Shifting the Focus: Anticoagulation in the Older Adult 7/24/2015. Faculty Disclosures

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1 Shifting the Focus: Anticoagulation in the Older Adult Faculty Disclosures Kelechi C. Ogbonna, PharmD, CGP Nothing to disclose Kelechi C. Ogbonna, PharmD, CGP Assistant Professor, Geriatrics Department of Pharmacotherapy & Outcomes Science Virginia Commonwealth University School of Pharmacy Learning Objectives Following this presentation, the participant will be able to: Learning Objectives Following this presentation, the participant will be able to: 1. Compare and contrast the pharmacology, pharmacokinetics, and other attributes of newly released target specific oral anticoagulants (TSOACs) to existing strategies for anticoagulation in atrial fibrillation and venous thromboembolism 2. Identify patient characteristics and clinical scenarios that may dissuade the use of TSOACs 1. When presented with a patient requiring anticoagulation, design a comprehensive and appropriate treatment plan 1. Compare and contrast the pharmacology, pharmacokinetics, and other attributes of newly released target specific oral anticoagulants (TSOACs) to existing strategies for anticoagulation in atrial fibrillation and venous thromboembolism 2. Identify patient characteristics and clinical scenarios that may dissuade the use of TSOACs 1. When presented with a patient requiring anticoagulation, design a comprehensive and appropriate treatment plan Audience Response If you were given the option to select antithrombotic therapy for an older adult, which of the following agents would YOU choose? A. dabigatran B. rivaroxaban C. apixaban D. edoxaban E. warfarin 1

2 Efficacy in Older Adults has been shown to reduce the risk of stroke by 60 70%, including among patients 75 years of age or older Caveat Efficacy depends on maintaining TTR at least 55 60% of the time It s Complicated use is complicated by numerous interactions with other medications, dietary supplements, and food leading to labile INRs Mant J et al. Lancet 2007;370: Connolly SJ et al. Circulation 2008;118: White HD et al. Arch Intern Med. 2007;167: Pharmacogenomic testing of CYP2C9 or VKORC1 alleles to predict warfarin responsiveness Target Vitamin K Metabolism Bioavailability (%) >95 Protein Binding (%) 99 Renal Excretion (%) 0 Interactions Food Vit. K rich foods Cytochrome P450 2C9, 3A4, 1A2 P glycoprotein none Major DDI Amiodarone, TMP SMX, others Pharmacokinetics Half life (h) Time to maximum plasma conc. (h) Variable Geriatric Focus A New Frontier? Efficacy vs. Reality Only 30 60% of NH residents with AF receive warfarin even in the absence of contraindications 20 30% of NH residents receive no antithrombotic at all To Bleed or Not to Bleed Providers tend to overestimate bleeding risk and underestimate the risk of stroke in older adults Abdel Latif AK et al. J Am Med Dir Assoc 2005;6: McCormick D et al. Arch Intern Med. 2001;161: Lau E et al. J Am Geriatr Soc 2004;52: June, 1954 Bill Haley's single "Rock Around the Clock released 1st TV soap opera "Secret Storm" premieres Eisenhower warns against US intervention in Vietnam October, 2010 Lil Wayne s Rebirth album released Season 5 of Keeping Up with the Kardashians begins Obama announces end to Operation Iraqi Freedom Timeline Atrial Fibrillation DVT & PE ximelagatran Intro: 2004* Class: 1 st oral direct thrombin inhibitor Study: EXTEND Removed in 2006 A. Fib dabigatran Recurrence Intro: 2010 Class: Oral direct thrombin inhibitor Study: RE LY rivaroxaban *NDA for ximelagatran submitted in 2004, however was never approved by FDA. This agent was approved in several other countries.. PPX Hip & Knee Intro: 2012 DVT & PE Focus: DVT & PE Class: Factor Xa inhibitor Study: EINSTEIN Program Intro: 2011 Class: Factor Xa inhibitor apixaban Study: Intro: 2012 ROCKET AF edoxaban Intro: 2015 Class: Factor Xa inhibitor Study: ENGAGE TIMI 48 Hokusai VTE studies Class: Factor Xa inhibitor Study: ARISTOTLE Characteristics Rivaroxaban Apixaban Edoxaban Oral Target Antithrombotic Agents Thrombin Factor Xa Factor Xa Factor Xa Metabolism Bioavailability (%) ~50 ~50 Protein Binding (%) ~ Renal Excretion (%) 80 ~ Interactions Food & absorption 2h delay Increased bioavailability None None Cytochrome P450 None Present Present Present P glycoprotein Present Present Present Present Major DDI Rifampin, Ritonavir, Ritonavir, Ritonavir, quinidine ketoconazole ketoconazole ketoconazole Pharmacokinetics Half life (h) Time to maximum plasma conc. (h)

3 Geriatric Focus Rate of Enrollment Median Age [years] >75 years of age Atrial Fibrillation RE LY 71 40% ROCKET AF 73 43% ARISTOTLE 70 31% AVERROES 70* 34% Acute VTE or Pulmonary Embolism EINSTEIN 56 13% EINSTEIN PE 58 18% Extended Treatment of VTE EINSTEIN Extension 58 16% AMPLIFY EXT 57 13% RE MEDY 54 9% Eur J Intern Med Jun;24(4): J Am Geriatr Soc. 2014;62: Finding The Perfect Balance Bleed To cause Stroke To prevent The Debate Miraculous Medications Lower stroke rates Lower bleeding rates Lower mortality rates Less hassle Middle Ground Dangerous Drugs Short half life Lack of monitoring Cannot titrate dose No antidote Drug cost Not enough dataa Learning objectives Following this presentation, the participant will be able to: 1. Compare and contrast the pharmacology, pharmacokinetics, and other attributes of newly released target specific oral anticoagulants (TSOACs) to existing strategies for anticoagulation in atrial fibrillation and venous thromboembolism 2. Identify patient characteristics and clinical scenarios that may dissuade the use of TSOACs 1. When presented with an patient requiring anticoagulation, design a comprehensive and appropriate treatment plan High Risk Patients Renal Impairment Study Intervention Control Design Exclusion RELY RE MEDY ROCKET AF EINSTEIN Investigators EINSTEIN PE Investigators 110mg or mg mg Rivaroxaban 20mg daily or 15mg daily Rivaroxaban 15mg for 3 wks, then 20mg daily Rivaroxaban 15mg for 3 wks, then 20mg daily Enoxaparin daily 5 doses, followed by therapeutic VKA Enoxaparin daily 5 doses, followed by therapeutic VKA NVAF DVT or PE NVAF symptomatic DVT symptomatic PE Morill et al. Ann Pharmacother Jun 23. [Epub ahead of print] 3

4 Study Intervention Control Design Exclusion ARISTOTLE AVERROES Lassen et al Hokusai VTE Investigators ENGAGE AF TIMI 48 Investigators Apixaban 5mg or 2.5mg Apixaban 5mg or 2.5mg Apixaban 2.5mg Edoxaban 60mg daily or 30mg daily Edoxaban 60mg daily or 30mg daily ASA mg daily Enoxaparin 40mg q12h NVAF Superiority NVAF DVT, PE, Mortality symptomatic VTE NVAF CrCL<25mL/min, SCr >2.5mg/dL CrCL<25mL/min, SCr >2.5mg/dL Significant renal impairment Rivaroxaban PK/PD study: AUC PK/PD study: In levels found to be 1.5, patients with CrCl of 3.2, and 6.3 fold higher ml/min,15mg in subjects with mild, dose achieved an AUC moderate and severe similar to a 20mg dose renal impairment in patients with normal Excretion time: renal 24 h function vs.96 h for patients with severe renal impairment Edoxaban Apixaban PK/PD study: In PK/PD study: Systemic patients with CrCl of exposure increases by ml/min a 43% 57%, 35%, and 11.6% increase in apixaban in patients with CrCl of exposure is expected 30, 50, and 80 ml/min, when compared to respectively, when patients without renal compared to patients impairment without renal impairment Morill et al. Ann Pharmacother Jun 23. [Epub ahead of print] Clin Pharmacokinet. 2010;49(4): Clin Pharmacokinet. 2011;50(10): Clin Pharmacol Ther. 2010;88(3): J Clin Pharmacol May 12. [Epub ahead of print] Several case reports have been sited describing negative outcomes with dabigatran in patients with renal impairment Nonvalvular A.Fib 50 ml/min ml/min ml/min <15 ml/min mg mg A 75mg Avoid Rivaroxaban 20mg daily 15mg daily 15mg daily Avoid Apixaban 5mg * 2.5mg * 2.5mg * Contraindicated Edoxaban 60mg daily 30mg daily 30mg daily Avoid A dose adjustment not recommended unless patient receiving dronedarone or ketoconazole *Apixaban should be dose reduced to 2.5mg for patient with SCr >1.5 mg/dl DVT/PE 50 ml/min ml/min ml/min <15 ml/min mg mg A Avoid Rivaroxaban 20mg daily 15mg daily Avoid Avoid Apixaban 5mg * 5mg * 5mg * Avoid Edoxaban 60mg daily 30mg daily 30mg daily Avoid Age(y) /Sex Weight (Kg) CrCl 66/F /M /F /F /F Dose (mg) Therapy duration (Months) Ann Pharmacother Jul Aug;46(7 8): Bleeding Event Plasma Conc. (ng/ml) 2 Upper GI bleed NR Retroperiton eal, GI, and pleural hemorrhage Rectal/Lower GI bleeding Recurrent epistaxis x 1 wk 280 NR Outcome D/C d Aggressive interventions D/C d Pericardiocentesis D/C d Nasal cauterization The two case reports below highlight the importance of renal dose adjustments and careful patient selection. Clinicians should also provide appropriate monitoring beyond the initial visit. As noted below adverse outcomes vary in their onset. Age(y) /Sex Weight (Kg) CrCl 66/F /M /F /F /F Dose (mg) Therapy duration (Months) Ann Pharmacother Jul Aug;46(7 8): Bleeding Event Plasma Conc. (ng/ml) 2 Upper GI bleed NR Retroperiton eal, GI, and pleural hemorrhage Rectal/Lower GI bleeding Recurrent epistaxis x 1 wk 280 NR Outcome D/C d Aggressive interventions D/C d Pericardiocentesis D/C d Nasal cauterization Age(y) /Sex Weight (Kg) CrCl 66/F /M /F /F /F Dose (mg) Therapy duration (Months) Ann Pharmacother Jul Aug;46(7 8): Bleeding Event Plasma Conc. (ng/ml) 2 Upper GI bleed NR Hemopericardium Hemopericardium Hemopericardium Retroperiton eal, GI, and pleural hemorrhage Rectal/Lower GI bleeding Recurrent epistaxis x 1 wk 280 NR Outcome D/C d Aggressive interventions D/C d Pericardiocentesis D/C d Nasal cauterization 4

5 If a patient has a CrCl < 15ml/min which TSOAC represents the best option? If a patient has a CrCl < 15ml/min which TSOAC represents the best option? a) a) b) Rivaroxaban c) Apixaban d) Edoxaban e) b) Rivaroxaban c) Apixaban d) Edoxaban e) None of the TSOACs are recommended for use in patients with a CrCl < 15mL/min High Risk Patients Clinical Application In the setting of renal impairment consider the following: 1 Ability to obtain baseline and routine serum creatinine levels 2 Degree of renal impairment 3 Reassess patients eligibility for warfarin therapy Frailty & Low Body Weight *Important* - Edoxaban: If CrCl >95mL/min DO NOT USE - risk of stroke observed in clinical trials Frailty & Body Weight - RE LY: Average weight = 82.5 kg or lbs Trough concentrations approx. 20% lower in patients >100 kg Limited data on patients < 50 kg - ROCKET AF: Average weight = 82.1 kg or lbs Cmax increased by approx. 24% in subjects weighing 50 kg, resulting in a small (15%) increase in prolongation of prothrombin time Patients 120kg unaffected - ARISTOTLE: Average weight = 82 kg or lbs AUC 20% higher in patient 50kg and 23% lower in patients 120kg - ENGAGE AF TIMI 48: Average weight = 84 kg or 185 lbs There is a limited amount of clinical data incorporating patients with body weight extremes. However, pharmacokinetic findings point to changes in drug concentrations in patients with extremely low or high body weights. Increase Exposure for patient 60kg [change in AUC not defined] Body Weight Clinical Application Patient characteristics and drug attributes should drive decision making. Body weight extremes may effect drug kinetics and should be taken into account when prescribing a TSOAC. The inability to titrate these medications and readily monitor a therapeutic index makes use in patients with body weight extremes challenging. Remember to dose adjust edoxaban and apixaban 1 Edoxaban & DVT/PE: Patient weight 60 kg 30 mg once daily 2 Apixaban: Patient weight 60 kg 2.5 mg twice daily Br J Clin Pharmacol Mar 14 Postgrad Med Jan;125(1):34 44 Drugs. 2014; 74(11):

6 High Risk Patients Bleeding risk is often the predominant factor that dictates anticoagulant therapy in older adults. Bleeding Expressed as RRR (%) 110mg RE LY ROCKET AF ARISTOTLE ENGAGE AF mg Rivaroxaban Apixaban Edoxaban Primary Outcome 10* 35* 21* 21* 21* Hemorrhagic Stroke 69* 74* 41* 49* 46* Ischemic/Unkno wn Stroke 11 24* 6 8 Major Bleed 20* * 20* Intracranial Hemorrhage** 70* 59* 33* 58* 53* GI Bleed 8 48* 46* 11 23* All death * 8* *P < Thrombosis. 2012;2012:1 **In modified intention to treat analysis, statistical significance was not reported Epub 2012 Sep 10 #Comparison using reported raw event frequencies, as annualized event rates were unavailable Expressed as RRR (%) 110mg The risk of intracranial hemorrhage appears to be much improved with the TSOACs, noted by the statistically significant RRR across trials. RE LY ROCKET AF ARISTOTLE ENGAGE AF mg Rivaroxaban Apixaban Edoxaban Primary Outcome 10* 35* 21* 21* 21* Hemorrhagic Stroke 69* 74* 41* 49* 46* Ischemic/Unkno wn Stroke 11 24* 6 8 Major Bleed 20* * 20* Intracranial Hemorrhage** 70* 59* 33* 58* 53* GI Bleed 8 48* 46* 11 23* All death * 8* *P < RRR = Relative Risk Reduction Thrombosis. 2012;2012: **In modified intention to treat analysis, statistical significance was not reported. #Comparison using reported raw event frequencies, as annualized event rates were unavailable Expressed as RRR (%) 110mg GI bleeding was increased when compared to warfarin with dabigatran mg and rivaroxaban. As discussed before this same trend has been observed in clinical practice RE LY ROCKET AF ARISTOTLE ENGAGE AF mg Rivaroxaban Apixaban Edoxaban Primary Outcome 10* 35* 21* 21* 21* Hemorrhagic Stroke 69* 74* 41* 49* 46* Ischemic/Unkno wn Stroke 11 24* 6 8 Major Bleed 20* * 20* Intracranial Hemorrhage** 70* 59* 33* 58* 53* GI Bleed 8 48* 46* 11 23* All death * 8* *P < RRR = Relative Risk Reduction Thrombosis. 2012;2012: **In modified intention to treat analysis, statistical significance was not reported. #Comparison using reported raw event frequencies, as annualized event rates were unavailable Apixaban is the only TSOAC that has been shown to reduce the risk of mortality. Expressed as RRR (%) 110mg RE LY ROCKET AF ARISTOTLE ENGAGE AF mg Rivaroxaban Apixaban Edoxaban Primary Outcome 10* 35* 21* 21* 21* Hemorrhagic Stroke 69* 74* 41* 49* 46* Ischemic/Unkno wn Stroke 11 24* 6 8 Major Bleed 20* * 20* Intracranial Hemorrhage** 70* 59* 33* 58* 53* GI Bleed 8 48* 46* 11 23* All death * 8 *P < RRR = Relative Risk Reduction Thrombosis. 2012;2012: **In modified intention to treat analysis, statistical significance was not reported. #Comparison using reported raw event frequencies, as annualized event rates were unavailable J Am Geriatr Soc. 2014;62:

7 Clinical Application - Bleeding with any anticoagulant will always be a concern. That being said, reviewing drug and patient characteristics may dissuade the use of one agent over another., rivaroxaban, and edoxaban associatied with GI bleeding. Caution in patients with history of GI bleeding or conditions that predispose them to GI bleeding (e.g. peptic ulcer disorder). Intracranial hemorrhage (ICH) is the most feared and lethal complication of oral anticoagulation. The reduction in ICH with the TSOACs is a major benefit. Providers will need to determine if this benefit outweighs added risk in other areas. TSOAC reduce the risk of when compared to warfarin. a) Intracranial hemorrhage b) Ischemic stroke c) Mortality d) All of the above Careful Consideration TSOAC reduce the risk of when compared to warfarin. a) Intracranial hemorrhage b) Ischemic stroke c) Mortality d) All of the above Conversion Conversion Considerations From/To From warfarin Agent Corresponding INR INR < 2 Rivaroxaban INR < 3 Apixaban INR < 2 Edoxaban INR 2.5 To warfarin Rivaroxaban, Apixaban, and Edoxaban: - Discontinue TSOAC and begin both a parenteral anticoagulant and warfarin at the time the next dose of TSOAC would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. Careful Consideration Adherence Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; Eliquis [package insert]. Princton, NJ: Bristol Myers Squibb Company; Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc., Inc;

8 Adherence Clinical Application - Adherence to TSOAC therapy remains a concern Although not ideal, warfarin s mechanism of action and dependence on the depletion of clotting factors provides a buffer period should a patient miss a dose TSOAC s relatively short half life leaves little room for error. Unlike warfarin, without routine monitoring identifying non adherent patients will require scrutiny of refill histories and direct patient questioning. It remains unknown how periods of non adherence with the TSOAC may affect outcomes. Providers should use discretion when prescribing TSOAC, particularly in the setting of patient adherence, and ensure patients are aware of the risks. Adherence Patient Counseling -, Apixaban, & Edoxaban If a dose is missed, take a dose as soon as possible on the same day. The dose should be skipped if it can not be taken at least 6 hours before the next scheduled dose The dose should not be doubled to make up for a missed dose. - Rivaroxaban If a dose is missed take a dose as soon as possible as follows: For patients receiving 15mg Take 2 tablets (30mg) at once and resume 15mg the following day For patients receiving 20mg, 15mg, or 10mg once daily Take the missed dose immediately Careful Consideration Drug Drug Interactions Rivaroxaban Apixaban Edoxaban Interactions Cytochrome P450 None Present Present Present P glycoprotein Present Present Present Present Moderate to strong PGP inhibitors have the potential to increase serum concentrations of dabigatran, rivaroxaban, and apixaban. Strong to Moderate PGP Inhibitors Verapamil Quinidine Amiodarone Ketoconazole Itraconazole Ritonavir Nelfinavir saquinavir Tacrolimus Cyclosporine Am J Hematol. 2011;86: , J Thromb Thrombolysis. 2010;29(1): , Ann Pharmacother. 2011; 45: Strong CYP3A4 inhibitors have the potential to increase serum concentrations of dabigatran, rivaroxaban, and apixaban. Evaluating TSOACs in conjunction with dual antiplatelet therapy Strong to Moderate CYP 3A4 Inhibitors Clarithromycin Ketoconazole Itraconazole Atazanavir Lopinavir Ritonavir Of the CYP enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the liver, but is used by more than 50% of medications on the market. Rivaroxaban Apixaban Edoxaban Interactions Cytochrome P450 None Present Present Present P glycoprotein Present Present Present Present Am J Hematol. 2011;86: , J Thromb Thrombolysis. 2010;29(1): , Ann Pharmacother. 2011; 45: Tsu LV et al. Ann Pharmacother 2013;47:

9 Synopsis: 5 randomized controlled trials have evaluated the safety and efficacy of using therapeutic doses of dabigatran, rivaroxaban, and apixaban in conjunction with dual antiplatelet therapy Results: Increases risk of major and clinically relevant nonmajor bleeding with triple therapy Tsu LV et al. Ann Pharmacother 2013;47: RE LY: Did not exclude dual antiplatelet therapy Only 40% of the population received aspirin therapy Only 5% of the population received clopidogrel therapy ROCKET AF: Excluded the use of aspirin >100mg Excluded the concomitant use of aspirin and clopidogrel ARISTOTLE: Excluded the use of aspirin >165mg Excluded the concomitant use of aspirin and clopidogrel ENGAGE AF: Did not exclude dual antiplatelet therapy Only 29% of the population received aspirin therapy Ann Pharmacother 2013;47: Clinical Application - The TSOACs are not devoid of drug drug interactions. Providers must once again weigh the benefits and risks of concomitant therapy PGP Inhibitors/Inducers: All of the TSOACs are effected by changes in the P glycoprotein efflux pump. and edoxaban are the most effected TSOACs and caution should be exercised when administration with a known inhibitor or inducer CYP3A4 Inhibitors/Inducers: As stated previously, CYP3A4 is the most prevalent CYP enzyme in the liver. Rivaroxaban, apixaban, and edoxaban s dependence on CYP3A4 for metabolism is a disadvantage. Providers should be mindful of this interaction when prescribing or managing these medications Clinical Application - Dual Antiplatelet Therapy Triple therapy leads to clinically relevant bleeding. In addition, the landmark trials that garnered FDA approval either excluded patients on ASA >165mg or had a very small proportion of patients on an antiplatelet drug. Providers should avoid triple therapy with the TSOAC until proven safe and effective Careful Consideration Monitoring Monitoring Monitoring - The TSOACs, in general, have predictable pharmacokinetics, pharmacodynamics, and metabolism. However, this predictability is sometimes lost when treating older adults as these parameters change with aging. At this point in time routine LABORATORY monitoring is NOT recommended and has not been correlated to clinical outcomes Coagulation test should be interpreted with caution Coagulation test results are mostly helpful as qualitative assessment only (e.g. determining if an anticoagulant is present or absent) 9

10 Monitoring Monitoring - There are scenarios where TSOAC measurement may be desirable, such as: Surgery or invasive procedures Hemorrhagic or thrombotic event Suspected drug failure Suspected overdose Extremes of age Assess adherence Extremes of weight Declining renal function Need for thrombolytics - Important: Standard anti factor Xa levels cannot be used to measure the effects of rivaroxaban and apixaban. An assay specific to each drug must be used Lab Test Rivaroxaban/apixaban/edoxaban PT/INR aptt TT (thrombin time) ECT (ecarin clotting time) Should not use (poor sensitivity) Normal aptt suggests minimal anticoagulant activity Normal TT excludes presence of significant levels Normal ECT excludes presence of significant levels Normal INR (+ normal aptt) suggests minimal anticoagulant activity Normal aptt (+ normal INR) suggests minimal anticoagulant activity Do not use Do not use Chromogenic assays Unavailable for anti IIa Normal anti Xa assay excludes presence of significant rivaroxaban or apixaban level dpt (diulute PT) Role still unclear (promising) Role still unclear (promising) Heptest PICT (prothrombinase induced clotting time) Am J Health Syst Pharm. 2012(69):e28 e39. Do not use Unknown Normal suggests minimal anticoagulant activity Normal suggests minimal anticoagulant activity Careful Consideration Reversal Which of the following agents can be used to reverse the effect of dabigatran, rivaroxaban, or apixaban? a) Vitamin K b) Prothrombin complex concentrate c) Factor VII d) None of the above Which of the following agents can be used to reverse the effect of dabigatran, rivaroxaban, or apixaban? a) Vitamin K b) Prothrombin complex concentrate c) Factor VII d) None of the above At this time, an antidote does not exists for the TSOACs Reversal Strategies Reversal - Unlike warfarin, there is no reversal agent for dabigatran, rivaroxaban, apixaban, or edoxaban. Management of life threatening bleeds remains empirical and anecdotal. 1 Hemodialysis HD removes ~62% of dabigatran in 2 hours Not an option for rivaroxaban or apixaban given protein binding 2 Activated Charcoal May be helpful if administered within 1 to 2 hours of acute overdose 3 Supportive care most likely option in clinical practice Early volume and RBS repletion Recombinant factor VII or PCC J Cardiovasc Electrophysiol.2011(22):

11 Reversal Strategies Emerging Therapies 1 Andexant Developed by Portola Pharmaceuticals, Inc. Recombinant molecule that is a direct reversal agent for factor Xa inhibitors Single IV bolus February 2015 Received orphan drug status from the FDA 2 Idarucizumab Developed by Boehringer Ingelheim Humanized antibody fragment that binds directly to dabigatran Two bolus infusions given <15 minutes apart March 2015 Received orphan drug status from the FDA 3 Aripazine Developed by PerosphereTM Pollack CV, et al. NEJM. 2015(June 22).[Epub ahead of print]. Ansell JE, et al. NEJM. 2015; 371(22): Lu G, et al. Nat Med. 2013; 19(4): Synthetic small molecule effective against ALL anticoagulants (except warfarin) Single IV bolus Summary Matching Patient Characteristics Mechanical valve or valvular A.Fib Rivaroxaban Apixaban Edoxaban Labile INRs CrCl ml/min CrCl <30 ml/min Child Pugh B or C Dual Antiplatelet GI Bleeding Swallowing Difficulty Shifting the Focus: Anticoagulation in the Elderly Case Discussion 11