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Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health.

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Presentation on theme: "Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health."— Presentation transcript:

1 Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health Sciences Clinical Assistant Professor of Medicine, UNC Clinical Pharmacy Specialist-Anticoagulation Cone Health, Greensboro, NC

2 Faculty Disclosure The speaker reported the following financial relationships or relationships to products or devices he or his spouse has with commercial interests related to the content of this CME activity: –James B. Groce III, PharmD, CACP Fees for non-CME services received directly from a commercial interest or their agents: Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Eisai Pharmaceuticals, Inc. Janssen Pharmaceuticals, Inc. Sanofi-aventis Stago-Diagnostica The Joint Commission

3 Objectives Review the cardiology focused indications of the new anticoagulant medications. Discuss the benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator. Identify key opportunities in the management of patients using the new anticoagulants.

4 Atrial Fibrillation and Anticoagulation An estimated 2.6 million Americans have AF –Prevalence of AF is increasing—estimated to be 12 million patients by 2050 AF is responsible for 15-20% of all strokes –Untreated stroke risk with AF is approximately 5% –AF strokes are severe: causing death and disability Anticoagulation therapy –Effectively lowers the incidence and severity of AF stroke Fewer than 60% of eligible patients with AF have received anticoagulation with warfarin –Many patients with AF have INRs below the recommended therapeutic range Ogilvie IM, et al. Am J Med. 2010;123: Hylek E et al. N Engl J Med. 2003; 349: AF=atrial fibrillation. INR=international normalized ratio.

5 warfarin (INR 2.0 to 3.0, target 2.5),* or dabigatran † Any high-risk factor or more than 1 moderate-risk factor (Previous stroke, TIA or embolism, mitral stenosis, and Prosthetic heart valve*) aspirin, mg daily, or warfarin (INR , target 2.5), or dabigatran † One moderate-risk factor (Age ≥75 yrs, HTN, CHF, LVEF ≤35%, and diabetes) aspirin, mg dailyNo risk factors Recommended TherapyRisk Category *If mechanical valve, target INR >2.5. † dabigatran is useful as an alternative to warfarin in patients with AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure, or advanced liver disease. Fuster V, et al. J Am Coll Cardiol. 2006;48:e149-e246. Wann SL, et al. Heart Rhythm. 2011;8:e1-e8. ACCF/AHA/HRS Focus Update 2011 Guidelines for Antithrombotic Therapy to Prevent Stroke HTN=hypertension. INR=international normalized ratio. CHF=congestive heart failure. LVEF=left ventricular ejection fraction.

6 Therapies to Prevent Thrombotic Stroke Anticoagulants Antiplatelet Agents New Anticoagulants aspirin +/- Non-warfarin Vitamin K Antagonists tecarfarin Direct Thrombin Inhibitors ximelagatran dabigatran AZD 0837 Factor Xa Inhibitors apixaban rivaroxaban idraparinux edoxaban YM150 betrixaban LY Non-antithrombotic Drugs Anti- hypertensive StatinAnti- arrhythmic Vitamin K Antagonist warfarin Left Atrial Appendage Occlusion or Excision Umbrella device External clip Surgical excision clopidogrel

7 Characteristics of an Ideal Anticoagulant Hirsh J et al. Blood. 2005;105(2): Predictable dose response (no need for monitoring) Minimal non-anticoagulant side effects Minimal drug-drug interactions Parenteral and oral administration Antidote High efficacy-to- safety index Rapid onset of action

8 Newer Oral Anticoagulants dabigatran 1,4* rivaroxaban 2 apixaban 3 ManufacturerBoehringer IngelheimBayer with Ortho-McNeil Bristol-Myers Squibb with Pfizer Brand Name Pradaxa ® Xarelto ® Eliquis ® Approval StatusApproved in U.S. 2010Approved in U.S Approved in the EU 2011 Indication Stroke prevention in patients with AF Thromboembolism in adult patients undergoing elective hip or knee replacement surgery Stroke prevention in patients with AF Not approved in US EU indication: Prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery Dosage Recommendation 150mg bid (Clcr > 30mL/min) 75mg bid (Clcr 15 – 30mL/min) 75mg bid (Clcr 30 – 50mL/min)* 10mg qd Ortho 20mg qd Afib Clcr > 50mL/min 15mg qd Afib (Clcr 15-50mL/min) 5 mg bid Mechanism of Action Direct factor IIa inhibitorDirect factor Xa inhibitor 1.dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc rivaroxaban prescribing information. Janssen Pharmaceuticals, Inc apixaban European Union summary of product characteristics. Pfizer and Bristol-Myers Squibb *dronedarone, systemic ketoconazole

9 Pharmacokinetic Properties of the New Oral Anticoagulants dabigatranrivaroxabanapixaban T 1/ hours5-9 hours8-15 hours Metabolism Conjugation (esterase catalyzed hydrolysis in liver or plasma) Oxidation (mainly via CYP3A4) and hydrolysis 70% unchanged 30% Inactive metabolites Renal Excretion 80%36%30% Substrate for p-glycoprotein Yes Metabolized by CYP3A4 NoYes Wittkowsky AK. J Thromb Thrombolysis. 2010;29: Ufer M. Thrombosis and Haemostasis. 2010;103:

10 Differences Between New Oral Anticoagulants and Warfarin ParameterOral AnticoagulantsWarfarin Onset/Offset of action RapidSlow Dose–anticoagulant effect relationship LinearPredictable Food–drug interactions Low probability of interaction Moderate probability of interaction Monitoring for anticoagulant effect Not required Not available Required POCT and PST Available POCT=point-of-care testing PST=patient self-testing

11 AF Stroke Risk

12 Stroke Risk Stratification in AF CHADS 2 CHA 2 DS 2 -VASc Risk FactorScore Cardiac Failure1 HTN1 Age ≥75 y1 Diabetes1 Stroke2 Risk FactorScore Cardiac Failure1 HTN1 Age ≥75 y2 Diabetes1 Stroke2 Vascular Disease (MI, PAD, Aortic Atherosclerosis) 1 Age y1 Sex Category (Female)1 Lip GY, Halperin JL. Am J Med. 2010;123(6): Camm AJ, et al. Eur Heart J. 2010;31(19): Total Score Annual Risk of Stroke (%) CHADS 2 CHA 2 DS 2 -VASc HTN=hypertension. MI=myocardial infarction. PAD=peripheral artery disease.

13 RE-LY: Study Design Atrial fibrillation ≥1 Risk Factor Absence of contra-indications 951 centers in 44 countries R warfarin (INR ) n=6000 dabigatran etexilate 110 mg bid n=6000 dabigatran etexilate 150 mg bid n= efficacy outcome=stroke or systemic embolism 1 0 safety outcome=major bleeding Non-inferiority margin=1.46 Open Blinded Connolly SJ, et al. N Engl J Med. 2009;361: bid=twice daily. INR=international normalized ratio. RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy. Performed December 2005-March 2009 Median follow-up: 2.0 years Follow-up 99.9% complete Mean TTR=64% (patients on warfarin)

14 Stroke/systemic embolism ( ) Myocardial Infarction ( ) Vascular death ( ) Intracranial Hemorrhage (ICH) ( ) Major GI bleeding ( ) Major bleeding ( ) Total bleeding ( ) Efficacy Outcomes Safety Outcomes Relative risk dabigatran 150 mg better warfarin better 0.90 ( ) 1.29 ( ) 0.90 ( ) 0.30 ( ) 1.06 ( ) 0.80 ( ) 0.78 ( ) 1.dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. March Connolly SJ, et al. N Engl J Med. 2009;361: RE-LY=Randomized Evaluation of Long-term Anticoagulation Therapy. RE-LY Trial: Primary Efficacy & Safety Outcomes

15 ROCKET AF Study Design  Enrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10% CHADS 2 Risk Factors Prior stroke, TIA, or non-CNS systemic embolus – OR – CHF or LVEF ≤35% Hypertension Age ≥75 years Diabetes CHADS 2 Risk Factors Prior stroke, TIA, or non-CNS systemic embolus – OR – CHF or LVEF ≤35% Hypertension Age ≥75 years Diabetes At least 2 required Abbreviations: CHADS 2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CrCl = creatinine clearance; INR = international normalized ratio. *Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter. 1. Patel MR et al. N Engl J Med. 2011;365(10): ROCKET AF Study Investigators. Am Heart J. 2010;159(3): rivaroxaban 20 mg/d (15 mg/d for CrCl 30 to <50 mL/min) rivaroxaban 20 mg/d (15 mg/d for CrCl 30 to <50 mL/min) warfarin INR target: 2.0 to 3.0 inclusive warfarin INR target: 2.0 to 3.0 inclusive NVAF Monthly assessments* warfarin management was determined by clinician Monthly assessments* warfarin management was determined by clinician Randomized double-blind/ double-dummy (N=14,264)

16 *Included all randomized subjects followed for events both on and off study drug until end of study site notification (N=14171). Patel MR et al. N Engl J Med. 2011;365(10): No. at risk Rivaroxaban Warfarin rivaroxabanwarfarin Rate/100 PTY HR (95% CI): 0.88 ( ) Noninferiority P value <.001 Days From Randomization Cumulative Event Rate (%) rivaroxaban warfarin Rocket-AF Primary Efficacy Outcome Stroke and Non–CNS Embolism

17 Rocket-AF Primary Safety Outcomes Events, No. (Rate/100 PTY) rivaroxaban (n=7061)* warfarin (n=7082)* HR (95% CI) P value Major bleeding (any)395 (3.60)386 (3.45)1.04 ( ).576 Bleeding causing death27 (0.24)55 (0.48)0.50 ( ).003 Critical organ bleeding † 91 (0.82)133 (1.18)0.69 ( ).007 Hgb drop ≥2 g/dL305 (2.77)254 (2.26)1.22 ( ).019 Transfusion (>2 units)183 (1.65)149 (1.32)1.25 ( ).044 Bleeding site Intracranial hemorrhage ‡ 55 (0.49)84 (0.74)0.67 ( ).019 GI bleeding § 224 (---)154 (---) Abbreviations: GI, gastrointestinal; hgb, hemoglobin. *Safety population on-treatment. †Critical bleeding sites included intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal. ‡Intracranial hemorrhage included intraparenchymal, intraventricular, subarachnoid, subdural hematoma, and epidural hematoma. §GI hemorrhage included upper GI, lower GI, and rectal bleeds. Patel MR et al. N Engl J Med. 2011;365(10):

18 warfarin (target INR 2-3) apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Primary outcome: stroke or systemic embolism Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa Randomize double blind, double dummy (n = 18,201) Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Exclusion  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine ARISTOTLE: Study Design

19 ARISTOTLE Main Trial Results 21% RRR 31% RRR ISTH major bleeding Stroke or systemic embolism Median TTR 66% apixaban 212 patients, 1.27% per year warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P=0.011 apixaban 327 patients, 2.13% per year warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001 Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa

20 What Is the Impact of Time in Target Range (TTR)?

21 Time in Target Range (TTR) What is the TTR for the patient below?

22 3 Methods for Calculating TTR: Percentage of Visits in Range For an individual patient, the number of visits “in range” is divided by the number of visits 3 Patient Visits with INR in range 5 Total Patient Visits = 60% TTR

23 3 Methods for Calculating TTR: Cross Section of Patients In Range For a group of patients, a date is selected and all patients are evaluated on the last reading prior to that date. Sept 30, 2011 is selected to assess TTR for 100 patients Patients are evaluated using last INR readings prior to Sept 30, 2011 Out of 100 patients, 71 had readings in therapeutic range 71 Patient with INR in range 100 Total Patients = 71% TTR As of Sept 30, 2011

24 More complicated methodology which looks at the amount of time between visits to determine how long the patient might have been within their therapeutic range –Between measurements on May 1 and May 31, it is assumed that the patient slowly moved from 2.5 to 3.5 over 30 days –On May 15th, the patient was probably over Methods for Calculating TTR: % Days in Range (Rosendaal Method) 15 days In range 15 days Out of range Patient was in range 50% of the time

25 Phase 3 Trials in Atrial Fibrillation: TTR and warfarin Efficacy Study Mean TTR (%) Mean CHADS 2 Score CHADS 2 ≥3 Patients (%) Primary Efficacy Rate (warfarin Arm)* OverallCHADS 2 2CHADS 2 ≥3 ROCKET AF RE-LY ARISTOTLE *Rate per 100 patient-years. 1. Patel MR et al. N Engl J Med. 2011;365(10): Connolly SJ, et al. N Engl J Med. 2009;361: doi: /NEJMoa Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa ♦ ROCKET AF enrolled a population of patients with AF at higher risk of stroke ♦ The overall event rate for the warfarin arm in ROCKET AF was higher than those reported in RE-LY and ARISTOTLE ♦ This difference may have been driven by the greater proportion of CHADS 2 ≥3 patients enrolled in ROCKET AF/

26 Benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator.

27 New oral anticoagulants –No coagulation testing Less time and travel No finger stick or venipuncture –Fixed dose: no dose finding –Primary Care or Cardiology Simplifies responsibility –Fewer strengths Possible decease in dosing errors –Diet Less effect Benefits and shortcomings of the currently available anticoagulant therapies.

28 Given the challenges associated with warfarin, an oral anticoagulant is especially attractive Features of oral anticoagulants that may be associated with greater adherence include –Do not require monitoring –Fewer adverse effects, drug-drug, and drug-food interactions Improved adherence may reduce the risk of subtherapeutic INR and may lead to better treatment outcomes and possibly lower costs Kirsch B. Manag Care. 2011;20(2): Benefits and shortcomings of the currently available anticoagulant therapies.

29 Identify key opportunities in the management of patients using the new anticoagulants

30 Review appropriateness prior to dispensing CBC q72h while inpatient Recommend CBC 7-10 days post discharge Discharge counseling Moses Cone Health System Pharmacy & Therapeutics Formulary Review. January Approved. CBC=complete blood count. Key opportunities in the management of patients

31 Creatinine Clearance Recommended Dose of Dabigatran > 30 mL/min150 mg twice daily* 15 – 30 mL/min 30 – 50 mL/min 75 mg twice daily † 75mg twice daily ‡ < 15 mL/min Dosing recommendations cannot be provided *With or without food. † Based upon pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. ‡ For patients on P-gp inhibitors (dronedarone or systemic ketoconazole) dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc Key opportunities in the management of patients

32 Converting from warfarin to dabigatran –Discontinue warfarin –Start with dabigatran when INR < 2.0 Converting from dabigatran to warfarin Creatinine ClearanceRecommended Starting Time of Warfarin > 50 mL/min3 days before discontinuing dabigatran mL/min2 days before discontinuing dabigatran mL/min1 day before discontinuing dabigatran < 15 mL/minNo recommendations can be made dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc INR=international normalized ratio. Key opportunities in the management of patients

33 Administration of Parenteral Anticoagulant Recommended Starting Time of Dabigatran Intermittent dosing0-2 hours before time of next dose Continuous infusionAt time of discontinuation dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc Key opportunities in the management of patients

34 Creatinine Clearance Recommended Starting Time of Parenteral Anticoagulant CrCl ≥30 mL/min12 hours after last dose of dabigatran CrCl ≤30 mL/min24 hours after last dose of dabigatran CrCl=creatinine clearance. dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc Key opportunities in the management of patients

35 Discontinue warfarin Initiate rivaroxaban when the INR is below 3.0 to avoid inadequate anticoagulation ♦ There are no clinical trial data to guide converting from rivaroxaban to warfarin ♦ Rivaroxaban may affect INR, so INR measurements made during coadministration of rivaroxaban with warfarin may not be useful ♦ One approach is to discontnue rivaroxaban and begin both a parenteral anticoagulant and warfarin when the next rivaroxaban dose would have been taken * warfarin  rivaroxaban rivaroxaban  warfarin *The recommendation to use a parenteral anticoagulant together with warfarin after discontinuing rivaroxaban is analogous to the bridging protocol recommended for starting moderate- to high-risk patients on warfarin. 1 Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198. Key opportunities in the management of patients

36 rivaroxaban (n=4637) warfarin (n=4691) No. of Strokes Anticoagulation after discontinuation was not stipulated in ROCKET AF Warfarin patients who completed the study were generally maintained on warfarin Rivaroxaban patients were generally switched to warfarin –There was no coadministration of warfarin and rivaroxaban –This resulted in inadequate anticoagulation after stopping rivaroxaban until attaining a therapeutic INR Patel MR et al. N Engl J Med. 2011;365(10): Key opportunities in the management of patients

37 Short half-life of oral anticoagulants makes adherence important Reduced monitoring may deny the physician the opportunity for patient education and the earlier detection of problems –Denies the practitioner the opportunity to tailor the intensity of anticoagulant therapy for patient-specific factors Acquisition costs associated with oral anticoagulants will be greater than for warfarin –Payers may erect barriers to access –Cost-sharing may decrease adherence Ansell J. Hematology. 2010; Key opportunities in the management of patients

38 Protocol development for use and management –Short half-life of oral anticoagulants makes adherence important Protocol development for use and management of life-threatening/catastrophic bleed(s) –No validated tests to measure anticoagulation effect –No antidote for most agents –Assessment of compliance more difficult than with vitamin K antagonists Sobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35: Key opportunities in the management of patients

39 The successful use of (anticoagulation) depends on an “essential triad” which includes a –Vigilant clinician –Cooperative (well educated) patient –Readily available and reliable laboratory If these factors are present, continuous use of anticoagulation is practical...and effective; if not, the use of the drug is dangerous… Foley WT, Wright IS. Am J Med Sci. 1949;217: Aske JM, Cherry CB. J Am Med Assoc. 1950;144: Key opportunities in the management of patients

40 Availability of new oral anticoagulants will impact the way we think about care delivery and management for patients with atrial fibrillation –We must STOP focusing upon INRs—and instead, as practitioners—focus upon assuring: The impact these new drugs have upon reduction of stroke and intracranial hemorrhage! Compliance, patient education—regarding their disease state as well as their drug therapies Continuing to deliver a “systematic means of oversight” for drug therapies and disease states—for which at their extremes—patients may either bleed to death—or clot to death: –Baseline and periodic assessment of renal function –Evaluation of drug-drug/drug-disease interactions Key opportunities in the management of patients

41 Anticoagulation therapy lowers the incidence and severity of AF stroke Less than 60% of eligible AF patients have received anticoagulation therapy Newer oral anticoagulants exhibit a rapid onset of action, linear kinetics, low probability of drug and food interactions, and do not require monitoring—and, relative to warfarin—have further reduced the liklihood of stroke in the setting of non-valvular atrial fibrillation Key opportunities in the management of patients

42 Summary Current cardiology indications of the new anticoagulant medications include prevention of stroke in setting of NVAF. Benefits and shortcomings –New oral agents eliminate a requirement of traditional monitoring and reduce stroke—when compared to warfarin—but lack a means of reversal Key opportunities for practitioner involvement in the management of patients: –Will remain: provision of a systematic means of oversight Appropriateness of drug relative to the approved indication(s) Focus upon renal function and Rx-Rx interaction prevention for new agents

43 Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health Sciences Clinical Assistant Professor of Medicine, UNC Clinical Pharmacy Specialist-Anticoagulation Cone Health, Greensboro, NC


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