Monty Yoder, PharmD 5/13/2011

Transcription

1 Anticoagulation Therapies Monty Yoder, PharmD May 2011 Anticoagulation Therapy Update Objective Review data describing the role of oral anticoagulants Disclosures No conflicts of interest to disclose Anticoagulation Recommended for all patients, except those with lone AF or contraindications (Class I) Risk Category Recommended Therapy No risk factors Aspirin mg daily 1 Moderate risk factor Aspirin mg daily OR warfarin INR 2-3; target 2.5 Any high risk factor or INR 2-3; target 2.5 >1 moderate risk factor Less validated risk factors Moderate-risk factors High-risk factors Female gender Age 75 H/o stroke, TIA, or embolism Age yoa Hypertension Mitral stenosis Coronary Artery Disease Heart Failure Prosthetic heart valve Thyrotoxicosis EF 35% Diabetes 1

2 Previous Recommendations for Anticoagulation Options: CHADS 2 scoring Score Risk Drug 0 Low ASA mg daily 1 Intermediate ASA or (INR 2-3) 2 high (INR 2-3) C=CHF, H=HTN, A=age>65, D=DM, S 2 =Stroke/TIA Clotting Cascade Clotting Cascade Factor Xa Inhibitors (apixaban, rivaroxaban) 2

3 vs in Atrial Fibrillation Phase 3, Multicenter, Prospective, Randomized trial: blinded outcomes 2 doses of dabigatran vs warfarin: prevent CVA in non-valvular AF pts, 1 RF dose blinded Primary Objective: Non-inferiority of dabigatran vs warfarin to prevent CVA, systemic embolism Inclusion AF 1 Risk Factor for CVA Protocol required a balance of anticoagulant naïve and VKA experienced subjects Exclusion Valvular heart disease CKD (CrCl < 30 ml/min) Active liver disease 3

4 18,113 subjects 951 centers 44 countries Follow-up N=18, Day 14 1 month 3 months Q 3 months (year 1-2) Q 4 months thereafter (INR 2 3) 110mg bid 150mg bid (INR 2 3) Characteristic 110mg 150mg Age (yr) Wt (kg) Male (%) CHADS 2 score (%) DM (%) HTN (%) Previous stroke /TIA (%) Median follow-up : 2 years 99.9% follow-up achieved Discontinuation rates similar in all groups 21% dabigatran arms (dyspepsia 11%) 16.6% warfarin arm (dyspepsia 6%) ASA use similar in all arms Mean % study period where INR was therapeutic: 64% 4

5 Kaplan-Meier Event Rates 110mg 150mg Kaplan-Meier Event Rates 110mg (non-inferior) 150mg (superior) Event 110mg 150mg N=6015 N=6076 N=6022 Stroke or 182 pts 134 pts 199 pts systemic 1.53 % annual 1.11% annual 1.69 % annual embolism Relative Risk P<0.001 for 110mg 150mg non inferiority vs vs 0.91 ( ) 0.66 ( ) 5

6 Event Major Bleeding 110mg 150mg N=6015 N=6076 N= (2.71) 375 (3.11) 197 (3.36) Life 145 (1.22) 175 (1.45) 212 (1.80) threatening Non life threatening 198 (1.66) 226 (1.88) 208 (1.76) GI 133 (1.12) 182 (1.51) 120 (1.02) 150mg vs 110mg Significantly less CVA or systemic embolism RR 0.74 (p=0.005) 150mg superior to 110mg dose, warfarin Trend towards increased major bleeding No difference in mortality (vascular or all cause) RR 1.16 (p=0.052) 2 endpoint: in MIs (Odds ratio 1.38) Authors conclusion: As compared with warfarin, the 110mg dose of dabigatran was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage; the 150mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage 6

7 When might dabigatran be superior to warfarin? : Less variability in anticoagulant response Elimination ½ life of hrs bid dosing reduces variability More selective coagulation cascade inhibition may account for less bleeding risk : Variable anticoagulant effect (TTR) Broad inhibition of coagulation cascade (II, VII, IX, X, C, S) 10/10: FDA approved for prevention of CVA and thrombosis in patents with AF Available in two doses: 150mg bid, 75mg bid ($6-8/day acquisition cost) 150mg bid: normal renal fxn (CrCl>30ml/min) 110mg bid: not approved by FDA 75mg bid: severe renal impairment (CrCl 15-30ml/min) Dose not studied in RE-LY trial Extrapolated from pharmacokinetic data from RELY & other studies 10/10: FDA approved for prevention of CVA and thrombosis in patents with AF 110mg bid: not approved by FDA In RE-LY, compared to warfarin, 110mg bid had major bleeding and was non-inferior I.E. drug that is equivalent to current standard & safer Why not approved? 150mg bid superior to warfarin, not inferior Is it ethical to offer 110mg when 150mg available? 7

8 Use Drug Interactions Not a CYP 3A4 substrate Avoid use with P-gp inducers (rifampin) No dose adjustment with P-gp inhibitors (ketoconazole, amiodarone, clarithromycin, verapamil) PPIs, H 2 blockers: low ph needed for absorption Elimination Renal (dialyzable) Use Dosing Not recommended for HD or CrCl<15 ml/min Converting from parenteral anticoagulants (give dabigatran 0-2 hrs prior) Converting dabigatran to parenteral anticoagulant (CrCl >30 ml/min: wait 12 hrs before starting parenteral agent) (CrCl < 30 ml/min: wait 24 hrs before starting parenteral agent) Procedures DC 1-2 days prior to event (CrCl >50 ml/min) DC 3-5 days prior to event (CrCl < 50 ml/min) Converting from warfarin dabigatran CrCl>50 ml/min: initiate warfarin 3 days before stopping dabigatran CrCl ml/min: initiate warfarin 2 days before stopping dabigatran CrCl ml/min: initiate warfarin 1 day before stopping dabigatran For CrCl < 15 ml/min: no recommendations 8

9 Updated Anticoagulation per ACC: CHADS 2 scoring Score Risk Drug 0 Low ASA mg daily 1 Intermediate ASA or (INR 2-3) or 2 high (INR 2-3) or Investigational Therapies Apixaban Betrixaban MOA Factor Xa inhibitor Factor Xa inhibitor Uses VTE prophylaxis in orthopedic procedures, Atrial Fibrillation Stroke prevention Edoxaban Factor Xa inhibitor Prevention & treatment of thromboembolic disorders Rivaroxaban Factor Xa inhibitor VTE prevention in orthopedic procedures, treatment of VTE, prevention of stroke in AF Case Scenario #1 58 YO AAF presents for annual checkup PMH Paroxysmal AF- (no Hx of systemic embolism) Compliant on Diltiazem CD 300mg daily; ASA 325mg daily GERD- Compliant on Ranitidine 150mg qhs Otherwise noncontributory VS (BP 129/77 mmhg; P 78; R 17) Labs: BMP, CBC are WNL; SCr 1.1; EKG =AF 9

10 Case Scenario #1: Patient has heard about a new blood thinner & wants to know if she is a candidate What is a reasonable management strategy/response to her inquiry? a. Patient now has high risk features by CHADS 2 score; switch warfarin (goal INR 2-3) b. Patient now has high risk features by CHADS 2 score; switch to dabigatran 150mg bid c. Patient has low risk features by CHADS 2 score; maintain current regimen of ASA 325mg daily d. Patient at no risk for systemic embolus; DC ASA Case Scenario #2: 64 YO WM presents as follow-up for AF management PMH Persistent AF- (no Hx of systemic embolism) Compliant on Carvedilol 3.125mg bid; 2mg daily qmwf, 3mg other days Non-compliant with dietary restrictions Frequent no show for INR evaluations; most recent 1.6 HTN HF Compliant with Lisinopril 5mg daily & Carvedilol CAD ASA 325mg daily, Carvedilol, Pravastatin 20mg daily Case Scenario #2 VS (BP 13529/82 mm Hg; P 71; R 19) Labs: BMP, CBC are WNL; SCr 1.3; Wt: 89 kg (CrCl ~ 70 ml/min) Most recent EF 30% EKG =AF 10

11 Case Scenario #2: You are concerned about how best to manage the anticoagulation for this patient. Possible options include: a. Continue anticoagulation as before; reinforce the need for close anticoagulation follow-up; patient at lower risk for systemic embolus b. Consider switching from warfarin to dabigatran 75mg bid; continue ASA 325mg daily; patient requires lower dosing b/c of renal function c. Consider switching from warfarin to dabigatran 150mg bid; ASA to 81mg daily; pt at higher risk for systemic embolus In Conclusion.. Mickey Mouse Philosophy More Intensive Collection of data is required in our CV Patients in order to improve survival and quality of life TheKEY to answering questions is for you to read and evaluate data through your own independent thought processes Then you ll get MO USE out of what you learned in school 11