New Anticoagulants- Dabigatran/Rivaroxaban JOHN NOVIASKY, PHARMD, BCPS, FNYSCHP CGH AT UPSTATE UNIVERSITY HOSPITAL SYRACUSE NY Objectives Describe the risks and benefits of dabigatran therapy Describe the risks and benefits of rivaroxaban therapy Compare and contrast dabigatran/rivaroxaban and warfarin use for stroke prevention in patients with atrial fibrillation 1
Atrial Fibrillation Definition: Supraventricular tachyarrhythmia characterized by uncoordinated atrial impulse formation and conduction Most common arrythmia Accounts for ~1/3 of hospital admissions for cardiac rhythm disturbances ~ 66% in hospital admissions within the past 20 years Estimated prevalence: ~ 0.4-1% Age adjusted prevalence: Men > Women (prevalence > 2x from 1970s 90s for men) Median age: ~75 years old ~70%: 65-85 years old Fuster et. al. Circulation. 2011;123:e269-367. Atrial Fibrillation 1/6 strokes occur in patients with A. Fib Rate of ischemic stroke in patients with non-valvular A. Fib: ~ 5 %/year 2-7 times > those without A. fib. When considering TIAs and clinically silent strokes: > 7%/yr Stroke risk attributable to A.Fib as age : Framingham Study Age (years) Risk of Stroke 50-59 1.5% 80-89 23.5% Fuster et. al. Circulation. 2011;123:e269-367. 2
High risk Low risk Intermediate Singer DE et al. CHEST risk 2008; 133:546S-592S CHF; LV dysfunction 1 Hypertension 1 Age > 75 1 Diabetes 1 S 2 troke/tia 2 Atrial Fibrillation 2011 ACC/AHA/ESC Practice Guidelines Fuster et. al. Circulation. 2011;123:e269-367. 3
In a Perfect Anticoagulation World Efficacy- Dabigatran>warfarin~rivaroxaban Predictable pharmacokinetic profile Dabigatran~rivaroxaban > warfarin Safety (bleeds)-dabigatran >(?) warfarin~rivaroxaban Easy to manage peri-operatively Warfarin>>>dabigatran/rivaroxaban Little/no dose variability Dabigatran~rivaroxaban > warfarin Little/no Drug Interactions Dabigatran>rivaroxaban>warfarin Cost-Dabigatran~rivaroxaban >>> warfarin 76 yo female with new onset atrial fibrillation and no previous stroke, has what chance of embolic stroke if no anti-thrombin therapy is present? Her current medications include; Amlodipine 10mg daily Glipizide 5mg twice daily Metformin 500 twice daily Timolol 0.5% 1 gtt ou BID 1.9 2.8 4 5.9 8.5 4
High risk Low risk Intermediate Singer DE et al. CHEST risk 2008; 133:546S-592S CHF; LV dysfunction 1 Hypertension 1 Age > 75 1 Diabetes 1 S 2 troke/tia 2 59 yo male with intermittent atrial fibrillation and no previous stroke, has what chance of embolic stroke if no anti-thrombin therapy is present? Current medications: HCTZ 25mg daily loratadine 10mg daily as needed 1.9 2.8 4 5.9 8.5 5
High risk Low risk Intermediate Singer DE et al. CHEST risk 2008; 133:546S-592S CHF; LV dysfunction 1 Hypertension 1 Age > 75 1 Diabetes 1 S 2 troke/tia 2 Dabigatran Etexilate (Pradaxa ) Oral direct, reversible thrombin inhibitor Prodrug converted in vivo to the active dabigatran Binds to and inhibits both free and fibrin-bound thrombin and prevents thrombin mediated effects FDA approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation 6
Rivaroxaban Direct Factor Xa Inhibitor Well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8 12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible Oxazolidinone derivative Match the drug to the factor most associated with its mechanism Rivaroxaban-II, Warfarin, II, VII, IX, X, Dabigatran II Rivaroxaban-X, Warfarin II, VI, X, XII, Dabigatran X Rivaroxaban-X, Warfarin II, VII, IX, X Dabigatran II Rivaroxaban-X, Warfarin II,VII,IX,X Dabigatran X 7
Drug-Factor of Interest Rivaroxaban- oral Anti-Xa activity Warfarin- Inhibits Vitamin K dependent factor activity-ii, VII, IX, X Dabigatran-Inhibits Thrombin Activity-Factor II RE-LY Dabigatran Efficacy Randomized, blinded, international, noninferiority trial published in NEJM Evaluated safety and efficacy in the reduction of stroke risk and systemic embolism between dabigatran and warfarin N= 18,113 pts w/ non-valvular AFib & 1 risk factor for stroke Pts followed x 2 years Primary efficacy outcome Stroke or systemic emboli Primary safety outcome Major hemorrhage 8
RE-LY Superiority Superiority All Show Superiority to Warfarin RE-LY 9
Rivaroxaban Efficacy (RECORD) Record 1, Record 2, Record 3, Record 4 All orthopedic studies All randomized, Double Blinded, double dummy Enoxaparin vs rivaroxaban About 2500-3000 patients per study Outcomes-PE, DVT, death Results-Outcomes-ARR-2-9% (p<0.05) in favor of rivaroxaban, bleeding-about the same between groups Rivaroxaban Efficacy (Rocket-AF) Double-blind, double-dummy 14k patients with atrial fibrillation. 20mg rivaroxaban once daily (or 15 mg in patients with moderate renal impairment at screening) or warfarin (titrated to an INR of 2.5). 10
Dabigatran/Rivaroxaban PK Absorption/Distribution Dabigatran F=3-7% Food-no change Vd-50-70 L PB-35% Tmax-1-2 hrs Rivaroxaban F=80-100% Food->10mg-increase AUC by 39%) Vd-50L PB-95% Tmax-2-4 hrs Dabigatran/Rivaroxaban PK Metabolism/Excretion Dabigatran CYP 450-No interact. P-Gp-substrate Elimination urine Dose adjust renal-yes Dose adjust hepatic-no Rivaroxaban CYP450-3A4/2J2 P-Gp-substrate Elimination Metabolites-Urine (30%), feces (21%) Dose concern renal-yes Dose concern hepaticyes 11
Pharmacokinetics Metabolism Warfarin Metabolized through CYP450 enzyme system Genetic alterations in enzyme change drug activity Poor Metabolizer Inadequate achievement of goal INR Fast Metabolizer Increased risk of bleed Dabigatran No CYP450 involvement Take home message: There is significant patient specific dose-response variability with warfarin which is NOT an issue with dabigatran Effect of Renal Dysfunction on Clearance- Rivaroxaban Renal Clearance (active secretion and passive filtration) Hepatic Clearance Kubitza D. Br J Clin Pharmacol 2010;70:703-712 12
Effect of Renal Dysfunction on Prothrombin- Rivaroxaban Severe (<30ml/min) Moderate (30-49) Mild (50-79) Mild renal impairment (CLCr 50 79 ml min-1) ( ); Moderate renal impairment (CLCr 30 49 ml min-1) ( ); Severe renal impairment (CLCr <30 ml min-1) ( ) Normal Renal Function Kubitza D. Br J Clin Pharmacol 2010;70:703-712 Effect of Hepatic Dysfunction Xarelto Package Insert 2011 13
Drug Interactions Dabigatran Amiodarone No dose modifications suggested Rivaroxaban Bleeding-Dabigatran 14
Patient Case: What s the correct dose of Dabigatran for Mrs Donnelly? 80 yo female, 47 kg, Cr-1, CrCl-34ml/min PMH-A.Fib, Hypertension, previous stroke Dabigatran 150mg BID Dabigatran 75mg BID Dabigatran 150mg daily Dabigatran 75mg daily Dosing per the package insert 15
HOWEVER, Impact of Other Variables on PK Gender Females-14% Increase AUC over males* Weight 1.1% increase Vd/kg (over 80kg)* <50kg-1.5x concentration of >100kg 50-100kg-1.3x concentration of >100kg Age Decrease clearance 0.66%/year (over 68yo)* >75 yo 1.7x concentration of <65 yo 65-75 yo- 1.3x concentration of <65 yo *2.1.4/5 page 9,10 Cost Medication 30 day supply Monitoring Annual Cost Warfarin $25 Hospital/clinic lab based: ~$35/test + visit fee +/- transportation + /- additional medication for dose adjustments ~ $3,000 Self testing: Machine: $2,500 Test strip/cuvette: $18.00/test Dabigatran $240 Creatinine monitoring ~$35/test ~$ 3,000 150 mg Rivaroxaban $240 ~$3,000 16
Recap Efficacy Similar between groups PK Varies between groups Safety Similar between groups Little/No dose variability Dose adjustments warfarin, rivaroxaban, dabigatran Cost Purchase cost-dabigatran~rivaroxaban>>warfarin 17