Learning Objectives Novel Oral Anticoagulants in the Geriatric Patient: To Bleed or Not to Bleed

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1 Learning Objectives Novel Oral Anticoagulants in the Geriatric Patient: To Bleed or Not to Bleed Jonathan D. Edwards, Pharm.D., BCPS, CGP Huntsville Hospital Department of Pharmacy Huntsville, Alabama n Discuss the characteristics of the ideal anticoagulant n Review the strengths and weaknesses of warfarin therapy n Review the mechanisms of action, indications, and dosing of the novel oral anticoagulants n Analyze available literature regarding bleeding risks of the novel oral anticoagulants in the elderly population n Discuss monitoring and reversal of the novel oral anticoagulants n Express key points when utilizing the novel oral anticoagulants in the elderly 2 Conflicts of Interest n Nothing to disclose Aging Trends Older Population by Age: Percent 60+, Percent 65+, and % 25% 20% 15% 10% 5% % 60+ % 65+ % 85+ 0% Reference: 1 4 The Geriatric Conundrum Safety n Clotting Risk of thromboembolism Risk of CV disease Risk of atrial fibrillation n Bleeding Risk of major bleed Risk of renal impairment n n n Warfarin Primary reason for ADE in the ED in older adults 2011 FDA Medwatch Report 1. Dabigatran 2. Warfarin Beers 2012 criteria Dabigatran 5 References:

2 The Ideal Anticoagulant Old Habits Die Hard - Warfarin n Oral n Once daily dosing n Reversibility n Low cost n Quick onset n Predictable effect n No monitoring required But available if needed n Limited or no drug interactions n Wide therapeutic index n Pros Effective Monitoring available Frequent follow-up appointments Long half life Not renally cleared Antidote Economical Familiarity n Cons Frequent monitoring Narrow therapeutic index Unpredictable response Fluctuating doses Slow onset/offset Many drug interactions Diet interactions Reference: Does New = Better? Mechanism of Action n Pros Fixed dose More predictable & stable response Rapid onset Broader therapeutic window No monitoring No diet interactions Fewer drug interactions n Cons Multiple daily doses Rapid offset Could become an issue with compliance in the elderly No monitoring available if needed Follow-up less often No reversal agent Much more expensive n Dabigatran Direct, reversible thrombin inhibitor, inhibiting both free and clotbound thrombin n Rivaroxaban & Apixaban Direct, reversible factor Xa inhibitor, inhibiting both free Xa and Xa within the prothrombinase complex Reference: 7 9 Reference: 8 10 Indications/Dosing Question n Non-valvular A-fib: 150mg bid w/ or w/out Reduce to 75mg bid if CrCl 15-30mL/min Consider reduction to 75mg bid when CrCl ml/min AND on dronedarone or systemic ketoconazole CrCl ml/min AND P-gp inhibitor Avoid use No recommendations for CrCl < 15mL/min or HD n Non-valvular A-fib: 20mg daily with. Reduce to 15mg daily if CrCl 15-50mL/min. Avoid use if CrCl < 15ml/min n Orthopedic prophylaxis 10mg daily w/ or w/out Avoid use if CrCl < 30mL/min n DVT/PE treatment: 15mg bid x 21 days, then 20mg daily with Avoid use if CrCl < 30mL/min n Non-valvular A-fib: 5mg bid w/ or w/out Reduce to 2.5mg bid if pt has 2 of the following: Age >/= 80 Wt </= 60kg SCr >/= 1.5mg/dL --OR If on strong 3A4 inhibitor + P glycoprotein inhibitor *If both criteria met, avoid use* Reference: 9 11 T.J. is an 80 year old female with non-valvular atrial fibrillation. You receive an order to initiate apixaban 5 mg po bid. Her current serum creatinine is 1.2. She is on no interacting meds and weighs 50 kg. What is the best course of action? a. Fill the medication as ordered b. Calculate the patient s creatinine clearance c. Refuse to fill the mediation due to the black box warning d. Recommend to reduce the dose to 2.5mg po bid 12 2

3 Question Efficacy Data A physician wants to save your institution money and increase patient satisfaction by bridging all his atrial fibrillation patients with a CHADS2 > 1 to warfarin using one of the novel oral anticoagulants rather than enoxaparin. Your response is: a. That is a great idea b. There is currently no data to support this practice c. It s ok as long as the INR is drawn as a trough level d. Bridging is not necessary for these patients Ischemic stroke Hemorrhagic stroke Major bleeding Intracranial bleeding dabigatran vs. VKA 0.92 vs (p=0.03) 0.10 vs vs (p=0.31) 0.30 vs ROCKET-AF rivaroxaban vs. VKA 1.34 vs (p=0.581) 0.26 vs (p=0.024) 3.6 vs. 3.4 (p=0.58) 0.5 vs. 0.7 (p=0.02) apixaban vs. VKA 0.97 vs (p=0.42) 0.24 vs vs vs GI bleeding 1.51 vs vs vs (p=0.37) *VKA = Vitamin K Antagonist 13 References: Older Population Representation (dabigatran) ROCKET-AF (rivaroxaban) (apixaban) Dabigatran (%/year) Warfarin (%/ year) RR (95% CI) P-value Mean age yrs. of age 40% 38% 31% 80 yrs 17% -- 13% Major Bleed ECH ( ) 1.18 ( ) < ( ) 1.39 ( ) < yrs 0.4% Mean weight (kg) CrCl > 50 ml/min 82% 79% 83% GI Bleed Non-GI ECH ( ) 1.79 ( ) ( ) 1.16 ( ) <0.001 References: Reference: n Bleeding risk with dabigatran increased as Age increased Creatinine Clearance decreased Concomitant aspirin use n Age could be a more dominate risk factor for bleeding than renal function in the elderly Reference: Major Bleed ICH Non-Major Bleed Fatal/Disabling Stroke ROCKET-AF Rivaroxaban (Event/100 pt yrs) Warfarin (Event/100 pt yrs) HR (95% CI) P-value 0.96 ( ) 1.11 ( ) ( ) 0.80 ( ) ( ) 1.15 ( ) ( ) 0.76 ( ) 0.72 Reference:

4 ROCKET-AF n Predictors for increased bleeding risk Renal impairment Increased diastolic blood pressure Decreased albumin levels Decreased platelet count Prior stroke P2Y12 inhibitor use Reference: Stroke/S. Embolism < 65 years 65 - Mortality < 65 years 65 - Major Bleed 65 - ICH 65 - Apixaban (%/year) Warfarin (%/year) HR (95% CI) P-value 1.16 ( ) 0.72 ( ) 0.71 ( ) ( ) 0.77 ( ) 0.91 ( ) ( ) 0.71 ( ) 0.64 ( ) ( ) 0.35 ( ) 0.34 ( ) 0.20 Reference: n More Effective Preventing stroke Reducing mortality n Less Bleeding Major bleeding Total bleeding Intracranial hemorrhage Question Which of the following statements is correct regarding bleeding rates as age increases? a. Major bleeding rates are lower with dabigatran vs. warfarin b. Major bleeding rates are lower with rivaroxaban vs. warfarin c. Intracranial hemorrhage rates are lower with the novel oral anticoagulants vs. warfarin d. Gastrointestinal bleeding rates are lower with dabigatran vs. warfarin Reference: Agent Selection in the Older Population n As age increases Embolism rates increase Major bleeding rates increase Dabigatran and rivaroxaban have higher rates compared to warfarin Apixaban has similar rates compared to warfarin Gastrointestinal bleeding rates increase Dabigatran Dyspepsia - tartaric acid Intracranial hemorrhage rates decrease Novel oral anticoagulants Kinetics t 1/2 = 12-17hrs t 1/2 = 5-13hrs t 1/2 = 6-12hrs n Pro-drug 5% bioavailability n Protein binding 35% n 80% renally eliminated n Bioavailability 50% if drug deposited directly into small intestine n Protein binding 93% n 36% renally eliminated n 50% bioavailability does not affect n Protein binding 87% n 27% renally eliminated 23 Reference:

5 Question J.W. is an 82 year old female with non-valvular atrial fibrillation. Her physician would like to place J.W. on dabigatran. Which of the following pharmacokinetic factors is the most important to evaluate in this patient? Monitoring PT Little effect aptt 2.3 x baseline 1.8 x baseline 1.2 x baseline ECT 5.2 x baseline NA NA a. Absorption b. Distribution c. Metabolism d. Excretion TT 27 x baseline NA NA Anti-Xa NA 22% w/5 mg 68% w/30 mg INR 1.8 x baseline NR 1.5 x baseline NR 25 References: Reversal Additional Considerations in Older Patients Oral activated charcoal In vitro No Data No Data Hemodialysis Humans No Data No Data Fresh frozen plasma Activated factor VIIa Mice No Data No Data Rat Rat & Baboon No Data 3-factor PCC No Data No Data No Data 4-factor PCC Human & Rat Human No Data n Living situation Do they have a way to get to the coumadin clinic? n Functional status Issues with opening medication bottles Dabigatran packaging issues n Cognitive impairment BID dosing Dose adjustments n Frailty Increased falling risk Less likely to leave home n Adherence Quick offset medications Complex dosing regimens n Cost Can the patient afford the medication? References: References: Formulation/Cost Increased Risk of ADEs Dabigatran Capsule n Do not open, crush, or chew Opening capsule increases bioavailability by 75% n Approx $3.25 per capsule Rivaroxaban Tablet n Can crush the 15 and 20mg Do not deliver into the proximal small intestine n Approx $5.00 per tab Apixaban Tablet n No recommendation on crushing n Approx $3.80 per tab n Extreme old age n Use of high risk medications n Use of narrow-therapeutic medications n Presence of 6 or more illnesses n History of prior adverse drug reaction n Low body weight n Decrease renal function n Polypharmacy References: Reference:

6 Safe Use of Anticoagulants in the Elderly Patient Education in Older Patients n Provider Education When to use each agent Appropriate dosing Appropriate transitions n Patient Selection Novel oral anticoagulants Warfarin n Agent Selection criteria Algorithm Check list n Systems in Place Transitions Monitoring Inappropriate warfarin monitoring is associated with worse anticoagulation control n Renal function Age-related decline n Drug interactions Polypharmacy n Patient Education Evaluate comprehension n Generally poor knowledge about warfarin therapy 81% had no knowledge about its benefits 45-70% had insufficient knowledge about potential risks 64% unaware that medications & diet can affect INR n Improved patient knowledge regarding warfarin Associated with improved adherence and outcomes Good understanding 85% well controlled Poor understanding 63% well controlled Higher bleeding rates n Ability to recall knowledge declines with age Written information Reference: References: Patient Education Key Points Selecting the appropriate candidate n What is it? n Why am I taking it? n Administration What to do if missed dose Dabigatran Do not open capsules Keep in original bottle Rivaroxaban Take with n Adverse drug event potential n Adherence Don t stop taking the medication Notify primary care physician of any planned procedures Pill boxes (NOT dabigatran) n Drug / Drug Interactions OTCs n Drug / Food Interactions n Follow up / Monitoring n Do they have an approved indication? n Do they have unstable INRs? Make sure this is not compliance related n Do they have road blocks to INR monitoring? n Do they have adequate renal function? n Do they have compliance issues? n Will the new agent cause any major drug interactions? 33 Reference: Which agent to choose? Conclusion n What s the indication? n Will compliance be an issue? n Will the medication need to be crushed? n Are drug interactions present? n Can the patient afford the medication? n History of bleeding problems? n History of gastrointestinal problems? n Patient selection Living situation Functional status Cognitive impairment Frailty Adherence Cost n Agent selection Bleeding risk Renal function Weight Gastrointestinal effects Drug interactions Adherence n Education and follow up are required for safe use of these medications

7 Case JE, an 82 year old male with non-valvular atrial fibrillation, is a resident of a local nursing home. His physician would like to change his current anticoagulation therapy from warfarin to one of the novel oral anticoagulants due to his fluctuating INR values. JE has been taking warfarin for approximately 2 years during which time his INR fluctuates drastically from 1.5 to 4.5. His past medical history includes hypertension, diabetes, gastrointestinal bleed, J-tube placement, and osteoarthritis. His calculated creatinine clearance is 45 ml/min and weighs 55 kg. He is currently not taking any interacting medications. Question Which of the following is the best option for changing his anticoagulation therapy? a. Initiate dabigatran 150 mg po BID b. Initiate dabigatran 75 mg po BID c. Initiate apixaban 2.5 mg po BID d. Initiate rivaroxaban 15 mg po daily References References 1. Projections for 2010 through 2050 are from: Table 12. 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Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. Haematologica. 2008;93(supp 1):abstr Marlu R, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108: Kaatz S, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87:S141-S Hylek EM. Translating the Results of Randomized Trials into Clinical Practice: The Challenge of Warfarin Candidacy Among Hospitalized Elderly Patients With Atrial Fibrillation. Stroke. 2006;37: Sudlow M, et al. Prevalence of atrial fibrillation and eligibility for anticoagulants in the community. Lancet. 1998;352(9135): Man-Son-Hing M, et al. Choosing Antithrombotic Therapy for Elderly Patients With Atrial Fibrillation Who Are at Risk for Falls. Arch Intern Med. 1999;159: Image of a dabigatran capsule. Photograph. n.d. Web. 03 Dec Image of a rivaroxaban tablet. Photograph. n.d. Web. 03 Dec Image of a apixaban tablet. Photograph. n.d. Web. 03 Dec Fouts MM, et al. Identification of Elderly Nursing Facility Residents at High Risk for Drug-Related Problems. Consult Pharm. 1997;12: Rose AJ, et al. Gaps in Monitoring During Oral Anticoagulation: Insights Into Care Transitions, Monitoring Barriers, and Medication Nonadherence. CHEST. 2013;143(3): Ansell JE. Empowering Patients to Monitor and Manage Oral Anticoagulation Therapy. JAMA. 1999;281(2): Kagansky N, et al. Safety of Anticoagulation Therapy in Well-informed Older Patients. Arch Intern Med. 2004;164: Roddie A, et al. Clin Lab Haematol. 1988;10: Nasser S, et al. Challenges of Older Patients Knowledge About Warfarin Therapy. J Prim Care & Comm Health. 2012;3(1): Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematology Am Soc Hematol Educ Program. 2012;2012: Novel Oral Anticoagulants in the Geriatric Patient: To Bleed or Not to Bleed Jonathan D. Edwards, Pharm.D., BCPS, CGP Jonathan.Edwards@hhsys.org 7