Experience matters: Practical management in your hospital

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1 Experience matters: Practical management in your hospital Dr AGG Turpie McMaster University, Hamilton, ON, Canada Disclosures AGG Turpie has acted as a consultant for Bayer HealthCare, Janssen, Sanofi-Aventis, GSK, Astellas, Takeda, Portola; participated in Speaker Bureau for Bayer HealthCare 1

2 Rivaroxaban Pharmacologic Profile Oral dosing Predictable pharmacokinetics and pharmacodynamics 1 Rapid onset C max in 2 to 4 hours Maximum inhibition of Factor Xa activity at 1 to 4 hours after administration* 2 Dual mode of clearance 1,3 ~1/3 direct renal excretion ~2/3 metabolized in the liver T 1/2 of 5 to 9 hours in healthy individuals aged 20 to 45 years T 1/2 11 to 13 hours in the elderly No requirement for routine coagulation monitoring 4,5 ~1/3 Unmetabolized ~2/3 Metabolized Direct Renal Excretion in Liver 1/2 excreted via the bile 1/2 excreted via renal elimination 1. Perzborn E et al. Arterioscler Thromb Vasc Biol. 2010;30(3): Kubitza D et al. Clin Pharmacol Ther. 2005;78(4): Weinz C et al. Drug Metab Dispos. 2009;37: Patel MR et al. N Engl J Med. 2011;365(10): Mueck W et al. Clin Pharmacokinet. 2008;47(3): Rivaroxaban approved indications Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) 2

3 Rivaroxaban dosing Program Indications Dose 14,264 patients vs warfarin Stroke/systemic embolism risk reduction in patients with NVAF* 20 mg once daily with food for CrCl >50 ml/min 15 mg once daily with food for CrCl 15 to 50 ml/min 9477 patients vs enoxaparin/vka or placebo Treatment of DVT and PE Reduction in the risk of recurrence of DVT and PE 15 mg twice daily with food for first 21 days On day 22, transition to 20 mg once daily with food 20 mg once daily with food ~12000 patients vs enoxaparin VTE prophylaxis after knee or hip replacement surgery Knee: 10 mg once daily for 2 weeks Hip: 10 mg once daily for 5 weeks Tablets shown not actual size. CrCl = creatinine clearance; NVAF = nonvalvular atrial fibrillation. Age, gender and body weight Rivaroxaban is currently not approved in patients <18 years of age No dose adjustment is required for age alone Stroke prevention or DVT/PE treatment: check renal function regularly for age >75 years No dose adjustment is required for gender alone No dose adjustment is required for body weight alone Long-term treatment: 15 mg od instead of 20 mg od for patients aged >75 years and with body weight of 50 kg to avoid increased rivaroxaban exposure 3

4 Rivaroxaban plasma concentration (µg/l) Timing of first dose after elective hip or knee replacement surgery 0 Time (hours) 6 10 Delay initiation if haemostasis not achieved within 10 hours Completion of surgery (wound closure) Start rivaroxaban (when haemostasis is achieved) If oral administration is not possible, start with a parenteral agent first and then rivaroxaban when oral administration is possible* (at next scheduled dose of the parenteral agent) *The rivaroxaban Summary of Product Characteristics (SPC) recommends starting rivaroxaban 0 2 hours before the next scheduled dose of a parenteral anticoagulant (e.g. low molecular weight heparin [LMWH]) Periprocedural management of rivaroxaban Rivaroxaban pharmacokinetic profile: half-life 5 13 hours; peak plasma levels reached 2 4 hours after drug intake mg rivaroxaban (n=8) 5 mg rivaroxaban (n=6) 10 mg rivaroxaban (n=8) 20 mg rivaroxaban (n=7) 40 mg rivaroxaban (n=8) 80 mg rivaroxaban (n=6) To minimize the risk of bleeding, carry out invasive procedures at lowest rivaroxaban plasma levels Time (hours) Kubitza D et al. Clin Pharmacol Ther 2005;78:

5 Periprocedural management of rivaroxaban Elective surgery in patients receiving long-term rivaroxaban Last tablet should be taken not less than 24 hours before surgery or not less than 48 hours before surgery in case of high risk of bleeding or before neurosurgery Restart rivaroxaban as soon as possible, if clinical situation allows and haemostasis has been established Bridging with parenteral agents is not required Emergency surgery in patients receiving rivaroxaban Assess the urgency of surgery against the risk of bleeding Avoid surgery at peak rivaroxaban activity (2 4 hours after dosing) In patients without bleeding, haemostatic agents such as prothrombin complex concentrate (PCC) should not be used as prophylaxis Restart rivaroxaban as soon as possible, if the clinical situation allows and haemostasis has been established Neuraxial anaesthesia Patients receiving anticoagulants who also have neuraxial anaesthesia are at risk of developing epidural or spinal haematoma These patients should be monitored frequently for signs and symptoms of neurological impairment Neuraxial anaesthesia is not recommended in patients receiving long-term rivaroxaban (e.g. 20 mg/15 mg for DVT and PE treatment or stroke prevention in patients with AF) VTE prevention after elective hip or knee surgery (10 mg rivaroxaban) In cases of traumatic puncture, rivaroxaban should be delayed by 24 hours 5

6 Bridging between anticoagulants before and after surgery Oral rivaroxaban has a fast onset of action similar to subcutaneous LMWH Enoxaparin 40 mg (n=10) Rivaroxaban 10 mg (n=11) Bridging with parenteral agents is not required when rivaroxaban is discontinued before or initiated after surgery Kubitza D et al. Submitted to Clinical Pharmacology in Drug Development (GP11) Switching Patients Between Warfarin and Rivaroxaban Warfarin Rivaroxaban Rivaroxaban Warfarin Discontinue warfarin Initiate rivaroxaban when the INR is below 3.0 (SPAF)/2.5 (VTE) to avoid inadequate anticoagulation No clinical trial data to guide converting from rivaroxaban to warfarin Rivaroxaban affects INR, so INR measurements made during coadministration of Rivaroxaban with warfarin may not be useful One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin when the next rivaroxaban dose would have been taken 6

7 Switching from and to parenteral anticoagulants Parenteral agent Rivaroxaban Start rivaroxaban when next dose of parenteral anticoagulant is due or at discontinuation of a continuously administered agent Start the parenteral anticoagulant when next rivaroxaban dose is due Rivaroxaban Drug-Drug Interaction Profile Drugs (examples) PK/PD Effects Recommendation Combined P-gp and strong CYP3A4 inhibitors Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, conivaptan Clarithromycin, erythromycin Combined P-gp and strong CYP3A4 inducers Concomitant use increases rivaroxaban exposure and pharmacodynamic effects; significant increases in rivaroxaban exposure may increase bleeding risk AUC and C max are increased if coadministered with rivaroxaban Avoid concomitant use No precautions necessary when clinical data suggest a change in exposure is unlikely to affect bleeding risk Carbamazepine, phenytoin, rifampin, St. John s wort Concomitant use may decrease efficacy of rivaroxaban Avoid concomitant use Combined P-gp and weak or moderate CYP3A4 inhibitor in the presence of renal impairment Amiodarone, diltiazem, verapamil, quinidine, ranolazine, felodipine, dronedarone, erythromycin, azithromycin, cimetidine, chloramphenicol Concomitant use may significantly increase exposure Use only if potential benefit justifies risk 7

8 Rivaroxaban Functional Drug Interactions Drugs PK/PD Effects Recommendation Anticoagulants NSAIDs/aspirin Clopidogrel Concomitant use may increase bleeding risk No PK/PD interaction Concomitant use; increased bleeding time Avoid concomitant use Bleeding risk may be increased when these drugs are used concomitantly; promptly evaluate any signs and symptoms of blood loss Promptly evaluate any signs or symptoms of blood loss Considerations for Use of Rivaroxaban in Special Patient Populations Hepatic impairment Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy Renal impairment in patients being treated for DVT/PE and the reduction in the risk of recurrence of DVT and of PE Avoid the use of rivaroxaban in patients with severe renal impairment (CrCl <15 ml/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population Pregnancy Rivaroxaban is a Pregnancy Category C drug There are no adequate or well-controlled studies of rivaroxaban in pregnant women, and dosing in pregnant women has not been established Risk of pregnancy-related hemorrhage: use rivaroxaban in pregnant patients only if benefit justifies the potential risk to mother and foetus Nursing mothers It is not known if rivaroxaban is excreted in human milk A decision should be made whether to discontinue nursing or discontinue rivaroxaban 8

9 Atrial fibrillation and acute coronary syndrome Clinical trials of rivaroxaban for the prevention of stroke in patients with AF excluded patients with acute coronary syndrome (ACS); therefore, there are no data on the use of rivaroxaban for stroke prevention in patients with AF who also have ACS Based on European Society of Cardiology guidelines, patients with AF and ACS who are receiving dual antiplatelet therapy should receive VKA treatment (INR ) and not the rivaroxaban doses approved for stroke prevention in patients with AF The ideal anticoagulant drug... does not require laboratory monitoring but should be measurable 9

10 PT (s) Monitoring vs. Measuring Monitoring implies dose adjustment according to test result Measuring (or quantifying) the drug or drug effect may be useful in Overdosage Questions of compliance Urgent surgery, interventions, thrombolysis Extreme body weights Children Renal insufficiency Correlation between rivaroxaban plasma concentrations and PT Population PK modelling: patients undergoing treatment for acute DVT INR should not be used Rivaroxaban plasma concentration (μg/l) Mueck W et al. Clin Pharmacokinet 2011;50:

11 PT Time (sec) Rivaroxaban and the PT Thromborel S Innovin Neoplastin Plus RecombiPlasTin Before surgery Before XARELTO dose 2 hours after XARELTO dose 12 hours after XARELTO dose Study of 47 patients undergoing THA/TKA who received XARELTO 10 mg once daily 4-5 days after surgery Reproduced with permission. Abbreviations: PT = prothrombin; THA = total hip arthroplasty; TKA = total knee arthroplasty. Indicated trademarks are registered of their respective owners. Mani H et al. Thromb Haemost. 2011;106(1): Management of Bleeding Hold drug(s) Supportive measures (i.v. access, fluid administration, blood product transfusion) Maintain diuresis to clear drug Mechanical compression and surgical methods to stop bleeding 11

12 If Bleeding Continues Prothrombin complex concentrates (PCC) II, VII, IX, X, C, S, units per kg Activated prothrombin complex concentrates (apcc) Recombinant factor VIIa (rviia) Antifibrinolytic agents (e.g., tranexamic acid) Reversal 12

13 PCC (Humans) Rivaroxaban (PT) Dabigatran (aptt) Eerenberg E, et al. Circulation 2011 Recombinant factor Xa Reversal Agent PRT A Universal fxa antidote that binds Xa and neutralizes catalytic prothrombinase reaction Universal binding activity to Xa inhibitors Immediate onset of action No procoagulant or anticoagulant activity Estimated human half-life of 90 minutes Reversal of Blood Loss (µl) in rat model Tail Transection Enox Alone % Reversal of rivaroxaban in vitro Antidot e Bolus Enox + Antidote No Enox Minutes Antidote (µm) Source: Portola Pharmaceutical Data on File ; Genmin Lu, Ph.D ESC 2011 Oral Presentation 13

14 New Anticoagulants Many new anticoagulant drugs are approved New oral anticoagulants have similar or greater efficacy and safety to VKAs, but are easier to administer The new oral anticoagulants offer important advantages for patients (convenience, efficacy, safety) Safe management requires knowledge of drug pharmacology 14