Practical Use of Rivaroxaban in Atrial Fibrillation Dr Seow Swee-Chong KHRS, Seoul Jun 2012 MBBS, MRCP(UK), EHRA (Electrophysiology), EHRA (Cardiac Pacing), FAMS (Cardiology), FESC, FACC Director, Cardiac Electrophysiology and Pacing Cardiology Department National University Hospital, Singapore
National University Hospital Singapore
Targets for Anticoagulants ORAL DIRECT TF/VIIa PARENTERAL INDIRECT VKAs inhibit the hepatic synthesis of several coagulation factors 3 Rivaroxaban Apixaban Edoxaban X VIIIa Va Xa IXa IX AT AT Fondaparinux LMWH II AT UFH Ximelagatran Dabigatran AZD 0837 Fibrinogen IIa Fibrin Adapted from: 1. Weitz et al, 2005 and 2. Weitz et al, 2008; 3. Ansell et al, 2008. 4
Rivaroxaban Selective, direct Factor Xa inhibitor 1 High oral bioavailability 2 Rapid onset of action 3 Half-life: 2 4 5 9 hours in young healthy individuals 11 13 hours in the elderly Dual mode of elimination: 5 1/3 of active drug excreted unchanged by the kidneys 2/3 of drug metabolized by the liver; half of which is excreted renally, half excreted via the Fibrinogen hepatobiliary route X TF/VIIa VIIIa Va Xa II IIa IXa IX Rivaroxaban Fibrin 1. Perzborn E et al, 2005; 2. Kubitza D et al, 2005; 3. Kubitza D et al, 2005; 4. Kubitza D et al, 2008; 5. Weinz C et al, 2009. Adapted from Weitz JI et al, 2005; 2008. 5
Pharmacological Characteristics of NOACs Parameter Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Oral bioavailability 6.5% 80 100%* ~66% Plasma protein binding 34 35% 92 95% 87% Dosing (for SPAF indication) Fixed, twice daily Fixed, once daily Fixed, twice daily Prodrug Yes No No Half life (h) 12 14 5 9 (young healthy) 11 13 13 (elderly) T max (h) ~6 2 4 1 3 Routine coagulation No No No monitoring 8 13 *15 20 mg to be taken with food NOACs, novel oral anticoagulants t Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; Rivaroxaban SmPC 2011; Rivaroxaban PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al, 2010. 6
Pharmacological Characteristics of NOACs Parameter Dabigatran Rivaroxaban Apixaban Renal clearance 80% 33%; additional 33% cleared after metabolic degradation to inactive drug ~25% Potential drug interactions Rifampicin, Potent inhibitors Potent CYP3A4 quinidine, of both CYP3A4 and inhibitors* amiodarone, potent P gp inhibitors P gp*, strong inducers of CYP3A4 *CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and P-gp include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; Rivaroxaban SmPC 2011; Rivaroxaban PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al, 2010. 7
ROCKET AF Rivaroxaban once-daily vs VKA for prevention of stroke and embolism in patients with non-valvular AF
ROCKET AF Study Design Risk factors Stroke, TIA or systemic embolus OR CHF Hypertension A 75 Diabetes Atrial fibrillation Age 75 At least 2 or 3 required* Rivaroxaban 20 mg once daily (15 mg once daily dil for CrCl 30 49 ml/min) Randomized double blind / double dummy Warfarin INR target: 2.5 (2.0 3.0 30inclusive) i Monthly monitoring Adherence to standard of care guidelines Primary endpoint: stroke or non CNS systemic embolism *Enrolment of patients without prior stroke, TIA or SE and only two factors capped at 10% Patel MR et al. N Engl J Med 2011;365:883 891 9
ROCKET AF Baseline Characteristics Characteristic Rivaroxaban (N=7,131) Warfarin (N=7,133) CHADS 2 score, mean ± SD 3.48±0.94 3.46±0.95 2, n (%) 925 (13.0) 934 (13.1) 3, n (%) 3,058 (42.9) 3,158 (44.3) 4, n (%) 2,092 (29.3) 1,999 (28.0) 5, n (%) 932 (13.1) 881 (12.4) 6, n (%) 123( (1.7) 159 (2.2) Co-existing conditions, n (%) Previous stroke/tia or SE 3,916 (54.9) 3,895 (54.6) Congestive heart failure 4,467467 (62.6) 6) 4,441441 (62.3) Hypertension 6,436 (90.3) 6,474 (90.8) Diabetes mellitus 2,878 (40.4) 2,817 (39.5) Previous MI 1,182 (16.6) 1,286 (18.0) Peripheral vascular disease 401 (5.6) 438 (6.1) COPD 754 (10.6) 743 (10.4) CrCl, median (25th, 75th), ml/min 67 (52, 88) 67 (52, 86) ITT population; Patel MR et al. N Engl J Med 2011;365:883 891 10
ROCKET AF Primary Efficacy Endpoint 6 Stroke or systemic embolism Cumulativ ve event ra ate (%) 5 4 3 2 1 HR=0.79 (0.66, 0.96) p<0.001 (non inferiority) Warfarin Rivaroxaban 0 0 120 240 360 480 600 720 840 Days since randomization Number of subjects at risk Rivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496 Warfarin 7,004 632 6,327 5,911 5,542 4461 4,461 34 3,478 2,539 1,538 Per-protocol population as treated Per-protocol population as-treated Patel MR et al. N Engl J Med 2011;365:883 891 11
ROCKET AF Primary Efficacy Endpoint Rivaroxaban (N=7,061) Warfarin Hazard ratio (N=7,082) and d95%ci CIs Endpoints n (% per year) n (% per year) Hazard ratio (95% CI) Primary efficacy endpoint 189 (1.7) 243 (2.2) 0.79 (0.65, 0.95)* All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70,1.03) Haemorrhagic stroke 29 (0.3) 50 (0.4) 0.59 (0.37,0.93)* Ischaemic stroke 149 (1.3) 161 (1.4) 0.94 (0.75,1.17) Unknown stroke type 7 (0.1) 11 (0.1) 0.65 (0.25,1.67) Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)* Safety population on-treatment analysis *Statistically significant 0.2 0.5 1 2 5 Favours rivaroxaban Favours warfarin Patel MR et al. N Engl J Med 2011;365:883 891 12
ROCKET AF Bleeding Analysis Parameter Principal safety endpoint Rivaroxaban (N=7,111) Warfarin (N=7,125) n (% per year) n (% per year) Hazard ratio (95% CI) 1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11) Major bleeding 395 (3.6) 386 (3.4) 104(090120) 1.04 (0.90,1.20) Hazard ratio and 95% CIs Haemoglobin drop ( 2 g/dl) 305 (2.8) 254 (2.3) 1.22 (1.03,1.44)* Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)* Critical organ bleeding 91 (0.8) 133 (1.2) 0.69 (0.53,0.91)* Intracranial 55 (0.5) 84 (0.7) 0.67 (0.47,0.93)* haemorrhage Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)* Non-major clinically relevant bleeding 1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13) Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001* Safety population on-treatment analysis; *Statistically significant 0.2 0.5 Favours 1 2 5 Favours rivaroxaban warfarin Patel MR et al. N Engl J Med 2011;365:883 891 13
ROCKET AF Subgroup Analyses
Patients with Renal Insufficiency Primary Endpoint: Patients with CrCl 30 49 ml/min Clinical endpoint Rivaroxaban Warfarin CrCl 50 ml/min HR (95% CI) Rivaroxaban P (% per year) (N=7,111) (N=7,116) CCl30 CrCl 30 49 ml/min vs warfarin (interaction) Primary efficacy endpoint* 1.57 2.32 2.00 2.77 0.78 (0.63 0.98) 0.84 (0.57 1.23) 0.76 PE + vascular death 2.76 4.64 3.32 4.83 0.83 (0.70 0.98) 0.96 (0.73 1.27) 0.38 PE + MI, vascular 3.55 4.16 0.85 (0.73 0.99) death 5.58 6.54 0.85 (0.67 1.09) 098 0.98 Stroke Ischaemic Haemorrhagic 120 1.20 134 1.34 090(069 0.90 (0.69 1.16) 116) 1.98 1.78 1.11 (0.71 1.73) 0.26 0.42 0.62 (0.37 1.03) 0.29 0.52 05 0.56 056(0.21 1.51) 0.41 0.88 Undetermined 0.07 0.05 0.10 0.09 0.68 (0.24 1.90) 0.51 (0.05 5.67) 0.84 Based on per-protocol population on treatment 0.01 0.1 1 10 *Stroke and systemic embolism; Rivaroxaban 20 mg od; Rivaroxaban 15 mg od Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394 15
2 Stroke Prevention: Primary Efficacy Endpoint Kaplan Meier survival curve showing time to the primary outcome (stroke or systemic embolism) oke or ) ate stro olism (%) ve event ra emic emb Cumulativ syste 7 6 5 4 3 2 1 0 0 6 12 18 24 30 Months from randomisation Previous stroke/ TIA, warfarin Previous stroke/ TIA, rivaroxaban No previous stroke/tia, warfarin No previous stroke/tia, rivaroxaban Intention-to-treat population Hankey G. Lancet Neurology epub ahead of print March 7, 2012 16
Elderly Patients : Relative Risks of Major Events Stroke + Embolism MajorBleeding Hemorrhagic (n=14,171) (n=14,236) Stroke (n=14,171) (years) Age <75 >75 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 0 0.5 1.0 1.5 2.0 Rivaroxaban better Warfarin better Rivaroxaban better Warfarin better Rivaroxaban better Warfarin better HR: 0.95 (0.76, 1.19) HR: 0.96 (0.78, 1.19) HR: 0.47 (0.25, 0.88) HR: 0.80 (0.63, 1.02) HR: 1.11 (0.92, 1.34) HR: 0.70 (0.39, 1.26) Interaction P=0.313 Interaction P=0.336 Interaction P=0.365 Presented at the ISC; February 2012, New Orleans, USA. Stroke. 2012; 43: A148 17
Ischaemic Cardiac Outcomes Vascular death, MI or unstable angina Total Rivaroxaban Events per 100 Pt-Yrs Total Warfarin Events per 100 Pt-Yrs HR (95% CI) 298 2.7 352 3.15 0.86 (0.73, 1.00) Vascular death or MI 260 2.35 304 2.70 0.87 (0.74, 1.02) All-cause mortality 208 1.87 250 2.21 0.85 (0.70, 1.02) Vascular death 170 1.53 193 1.71 0.89 (0.73, 1.10) Non-vascular death 21 0.19 34 0.30 0.63 (0.36, 1.08) Death unknown cause 17 0.15 23 0.20 0.75 (0.40, 1.41) MI 101 0.91 126 1.12 0.81 (0.63, 1.06) Unstable angina 41 0.37 57 0.51 0.73 (0.49, 1.09) MI, myocardial infarction Presented at the AHA Scientific Sessions; November 2011; Orlando, USA Circulation. 2011; 124: A13482 18
ROCKET AF: Conclusions Efficacy: A once-daily fixed dose regimen of rivaroxaban was non-inferior to warfarin for prevention of stroke or systemic embolism Safety: Similar overall incidence of bleeding and adverse events Fewer intracranial haemorrhages and less fatal bleeding with rivaroxaban Subgroup analyses: Similar efficacy and safety across these patient populations: Moderate renal impairment Secondary stroke prevention Elderly Previous MI 19
Practical use of rivaroxaban
How to Convert from VKA to Rivaroxaban? VKA therapy should be stopped INR measurement has to continue Rivaroxaban should be initiated when INR is 3.00 Start rivaroxaban when INR 3.0 Stop VKA Days INR testing 21
How to Convert from Rivaroxaban to VKA? Overlapping therapy of both Rivaroxaban and VKA is crucial to ensure proper anticoagulation Rivaroxaban can be stopped once INR is >2.0 INR measurement should be done 24h after the last administration of Rivaroxaban and prior to the next dose Start VKA INR testing before rivaroxaban administration * * * Days Stop rivaroxaban when INR >2.0 22
How to Convert from Rivaroxaban to Heparin/LMWH & vice versa? IV Heparin: Rivaroxaban should be started at the time of discontinuation LMWH: Rivaroxaban should be started 0 2 hours before the time of the next scheduled administration of the parenteral drug Rivaroxaban to parenteral anticoagulation: The first dose of the parenteral drug should be administered instead of the next Rivaroxaban dose at the planned time 23
What about INR Measurement / Lab Assays? Rivaroxaban does not require routine coagulation monitoring i INR is not appropriate for Rivaroxaban Although PT, appt, INR are increased Does not reflect degree of anti-xa activity Anti-FXa chromogenic assays have been developed and are now commercialized If necessary, hemostatic status can also be assessed with PT using Neoplastin only 24
Who are the Patients with Potentially Higher Risk of Bleeding? Like all anticoagulants, Rivaroxaban may increase the risk of bleeding Patient populations at higher risk of bleeding: Renal impairment Hepatic impairment Patients with other hemorrhagic risk factors Treatment decision in these patients should be done after assessment of treatment benefit against the risk for bleeding 25
Potential Higher Risk of Bleeding: Patients with Renal Impairment General advice: In patients with severe renal impairment (CrCl <30 ml/min), Rivaroxaban plasma levels may be significantly increased (1.6 fold on average) Use with caution in patients with CrCl 15 29 ml/min Use not recommended in patients with CrCl <15ml/min SPAF patients with moderate renal impairment (30 49 ml/min) Dose reduction to 15 mg OD 26
Potential Higher Risk of Bleeding: Patients with Hepatic Impairment Rivaroxaban is contraindicated d in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child-Pugh B and C 27
Potential Higher Risk of Bleeding: Concomitant Drug Usage Due to the dual mode of metabolism of rivaroxaban, drugs that are strong inhibitors of both CYP3A4 and P-gp pathways are not recommended for concomitant use systemic azole-antimycotics or HIV protease inhibitors dual antiplatelet therapy (e.g. coronary stenting) Care is to be taken in patients receiving other drugs that affect hemostasis, such as NSAIDs ASA platelet aggregation inhibitors other anti-thrombotic agents 28
Examples of Concomitant Drug Usage (1) Co medications Strong CYP3A4 inducers Rifampicin Phenytoin Carbamazepine Phenobarbital St. John s Wort Recommendation Medications in this class should be co administered with caution. Strong CYP3A4 and P gp inhibitors: Systemic use of azole antimycotics It is not recommended to co administer these drugs with Rivaroxaban due to an increased bleeding risk. Ketoconazole BUT Itraconazole Fluconazolel is expected tdto have less effect on Voriconazole Rivaroxaban exposure and can be co administered with caution Posaconazole Or HIV protease inhibitors: e.g. Ritonavir Anti arrhythmics: No significant clinical interaction noted between Amiodarone Amiodarone and Rivaroxaban. Dronedarone Co administration of Dronedarone with Rivaroxaban should be avoided due to limited clinical data 29
Examples of Concomitant Drug Usage (2) Co medications Macrolide antibiotics Clarithromycin Erthryomycin NSAIDs, ASA, platelet aggregation inhibitors or other antithrombotic agents such as: Naproxen Acetylsalicylic acid Clopidogrel Enoxaparin Warfarin Acenocoumarol, etc Other commonly used medications: Midazolam (substrate of CYP3A4) Digoxin (substrate of P gp) Atorvastatin (substrate of CYP3A4 and P gp). Recommendation No clinical relevant interactions have been noted and Rivaroxaban can be used in patients taking these medications Care is to be taken, due to the increased bleeding risk. No clinically significant PK or PD interactions were observed with Rivaroxaban when these drugs were coadministered d 30
Potential Higher Risk of Bleeding: Patients with Other Hemorrhagic Risk Factors Patients with ihmedical conditions dii that are predisposing i for bleeding are at higher risk when receiving anticoagulation therapy Caution advised in patients with other bleeding risk factors : uncontrolled severe arterial hypertension active/recent ulcerative gastrointestinal disease vascular retinopathy recent intracranial haemorrhage recent brain, spinal or eye surgery bronchiectasis or pulmonary bleeding Rivaroxaban is contraindicated in pregnant and lactating women 31
How Do I Manage Drug Overdose? Due to limited i absorption, a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg Rivaroxaban and above A specific antidote antagonising the pharmacodynamic effect of Rivaroxaban is not available Activated charcoal to reduce absorption may be considered within the first hours after intake (C max : 2 4 hours) In the event of bleeding, consider the information on bleeding management Due to the high plasma protein binding, Rivaroxaban is not expected to be dialyzable 32
What About Bleeding Management? Next dose of Rivaroxaban should be delayed d or discontinued d as appropriate. Individualized bleeding management : Symptomatic treatment (compression, surgical intervention, fluid replacement) Hemodynamic support (such as blood products or blood components) For life-threatening bleeding, use of specific procoagulant agents should be considered : Prothrombin complex concentrate (PCC) apcc Factor VIIa Note: There is currently limited clinical experience with these measures 33
What About Perioperative Management? The last dose of Rivaroxaban should be given not later than 24 hours before the intervention Restart as soon as possible after the intervention, provided the clinical situation allows and adequate hemostasis has been established 34
Practical Use of Rivaroxaban: Conclusion Novel anticoagulants such as Rivaroxaban simplify treatment for patients and physicians Responsible use of rivaroxaban will ensure that the right patients benefit from its efficacy, safety and convenience. 35