Presentation on theme: "Pharmacology – What’s New in Anticoagulation Medications"— Presentation transcript:
1 Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACPProfessorCampbell University College of Pharmacy and Health SciencesClinical Assistant Professor of Medicine, UNCClinical Pharmacy Specialist-AnticoagulationCone Health, Greensboro, NC
2 Faculty DisclosureThe 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, CACPFees for non-CME services received directly from a commercial interest or their agents:Boehringer Ingelheim Pharmaceuticals, Inc.,Bristol-Myers SquibbEisai Pharmaceuticals, Inc.Janssen Pharmaceuticals, Inc.Sanofi-aventisStago-DiagnosticaThe Joint Commission
3 ObjectivesReview 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 AFPrevalence of AF is increasing—estimated to be 12 million patients by 2050AF is responsible for 15-20% of all strokesUntreated stroke risk with AF is approximately 5%AF strokes are severe: causing death and disabilityAnticoagulation therapyEffectively lowers the incidence and severity of AF strokeFewer than 60% of eligible patients with AF have received anticoagulation with warfarinMany patients with AF have INRs below the recommended therapeutic rangeAF=atrial fibrillation.INR=international normalized ratio.Ogilvie IM, et al. Am J Med. 2010;123:Hylek E et al. N Engl J Med. 2003; 349:
5 ACCF/AHA/HRS Focus Update 2011 Guidelines for Antithrombotic Therapy to Prevent Stroke Risk CategoryRecommended TherapyNo risk factorsaspirin, mg dailyOne moderate-risk factor(Age ≥75 yrs, HTN, CHF, LVEF ≤35%, and diabetes)aspirin, mg daily, orwarfarin (INR , target 2.5), ordabigatran†Any high-risk factor ormore than 1 moderate-risk factor(Previous stroke, TIA or embolism, mitral stenosis, and Prosthetic heart valve*)warfarin (INR 2.0 to 3.0, target 2.5),* ordabigatran †* 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.HTN=hypertension.INR=international normalized ratio.CHF=congestive heart failure.LVEF=left ventricular ejection fraction.5
6 Therapies to Prevent Thrombotic Stroke AnticoagulantsAntiplatelet AgentsNon-antithrombotic DrugsVitamin K AntagonistNew Anticoagulantsaspirin +/-clopidogrelAnti-hypertensiveStatinAnti-arrhythmicLeft Atrial Appendage Occlusion or ExcisionUmbrella deviceExternal clipSurgical excisionwarfarinNon-warfarinVitamin KAntagoniststecarfarinDirect Thrombin InhibitorsximelagatrandabigatranAZD 0837Factor XaInhibitorsapixabanrivaroxabanidraparinuxedoxabanYM150betrixabanLY517717
7 Characteristics of an Ideal Anticoagulant Predictable dose response (no need for monitoring)High efficacy-to-safety indexHirsh, 2005, p454, c2, table 1Parenteral and oral administrationRapid onset of actionAntidoteAs shown with the schematic, characteristics of an ideal anticoagulant include a high efficacy-to-safety index, predictable dose response (no need for monitoring), availability of parenteral and oral dosage routes, rapid onset of action, antidote, minimal nonanticoagulant side effects, and minimal drug-drug interactions.Hirsh, 2005, p454, c2, table 1Minimal non-anticoagulant side effectsMinimaldrug-drug interactionsHirsh J et al. Blood. 2005;105(2):Hirsh J, O’Donnel M, Weitz JI. New anticoagulants. Blood. 2005;105(2):
8 Newer Oral Anticoagulants dabigatran1,4*rivaroxaban2apixaban3ManufacturerBoehringer IngelheimBayer with Ortho-McNeilBristol-Myers Squibb with PfizerBrand NamePradaxa®Xarelto®Eliquis®Approval StatusApproved in U.SApproved in U.S. 2011Approved in the EU 2011IndicationStroke prevention in patients with AFThromboembolism in adult patients undergoing elective hip or knee replacement surgeryNot approved in USEU indication: Prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgeryDosage Recommendation150mg bid (Clcr > 30mL/min)75mg bid (Clcr 15 – 30mL/min)75mg bid (Clcr 30 – 50mL/min)*10mg qd Ortho20mg qd Afib Clcr > 50mL/min15mg qd Afib (Clcr 15-50mL/min)5 mg bidMechanism of ActionDirect factor IIa inhibitorDirect factor Xa inhibitordabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Incapixaban European Union summary of product characteristics. Pfizer and Bristol-Myers Squibbrivaroxaban prescribing information. Janssen Pharmaceuticals, Inc*dronedarone, systemic ketoconazole
9 Pharmacokinetic Properties of the New Oral Anticoagulants dabigatranrivaroxabanapixabanT1/212-14 hours5-9 hours8-15 hoursMetabolismConjugation (esterase catalyzed hydrolysis in liver or plasma)Oxidation (mainly via CYP3A4) and hydrolysis70% unchanged30% Inactive metabolitesRenal Excretion80%36%30%Substrate for p-glycoproteinYesMetabolized by CYP3A4NoWittkowsky AK. J Thromb Thrombolysis. 2010;29:Ufer M. Thrombosis and Haemostasis. 2010;103:
10 Differences Between New Oral Anticoagulants and Warfarin ParameterOral AnticoagulantsWarfarinOnset/Offset of actionRapidSlowDose–anticoagulant effect relationshipLinearPredictableFood–drug interactionsLow probability of interactionModerate probability of interactionMonitoring for anticoagulant effectNot requiredNot availableRequired POCT and PST AvailablePOCT=point-of-care testingPST=patient self-testing
15 ROCKET AF Study Design NVAF rivaroxaban 20 mg/d CHADS2 Risk FactorsPrior stroke, TIA, or non-CNS systemic embolus– OR –CHF or LVEF ≤35%HypertensionAge ≥75 yearsDiabetesAt least 2 requiredRandomized double-blind/ double-dummy(N=14,264)rivaroxaban 20 mg/d(15 mg/d for CrCl 30 to <50 mL/min)warfarin INR target:2.0 to 3.0 inclusiveMonthly assessments*warfarin management was determined by clinicianEnrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10%Abbreviations: CHADS2 = 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 ;159(3):15
16 Rocket-AF Primary Efficacy Outcome Stroke and Non–CNS Embolism 6rivaroxabanwarfarinRate/100 PTY2.122.4254Cumulative Event Rate (%)3rivaroxabanwarfarin21HR (95% CI): 0.88 ( )Noninferiority P value <.0011202403604806007208409601080No. at riskRivaroxaban70816879668364705264410529511785768155Warfarin70906871665664405225408729441783776154Days From Randomization*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):
17 Rocket-AF Primary Safety Outcomes Events, No. (Rate/100 PTY)rivaroxaban (n=7061)*warfarin (n=7082)*HR (95% CI)P valueMajor bleeding (any)395 (3.60)386 (3.45)1.04 ( ).576Bleeding causing death27 (0.24)55 (0.48)0.50 ( ).003Critical organ bleeding†91 (0.82)133 (1.18)0.69 ( ).007Hgb drop ≥2 g/dL305 (2.77)254 (2.26)1.22 ( ).019Transfusion (>2 units)183 (1.65)149 (1.32)1.25 ( ).044Bleeding siteIntracranial hemorrhage‡55 (0.49)84 (0.74)0.67 ( )GI bleeding§224 (---)154 (---)---.001Note that ICH is a component of critical organ bleeding in notes.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 ARISTOTLE: Study Design Inclusion risk factorsAge ≥ 75 yearsPrior stroke, TIA or SEHF or LVEF ≤ 40%Diabetes mellitusHypertensionRandomizedouble blind, double dummy(n = 18,201)ExclusionMechanical prosthetic valveSevere renal insufficiencyNeed for aspirin plus thienopyridineapixaban 5 mg oral twice daily(2.5 mg BID in selected patients)warfarin(target INR 2-3)warfarin/warfarin placebo adjusted by INR/sham INRbased on encrypted point-of-care testing devicePrimary outcome: stroke or systemic embolismGranger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa
19 ARISTOTLE Main Trial Results Stroke or systemic embolismISTH major bleeding21% RRR31% RRRapixaban 212 patients, 1.27% per yearwarfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P=0.011apixaban 327 patients, 2.13% per yearwarfarin 462 patients, 3.09% per yearHR 0.69 (95% CI, 0.60–0.80); P<0.001Median TTR 66%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 visits3 Patient Visits with INR in range=60% TTR5 Total Patient Visits
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 patientsPatients are evaluated using last INR readings prior to Sept 30, 2011Out of 100 patients, 71 had readings in therapeutic range71 Patient with INR in range71% TTRAs of Sept 30, 2011=100 Total Patients
24 3 Methods for Calculating TTR: % Days in Range (Rosendaal Method) More complicated methodology which looks at the amount of time between visits to determine how long the patient might have been within their therapeutic rangeBetween measurements on May 1 and May 31, it is assumed that the patient slowly moved from 2.5 to 3.5 over 30 daysOn May 15th, the patient was probably over 3.015 daysIn range15 daysOut of rangePatient was in range50% of the time
25 Phase 3 Trials in Atrial Fibrillation: TTR and warfarin Efficacy StudyMean TTR (%)Mean CHADS2 ScoreCHADS2 ≥3 Patients (%)Primary Efficacy Rate (warfarin Arm)*OverallCHADS2 2CHADS2 ≥3ROCKET AF1553.587.02.21.32.3RE-LY2618.104.22.168.42.7ARISTOTLE3622.214.171.124ROCKET AF enrolled a population of patients with AF at higher risk of strokeThe overall event rate for the warfarin arm in ROCKET AF was higher than those reported in RE-LY and ARISTOTLEThis difference may have been driven by the greater proportion of CHADS2 ≥3 patients enrolled in ROCKET AF/*Rate per 100 patient-years.1. Patel MR et al. N Engl J Med. 2011;365(10):2. Connolly SJ, et al. N Engl J Med. 2009;361: doi: /NEJMoa3. Granger CB, et al. N Engl J Med [Aug 28]. ePub ahead of print. doi: /NEJMoa
26 Benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator.
27 New oral anticoagulants Benefits and shortcomings of the currently available anticoagulant therapies.New oral anticoagulantsNo coagulation testingLess time and travelNo finger stick or venipunctureFixed dose: no dose findingPrimary Care or CardiologySimplifies responsibilityFewer strengthsPossible decease in dosing errorsDietLess effect
28 Benefits and shortcomings of the currently available anticoagulant therapies. Given the challenges associated with warfarin, an oral anticoagulant is especially attractiveFeatures of oral anticoagulants that may be associated with greater adherence includeDo not require monitoringFewer adverse effects, drug-drug, and drug-food interactionsImproved adherence may reduce the risk of subtherapeutic INR and may lead to better treatment outcomes and possibly lower costsKirsch B. Manag Care. 2011;20(2):33-36.
29 Identify key opportunities in the management of patients using the new anticoagulants
30 Key opportunities in the management of patients Review appropriateness prior to dispensingCBC q72h while inpatientRecommend CBC 7-10 days post dischargeDischarge counselingCBC=complete blood count.Moses Cone Health System Pharmacy & Therapeutics Formulary Review. January Approved.
31 Key opportunities in the management of patients Creatinine ClearanceRecommended Dose of Dabigatran>30 mL/min150 mg twice daily*15 – 30 mL/min30 – 50 mL/min75 mg twice daily†75mg twice daily‡<15 mL/minDosing 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
32 Key opportunities in the management of patients Converting from warfarin to dabigatranDiscontinue warfarinStart with dabigatran when INR <2.0Converting from dabigatran to warfarinCreatinine ClearanceRecommended Starting Time of Warfarin>50 mL/min3 days before discontinuing dabigatran31-50 mL/min2 days before discontinuing dabigatran15-30 mL/min1 day before discontinuing dabigatran<15 mL/minNo recommendations can be madeINR=international normalized ratio.dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc
33 Key opportunities in the management of patients Administration of Parenteral AnticoagulantRecommended Starting Time of DabigatranIntermittent dosing0-2 hours before time of next doseContinuous infusionAt time of discontinuationdabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc
34 Key opportunities in the management of patients Creatinine ClearanceRecommended Starting Time of Parenteral AnticoagulantCrCl ≥30 mL/min12 hours after last dose of dabigatranCrCl ≤30 mL/min24 hours after last dose of dabigatranCrCl=creatinine clearance.dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc
35 Key opportunities in the management of patients warfarin rivaroxabanrivaroxaban warfarinThere are no clinical trial data to guide converting from rivaroxaban to warfarinRivaroxaban may affect INR, so INR measurements made during coadministration of rivaroxaban with warfarin may not be usefulOne approach is to discontnue rivaroxaban and begin both a parenteral anticoagulant and warfarin when the next rivaroxaban dose would have been taken*Discontinue warfarinInitiate rivaroxaban when the INR is below 3.0 to avoid inadequate anticoagulationThere are recommendations for switching patients from warfarin to rivaroxaban to help support continued anticoagulationFor patients who are currently receiving warfarin, warfarin should be discontinued and the INR of the patient should be monitored. rivaroxaban should be initiated once the INR of the patient falls below 3.0 to avoid periods of inadequate anticoagulationThis is the same methodology used in the ROCKET AF study to transition patients from warfarin to study drug1No clinical trial data are available to guide converting patients from rivaroxaban® to warfarin. rivaroxaban® affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach, based on published guidelines, is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban® would have been takenThe 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 warfarin2Reference: 1. Data on file. Janssen Pharmaceuticals, Inc., Raritan, NJ. 2. Fuster V, Rydén LE, Cannom DS, et al ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-e198.*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.1Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198.
36 Key opportunities in the management of patients Anticoagulation after discontinuation was not stipulated in ROCKET AFWarfarin patients who completed the study were generally maintained on warfarinRivaroxaban patients were generally switched to warfarinThere was no coadministration of warfarin and rivaroxabanThis resulted in inadequate anticoagulation after stopping rivaroxaban until attaining a therapeutic INRNo. of StrokesAlthough more strokes occurred in patients discontinuing rivaroxaban than warfarin at study completion, this imbalance was likely due to inadequate anticoagulationDuring the 28 days following the end of the study, there were 22 strokes in the patients taking rivaroxaban compared with 6 in the 4691 patients taking warfarinThe ROCKET AF protocol did not stipulate anticoagulation after study drug discontinuation. In general, however, patients who were randomized to warfarin were maintained on warfarin while those randomized to rivaroxaban were switched to warfarin without a period of coadministration of rivaroxaban and warfarin. As a result, these latter patients were not adequately anticoagulated during the period between stopping rivaroxaban and achieving a therapeutic INR. This was likely responsible for the imbalance of events between the two treatment armsrivaroxaban (n=4637)warfarin (n=4691)Patel MR et al. N Engl J Med. 2011;365(10):
37 Key opportunities in the management of patients Short half-life of oral anticoagulants makes adherence importantReduced monitoring may deny the physician the opportunity for patient education and the earlier detection of problemsDenies the practitioner the opportunity to tailor the intensity of anticoagulant therapy for patient-specific factorsAcquisition costs associated with oral anticoagulants will be greater than for warfarinPayers may erect barriers to accessCost-sharing may decrease adherenceAnsell J. Hematology. 2010;
38 Key opportunities in the management of patients Protocol development for use and managementShort half-life of oral anticoagulants makes adherence importantProtocol development for use and management of life-threatening/catastrophic bleed(s)No validated tests to measure anticoagulation effectNo antidote for most agentsAssessment of compliance more difficult than with vitamin K antagonistsSobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:38
39 Key opportunities in the management of patients The successful use of (anticoagulation) depends on an “essential triad” which includes aVigilant clinicianCooperative (well educated) patientReadily available and reliable laboratoryIf 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:
40 Key opportunities in the management of patients Availability of new oral anticoagulants will impact the way we think about care delivery and management for patients with atrial fibrillationWe 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 therapiesContinuing 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 functionEvaluation of drug-drug/drug-disease interactions
41 Key opportunities in the management of patients Anticoagulation therapy lowers the incidence and severity of AF strokeLess than 60% of eligible AF patients have received anticoagulation therapyNewer 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
42 SummaryCurrent cardiology indications of the new anticoagulant medications include prevention of stroke in setting of NVAF.Benefits and shortcomingsNew oral agents eliminate a requirement of traditional monitoring and reduce stroke—when compared to warfarin—but lack a means of reversalKey opportunities for practitioner involvement in the management of patients:Will remain: provision of a systematic means of oversightAppropriateness 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, CACPProfessorCampbell University College of Pharmacy and Health SciencesClinical Assistant Professor of Medicine, UNCClinical Pharmacy Specialist-AnticoagulationCone Health, Greensboro, NC