Management of Oral Anticoagulation in the Era of Target-Specific Agents

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1 Mount Sinai Heart Nurse Practitioner Symposium November 21, 2014 Management of Oral Anticoagulation in the Era of Target-Specific Agents Elizabeth B. Rothlauf, MS, RN, NP-C Cardiovascular Institute The Mount Sinai Medical Center New York City

2 Oral Anticoagulants Approved for Clinical Use in the U.S. Ø Warfarin 1954 Ø Dabigatran 2010 Ø Rivaroxaban 2011 Ø Apixaban 2012

3 Comparison of Newer Anticoagulants with Warfarin Features Warfarin New Agents Onset Slow Rapid Dosing Variable Fixed Food Effect Yes No Drug Interactions Many Few Monitoring Yes No Half Life Long Short Antidote Yes No

4 Features of Oral Anticoagulants Warfarin Dabigatran Rivaroxaban Apixaban Target Vitamin K epoxide reductase Thrombin (Factor IIa) Factor Xa Factor Xa Peak Effect hours 2 hours 2-4 hours 3 hours Half Life 40 hours hours 5-13 hours 8-15 hours Monitoring INR none none none Assay PT/INR aptt/tt AntiXa AntiXa Metabolism/Excretion Cytochrome P450 80% renal 20% biliary 64% renal 36% biliary 25% renal 75% biliary Reversal Vit K, FFP PCC, coag factors PCC?, coag factors dialysis PCC? PCC? Absorption Small intestine; Take with or without food Requires gastric acid Take with or without food Proton pump Inhibitors decrease absorption Proximal duodenum Take with food Distal small bowel and ascending colon Take with or without food Formulation Can be crushed, broken Cannot be crushed, broken or chewed Can be put through G- tube, but not J-tube Can be put through J- tube but not G-tube Drug Interactions Numerous CYP3A4 inhibitors P-gp inducers Antiarrythmic agents Platelet inhibitors CYP3A4 inhibitors and P-gp inducers Antivirals, analeptics, Platelet Inhibitors CYP3A4 inhibitors P-gp inducers platelet Inhibitors Special Populations Caution in patients with liver disease Avoid in patients with CrCl <15 ml/min Avoid in patients with CrCl <30 ml/min Caution used with HIV drugs Age >80 Creatinine >1.5 mg/dl Weight <60 kg

5 Indications for the Target-Specific Oral Anticoagulants Stroke prevention in AF Dabigatran Rivaroxaban Apixaban yes yes yes Acute VTE yes yes yes Acute PE yes yes yes Long-term 2 o prevention of VTE Hip or knee replacement prophylaxis Prophylaxis in acute medically ill patients ACS yes yes yes Phase lll yes yes Phase ll Phase lll Completed, not approved Phase lll no

6 Indications and Doses of the New Oral Anticoagulants Drug and Indication Creatinine Clearance Recommended Dose Dabigatran NVAF >30 ml/min ml/min 150 mg BID 75 mg BID VTE/PE >30 ml/min 150 mg BID Rivaroxaban NVAF VTE/PE >50 ml/min ml/min >30 ml/min 20 mg qd 15 mg qd 15 mg BID x 21 days the 20 mg qd VTE Prophylaxis Joint Replacement >30 ml/min Hip - 10 mg x 35 days Knee - 10 mg qd x 12 days Apixaban NVAF In patients with NVAF dose 2.5 mg daily if any of 2 following: 1. Age >80 years 2. Body Weight < 60 kg 3. Serum creatinine > 1.5 mg/dl VTE/PE >30 ml/min ml/min >30 ml/min 5 mg BID 2.5 mg bid 10 mg bid x 7 days then 5 mg bid VTE Prophylaxis Joint Replacement >30 ml/min 2.5 mg bid

7 Choice of Anticoagulant Ø Patient or prescriber preference Ø Warfarin resistance Ø Bleeding risk Ø Renal or hepatic dysfunction Ø Poor compliance Ø Dyspepsia or other intolerance Ø Hypersensitivity Ø Cost Ø Recommended indications

8 Care of Patients on the New Oral Anticoagulants Blood testing Ø Baseline hemoglobin, renal and liver function prior to initiation of drug then: Ø Every 3 months renal function if creatinine clearance ml/min Ø Every 6 months renal function if creatinine clearance ml/min In-clinic follow-up Ø Every 3-6 months Ø Phone calls between visits At each visit, check for Ø Compliance Ø Thromboembolic events Ø Bleeding events Ø Side effects Ø Concomitant medications Ø Frailty

9 Effects of Target-Specific Oral Anticoagulants On Coagulation Assays Dabigatran Ø Elevates aptt ~2x control at peak and 1.5 at 12 hours Ø Normal PTT or thrombin time indicates absent activity Ø PT/INR may also be elevated, but correlation with plasma level is poor Ø Not recommended for bridging therapy Rivaroxaban Ø PT/INR elevated in linear dose-response Ø Elevated PT/INR indicates anticoagulation effect Ø Normal PT/INR indicates absent activity Ø Not recommended for bridging therapy Apixaban Ø Minimal effect on PT/INR Ø Minimal effect on PTT Ø PT/INR and PTT not useful in predicting drug activity Ø Not recommended for bridging therapy

10 New Oral Anticoagulants and the Role of Laboratory Coagulation Testing Ø There is no role for routine laboratory coagulation testing and monitoring Ø NOACs do affect various anticoagulation tests Ø Sensitivity varies with assays used Ø Bleeding or over-dosage may prompt specialized testing Ø When in doubt, call the lab

11 Drug Effect on Coagulation Testing Ø Test Dabigatran Rivaroxiban Apixaban Ø PT Increase Linear dose Small Increase Response Ø aptt Increase Increase Small Increase Ø TT Increase No Effect No Effect Ø TCT Sensitive No Effect No Effect Ø Ecarin Sensitive No Effect No Effect Fibrinogen, D-Dimer, Free Protein S, Reptilase Time, not affected by NOACS

12 Target Specific Oral Anticoagulants Drug Interactions Mechanism Dabigatran Rivaroxaban Apixaban P-gp Inhibition Interacting Drug Interacting Drug Interacting Drug Ketoconazole +150% Ketoconazole +160% Ketoconazole Reduce dose by half if giving greater than 2.5 mg bid Quinidine +53% Itraconazole Amiodarone +60% Ritonavir Dronedarone Clarithromycin Verapamil +50% P-gp induction Rifampicin -67% Rifampicin -50% Rifampin Carbamazepine phenytoin St. Johns wort St Johns wort St. Johns Wort CY3A4 Inhibition Ketoconazole +160% Ketoconazole Clarithromycin +50% Itraconazole Ritonavir +50% Ritonavir and Clarithromycin CYP34A Induction Rifampicin -50% Rifampin Carbamazepine Phenytoin St.Johns Wort St. Johns Wort

13 Conversion from Warfarin to the Target-Specific Oral Anticoagulants Ø Dabigatran Re-Ly: INR <2.0 Ø Rivaroxaban ROCKET AF: INR <3.0 Ø Apixaban ARISTOTLE: INR <2.0

14 Converting from Warfarin to Target-Specific Oral Anticoagulants Dabigatran Ø Check INR Ø Start dabigatran when INR is <2.0 Ø Stop warfarin Ø Twice daily with or without food Ø Keep in original packaging Rivaroxaban Ø Check INR Ø Start rivaroxaban when INR <3.0 Ø Stop warfarin Ø Once daily with evening meal Apixaban Ø Check INR Ø Start apixaban when INR < 2.0 Ø Stop warfarin Ø Twice daily with or without food

15 Switching from Target-Specific Oral Anticoagulants to Warfarin Drug Creatinine Clearance Warfarin Start Time INR Dabigatran >50 ml/min 3 days prior to stopping dabigatran ml/min 2 days prior to stopping dabigatran ml/min 1 days prior to stopping dabigatran 2 days after stopping dabigatran 2 days after stopping dabigatran 2 days after stopping dabigatran Rivaroxaban No recommendation in package insert 4 days prior to stopping rivaroxaban 2-3 days after starting warfarin Immediately before rivaroxaban dose Apixaban No recommendation in package insert 4 days prior to stopping apixaban 2-3 days after starting warfarin Immediately before apixaban dose

16 Interruption of Target Specific Anticoagulants Before Surgery or Invasive Procedures Creatinine Clearance Average Risk of Bleeding High Risk of Bleeding Dabigatran Time of Last dose Time of Last dose >50 ml/min 1 day 2 days ml/min 2 days 4 days Rivaroxaban Time of Last Dose Time of Last Dose >50 ml/min 1 day 2 days ml/min 2 days 4 days Apixaban Time of Last Dose Time of Last Dose >1 day Longer

17 Postoperative Management of Target-Specific Anticoagulants Ø Good hemostasis resume at least 4-6 hours after surgery Ø Continuing drainage, questionable hemostasis do not restart until wound is stable and hemostasis is confirmed Ø Postoperative bridging with unfractionated heparin may be appropriate in some instances Ø Minor procedures may not need anticoagulation stopped pre-operatively

18 Management of Bleeding Ø Discontinue anticoagulation Ø Clinical support Ø Maintain renal perfusion (hydration) Ø Address source of bleeding Ø Transfuse blood products as necessary Ø Activated charcoal or gastric lavage if within a few hours of oral dose Ø Check PT/PTT l Ecarin clotting time (ECT) or thrombin time (TT) for dabigatran Ø Consider hemodialysis for dabigatran Ø Hematology consultation

19 Management of Severe Bleeding Ø Fresh frozen plasma and vitamin K are ineffective Ø Factors VIIa, 3- or 4-factor PCC, increase the risk of thrombosis Ø Factor VIIa and 3 (or 4) factor PCC has not been proven useful in reversing bleeding effects of new anticoagulants but may be tried Ø Unknown whether factors are useful in preparing patients for urgent surgery, but may be tried Ø Antidotes are currently under investigation

20 Conclusions Ø Dabigatran rivaroxaban and apixaban are the first oral anticoagulants approved since warfarin was introduced in Ø Large clinical trials support safety and efficacy for longterm anticoagulation in patients with NVAF, DVT and PE Ø Management of the new anticoagulants (choice of agent, switching between agents and perioperative interruption) require familiarity with their characteristics of rapid onset, renal excretion, no routine coagulation monitoring and the risk of bleeding. Ø Long-term patient care requires knowledge of the effects of dabigatran, rivaroxaban and apixaban and the patient s medical condition.