avoid use with strong P-gp inducers Carbamazepine Phenytoin Rifampin St. John's wort EMA SSRIs and SNRIs risk of bleeding

Rivaroxaban pharmacokinetic interactions Substrate for the efflux transporter P-gp + hepatically metabolized by CYP3A4 Combined P-gp and strong CYP3A4 inhibitors: Boceprevir Cobicistat Conivaptan Delavirdine HIV protease inhibitors Imatinib Itraconazole Ketoconazole Nefazodone Posaconazole Telaprevir Telithromycin Voriconazole EMA Not recommended Strong inhibitors of both P-gp and CYP3A4, including: Ketoconazole Itraconazol Traconazole Posaconazole Voriconazole HIV protease inhibitors

Rivaroxaban pharmacokinetic interactions Substrate for the efflux transporter P-gp + hepatically metabolized by CYP3A4 Combined inhibitors of P-gp and/or moderate inhibitors of CYP3A4 Amiodarone Azithromycin Chloramphenicol Cimetidine Erythromycin Clarithromycin Cyclosporine Diltiazem Dronedarone Felodipine Fluconazole Grapefruit juice Lapatinib Mifepristone Nicardipine Quinidine Ranolazine Tamoxifen Telithromycin Ticagrelor Verapamil EMA - Avoid due to limited clinical data Dronedarone - Caution clarithromycin, telithromycin + renal impairment

Rivaroxaban pharmacokinetic interactions Substrate for the efflux transporter P-gp + hepatically metabolized by CYP3A4 Combined P-gp and strong inducers of CYP3A4: EMA Caution with strong inducers of CYP3A4 Rifampin Phenytoin Carbamazepine Phenobarbital St John s wort FDA, CANADA Avoid concomitant use of rivaroxaban with.

Effect on NOAC plasma levels (AUC) from drug drug interactions and recommendations towards NOAC dosing Europace 2013; 15:625-51

MONITORING

Drawbacks of Warfarin Drug and food interactions Follow-up monitoring (INR) Require dosage adjustments Late onset of action: 5-7 days Prolonged effect after suspension after 5 days INR 1.5 Bleeding risk

Mechanical heart valve Mitral stenosis CrCl <15 ml/min or Hemodialysis

Dosage adjustments

Dose Selection of Oral Anticoagulant Options for Patients with Nonvalvular AF and CKD Based on Prescribing Information for the United States Renal Function Warfarin Dabigatran Rivaroxaban Apixaban Normal/Mild Impairment Dose adjusted for INR 2.0 3.0 150 mg BID (CrCl >30 ml/min) 20 mg QD with the evening meal (CrCl >50 ml/min) 5.0 or 2.5 mg BID Moderate Impairment Dose adjusted for INR 2.0 3.0 150 mg BID or 75 (110) mg BID (CrCl >30 ml/min) 15 mg QD with the evening meal (CrCl 30 50 ml/min) 5.0 or 2.5 mg BID Severe Impairment Dose adjusted for INR 2.0 3.0 75 (110) mg BID (CrCl 15 30 ml/min) 15 mg QD with the evening meal Avoid (Caution) (CrCl 15 30 ml/min) No recommendation End-Stage CKD Not on Dialysis Dose adjusted for INR 2.0 3.0 Not recommended (CrCl <15 ml/min) Not recommended (CrCl <15 ml/min) No recommendation (CrCl <15 ml/min) End-Stage CKD on Dialysis Dose adjusted for INR 2.0 3.0 Not recommended Not recommended No recommendation Circulation. published online March 28, 2014

Non-valvular atrial fibrillation (300 mg/day) Pradaxa is 220 mg taken as one 110 mg capsule twice daily: Patients aged 80 years or above Patients who receive concomitant verapamil N Engl J Med 2011; 364:1788-90

300 mg/d Anticoagulantes na Fibrilhação Auricular Preço pago pelo doente em Portugal Não comparti Não comparti Não comercializado Não comercializado 180 160 140 120 100 80 60 40 20 0 46,95 Euros / mês 78,24 79,28 23,28 23,68 112,10 163,94 0,76 Infarmed, Abril 2014

Conclusions Dabigatran 150 mg was cost-effective for higher-risk patients (CHADS 2 of 3) or for patients CHADS 2 of 2 and high risk of major hemorrhage (6%/y) Dabigatran 150 mg was not cost-effective for patients already taking warfarin who have excellent INR control Dabigatran 110 mg was not cost-effective for any realistic rate of stroke and hemorrhage because of the greater efficacy of dabigatran 150 mg Circulation 2011;123:2562-70

Drawbacks of Warfarin Drug and food interactions Follow-up monitoring (INR) Require dosage adjustments Late onset of action: 5-7 days Prolonged effect after suspension after 5 days INR 1.5 Bleeding risk

Algorithm for the management of a warfarin-treated patient whose INR > 4 Circulation 2012;125:2944-7

Warfarin Recommended Interval between Last Dose and Procedure 1-8 days; INR decreases to 1.5 in 93% of patients within 5 days Reversal Agents (in cases of severe bleeding) Oral or intravenous vit K, with or without freshfrozen plasma; PCCs For patients receiving treatment with newer anticoagulant agents, 1-2 days Clcr 50 ml/min Dabigatran when surgery 3 - is 5 days imminent Clcr but < 50 the timing is unpredictable (e.g., organ transplantation), 1 day Clcr 100 ml/min we recommend 2 days switching Clcr to 60-90 warfarin because its effects can be Rivaroxaban 3 days Clcr 30-59 rapidly and reliably reversed. 4 days Clcr 15-29 None, but consider factor VIII inhibitor or recombinant factor VIIa, and hemodialysis None, but consider PCCs Apixaban PCC: prothrombin complex concentrate 1-2 days Clcr > 60 ml/min 3 days Clcr 50-59 5 days Clcr < 30-49 None, but consider charcoal hemoperfusion or PCCs N Engl J Med 2013;368:2113-24

Drawbacks of Warfarin Drug and food interactions Follow-up monitoring (INR) Require dosage adjustments Late onset of action: 5-7 days Prolonged effect after suspension after 5 days INR 1.5 Bleeding risk

Outcome OR (95% CI)* Death 1.76 (1.44-2.14) Stroke 1.73 (1.20-2.51) Major bleed 1.16 (0.95-1.41) Minor bleed 1.16 (0.90-1.50) Outcome OR (95% CI)* Death 10.71 (8.27-13.85) Stroke 3.42 (2.08-5.63) Major bleed 1.60 (1.13-2.26) Minor bleed 2.13 (1.39-3.27 J Thromb Haemost 2013; 11: 107 15

www.clotcare.org/inrselftestingvideo.aspx. Circulation 2012;126:e52-e54

Major bleeding Lancet 2014; 383:955-62

Gastroenterology 2013;145:105-12

Dabigatran might not directly increase the risk of MI, but it may lack the beneficial effects that warfarin and aspirin have in MI prevention Arch Intern Med 2012;172:397-402

Compliance Less is More? Clinical trials No / Real monitoring world No antidote Posology Once / twice daily Missed dose time The forgotten dose may be taken until halfway the dosing interval (12 or 6 h) Poor adherence without INR monitoring Cost

Prescrições de Dabigatrano Local da 1ª Prescrição de Dabigatrano N= 813 400 350 300 250 200 150 100 50 0 340 Hospitais 296 Medicina Privada 140 41.8% 36.4% 17.2% 4.6% Centros de Saúde 37 Outros Contextos Boletim Nº 5, Novembro 2013, Comissão de Farmácia e Terapêutica da ARSLVT

Prescrições de Dabigatrano Continuidade da Prescrição de Dabigatrano 125 (15.4%) sob AVK nos 6 meses anteriores 900 800 700 600 500 400 813 629 544 + 96 sem dabigatrano 448 20 estavam sob AVK 3 reiniciaram AVK + 108 sem dabigatrano 340 20 pré-avk 2 re-avk + 108 sem dabigatrano 13 pré-av 1 re-avk 300 274 200 100 0 77% 67% 55% 42% 34% 1ª vez 2ª vez 3ª vez 4ª vez 5ª vez 6ª vez Boletim Nº 5, Novembro 2013, Comissão de Farmácia e Terapêutica da ARSLVT

NOAC: New Oral Anticoagulant

Pra nós, isso são peanuts!

Photoshop Effects

Which patients should be treated preferably with warfarin? An Optimistic View Patients already on warfarin who are comfortable with periodic INR measurement and whose INR has been relatively easy to control. Patients who are not likely to comply with the 2 daily dosing of dabigatran or apixaban. Patients for whom the use of any of these other anticoagulants will lead to an unacceptable increase in cost. Patients with severe CKD, whose ecrcl < 30 ml/min.

I would never die for my beliefs because I might be wrong. Bertrand Russell British mathematician & philosopher (1872-1970)

If fifty millions people say a foolish thing, it is still a foolish thing.