How To Understand The History Of Analgesic Drugs

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1 New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Associate Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy Disclosures Speaker s Bureau for: Boehringer Ingelheim Pharmaceuticals Janssen Pharmaceuticals 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 healthcareproviders 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 1

2 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 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 Sputnik I & 2 Yuri Gargarin Orbits Earth Alan Shephard Suborbital Flight Americans Land on the Moon 1 st Flight of Columbia (STS 1) Soviets International Deploy Space Station Manned is Inhabited Space Station Warfarin Pros Experience Inexpensive Reversible Monitoring available Cons Time of onset Frequent monitoring Dosing variability Numerous drug interactions 2

3 21 st Century New therapies with FDA Approval Dabigatran Rivaroxaban Additional emerging new therapies Apixaban (Phase III trials complete) Edoxaban (Phase III trials ongoing) 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. Warfarin is an... 0% 0% 0% 0% 0% Warfarin has m... I m still a li... I prefer the n... I have serious... 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 0% 0% 0% 0% I routinely pr... I prescribe th... I am very hesi... I have never p... 3

4 Clinical Pharmacology Comparison Coagulation Cascade Intrinsic Pathway (PTT) XII XI IX XIIa XIa IXa Extrinsic Pathway (PT) VIIa VII Warfarin Rivaroxan & Apixaban Dabigatran X VIII II Xa Fibrinogen Va IIa XIII XIIIa Fibrin 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 ml/min Avoid < 15 ml/min Avoid < 30 ml/min Drug Drug Interact. CYP3A4/P gp Rifampin (P gp) CYP3A4/P gp Onset of activity 3 4hrs 1 2 hrs 2 4 hrs t½ 8 15 hrs hrs 5 9hrs Dosing interval Twice daily Twice daily Daily Measuring tests PT/Anti factor Xa ECT, TT, +/ aptt PT/Anti factor Xa 4

5 Monitoring vs. Measuring Measuring Dabigatran Thromb Haemost 2010;103: 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:

6 Measuring Rivaroxaban PT is sensitive (Don t rely on INR) aptt not sensitive Highlights peak concentrations J Thromb Haemost 2011;9: Reversal of New Anticoagulants FFP No data, unclear/unknown benefit 3 factor PCC Unknown 4 factor PCC Reverse rivaroxaban but not dabigatran (not available in US) apcc Baboon data showed transient reversal of rivaroxaban Recombinant Factor VIIa Case reports only Risk of arterial thrombosis All PCC s and RFVIIa increase the risk of arterial thrombotic events in non hemophiliac patients Must weigh potential risks with potential benefits These effects may all be only transient Am J Hematol. 2012;84:S Am J Health Syst Pharm. 2012;69: Circulation. 2011;124: 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... 6

7 Clinical Utilization 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 0% 0% 0% 0% Non valvular A... Prevention of... Treatment of V... All of the abo... Issues with New Anticoagulants 7

8 Atrial Fibrillation Summary of Afib Data Apixaban (ARISTOTLE) Dabigatran (RE LY) Rivaroxaban (ROCKET AF) # Patients > 18,000 > 18,000 > 14,000 Mean CHADS TTR 62% 64% 55% Efficacy vs. VKA Superior Superior 1 Non Inferior Bleeding 2 vs. VKA Decreased Similar Similar 1 Dabigatran 150 mg BID group. 2 Major bleeding per study design. New Engl J Med 2009;DOI: /NEJMoa New Engl J Med 2011;DOI: /NEJMoa New Engl J Med 2011;DOI: /NEJMoa Treatment of Acute Venous Thromboembolism 8

9 Both dabigatran and rivaroxaban have been shown to be effective in the treatment of acute VTE. 1. True 2. False 0% 0% True False Summary of VTE 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 & PE 1 Apixaban data in VTE are not available, AMPLIFY & AMPLIFY EXT are ongoing. 2 Initial therapy in study group, both studies bridged control group. New Engl J Med 2012;DOI: /NEJMoa New Engl J Med 2010;DOI: /NEJMoa New Engl J Med 2009;DOI: /NEJMoa Prevention of Venous Thromboembolism in Orthopedic Surgery Patients 9

10 Summary of Orthopedic VTE Data 1 Comparator Enoxaparin 40 mg daily Enoxaparin 20 mg q12h Enoxaparin 30 mg q12h Bleeding vs. Enoxaparin Apixaban (2.5 mg q12h) Dabigatran (150 or 220mg/day) Edoxaban (30 mg/day) Rivaroxaban (10 mg/day) Superior Non Inferior Superior Superior Non Inferior Inferior Superior Similar Similar Similar 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: Additional Therapeutic Uses VTE Prophylaxis in Medical Patients Only evaluated in extended durations vs. enoxaparin No benefit for extended prophylaxis Acute Coronary Syndrome Apixaban significantly increased risk of bleeding Rivaroxaban (evaluated 2.5 mg and 5 mg BID) Primary Endpoint (CV Death, MI or CVA) showed benefit TIMI Major Bleeding higher with rivaroxaban Intracranial Hemorrhage higher with rivaroxaban New Engl J Med 2011;365: New Engl J Med 2012;366:9 19. New Engl J Med 2011 Online;DOI: /NEJMoa Dabigatran and Myocardial Infarction 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 Arch Intern Med. Online Jan 9, 2012;DOI:10.101/archinternmed

11 Summary 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 Adverse event rates are high h when not used/dosed d appopriately Agents vary based on various pharmacologic and pharmacokinetic parameters None of the new agents require monitoring Would base choice of agent on patient specific factors All of them can be measured if needed Best technique for reversal is unknown for most at this time but likely is either expensive, locally unavailable, or both Cost will be a limitation if not covered by insurance Practical Provider Information Parameter Dabigatran Rivaroxaban 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 Px N/A 10 mg QD Primary Elimination Renal CYP3A4/P gp 1 Drug Drug Interact. Rifampin, Dronedarone 2, Ketoconazole 2 Timing of Dose Anytime (With or Without Food) CYP3A4/P gp Inhibitors 15, 20 mg Dose With Food 10 mg Dose Anytime Practical Measuring Test aptt PT Common Complaints Dyspepsia 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. 11

12 Patient Education 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 ) 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... New Developments in Oral Anticoagulants: Treating and Preventing Embolic Events in the 21 st Century David Stewart, PharmD, BCPS Associate Professor of Pharmacy Practice East Tennessee State University Bill Gatton College of Pharmacy stewardw@etsu.edu 12