9/8/2014. None. Identify the under-recognized risk of cardioembolic stroke in untreated and undertreated. morbidity, mortality and cost burdens

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1 Optimizing Anticoagulation Therapy for Older Adults with Atrial Fibrillation: The New Oral Agents" None Disclosures Brad Hein, PharmD Associate Professor of Pharmacy The University of Cincinnati Winkle College of Pharmacy Learning Objectives Describe recent changes to clinical practice guidelines that reflect new best practices in the use of antithrombotic therapy for patients with AF. Identify the under-recognized risk of cardioembolic stroke in untreated and undertreated NVAF patients and the diseaseassociated morbidity, mortality and cost burdens Learning Objectives Compare the current guidance and new developments for reversing the anticoagulant effect of VKAs, direct thrombin inhibitors, or factor Xa inhibitors. Effectively assess the risk/benefit ratio of cardioembolic stroke prophylaxis for the NVAF Explain key differences in the pharmacologic profiles of the new oral anticoagulants that may impact selection of a specific agent for an individual older adult patient. Atrial Fibrillation Paroxysmal Persistent Permanent Introduction Self-Terminating Lasts > 7 Days Cardioversion Failed or Not Attempted Normal Sinus Rhythm Atrial Fibrillation Paroxysmal AF is as likely to cause stroke as persistent or permanent AF 1

2 Factors contributing to increased risk for stroke in NVAF1 FLORIDA ASCP 14 FLORIDA ASCP 14 CHADS 2 CHA 2 DS 2 VASc C= Congestive Heart Failure H= Hypertension A= Age > 75 D= Diabetes S= Stroke/TIA (2pts) CHADS 2 Score Risk Level 0 Low 1% 1 Lowmoderate Stroke Rate/Yr 1.5% 2 Moderate 2.5% 3 High 5% 4-6 Very high 7%-18% C= Congestive Heart Failure H= Hypertension A= Age 75 (2 pts) D= Diabetes S= Stroke/TIA (2 pts) V = Vascular disease A= S= Female CHA 2 DS 2 VASc Score Risk Level Stroke Rate/Yr 0 Low 0% 1 Low 1.3% 2 Moderate 2.2% 3 Moderate 3.2% 4 High 4% 5 High 6.7% 6-8 High % 9 Very high 15.2% Prevalence, percent Relationship BetweenAtrial Fibrillation and Age Epidemiology and Health Burden 75% of strokes occur in individuals > 65 years of age 9% of those aged 80 have AFIB 24% of strokes between the ages of are secondary to AFIB Total = $34 billion/year o Economic burden of ischemic stroke and hemorrhage are similar, about $26,000/year Age, years Go AS, et al. JAMA. 2001; 285:

3 Benefits of Anticoagulation in Atrial Fibrillation in the Elderly Benefits oanticoagulants are more effective at stroke prevention in patients 65 and over versus younger patients At least a 65% reduction in stroke risk Benefit increases with age Warfarin reduces risk of stroke by >50% compared to aspirin Risksof Anticoagulation in Atrial Fibrillation in the Elderly Risks o Elderly patients have a higher risk of bleeding This is true in warfarin as well as in novel anticoagulant studies Age 80 and greater, 13% risk of major bleeding on warfarin (5% risk for those less than 80 years) Mortality doubles after a fall for patients on oral anticoagulants versus those who are not overy small absolute risk (1 or 2 additional SDH per 10,000 falls) opatients with AFIB are 2.5 times more likely to fall vs those without Eligible AFIB Patients Receiving Anticoagulation Prophylaxis Suboptimal o Falls, dementia, short life expectancy, history of bleeding Warfarin use in patients with AFIB and no contraindications (ATRIA study) o years, 60% of eligible patients o >84 years, 35% of eligible patients In a study of > 10,000 US elderly long term care residents with a history of stroke and AFIB o 54% of patients received nothing o 27% warfarin o 14% aspirin Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Singer DE, et al. Circ Cardiovasc Qual Outcomes. 2009;2(4): Quilliam BJ, et al. Stroke. 2001; 32: Hylek EM, et al. NEHM 1996;335: Known Issues with Warfarin 1) Delayed onset/offset 2) Unpredictable dose response o Elderly intrinsically more sensitive to warfarin 3) Narrow therapeutic index 4) Drug-drug, drug-food interactions o Polypharmacy 5) Problematic monitoring 6) High bleeding rate 7) Slow reversibility Therapy Novel Oral Anticoagulants (NOAC) (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) 3

4 Warfarin Rivaroxaban Apixaban Characteristics of Novel Agents Rivaroxaban Apixaban Target Thrombin Xa Xa Prodrug Yes No No Time to peak (h) Half-life(h) CYP metabolism None 32% 15% Renal elimination 80% 35% 25% Antidote None None None Daily dosing 150mg BID 20mg QD 5mg BID Lip GYH, et al. JACC 2012;60: Clinical Trial Comparison Pivotal Trials: Baseline Characteristics RE-LY () ARISTOTLE (Apixaban) ROCKET-AF (Rivaroxaban) # Enrolled 18,113 18,201 14,264 Age (yrs) 72 ±9 70 [63-76] 73 [65-78] Female 36% 35% 40% CHADS 2 score 3 32% 30% 87% VKA naive 50% 43% 38% Paroxysmal AF 33% 15% 18% Prior stroke/tia 20% 19% 55% Diabetes 23% 25% 40% Prior CHF 32% 35% 62% Hypertension 79% 87% 91% Connolly SJ et al. N Engl J Med 2009; 361: Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med 2011; 365: Pivotal Trials: Key Results Pooled Efficacy Drug Dose (mg) RE-LY ROCKET-AF ARISTOTLE 110 bid 150 BID Stroke + SEE non-infer Superior Rivaroxaban 20 mg qd ITT cohort: non-infer. On Rx cohort: Superior Apixaban 5 mg bid Superior ICH Superior Superior Superior Superior Bleeding Lower similar similar Lower Mortality similar P = similar Superior: P = Ischemic stroke similar Lower similar similar Mean TTR 64% 55% 62% Stopped drug 21% 23% 23% WD consent 2.3% 8.7% 1.1% Stroke & SEE Ischemic & Unsp. Stroke Hemorrhagic Stroke 22% 13% 55% Connolly SJ et al. N Engl J Med 2009; 361: Patel MR et al. N Engl J Med 2011; 365: Granger CB et al. N Engl J Med 2011; 365: Favors NOACs Miller CS, et al. Am J Cardiol 2012;110(3): Favors Warfarin 24 4

5 Bleeding Major ICH GI Pooled Safety 51% 25%, NS Clinical Findings in Elderly Subpopulations o No change in efficacy for those > 75 years o Incidence of major bleeding similar to warfarin in those > 75 years Less intracranial bleeding but more extracranial bleeding Rivaroxaban o 20% more effective than warfarin for those > 75 years o Similar safety Apixaban o Trend toward improved efficacy and safety for those > 75 years Favors NOACs Miller CS, et al. Am J Cardiol 2012;110(3): Favors Warfarin Consensus Guidelines Recommendations CHEST 2012 Stroke Prevention in Non-Valvular Atrial Fibrillation CHADS 2 Score Risk Level Stroke Rate/Yr Treatment 0 Low 1% No therapy preferred otherwise ASA(75-325mg) or ASA-clopidogrel 1 Low-moderate 1.5% (1)over Warfarin (2) over 2 Moderate 2.5% ASA/clopidogrel (3) over ASA (4) 3 High 5% 4 Very high 7%-18% Chest 2012;141(2)(Suppl):e531S-e575S AHA/ACC/HRS Guidelines CHA2DS2-VASc Score Treatment 0 No therapy preferred 1 Nothing, aspirin or oral anticoagulant 2 Warfarin,apixaban, dabigatran or rivaroxaban all equally recommended Chest 2012;141(2)(Suppl):e531S-e575S FLORIDA ASCP 14 5

6 Issues for Pharmacists Caring for the Elderly Agent CrCl > 50mL/min Renal Function CrCl ml/min CrCl ml/min 150mg BID 150mg BID 75mg BID CI Rivaroxaban 20mg QD 15mg QD 15mg QD CI Apixaban 5mg BID N/A* N/A* CI CrCl< 15mL/min *Apixaban o2.5mg po BID if at least 2 of the following: age 80 years, 60kg or SCr 1.5mg/dL Capsule Side Effects All agents: bleeding : GI (dyspepsia, gastritis) 21% discontinuation rate in clinical trials Coat Pellet Tartaric Acid Core Seal Coating Drug Interactions o P glycoprotein inhibitors not likely clinically important Rivaroxaban/apixaban o Drugs that are combined CYP 3A4 and P-glycoprotein inhibitors may be an issue Ketoconazole, fluconazole Ritonavir Clarithromycin, erythromycin o Avoid rivaroxaban/decrease apixaban to 2.5mg BID o Drugs that are combined CYP 3A4 and P-glycoprotein inducers may be an issue Carbamazepine Phenytoin o Avoid both rivaroxaban and apixaban Black Box Warning (A)PREMATURE DISCONTINUATION OF [ANY ANTICOAGULANT] INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, increases the risk of thrombotic events. If anticoagulation with is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. LTC Pharmacist Monitoring Considerations CBC Stool guaiac (infrequently) Renal function S/S bleeding, stroke Pharmacokinetic and pharmacodynamic drug interactions o Modify bleeding risk Minimize fall risk o Education for close CNS monitoring after a fall 6

7 Other Considerations Keep dabigatran in original blister pack o No pillbox storage or repackaging Don t break, chew or open dabigatran Take rivaroxaban with food Can crush rivaroxaban and mix with applesauce or give through G-tube Monthly Cost Warfarin: $4/month, $10/3 months o ~$80/month including INR checks Pradaxa: $260/month Xarelto: $260/month Eliquis: $260/month Cost Effectiveness Recent data supports all 3 NOAC agents are more cost-effective than warfarin <$50,000 per quality-adjusted life year (QALY) is generally considered cost-effective o Rivaroxaban: $3190/QALY o : $11150/QALY o Apixaban: $15026/QALY Coverage Rivaroxaban is covered on 90% of Medicare Part D plans and 99% of commercial plans in Florida is covered on 95% of Medicare Part D plans and commercial plan in Florida Apixaban data not readily available but appears to be similar Deitelzweig, et al. J Med Econ. 2012;15: Pink, et al. Clin Pharmacol Ther. 2013;94: HAS-BLED Score Bleeding Considerations Risk Score for Predicting Bleeding in Anticoagulated Patients with Atrial Fibrillation Weight (points) Hypertension (> 160 mm Hg systolic) 1 Abnormal renal or hepatic function 1-2 Stroke 1 Bleeding history or anemia 1 Labile INR (TTR < 60%) 1 Elderly (age > 75 years) 1 Drugs (antiplatelet, NSAID) or alcohol 1-2 High risk (> 4%/year) > 4 Moderate risk (2-4%/year) 2-3 Low risk (< 2%/year) 0-1 Pisters R, et al. Chest 2010; 138: Lip GYH, et al. J Am Coll Cardiol 2010; 57:

8 Management of Bleeding - Warfarin Minor ohold/omit dose. Vitamin K in some cases. Major/life-threatening Kcentra (4 factor PCC) OR FFP + Vitamin K Management of Bleeding on Novel Agents Mild bleeding Delay next dose or discontinue treatment as appropriate FFP ineffective Vitamin K ineffective Patients with bleeding on NOAC therapy Moderate-Severe bleeding Mechanical compression Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal (dabigatran) Hemodialysis (dabigatran) Prothrombin Complex Concentrate 4 factor (rivaroxaban, apixaban) (Circulation 2011; 2011: 124: ) Life-threatening bleeding Mechanical compression Fluid replacement and hemodynamic support Consideration of rfviia or apcc Charcoal (dabigatran) Prothrombin Complex Concentrate - 4 factor (rivaroxaban, apixaban) (Circulation 2011; 2011: 124: ) Hankey GJ and Eikelboom JW. Circulation. 2011; 123: Known Issues with Novel Agents No established monitoring parameters No known therapeutic ranges Unknown risk of non-compliance Lack of a proven antidote Uncertain management of bleeding No head-to-head comparisons of new agents Not all populations studied adequately Long term safety? Warfarin Will Survive Established efficacy Low cost Long track record Anticoagulation clinics that maintain TTR > 60% Genetic testing on the horizon Point of care testing validated as safe and effective INR testing Q12 weeks if stable, though would not recommend this in LTC Selection Criteria Consider novel agents o Unstable INRs on warfarin (unrelated to non-compliance) o Difficulty or hardship with INR monitoring o CrCl > 30 ml/min o History of good medication compliance o High stroke risk or intracranial hemorrhage risk o Prescription coverage Consider/continue warfarin o Consistently therapeutic INRs o Valve replacement o Renal dysfunction CrCl < 15 ml/min o History of GI bleeding o Medication non-compliance (?) o No prescription coverage Which NOAC for Your Resident? All agents are likely equally effective Apixaban may be safer than others for those > 75 years, though this is not well established o Likely the case in those with a history of or risk for GI bleeding is most reliant on renal function for clearance is most likely to cause intolerable GI side effects Rivaroxaban was studied in the highest risk AFIB patients Coverage 8

9 Case RY is a 72 year old resident with CHF, CAD, HTN, GERD and AFIB. He was recently placed in the nursing home due to decline in ADLs and IADLs. He has been diagnosed with cognitive impairment and his spouse is unable to care for him due to her own health limitations. Medications Labs Lisinopril 10mg QD Na 133 BUN 23 Carvedilol 12.5mg BID K 4.2 SCr 1.2 Aspirin 325mg QD Cl 99 Glu 109 Atorvastatin 20mg QD CO2 22 Hgb 12 Omeprazole 20mg QD BP: 119/72 P: 77 EKG: AFIB Questions 1. Is this resident a candidate for anticoagulation? 2. What is this resident s bleeding risk? 3. Which anticoagulant would you choose? Why? What do guidelines recommend? 4. Regardless of choice, what are you going to monitor with your monthly chart reviews? Thank you for your attention! 9