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New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Assistant Professor of.

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Presentation on theme: "New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Assistant Professor of."— Presentation transcript:

1 New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Assistant Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy

2 Disclosures Speaker’s Bureau for: Boehringer-Ingelheim Pharmaceuticals Janssen Pharmaceuticals

3 At the conclusion of this program, the audience should be able to: List the new oral anticoagulant medications currently approved or in the approval process by the United States Food and Drug Administration Communicate basic principles of pharmacokinetics to other healthcare providers Identify appropriate indications for the use of new oral anticoagulant medications Develop patient specific plans utilizing newly approved oral anticoagulant agents for the treatment and prevention of venous thromboembolic events in various patient populations

4 Including warfarin, how many oral anticoagulants are currently FDA approved in the United States? 1.One 2.Two 3.Three 4.Four 5.Five

5 1943 Heparin Approved by FDA 1954 Warfarin Approved by FDA 2005 Ximelagatran Research Discontinued 2010 Dabigatran Approved by FDA 2011 Rivaroxaban Approved by FDA 2012 Apixaban to be Voted on by FDA Anticoagulant Medications 1957 Sputnik I & Yuri Gargarin Orbits Earth 1961 Alan Shephard Suborbital Flight 1969 Americans Land on the Moon st Flight of Columbia (STS-1) 1982 Soviets Deploy Manned Space Station 2000 International Space Station is Inhabited Humans in Space

6 Warfarin Pros Experience Inexpensive Reversible Monitoring available Cons Time of onset Frequent monitoring Dosing variability Numerous drug interactions

7 21 st Century New therapies with FDA Approval – Dabigatran – Rivaroxaban Additional emerging new therapies – Apixaban (Phase III trials complete) – Edoxaban (Phase III trials ongoing)

8 Which of the following best describes your opinion regarding the novel new anticoagulant medications? 1.Warfarin is an adequate medication with good data so I’ll continue to use warfarin. 2.Warfarin has many shortcomings and I would prefer to use newer agents. 3.I’m still a little hesitant about the newer agents because I’m unfamiliar with them. 4.I prefer the newer agents over warfarin; however, I am concerned about the cost of new agents. 5.I have serious concerns about the safety of newer anticoagulant medications.

9 Which of the following best describes your current prescribing of dabigatran (Pradaxa®) or rivaroxaban (Xarelto®)? 1.I routinely prescribe them 2.I prescribe them in a limited and select group of patients 3.I am very hesitant to prescribe them 4.I have never prescribed them

10 Clinical Pharmacology Comparison

11 Rivaroxan & Apixaban Coagulation Cascade XIIXIIa XIXIa IX IXa VIIa Intrinsic Pathway (PTT)Extrinsic Pathway (PT) XaX VIII II IIa XIII FibrinogenFibrin XIIIa Warfarin Dabigatran Va VII

12 Summary Table ParameterApixabanDabigatranRivaroxaban Target ProteinFactor XaThrombin (IIa)Factor Xa Pro-DrugNoYes (etexilate)No 1˚ EliminationCYP3A4/P-gpRenalCYP3A4/P-gp Renal AdjustmentAvoid < 15 ml/min↓ ml/min Avoid < 15 ml/min Avoid < 30 ml/min Drug-Drug Interact.CYP3A4/P-gpRifampin (P-gp)CYP3A4/P-gp Onset of activity3-4 hrs1-2 hrs2-4 hrs t½8-15 hrs12-18 hrs5-9 hrs Dosing intervalTwice daily Daily Measuring testsPT/Anti-factor XaECT, TT, +/- aPTTPT/Anti-factor Xa

13 Monitoring vs. Measuring

14 Measuring Dabigatran Thromb Haemost 2010;103:

15 Measuring Rivaroxaban & Apixaban Role of aPTT & PT/INR Anti-Xa Assays – Chromagenic anti-Xa assays may be useful Different assays vary in sensitivity Must calibrate standard curve based on drug concentration – HepTest® is not accurate for rivaroxaban (and likely apixaban) Incubation period too long Modified HepTest® may be useful but no current data Ther Drug Monit 2010;32:673-9.

16 Measuring Rivaroxaban J Thromb Haemost 2011;9: aPTT not sensitive PT is sensitive (Don’t rely on INR) Highlights peak concentrations

17 Which of the following are significantly affected by moderate/severe renal insufficiency? 1.Apixaban 2.Dabigatran 3.Rivaroxaban 4.Both 2 & 3 5.All of the above

18 Clinical Utilization

19 What are the current approved indications for dabigatran (Pradaxa®) in the United States? 1.Non-valvular Afib 2.Prevention of VTE 3.Treatment of VTE 4.All of the above

20 Atrial Fibrillation

21 Summary of Afib Data Apixaban (ARISTOTLE) Dabigatran (RE-LY) Rivaroxaban (ROCKET – AF) # Patients> 18,000 > 14,000 Mean CHADS 2 ≈ 2 ≈ 3.5 TTR62%64%55% Efficacy vs. VKASuperiorSuperior 1 Non-Inferior Bleeding 2 vs. VKADecreasedSimilar 1 Dabigatran 150 mg BID group. 2 Major bleeding per study design.

22 RE-LY - Results EventDabi 110 vs Warf HR (95% CI) Dabi 150 vs Warf HR (95% CI) Dabi 150 vs Dabi 110 HR (95% CI) Efficacy 1˚ Endpoint*0.91 ( )0.66 ( )0.73 ( ) All stroke0.92 ( )0.64 ( )0.70 ( ) Ischemic Stroke1.11 ( )0.76 ( )0.69 ( ) Hemorrhagic Stroke0.31 ( )0.26 ( )0.85 ( ) MI published1.35 ( )1.38 ( )1.02 ( ) MI revised1.29 ( )1.27 ( )Not available All cause mortality0.91 ( )0.88 ( )0.97 ( ) Safety Major bleeding0.80 ( )0.93 ( )1.16 ( ) GI bleeding1.10 ( )1.50 ( )1.36 ( ) All bleeding0.78 ( )0.91 ( )1.16 ( ) IC bleeding0.31 ( )0.40 ( )1.32 ( ) New Engl J Med 2009;361: New Engl J Med 2010;363: *Non-inferiority margin = 1.46

23 RE-LY Summary Dabigatran 110 mg BID vs. warfarin – Non-Inferior Efficacy – Lower major and overall bleeding rates – Similar GI bleeding rates Dabigatran 150 mg BID vs. warfarin – Superior efficacy – Lower overall bleeding rates – Similar major bleeding rates – Elevated rates of GI bleeding Both doses showed decreased ICH compared to warfarin (60-70% RRR)

24 ROCKET-AF Results EventRivaroxaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint* ( ) All stroke ( ) Ischemic Stroke ( ) Hemorrhagic Stroke ( ) MI ( ) All-cause mortality ( ) Safety Major bleeding ( ) All bleeding ( ) Major GI bleeding3.2 (% overall)2.2 (% overall)p < IC bleeding ( ) New Engl J Med 2011;365: *Non-inferiority margin = 1.46

25 ROCKET-AF Summary Rivaroxaban vs. warfarin – Non-Inferior Efficacy – Similar bleeding rates – Lower ICH rates High risk patient population (Mean CHADS 2 score > 3) TTR 55% New Engl J Med 2011;365:

26 ARISTOTLE Results EventApixaban (% per year) Warfarin (% per year) HR (95% CI) Efficacy 1˚ Endpoint* ( ) All stroke ( ) Ischemic Stroke ( ) Hemorrhagic Stroke ( ) MI ( ) All-cause mortality ( ) Safety Major bleeding ( ) All bleeding ( ) IC bleeding ( ) New Engl J Med 2011;365: *Non-inferiority margin = 1.38

27 ARISTOTLE Summary Apixaban vs. warfarin – Superior efficacy with apixaban – ↓ overall mortality with apixaban (NNT = 238) – Lower bleeding rates with apixaban – Lower ICH rates Apixaban vs. Aspirin – 6,000 high-risk patients (mean CHADS 2 = 2) – Not candidates for warfarin – 1 year follow-up – Superior efficacy to aspirin – Similar bleeding (including ICH) rates New Engl J Med 2011;365: New Engl J Med 2011;364:

28 Which of the following have been shown at least as effective as warfarin for the prevention of stroke in patients with atrial fibrillation? 1.Apixaban 2.Dabigatran 3.Rivaroxaban 4.Both 1 & 2 5.All of the above

29 Summary of Afib Data Apixaban (ARISTOTLE) Dabigatran (RE-LY) Rivaroxaban (ROCKET – AF) # Patients> 18,000 > 14,000 Mean CHADS 2 ≈ 2 ≈ 3.5 TTR62%64%55% Efficacy vs. VKASuperiorSuperior 1 Non-Inferior Bleeding 2 vs. VKADecreasedSimilar EliminationCYP3A4/P-gpRenalCYP3A4/P-gp/Renal 1 Dabigatran 150 mg BID group. 2 Major bleeding per study design.

30 Use of Concomitant Antiplatelet Agents Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-AF (Rivaroxaban) ASA< 165 mg/dayYes< 100 mg/day ClopidogrelYes CombinationNoYesNo Aspirin Use (%)31%40%36% New Engl J Med 2009;361: New Engl J Med 2011;365: New Engl J Med 2011;365:

31 Treatment of Acute Venous Thromboembolism

32 Both dabigatran and rivaroxaban have been shown to be effective in the treatment of acute VTE. 1.True 2.False

33 Summary of VTE Data 1 Dabigatran (RE-COVER) Rivaroxaban (EINSTEIN) # Patients> 2,500> 3,400 Treatment Duration6 months Initial Therapy 2 LMWHRivaroxaban TTR60%58% Efficacy vs. VKANon-Inferior Bleeding vs. VKASimilar VTE TypeDVT & PEDVT 1 Apixaban data in VTE are not available, AMPLIFY & AMPLIFY-EXT are ongoing. 2 Initial therapy in study group, both studies “bridged” control group.

34 Prevention of Venous Thromboembolism in Orthopedic Surgery Patients

35 Summary of Orthopedic VTE Data 1 ComparatorApixaban (2.5 mg q12h) Dabigatran (150 or 220mg/day) Edoxaban (30 mg/day) Rivaroxaban (10 mg/day) Enoxaparin 40 mg daily SuperiorNon-Inferior---Superior Enoxaparin 20 mg q12h --- Superior--- Enoxaparin 30 mg q12h Non-InferiorInferior---Superior Bleeding vs. Enoxaparin Similar 1 Includes patients undergoing both TKA and THA. Most studies excluded patients with CrCl < 30 ml/min. Summary of these data available in: Pharmacother 2011;31:

36 VTE Prophylaxis in Medical Patients

37 Extended Apixaban vs. Standard Enoxaparin in Medical Patients ADOPT Trial Medical patients at high risk for VTE (n=4,495) Treatment Groups – Apixaban 2.5 mg BID for 30 days – Enoxaparin 40 mg SQ daily during admission Results – No difference in primary outcome VTE death, PE, symptomatic DVT or asymptomatic proximal DVT (0.87; ) – No difference in other outcomes Did not meet criteria for non-inferiority (Key 2˚ outcome) – Higher rate of major bleeding (2.58; ) Summary – Extended apixaban was not better than standard enoxaparin in this superiority trial – Study was underpowered by over 2,250 patients (goal of 6,758) New Engl J Med 2011;365:

38 Extended Rivaroxaban vs. Standard Enoxaparin Data not yet published 8,101 medical patients Treatment Groups – Rivaroxaban 10 mg daily for 35 days – Enoxaparin 40 mg SQ daily for 6-14 days Primary Outcome Reduced – 0.77 ( ) Increased Major & Clinically Relevant Bleeding No net clinical benefit

39 Acute Coronary Syndrome

40 Apixaban Acute Coronary Syndrome (APPRAISE-2) Double blind, placebo controlled, RCT ACS plus 2 additional risk factors Apixaban – 5 mg twice daily – 2.5 mg twice daily (CrCl < 40 ml/min) No benefit in any efficacy outcomes Safety – Major & minor TIMI, ISTH, and GUSTO criteria bleeding was increased with apixaban – Increased fatal and intracranial bleeding Study terminated early at 1 year New Engl J Med 2011;365:

41 Rivaroxaban ATLAS-ACS 2 TIMI 51 Trial All patients received low dose ASA with either: – Rivaroxaban 2.5 mg twice daily or – Rivaroxaban 5 mg twice daily – Groups were stratified based on clopidogrel use – Large number of patients from Eastern Europe (40%); however North America data were independently consistent/significant Results – Primary Endpoint (CV Death, MI or CVA) Both doses better than placebo – TIMI Major Bleeding Rivaroxaban 2.5 mg BID vs Placebo: HR = 3.46 ( ) Rivaroxaban 5 mg BID vs Placebo: HR = 4.47 ( ) – Intracranial Hemorrhage Rivaroxaban 2.5 mg BID vs Placebo: HR = 2.83 ( ) Rivaroxaban 5 mg BID vs Placebo: HR = 3.74 ( ) Summary – Improved outcomes but 3-fold increased risk of major bleeding New Engl J Med 2012;366:9-19.

42 Dabigatran Phase II study completed & published 2/2011 Meta-analysis (January 2012) – 30,514 patients included – Multiple indications/populations – Majority of patients & events from RE-LY – MI vs. Warfarin RR: 1.33 ( ) AR: 0.40% – Mortality vs. Warfarin RR: 0.89 ( ) AR: 0.19 – Interpret in light of stroke reduction – More investigation warranted

43 Summary

44 Take Home Points for Providers Several new options currently or will exist to replace warfarin Current approved indications include: – Prophylaxis of VTE in orthopedic patients – Prevention of stroke in patients with Afib Date also exists to support their use in: – Treatment of VTE Agents vary based on various pharmacologic and pharmacokinetic parameters – None of the new agents require monitoring – Would base choice of agent o patient specific factors – All of them can be “measured” if needed – Best technique for reversal is unknown for most at this time Cost will be a limitation if not covered by insurance

45 Practical Provider Information ParameterDabigatranRivaroxaban Dosing Non-valvular Atrial Fibrillation 150 mg BID (CrCl > 30 ml/min) 75 mg BID (CrCl ml/min) 20 mg QD (CrCl > 50 ml/min) 15 mg QD (CrCl ml/min) Orthopedic VTE PxN/A10 mg QD Primary EliminationRenalCYP3A4/P-gp 1 Drug-Drug Interact.Rifampin, Dronedarone 2, Ketoconazole 2 CYP3A4/P-gp Inhibitors Timing of DoseAnytime (With or Without Food) 15, 20 mg Dose – With Food 10 mg Dose – Anytime Practical Measuring TestaPTTPT Common ComplaintsDyspepsia 3 Well Tolerated % of elimination is renal and rivaroxaban does require dosage adjustment with CrCl < 50 ml/min. 2 With dronedarone & ketoconazole when CrCl is ml/min, decrease dabigatran to 75 mg BID; do not use when CrCl < 30 ml/min. 3 As with any anticoagulant, adverse bleeding is still a concern. Both dabigatran and rivaroxaban demonstrated increased rates of GI bleeding, but lower rates of intracranial hemorrhage and similar overall rates of bleeding compared to warfarin.

46 Practical Patient Information Dabigatran – Store in original container – Discard opened product after 4 months – Dyspepsia most common side effect (up to 30%) – Do not open capsule – Comprehensive Patient Guide Available Online 1 Rivaroxaban – Ask pharmacist or physician about DDIs – At Afib dose should take with supper – Do not crush, chew, or split tablet – Overall tolerated well 1 Circ 2011;124:e209-e211. (DOI: /CIRCULATIONAHA )

47 Which of the following best describes your opinion regarding prescribing of dabigatran (Pradaxa®) or rivaroxaban (Xarelto®) after this program? 1.I will begin routinely prescribing these agents. 2.I may prescribe them in a limited and select group of patients. 3.I am still very hesitant to prescribe them. 4.I will not prescribe them at all for now.

48 Summary Table ParameterApixabanDabigatranRivaroxaban Target ProteinFactor XaThrombin (IIa)Factor Xa Pro-DrugNoYes (etexilate)No 1˚ EliminationCYP3A4/P-gpRenalCYP3A4/P-gp Renal AdjustmentAvoid < 15 ml/min↓ 15-29ml/min Avoid < 15 ml/min Avoid < 30 ml/min Drug-Drug Interact.CYP3A4/P-gpRifampin (P-gp)CYP3A4/P-gp Onset of activity3-4 hrs1-2 hrs2-4 hrs t½8-15 hrs12-18 hrs5-9 hrs Dosing intervalTwice daily Daily Monitoring testsAnti-factor XaECT, TT, +/- aPTTAnti-factor Xa FDA IndicationsNoneNon-valvular Afib.Non-valvular Afib. Ortho VTE Proph. Clinical UsesAfib Ortho VTE Proph Afib, VTEAfib, Ortho VTE Proph, VTE

49 New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Assistant Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy

50 Use of Concomitant Antiplatelet Agents Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET-AF (Rivaroxaban) ASA< 165 mg/dayYes< 100 mg/day ClopidogrelYes CombinationNoYesNo Aspirin Use (%)31%40%36% New Engl J Med 2009;361: New Engl J Med 2011;365: New Engl J Med 2011;365:

51 Summary Table ParameterApixabanDabigatranRivaroxaban Target ProteinFactor XaThrombin (IIa)Factor Xa Pro-DrugNoYes (etexilate)No 1˚ EliminationCYP3A4/P-gpRenalCYP3A4/P-gp Renal AdjustmentAvoid < 15 ml/min↓ 15-29ml/min Avoid < 15 ml/min Avoid < 30 ml/min Drug-Drug Interact.CYP3A4/P-gpRifampin (P-gp)CYP3A4/P-gp Onset of activity3-4 hrs1-2 hrs2-4 hrs t½8-15 hrs12-18 hrs5-9 hrs Dosing intervalTwice daily Daily Monitoring testsAnti-factor XaECT, TT, +/- aPTTAnti-factor Xa FDA IndicationsNoneNon-valvular Afib.Non-valvular Afib. Ortho VTE Proph. Clinical UsesAfib Ortho VTE Proph Afib, VTEAfib, Ortho VTE Proph, VTE


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