David Stewart, PharmD, BCPS Assistant Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy

David Stewart, PharmD, BCPS Assistant Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu

At the conclusion of this program, the audience should ldbe 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 i 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

Including warfarin, how many oral anticoagulants are currently FDA approved in the United States? 1. One 2. Two 3. Three 4. Four 5. Five 0% 0% 0% 0% 0% One Two Three Four Five

Anticoagulant Medications 1943 1954 2005 2010 2011 2012 Heparin Approved by FDA Warfarin Approved by FDA Ximelagatran Research Discontinued Dabigatran Approved by FDA Rivaroxaban Approved by FDA Apixaban to be Voted on by FDA Humans in Space 1957 1961 1961 1969 1981 1982 2000 Sputnik iki & 2 Yuri igargarin Orbits Earth Alan Shephard Suborbital Flight Americans Land on the Moon 1 st Flight of Columbia (STS 1) Soviets International ti Deploy Space Station Manned is Inhabited Space Station

Vitamin K Antagonists (Warfarin) Vitamin K Dependent Proteins Protein Half-life life (hours) Factor II (Prothrombin Prothrombin) 42-72 Factor VII 4-6 Factor IX 21-30 Factor X 27-48 Protein C 9 Protein S 60 Managing Oral Anticoagulation Therapy. St. Louis, MO: WKH, 2009:149 60.

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

21 st Century New therapies with phase III data Dabigatran Rivaroxaban Apixaban Developing therapies Edoxaban

Which of the following best describes your opinion regarding the novel new anticoagulant medications? 1. Warfarin is a 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 Im still a little hesitant aboutthe 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 aboutthethe safety of newer anticoagulant medications. 0% 0% 0% 0% 0% 1 2 3 4 5

Which of the following best describes your current prescribing of dabigatran (Pradaxa )? 1. I routinely prescribe dabigatran. 2. I prescribe dabigatran in a limited and select group of patients. 3. I am very hesitant to prescribe dabigatran. 4. I have never prescribed dabigatran. 0% 0% 0% 0% 1 2 3 4

Part I Clinical Pharmacology Comparison

Coagulation Cascade Intrinsic Pathway (PTT) Extrinsic Pathway (PT) XII XI IX XIIa XIa IXa VIIa VII Warfarin Rivaroxan & Apixaban Dabigatran X VIII II Xa Va IIa XIII XIIIa Fibrinogen Fibrin

Dabigatran Etexilate (Pradaxa ) (Approved 2010) Direct Thrombin Inhibitor Adverse Effects Competitive Prodrug Hydrolysis GI bleeding Peak effect 1 hr (empty stomach) 2 hr (with food) t½ 12 18 hours Elimination Renal (> 80%) Monitoring Not routinely required Bleeding GI symptoms (35%) compared d to warfarin Consider with ICH Note rate similar to warfarin in VTE trial Pharmacoth 2008;28(11):1345 73. Drug Metab Dispos 2008;36(2):386 99. Pradaxa PI Revised 8/11.

Rivaroxaban (Xarelto ) (FDA Approved 2011) Direct Factor Xa Inhibitor Adverse Events Competitive Peak effect 1 hr (empty stomach) 4 hr (with food) t½ 5 9 hours Metabolism & Elimination CYP3A4/5 & P gp Renal (36 % parent) Biliary fecal l(7% parent) Monitoring Not routinely required Bleeding Liver enzymes elevated less frequently in rivaroxaban groupcompared to enoxaparin GI bleeding compared to warfarin Consider with ICH Note rate similar to warfarin in VTE trial Pharmacoth 2009;29(2):167 81. Xarelto PI Revised 7/11.

Apixaban (Eliquis ) (Not currently approved by the FDA) Direct Factor Xa Inhibitor Adverse Events Competitive Bleeding Peak effect Nausea 3 4 hrs t½ 8 15 hrs Metabolism & Elimination CYP3A4/5 & P gp Renal (27 % parent) Biliary fecal Additional CYP isozymes Monitoring Not routinely required Eliquis PI (EU) Revised 5/11.

Monitoring vs. Measuring

Thromb Haemost 2010;103:1116 27. Measuring Dabigatran

Measuring Rivaroxaban & Apixaban The aptt is not sensitive enough for anti Xa agents The PT correlates well with serum concentrations The INR is specific to warfarin and is not accurate for anti Xa agents PT is not sensitive enough to detect C trough 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 dlikely l apixaban) Incubation period too long Modified dheptest may be useful lbut no current dt data Ther Drug Monit 2010;32:673 9.

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 0% 0% 0% 0% 0% Apixaban Dabigatran Rivaroxaban Both 2 & 3 All of the abo...

Summary Table Parameter Apixaban Dabigatran Rivaroxaban Target Protein Factor Xa Thrombin (IIa) Factor Xa Pro Drug No Yes (etexilate) No 1 Elimination CYP3A4/P gp Renal CYP3A4/P gp Renal Adjustment Avoid < 15 ml/min 15 29ml/min Avoid < 30 ml/min Avoid < 15 ml/min Drug Drug Interact. CYP3A4/P gp Rifampin (P gp) CYP3A4/P gp Onset of activity 3 4 hrs 1 2 hrs 2 4 hrs t½ 8 15 hrs 12 18 hrs 5 9hrs Dosing interval Twice daily Twice daily Daily Monitoring tests Anti factor Xa ECT, TT, +/ aptt Anti factor Xa

Part II Clinical Utilization

What are the current approved indications for dabigatran in the United States? 1. Non valvular Afib 2. Prevention of VTE 3. Treatment of VTE 4. All of the above 0% 0% 0% 0% Non valvular A... Prevention of... Treatment of V... All of the abo...

Atrial Fibrillation

Dabigatran vs. Warfarin in Atrial Fibrillation (RE LY) >18,000 patients with non valvular Afib Non inferiority design Open lbl label Warfarin vs. dabigatran 110 mg BID & dabigatran 150 mg BID Follow up approximately 2 years INR Time in Therapeutic Range (TTR): 64% New Engl J Med 2009;361:1139 51.

RE LY Patient Population InclusionCriteria Afib in addition to: Hx Stroke/TIA LVEF < 40% NYHA Class II HF Age 75 Age 65 74 in addition to: DM HTN CAD Exclusion Criteria Severe heart valve disorder Recent stroke CrCl < 30 ml/min Liver disease New Engl J Med 2009;361:1139 51.

RE LY Endpoints Primary Composite: stroke & systemic embolization Secondary/Other Stroke Systemic embolization MI PE TIA Mortality New Engl J Med 2009;361:1139 51.

RE LY Patient Demographics Characteristic i Dbi Dabigatran 110 mg Dbi Dabigatran 150 mg Warfarin Age 71.4 ± 8.6 71.5 ± 8.8 71.6 ±8.6 Male Sex 64.3 % 63.2% 63.3% CHADS 2 Score 2.1 ±1.1 2.2 ±1.2 2.1 ±1.1 Prior Stroke or TIA 19.9% 20.3% 19.8% Prior MI 16.8% 16.9% 16.1% 1% Aspirin at baseline 40.0% 38.7% 40.6% VKA at baseline 50.1% 50.2% 48.6% New Engl J Med 2009;361:1139 51.

RE LY Results Event Dbi110 Dabi vs Warf Dbi150 Dabi vs Warf Dbi150 Dabi vs Dbi110 Dabi HR (95% CI) HR (95% CI) HR (95% CI) Efficacy 1 Endpoint* 0.91 (0.74 1.11) 0.66 (0.53 0.82) 0.73 (0.58 0.91) All stroke 0.92 (0.74 1.13) 0.64 (0.51 0.81) 0.70 (0.56 0.89) Ischemic c Stroke 1.11 (0.89 1.40). 0) 0.76 (0.60 0.98) 0.98) 0.69 (0.54 0.88) 0.88) Hemorrhagic Stroke 0.31 (0.17 0.56) 0.26 (0.14 0.49) 0.85 (0.39 1.83) MIpublished 1.35 (0.98 1.87) 1.38 (1.00 1.91) 1.02 (0.76 1.38) MI revised 129(0 1.29 (0.96 1.75) 127(0 1.27 (0.94 1.71) Not available All cause mortality 0.91 (0.80 1.03) 0.88 (0.77 1.00) 0.97 (0.85 1.11) Safety Major bleeding 0.80 (0.69 0.93) 0.93 (0.81 1.07) 1.16 (1.00 1.34) GI bleeding 1.10 (0.86 1.41) 1.50 (1.19 1.89) 1.36 (1.09 1.70) All bleeding 078(0 0.78 (0.74 0.83) 0 091(0 0.91 (0.86 0.97) 0 116(1 1.16 (1.09 1.23) 1 IC bleeding 0.31 (0.20 0.47) 0.40 (0.27 0.60) 1.32 (0.80 2.17) New Engl J Med 2009;361:1139 51. New Engl J Med 2010;363:1875 76. *Non inferiority margin = 1.46

RE LY Summary Dabigatran 110 mg BID vs. warfarin Non Inferior Efficacy Lower major and overall bleeding rates Similar il 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)

Rivaroxaban vs. Warfarin in Atrial Fibrillation (ROCKET AF) >14,000 patients Non valvular Afib High risk of stroke Non inferiority i i design Double blind, double dummy Warfarin vs. rivaroxaban 20 mg daily (CrCl 50 ml/min) 15 mg daily (CrCl 30 49 ml/min) Follow up approximately 2 years INR Time in Therapeutic Range (TTR): 55% New Engl J Med 2011;365:883 91.

ROCKET AF Patient Population InclusionCriteria Afib with CHADS 2 Score 2 Exclusion Criteria Severe heart valve disorder Recent stroke CrCl < 30 ml/min Liver disease New Engl J Med 2011;365:883 91.

ROCKET AF Endpoints Primary Composite: stroke or systemic embolization Secondary/Other Composite: Stroke, systemic embolization, CV death, or MI Individual components New Engl J Med 2011;365:883 91.

ROCKET AF Patient Demographics Characteristic i Rivaroxaban Warfarin Age 73 73 Male Sex 60.3% 60.3% CHADS 2 Score 3.5 ±0.9 3.5 ±0.9 Prior Stroke or TIA 54.9% 54.6% Prior MI 16.6% 6% 18% Aspirin at baseline 36.3% 36.7% VKA at baseline 62.3% 62.5% New Engl J Med 2011;365:883 91.

Event ROCKET AF Rivaroxaban (% per year) Results Efficacy Warfarin (% per year) HR (95% CI) 1 Endpoint* 2.1 2.4 0.88 (0.75 1.03) All stroke 1.65 1.96 0.85 (0.70 1.03) Ischemic Stroke 1.34 1.42 0.94 (0.75 1.17) Hemorrhagic Stroke 0.26 0.44 0.59 (0.37 0.93) MI 091 0.91 112 1.12 081(0 0.81 (0.63 1.06) 06) All cause mortality 1.87 2.21 0.85 (0.70 1.02) Safety Major bleeding 3.6 3.4 1.04 (0.90 1.20) All bleeding 14.9 14.5 1.03 (0.96 1.11) MajorGI bleeding 3.2(% overall) 2.2(% overall) p < 0.001001 IC bleeding 0.5 0.7 0.67 (0.47 0.93) *Non inferiority margin = 1.46 New Engl J Med 2011;365:883 91.

ROCKET AF Summary Rivaroxabanvs vs. warfarin Similar bleeding rates Lower ICH rates High risk patient population (Mean CHADS 2 score > 3) TTR 55% New Engl J Med 2011;365:883 91.

Apixaban vs. Warfarin in Atrial Fibrillation (ARISTOTLE) >18,000 patients with non valvular Afib Non inferiority design Double blind, double dummy Warfarin vs. apixaban 5 mg twice daily 2.5 mg twice daily if: Age 80 Weight 60 kg SCr 1.5 mg/dl Follow up approximately years INR Time in Therapeutic Range (TTR): 62% New Engl J Med 2011;365:981 92.

InclusionCriteria Afib in addition to: Age 75 years Hx Stroke/TIA HF or LVEF 40% DM ARISTOTLE Patient Population Exclusion Criteria Severe heart valve disorder Recent stroke SCr. > 2.5 mg/dl or CrCl < 25 ml/min THN Liver disease New Engl J Med 2011;365:981 92.

ARISTOTLE Endpoints Primary Composite: stroke or systemic embolization Secondary/Other All cause mortality MI New Engl J Med 2011;365:981 92.

ARISTOTLE Patient Demographics Characteristic i Apixaban Warfarin Age 70 70 Male Sex 64.5% 65.0% CHADS 2 Score 2.1 ±1.1 2.1 ±1.1 Prior Stroke or TIA 19.2% 19.7% Prior MI 14.5% 13.9% Aspirin at baseline 31.3% 30.5% VKA at baseline 57.1% 57.2% New Engl J Med 2011;365:981 92.

Event ARISTOTLE Apixaban (% per year) Results Efficacy Warfarin (% per year) HR (95% CI) 1 Endpoint* 1.27 1.60 0.79 (0.66 0.95) All stroke 1.19 1.51 0.79 (0.65 0.95) 0.95) Ischemic Stroke 0.97 1.05 0.92 (0.74 1.13) Hemorrhagic Stroke 0.24 0.47 0.51 (0.35 0.75) MI 053 0.53 061 0.61 088(0 0.88 (0.66 1.17) 17) All cause mortality 3.52 3.94 0.89 (0.80 0.998) Safety Major bleeding 4.07 6.01 0.68 (0.61 0.75) All bleeding 18.1 25.8 0.71 (0.68 0.75) IC bleeding 033 0.33 080 0.80 042(0 0.42 (0.30 0.58) 0 *Non inferiority margin = 1.38 New Engl J Med 2011;365:981 92.

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;365:981 92. New Engl J Med 2011;364:806 17.

Which of the following have been shown at least as effective as warfarin for the prevention of stroke in patients with ihatrial ilfibrillation? ill i 1. Apixaban 2. Dabigatran 3. Rivaroxaban 4. Both 1 & 2 5. All of the above Apixaban 0% 0% 0% 0% 0% Dabigatran Rivaroxaban Both 1 & 2 All of the abo...

Summary of Afib Dt Data Apixaban (ARISTOTLE) Dabigatran (RE LY) Rivaroxaban (ROCKET AF) # Patients > 18,000 > 18,000 > 14,000 Mean CHADS 2 2 2 3.5 TTR 62% 64% 55% Efficacy vs. VKA Superior Superior 1 Non Inferior Bleeding 2 vs. VKA Decreased Similar Similar Elimination CYP3A4/P gp Renal CYP3A4/P gp/renal 1 Dabigatran 150 mg BID group. 2 Major bleeding per study design.

Use of Concomitant Antiplatelet Agents Antiplatelet Agents ARISTOTLE (Apixaban) RELY (Dabigatran) ROCKET AF (Rivaroxaban) ASA < 165 mg/day Yes < 100 mg/day Clopidogrel Yes Yes Yes Combination No Yes No Aspirin Use (%) 31% 40% 36% New Engl J Med 2009;361:1139 51. New Engl J Med 2011;365:883 91. New Engl J Med 2011;365:981 92.

Treatment of Acute Venous Thromboembolism

Both dabigatran and rivaroxaban have been shown to be effective in the treatment of acute VTE. 1. True 2. Fl False 0% 0% True False

Dabigatran vs. Warfarin Treatment of VTE (RE COVER) Acute DVT or PE for 6 months Double blind, double dummy, RCT Non inferiority trial > 2,500 patients Treatment UFH or LMWH X 5 days and INR > 2.0 20 Then dabigatran 150 mg BID or warfarin Outcomes Efficacy (1 endpoint = VTE or related death) Dabigatran non inferior to warfarin Safety Major bleeding: dabigatran & warfarin had similar rates Overall bleeding: dabigatran had lower rates Conclusions Dabigatran was non inferior to warfarin for the acute treatment of VTE Did use standard bridging regimen for both groups UFH/LMWH Dabigatran (active & placebo) started after therapeutic INR in both groups New Engl J Med 2009;361:2342 52.

Rivaroxaban vs. Warfarin Treatment of VTE (EINSTEIN) Acute DVT for 3, 6, or 12 months Open label, RCT Non inferiority trial > 3,400 patients Treatment Rivaroxaban 15 mg BID X 3 weeks, then 20 mg daily for 3, 6, or 12 mos. (duration determined by MD) Enoxaparin followed by warfarin (INR 2.0 3.0) Outcomes Efficacy (1 endpoint = Recurrence of VTE) Rivaroxaban non inferior to warfarin Safety Major bleeding: rivaroxaban & warfarin had similar rates Overall bleeding: rivaroxaban & warfarin had similar rates Conclusions Rivaroxaban was non inferior to warfarin for the acute treatment of DVT Used Rivaroxaban monotherapy compared to standard of care Rivaroxabanbetter better thanplacebo inthe Extension study (EINSTEIN EXT) EXT) PE arm of the study series is still ongoing New Engl J Med 2009;363:2499 510.

Summary of VTE Dt Data 1 Dabigatran (RE COVER) Rivaroxaban (EINSTEIN) # Patients > 2,500 > 3,400 Treatment Duration 6 months 6 months Initial Therapy 2 LMWH Rivaroxaban TTR 60% 58% Efficacy vs. VKA Non Inferior Non Inferior Bleeding vs. VKA Similar Similar VTE Type DVT & PE DVT 1 Apixaban data in VTE are not available, AMPLIFY & AMPLIFY EXT are ongoing. 2 Initial therapy in study group, both studies bridged control group.

Prevention of Venous Thromboembolism in Orthopedic Surgery Patients

Dabigatran Studied in TKA and THA Compared to enoxaparin (European dosing) 40 mg daily Commonly administered prior to surgery Dabigatran dosed once daily 220 mg & 150 mg evaluated EU labeling is 220 mg daily & adjusted for age and CrCl ½ maintenance dose administered i dpost op day 0 Efficacy Non inferior to European dosing of enoxaparin Inferior to US FDA approved dosing of enoxparin (30 mg SQ q12h) Safety Bleeding rates similar between all groups J Thromb Haemost 2005;3:103 11. J Thromb Haemost 2007;5:2175 7. Lancet 2007;370:949 56. J Arthro 2009;24:1 9.

Rivaroxaban Studied in TKA and THA Compared to enoxaparin 40 mg SQ daily 30 mg SQ twice daily Rivaroxaban dosed 10 mg once daily Efficacy Superior to enoxaparin at both dosages Safety Similar rates of bleeding compared to enoxaparin New Engl J Med 2008;358:2765 75. Lancet 2008;372:31 9. N Engl J Med 2008;358:2776 86. Lancet 2009;373:1673 80.

Apixaban Studied in TKA and THA Compared to enoxaparin 40 mg SQ daily 30 mg SQ twice daily Apixaban dosed 2.5 mg twice daily Efficacy Superior to enoxaparin at 40 mg daily Non inferior to enoxaparin 30 mg twice daily Safety Similar bleeding compared to enoxaparin 40 mg daily Less bleeding compared to enoxaparin 30 mg twice daily New Engl J Med 2009;361:594 604. Lancet 2010;375:807 15. New Engl J Med 2010;363:2487 98.

Acute Coronary Syndrome

Apixaban Acute Coronary Syndrome (APPRAISE 2) Double blind, placebo controlled, RCT ACS plus 2 additional risk factors Apixaban 5 mg twice dil 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;365:699 708.

Rivaroxaban ATLAS ACS ACS 2 TIMI 51 Trial is ongoing All patients received low dose ASA with either: Rivaroxaban2.5 25mg twice dil daily or Rivaroxaban 5 mg twice daily Groups were stratified based on clopidogrel use Results expected in November Am Heart J 2011;161:815 21.

Additional Developing Information apixabanaban is currently being ealatedfor evaluated VTE prophylaxis in medical patients An additional factor Xa inhibitor (edoxaban) is currently in phase 3 clinical trials Afib VTE treatment

Dabigatran Patient Information Store in original container Discard opened product after 60 days Dyspepsia most common side effect (15%) Do not open capsule Rivaroxaban Ask pharmacist or physician about DDIs Do not crush, chew, or split tablet Overall tolerated well

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. I will begin r... 0% 0% 0% 0% I may prescrib... I am still ver... I will not pre...

David Stewart, PharmD, BCPS Assistant Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu