New Oral Anticoagulants: Thinning out the competition

Transcription

1 New Oral Anticoagulants: Thinning out the competition Ashlee D. Gerfen, Pharm.D. University of Arizona Medical Center PGY2 Critical Care Pharmacy Resident

2 DISCLOSURE I have no financial interest, arrangement, or affiliation that would constitute a conflict of interest

3 OBJECTIVES Compare pharmacology, pharmacokinetics, and pharmacodynamics characteristics, and other attributes of new anticoagulants Identify patient care issues revolving new oral anticoagulant agents Select most appropriate oral anticoagulant agent using evidence based medicine for individual patients

4 ATRIAL FIBRILLATION AND RISK OF STROKE Evidence-based guidelines recommend use of oral anticoagulant or antiplatelet therapy to reduce the incidence of stroke in patients with AF, regardless of the method used to manage arrhythmia Warfarin reduces risk of stroke by 64% Aspirin reduces risk of stroke by 19% Camm. J Intern Med 2012.

5 Stroke Rate % THROMBOSIS RISK ASSESSMENT: CHADS 2 SCORE Risk Factor Score C = CHF 1 H = hypertension 1 A = age 75 years 1 D = DM 1 S 2 = hx of stroke or TIA 2 TOTAL 6 Stroke Risk with CHAD 2 Score 20.00% 18.2% 18.00% 16.00% 14.00% 12.5% 12.00% 10.00% 8.5% 8.00% 5.9% 6.00% 4% 4.00% 1.9% 2.8% 2.00% 0.00% CHADS 2 Score Gage. JAMA 2001.

6 Stroke Rate % THROMBOSIS RISK ASSESMENT: CHA 2 DS 2 - VASc SCORE Risk Factor Score C = CHF 1 H = hypertension 1 A 2 = age 75 years 2 D = DM 1 S 2 = hx of stroke or TIA 2 V = vascular disease 1 A = age years 1 Sc = Sex category 1 TOTAL 9 Stroke Risk with CHA 2 DS 2 -VASc Score [VALUE]% 10.1% % 4.7% 5 3.9% 2.3% 1.9% 0.7% 0% 0 CHADS 2 Score [VALUE]% Gage. JAMA 2001., Lip. CHEST 2010.

7 HAS-BLED SCORE Category Score H = HTN (SBP > 160) 1 A = Abnormal renal and liver fx - chronic HD, renal txp, SCr 2.26 mg/dl - Chronic hepatic dz, bilirubin > 2x UNL in association with AST/ALT/Alk Phos > 3x UNL S = Stroke 1 B = Bleeding (hx or predisposition such as anemia) L = Labile INRS (unstable/high, time in therapeutic range < 60%) E = Elderly (>65 yrs old) 1 D = Drugs or alcohol - Antiplatelet or NSAIDs 1 or 2 (1 point each) or 2 (1 point each) Pisters. Chest 2010.

8 HAS-BLED SCORE Predictive accuracy consistent in overall population using significant risk factors Score 3 = high risk bleed Pisters. Chest 2010.

9 ANTICOAGULATION GUIDELINES ACCF/AHA/HRS CCS ESC CHADS 2 = 0 Aspirin Aspirin or none Evaluate further with CHA 2 DS 2 VASc score, none or aspirin CHADS 2 = 1 Aspirin or Dabigatran/Warfarin Aspirin or Dabigatran*/Warfarin Evaluate further with CHA 2 DS 2 VASc score CHADS 2 2 Dabigatran/Warfarin Dabigatran*/Warfarin Anticoagulation CHA 2 DS 2 VASc Not used Not used 0 = none 1 = anticoagulation or none > 1 = anticoagulation * Dabigatran preferred over warfarin Wann. Circulation 2011., Gillis. Can J Cardiol 2011., European Heart Rhythm Assoc. European Heart J 2010.

10 FUTURE OF WARFARIN? >50 years, the vitamin K antagonist was the only available oral anticoagulant (OA) Safety, compliance, efficacy all effected by its narrow therapeutic index, often complex dosing regimens, and rigorous monitoring Optimal anticoagulation also complicated by long half life, slow onset of action, and multiple drug/food interactions This shortcomings have prompted development of new OA s Gonsalves. Mayo Clinic 2013.

11 THE IDEAL ANTICOAGULANT Oral, fixed once daily dosing Rapid onset No renal/hepatic adjustments No drug-drug interactions Predictable 1 st order pharmacokinetics/dynamics Wide therapeutic window No routine anticoagulant effect monitoring Limited drug/food interactions Available antidote Reasonable cost

12 NEW ORAL ANTICOAGULANTS Dabigatran Rivaroxaban Apixaban Mechanism Direct IIa inhibitor Direct Xa inhibitor Direct Xa inhibitor Brand Name Pradaxa Xarelto Eliquis Approval Status in US 10/2010: approved by FDA for stroke prevention in AF 7/2011: approved by FDA for VTE ppx in ortho surgery and DVT/PE tx 12/2012: approved by FDA for stroke prevention in AF 11/2011: approved by FDA for stroke prevention in AF Gonsalves. Mayo Clinic 2013.

13 REVIEW OF CLOT FORMATION Di Nisio. N Engl J Med 2005.

14 MECHANISM OF ACTION OF NEW OA s Smythe. Pharmacotherapy 2013.

15 COMPARATIVE PROPERTIES OF OA s Warfarin Dabigatran Rivaroxaban Apixaban Prodrug No Yes No No Bioavailability (%) >95 65 >80 50 Protein binding (%) T 1/2 40 hrs hrs 5-9 hrs, 9-13 hrs hrs Peak effect hrs 2 hrs 2-4 hrs 3-4 hrs Hepatic met Yes No Yes Yes Renal elimination 92% (metabolites) 80% 66% 27% Renal dosing No Yes Yes No? Dialyzable No Yes No No Drug Interactions CYP 2C9, 1A2, 3A4 P-gp inducer/inhibitor CYP3A4 CYP3A4, P-gp inducer/inhibitor Monitoring INR None needed None needed None needed Antidote Vitamin K None None None Gonsalves. Mayo Clinic 2013.

16 CASE #1 A patient has recently diagnosed atrial fibrillation and is currently on dronadrerone therapy. The last CrCl of the patient was calculated at 25 ml/hr. Which of the following medications would be contraindicated for use of atrial fibrillation stroke prevention? A. Rivaroxaban B. Dabigatran C. Apixaban D. Warfarin

17 DABIGATRAN Brand Name: Pradaxa 1 st oral direct thrombin inhibitor approved by FDA Prodrug, rapidly converted to active compound by esterases in plasma and liver MOA: active compound competitively and reversibly binds to active side of free and clotbound thrombin, blocking its procoagulant activity Gonsalves. Mayo Clinic 2013.

18 DABIGATRAN- MOA Di Nisio. N Engl J Med 2005.

19 DABIGATRAN PK/PD Supplied: 75 mg or 150 mg capsules Absorption: Bioavailability with oral is 3 7 % by 75% when pellets are taken without capsule Capsule have tartaric acid core to absorption Should NOT be broke, chewed, or opened Dabigatran etexilate is a substrate of the efflux transport P-gp High-fat meals delays time to C max by 2 hours (no effect of bioavailability) Can be administered with or without food Pradaxa. PI 2010.

20 DABIGATRAN PK/PD Distribution: 35% bound to plasma proteins Metabolism: Prodrug that is converted from dabigatran etexilate to active dabigatran Elimination: Primarily renal (80%), T 1/2 = hrs DDI: P-gp inducers (rifampin), P-gp inhibitors (ketoconazole, verapamil, amiodarone, dronedarone) Pradaxa. PI 2010.

21 DABIGATRAN PK/PD Estimated PK parameters by renal function Renal Function CrCl (ml/min) In AUC In Cmax T 1/2 (hr) Normal 80 1x 1x 13 Mild x 1.1x 15 Moderate x 1.7x 18 Severe* <30 6.3x 2.1x ml/min on HD with 50 mg dose *Pts with CrCl < 30 should avoid concurrent use of P-gp inhibitors 34.1 (62-68% removed by HD) Pradaxa. PI 2010., Stangier. Clin Pharmacokinetics 2010.

22 DABIGATRAN - INDICATIONS FDA approved indication: Prevention of stroke and systemic embolism in nonvalvular Atrial Fibrillation Dose: CrCl > 30 ml/min: 150 mg BID CrCl ml/min: 75 mg BID CrCl < 15 ml/min or dialysis: no recommendations Pradaxa. PI 2010.

23 DABIGATRAN - LITERATURE Indication Trial Name Stroke prevention in AF RE-LY Acute VTE RE-COVER VTE ppx in TKA VTE ppx in THA RE-MODEL RE-MOBILIZE RE-NOVATE I RE-NOVATE II

24 DABIGATRAN - LITERATURE Indication Trial Name Stroke prevention in AF RE-LY Acute VTE RE-COVER VTE ppx in TKA VTE ppx in THA RE-MODEL RE-MOBILIZE RE-NOVATE I RE-NOVATE II

25 DABIGATRAN RE-LY TRIAL Atrial Fibrillation 1 risk factor 951 centers in 44 countries N = 18, 113 Warfarin dose adjusted (INR 2-3) N = 6022 Open Blinded Dabigatran Etexilate 110mg BID N = 6015 Dabigatran Etexilate 150mg BID N = 6076 Inclusion criteria: EKG documented AF and at least one of the following: previous stroke or TIA, left ventricular EF < 40%, NYHA class II or higher heartfailure sx, age of at least 75 yrs or age of yrs + DM, HTN or CAD. Connolly. N Engl J Med 2009.

26 DABIGATRAN RE-LY TRIAL Event Warfarin (% per yr) Dabigatran 110 mg (% per yr) Stroke or systemic embolism Stroke Hemorrhagic Ischemic * 1.11* Dabigatran 150 mg (% per yr) 1.01* 0.10* 0.92* Mortality Major bleed * 3.11 *statistically significant (p < 0.05) 64% Time-in range for warfarin (INR 2-3) Connolly. N Engl J Med 2009.

31 DABIGATRAN RE-LY TRIAL Non-hemorrhagic Adverse Effects Dabigatran 150 mg BID (%) Warfarin (%) P-values Dyspepsia* <0.001 Dizziness NS Peripheral edema NS Fatigue NS Arthralgia NS Nasopharyngitis NS Diarrhea NS ALT/AST > 3x UNL NS ALT/AST > 3x UNL w/ bilirubin > 2x UNL NS * Leading to discontinuation of therapy in 21% of patients Connolly. N Engl J Med 2009.

32 DABIGATRAN RE-LY TRIAL Non-hemorrhagic Adverse Effects Dabigatran 150 mg BID (%) Warfarin (%) P-values Dyspepsia* <0.001 Dizziness NS Peripheral edema NS Fatigue NS Arthralgia NS Nasopharyngitis NS Diarrhea NS ALT/AST > 3x UNL NS ALT/AST > 3x UNL w/ bilirubin > 2x UNL NS * Leading to discontinuation of therapy in 21% of patients Connolly. N Engl J Med 2009.

33 DABIGATRAN RE-LY TRIAL Hemorrhagic Adverse Events Dabigatran 110mg (%/yr) Dabigatran 150mg (%/yr) Warfarin (%/yr) P-value Major Bleeding GI bleed , , <0.001 Minor Bleeding <0.001, Connolly. N Engl J Med 2009.

36 DABIGATRAN RE-LY TRIAL Conclusions: Dabigatran 110 mg BID associated with similar rates of stroke and systemic embolism compared to warfarin, with lower raters of major hemorrhage. Dabigatran 150 mg BID associated with lower rates of stroke and systemic embolism compared to warfarin but similar rates of major hemorrhage. GI bleed was higher compared to warfarin. Connolly. N Engl J Med 2009.

37 DABIGATRAN RE-LY TRIAL SUBSEQUENT SUBGROUP ANALYSES Analysis Results Cohort with prior history of stroke or TIA Warfarin naïve vs. warfarin experienced patients Subgroups undergoing cardioversion Study site-specific INR control Older vs. younger patients Consistent with RE-LY overall population No difference b/w dabigatran vs. warfarin No difference b/w dabigatran vs. warfarin Advantages of dabigatran (vs. warfarin) more pronounced at study sites with poor INR control < 75 yrs: bleed lower in dabigatran > 75 yrs: extracranial, GI and non-gi extracranial bleeding higher in dabigatran Lancet Neurol 2010., Circulation 2010., Circulation 2011., Circulation 2011., Lancet 2010.

38 DABIGATRAN ACCF/AHA/HRS 2011 GUIDELINE FOCUS UPDATE Wann. Circulation 2011.

39 DABIGATRAN ACCF/AHA/HRS 2011 GUIDELINE FOCUS UPDATE Wann. Circulation 2011.

40 CASE #1 A patient has recently diagnosed atrial fibrillation and is currently on dronadrerone therapy. The last CrCl of the patient was calculated at 25 ml/hr. Which of the following medications would be contraindicated for use of atrial fibrillation stroke prevention? A. Rivaroxaban B. Dabigatran C. Apixaban D. Warfarin

41 CASE # 2 A 71 year old male comes into your anticoagulation clinic asking to be switched from Xarelto due to high cost the cheaper alternative warfarin. He is using this medication for atrial fibrillation stroke prevention. What is the appropriate way to convert this patient? A. Initiate warfarin and continue Xarelto until INR within 2-3 B. Discontinue Xarelto and initiate warfarin in 48 hrs (due to Xarelto T 1/2 ) C. Initiate warfarin, discontinue Xarelto, and initiate enoxaparin 1 mg/kg SC BID until INR within 2-3 D. Initiate warfarin and discontinue Xarelto at the same time

42 RIVAROXABAN Brand Name: Xarelto 1 st oral direct factor Xa inhibitor approved in US MOA: reversibly binds to active site of coagulation factor Xa without antithrombin mediation Gonsalves. Mayo Clinic 2013.

43 RIVAROXABAN PK/PD Supplied: 10 mg, 15 mg, and 20 mg tablets Absorption: Bioavailibility is dose-dependent. 10 mg dose = % and not effected by food. 20 mg dose = 66%, increases with food to 76% 15 mg and 20 mg tablets recommended to take with food Drugs altering gastric ph do not effect bioavailability AUC and C max decrease by 29% and 56% respectively when administered distal to the stomach (ie. Small intestine via feeding tube) C max occurs 2-4 hrs after administration Xarelto. PI 2011.

44 RIVAROXABAN PK/PD Distribution: Plasma protein binding 92 95% Volume of distribution = 50L Metabolism: CYP3A4/5, CYP2J2, and hydrolysis to inactive metabolites Excretion: 33% unchanged in urine, rest in urine/feces as inactive metabolites DDI: CYP 3A4 inhibitors/inducers Xarelto. PI 2011.

45 RIVAROXABAN INDICATIONS FDA approved indications/dose: Non-valvular atrial fibrillation CrCl 50 ml/min: 20 mg daily, with evening meal CrCl ml/min: 15 mg daily, with evening meal *CrCl < 30 ml/min: excluded from ROCKET AF trial DVT/PE treatment 15 mg twice daily with food x 21 days, 20 mg daily with food DVT ppx following hip or knee replacement 10 mg daily Xarelto. PI 2011.

46 RIVAROXABAN BLACK BOX WARNING Discontinuing Xarelto places patients at an increased risk of thrombotic events. To reduce this risk, consider administering another anticoagulant if Xarelto must be discontinued for a reason other than pathological bleeding Epidural or spinal hematomas have occurred in patients treated with Xarelto who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis Xarelto. PI 2011.

47 RIVAROXABAN SWITCHING FROM XARELTO TO WARFARIN No clinical trial data available Xarelto affects INR, so INR measurements may not be accurate for determining appropriate dose of warfarin From warfarin to Xarelto From Xarelto to warfarin Between Xarelto and anticoagulants other than warfarin Discontinue warfarin, initiate Eliquis once INR is < 3.0 Discontinue Eliquis, begin both parenteral anticoagulant and warfarin at the time of the next Eliquis dose, discontinue parenteral once INR with goal range Discontinue one being taken and begin other at the next scheduled dose Xarelto. PI 2011.

48 RIVAROXABAN LITERATURE Indication VTE ppx in THA VTE ppx in TKA VTE treatment Stroke prevention in AF Trial RECORD I RECORD II RECORD III RECORD IV EINSTEIN DVT EINSTEIN EXT EINSTEIN PE ROCKET AF ACS ATLAS ACS 2 TIMI 51

49 RIVAROXABAN LITERATURE Indication VTE ppx in THA VTE ppx in TKA VTE treatment Stroke prevention in AF Trial RECORD I RECORD II RECORD III RECORD IV EINSTEIN DVT EINSTEIN EXT EINSTEIN PE ROCKET AF ACS ATLAS ACS 2 TIMI 51

50 RIVAROXABAN ROCKET AF TRIAL Atrial Fibrillation Randomized, double blind, double dummy N = 14,171 Inclusion: CHADS 2 2 -mean CHADS 2 = 3.1 -INR w/in target 55% of time Rivaroxaban 20 mg daily 15 mg for CrCl Warfarin INR target 2.5 ( inclusive) Exclusion: CrCl < 30 Monthly monitoring and adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns systemic embolism Secondary Endpoints: composite of stroke, systemic embolism, or death from CV causes; MI; major and non-major bleeding events Patel. N Engl J Med 2011.

51 RIVAROXABAN ROCKET AF TRIAL Events: stroke or systemic embolism Rivaroxaban = 1.7 %/yr Warfarin = 2.2 %/yr P-value = < for noninferiority Patel. N Engl J Med 2011.

52 RIVAROXABAN ROCKET AF TRIAL Events: stroke or systemic embolism Rivaroxaban = 2.1%/yr Warfarin = 2.4 %/yr P-value = < for noninferiority Patel. N Engl J Med 2011.

53 RIVAROXABAN ROCKET AF TRIAL Patel. N Engl J Med 2011.

57 RIVAROXABAN ROCKET AF TRIAL Conclusions: Rivaroxaban is noninferior to warfarin for the prevention of stroke or systemic embolism No significant difference in risk of major bleeding, however intracranial and fatal bleeding occurred less frequently in the rivaroxaban group

58 CASE # 2 A 71 year old male comes into your anticoagulation clinic asking to be switched from Xarelto due to high cost the cheaper alternative warfarin. He is using this medication for atrial fibrillation stroke prevention. What is the appropriate way to convert this patient? A. Initiate warfarin and continue Xarelto until INR within 2-3 B. Discontinue Xarelto and initiate warfarin in 48 hrs (due to Xarelto T 1/2 ) C. Initiate warfarin, discontinue Xarelto, and initiate enoxaparin 1 mg/kg SC BID until INR within 2-3 D. Initiate warfarin and discontinue Xarelto at the same time

59 CASE #3 A patient taking Eliquis 5 mg orally twice daily is to be started on fluconazole 400 mg daily for an extended period of time to treat a fungal infection. What is the appropriate action to take while fluconazole is being administered? A. Reduce the dose to 2.5 mg twice daily B. Reduce the dose to 5 mg once daily C. Discontinue Eliquis until the infection resolves D. Switch the patients anticoagulation to Xarelto

60 APIXABAN Brand Name: Eliquis Most recently FDA approved NOA in U.S. December 2012 MOA: selectively and reversibly inhibits free- and clot-bound factor Xa as well as prothrombinase activity Eliquis. PI 2011.

61 APIXABAN PK/PD Supplied: 2.5 mg and 5 mg tablets Absorption: Bioavailability = 50%, food does not affect Absorbed throughout entire GI tract, distal small bowel and ascending colon = 55% of absorption C max = 3 to 4 hrs after administration Distribution: Plasma protein binding = 87%, volume of distribution = 21 L Eliquis. PI 2011.

62 APIXABAN PK/PD Metabolism: Mainly via CYP3A4, minor CYP1A2, 2C9, 2C8, 2C19, 2J2 to inactive metabolites Elimination: Oral T 1/2 = 12 hrs Renal excretion accounts for 27% of total clearance DDI: Inhibitors/inducers of CYP3A4 and P-gp PI states Reduce dose to 2.5 mg or avoid use Eliquis. PI 2011.

63 APIXABAN INDICATIONS FDA approved Indication: Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Dose: 5 mg twice daily In patients with 2 of the following characteristics, 2.5 mg twice daily: *in ARISTOTLE trial Age 80 years ABW 60 kg SrCr 1.5 mg/dl Eliquis. PI 2011.

64 APIXABAN BLACK BOX WARNING Discontinuing Eliquis places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of Eliquis in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with Eliquis must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered Eliquis. PI 2011.

65 APIXABAN CONVERTING FROM OR TO ELIQUIS No clinical trial data available Eliquis affects INR, so INR measurements may not be accurate for determining appropriate dose of warfarin From warfarin to Eliquis Discontinue warfarin, initiate Eliquis once INR is < 2.0 From Eliquis to warfarin Discontinue Eliquis, begin both parenteral anticoagulant and warfarin at the time of the next Eliquis dose, discontinue parenteral once INR with goal range Between Eliquis and anticoagulants other than warfarin Discontinue one being taken and begin other at the next scheduled dose Eliquis. PI 2011.

66 APIXABAN - LITERATURE Indication Trial VTE ppx in THA ADVANCE 3 VTE ppx in TKA ADVANCE 1 ADVANCE 2 Stroke prevention in AF ACS AVERROES ARISTOTLE APPRAISE

67 APIXABAN - LITERATURE Indication Trial VTE ppx in THA ADVANCE 3 VTE ppx in TKA ADVANCE 1 ADVANCE 2 Stroke prevention in AF ACS AVERROES ARISTOTLE APPRAISE

68 Inclusion: CHADS Mean CHADS 2 = 2.1 Exclusion: - SrCr >2.5 mg/dl or CrCL < 25 ml/min APIXABAN ARISTOTLE TRIAL Randomized, double blind, double dummy N = 18,201 *2.5 mg BID in pts with 2 of the following: - age 80 years - ABW 60 kg - SCr 1.5 mg/dl Apixaban 5 mg BID *2.5mg in select pts Warfarin (target INR 2-3) Primary outcomes: stroke or systemic embolism Granger. N Engl J Med 2011.

69 APIXABAN ARISTOTLE TRIAL Granger. N Engl J Med 2011.

72 APIXABAN ARISTOTLE TRIAL Conclusions: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality

73 CASE #3 A patient taking Eliquis 5 mg orally twice daily is to be started on fluconazole 400 mg daily for an extended period of time to treat a fungal infection. What is the appropriate action to take while fluconazole is being administered? A. Reduce the dose to 2.5 mg twice daily B. Reduce the dose to 5 mg once daily C. Discontinue Eliquis until the infection resolves D. Switch the patients anticoagulation to Xarelto

74 ATRIAL FIBRILLATION STROKE PREVETION SUMMARY Primary efficacy Stroke or Systemic Embolism: All agents non-inferior to warfarin Dabigatran and apixaban demonstrated superiority Rivaroxaban only demonstrated superiority in per-protocol analysis Hemorrhagic stroke: All agents significantly better than warfarin Ischemic stroke: Only dabigatran significantly better than warfarin Major bleed: Only apixaban significantly safer than warfarin No difference with dabigatran and rivaroxaban All cause mortality: Only apixaban significantly lower than warfarin All agents provide an approximate 10% reduction

75 CONCLUSIONS FOR NEW OA s Increased oral therapeutic options for patients that work independent of Vitamin K pathway Overcome some of warfarin's shortcomings: slow onset of action, variable pharmacologic effects, food-drug interactions, need for close monitoring Limited by high cost, lack of specific antidotes and long term safety data Until further data available, avoid new OA s in pregnancy, patients with mechanical heart valves, and severe renal insufficiency