9/14/2015. Disclosures. Learning Objectives. Clinical Case. What s in a name? NOAC Uses and Indications

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1 NON VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS (NOACS) AND THEIR IMPACT ON THE OBSERVATION UNIT! Carol Lynn Clark MD MBA FACEP Associate Director of Research Department of Emergency Medicine Beaumont Health System Professor, Oakland University William Beaumont School Of Medicine September 2015, Nashville, TN Disclosures No Promotional disclosures to report Hospital research support from Biocryst, Cardiorentis, Glaxo Smith Kline, Janssen, Nexbio,Novartis, Portola, Pfizer, Radiometer, ZS Pharmaceuticals Advisory boards/ Educational Consulting for Health Quality Foundation, Janssen, Pfizer, Portola, Society of Cardiovascular Patient Care Will be setting up a GOFUNDME Account just because...i need an expensive vacation!?? Learning Objectives Learn what NOACS are currently approved and for what indications Discuss the NOAC Indications for Atrial Fibrillation(AF) and Venous Thromboembolism (VTE) Learn some of the nuances of these medications Learn how Observation Medicine protocols using the NOACS in particular can prevent hospital admissions for Atrial Fibrillation and VTE Clinical Case 65 year old female history of hypertension presents to her doctor with newly found atrial fibrillation found on routine ECG, at yearly visit Exam normal, Blood pressure 135/60 on medication, all other vitals Within Normal Limits, no murmur, normal exam other than Irregularly Irregular Heart Beat Patient feels well, negative for cardiac/ pulmonary on review of systems Sent to ED for further evaluation so Does patient need to be hospitalized? Does patient need to be anticoagulated? What s in a name? NOACS Novel Oral Anticoagulants DOACS Direct Oral Anticoagulants TOACS Targeted Oral Anticoagulants TSOACS Target Specific Oral Anticoagulants And now back to NOACS Non Vitamin K Antagonist Oral Anticoagulants NOACs But no longer called Novel NOAC Uses and Indications Used to reduce the risk of stroke and systemic embolism in Non-Valvular Atrial Fibrillation (NVAF) Used to reduce the risk of VTE after hip/knee surgery Used for treatment of Venous Thromboembolism (VTE) Prevention of recurrent VTE In this lecture we are going to focus mainly on the first and third indication 1

2 General Advantages of NOACS Rapid onset of action No need for monitoring, no PT,INRs Anticoagulation effect very predictable Minimal food interaction Low potential for drug interactions Less intracranial bleeding than warfarin in all studies! Less fatal bleeding than warfarin! NOACS Onset of Action Apixaban (Eliquis): 1-3 hours Edoxaban (Savaysa): 1-2 hours Rivaroxaban (Xarelto): 2-4 hours Dabigatran (Pradaxa): 1-2 hours So all have very rapid onset of action NOAC Half Lives Apixaban: hours Edoxaban: 9-14 hours Rivaroxaban: 5-9 hours, longer in > 60 y.o hours Dabigatran: hours, increases to 27.2 hours with severe renal dysfunction Betrixaban:19 hours So this is one of the things that make these medications so attractive, oral agents with quick onset of action and relatively short half lives! So all have relatively short half lives General Disadvantages of NOACS Reversal agents just currently being developed Not approved in patients with valvular atrial fibrillation or severe mitral stenosis Some interactions with CYP3A4 and P-gp inhibitors and inducers Not approved in pregnancy, breastfeeding Caution in renal failure Not evaluated in severe liver failure Potent blood thinners, as with warfarin So still a concern in trauma, emergency surgery! Black box warning all NOACS Increased risk of stroke with discontinuation of drug when treating Atrial Fibrillation Risk of spinal/ epidural hematoma with lumbar puncture or spinal anesthesia None approved for Valvular Atrial Fibrillation patients 2

3 NOACS Factor Xa cleaves Prothombin to Thrombin Thrombin Activates Fibrinogen to Fibrin, Fibrin plus platelets equals clot formation Factor Xa inhibitors prevents breakdown of Prothrombin to Thrombin (Apixaban, Rivaroxaban, Edoxaban, Betrixaban) Dabigatran is a Direct Thrombin inhibitor Apixaban Edoxaban Rivaroxaban Betrixaban PRO THROM BIN X FACT OR XA FIBRINOGEN THROMBI N X X Enoxaparin X FIBRIN Dabigatra n + platelets = CLOT Coagulation Cascade Affected Current Available NOACS in the USA Apixaban (Eliquis), Factor Xa Inhibitor Edoxaban (Savaysa), Factor Xa Inhibitor Rivaroxaban (Xarelto), Factor Xa Inhibitor Dabigatran (Pradaxa), Direct Thrombin Inhibitor Others coming to market Research studies for NOAC FDA approval in NVAF Apixaban(Eliquis): ARISTOTLE, AVERROES Dabigatran(Pradaxa): RE-LY Edoxaban(Savaysa): ENGAGE-AF TIMI 48 Rivaroxiban (Xarelto): ROCKET-AF, X-Vert NOAC Studies for VTE FDA approval Apixaban, AMPLIFY Study Dabigatran, RE-COVER Study Edoxaban, Hokusai-VTE study NOACS currently approved indications: Apixaban: Stroke/Embolic Prevention in Nonvalvular AF (NVAF), Prevention VTE in hip/knee surgery, Prevention of Recurrent VTE Treatment of VTE, NO Bridging Rivaroxaban, EINSTEIN study 3

4 NOACS currently approved indications: Dabigatran: Stroke/Embolic Prevention in Nonvalvular AF(NVAF) Prevention VTE in hip/knee surgery Prevention of Recurrent VTE Treatment of VTE, After 5-10 days of parenteral/injection therapy NOACS currently approved indications: Edoxaban: Stroke/Embolic Prevention in Nonvalvular AF (NVAF), Prevention VTE in hip/knee surgery, In Japan not in US yet Prevention of Recurrent VTE Treatment of VTE, After 5-10 days of parenteral/injection therapy NOACS currently approved indications: Rivaroxaban: Stroke/Embolic Prevention in Nonvalvular AF, Prevention VTE in hip/knee surgery, Prevention of Recurrent VTE Treatment of VTE, NO bridging NOACS in Atrial Fibrillation All Four currently approved NOACs are approved for NVAF No Bridging is needed for treatment of Atrial Fibrillation in any of the four currently approved NOACS for Atrial Fibrillation! No Bridging for Rivaroxaban or Apixaban for VTE treatment Special Situations in Atrial Fibrillation Warfarin is still recommended in patients already on warfarin and stable In the previous NVAF studies warfarin in therapeutic window ranged from percent Caution with the NOACs in renal patients, may need lower dose or not at all Trials still being done in renal patients, cancer patients, obese patients and other special subgroups Heparin or Enoxaparin recommended in Pregnancy/Breast Feeding Anticoagulation in Atrial Fibrillation All patients with atrial fibrillation 48 hours in duration or for which the duration is unknown should be anticoagulated in the ED to lower stroke risk These patients should not have any type of cardioversion attempted unless fully anticoagulated and a transesophageal echo(tee) is obtained Rate control only and anticoagulation for these patients 4

5 Atrial Fibrillation 48 hours duration Recent Study from Finland Still may have cardiac stunning after any type of cardioversion This can occur after electrical, pharmacologic or spontaneous cardioversion ED literature has advocated early cardioversion in these patients (Ottawa Protocol) Recent large Finnish study? this timeline down to 12 hours (retrospective, didn t delineate exactly who) Timeline is probably a continuum 7 year review of patients with <48 hours duration, 30 day risks, retrospective 0.7% Thromboembolic Rate (TE) overall, 1.5 % patients This number variation due to repeat offenders Higher CHA 2 DS 2 VASc had higher stroke rate, Odds Ratios (OR), highly predictive Thromboembolic Events(TEs) in 30-days Duration of time increased ORs for stroke risks < 12 hours, hours, hours Risk at 30 days < 12 hours (0.3%) hours( 1.1%) hours (1.1%) CHA 2 DS 2 -VASc 0-1, 30 days, 10 TEs, 0.2 % cardio versions, 0.4 % patients Remember stroke risk on warfarin, 0.3% per 30 days Anticoagulation in NVAF In this Finnish study, we don t know which patients were which? Time is probably a continuum Be cautious and err on side of at least short term anticoagulation Long term anticoagulation determined by CHA 2 DS 2 -VASc score CHA 2 DS 2 -VASc Score Congestive Heart Failure 1 point Hypertension 1 point Age< 65 years 0 point Age years 1 point Age 75 years 2 points Diabetes 1 point Hx Stroke/ TIA/Thromboembolism 2 points Hx of Vascular Disease 1 point Female Sex 1 point Vascular Disease include Myocardial Infarction, aortic plaque, peripheral vascular disease 2 moderate-high risk should anticoagulate, score 1 consider, score 0 none CHA 2 DS 2 -VASc Score 9 stroke risk/ year 15.2% Score 8 stroke risk/ year 6.7 % Score 7 stroke risk/ year 9.6 % Score 6 stroke risk/ year 9.8 % Score 5 stroke risk/ year 6.7 % Score 4 stroke risk/ year 4.0 % Score 3 stroke risk/ year 3.2 % Score 2 stroke risk/ year 2.2 % Score 1 stroke risk/ year 1.3 % Score 0 stroke risk/ year 0.0 % Note score 8, not a mistake, had less patients in category Yip et al, European Guidelines Yip et al, European Guidelines 5

6 Anticoagulation Should definitely anticoagulate all longer duration atrial fibrillation patients ( 48 hours) Should definitely anticoagulate all CHA 2 DS 2 -VASc patients 2, and usually scores of 1 (female caveat) Should probably anticoagulate short term (until TEE) all others unless very recent onset and very low CHA 2 DS 2 - Vasc score (0) Should always work with your cardiology colleagues regarding therapy Falls and Anticoagulation Remember one study done on warfarin showed a patient would have to fall greater than 295 times per year to equal stroke risk NOACS show less intracranial bleeding than warfarin so this number would have to be even greater Airaksinen KE et al.,2013 Atrial Fibrillation ED/EDOU So now anticoagulation can be accomplished within a very short time so it can be easily started in the ED and EDOU setting! So rhythm control or rate control can be started in the ED and continued in the Emergency Department Observation Unit (EDOU) Anticoagulation can be started and continued in the ED/EDOU Unless other comorbidities would put the patient in the hospital (i.e. sepsis, MI etc.) the patient can be managed in the ED/EDOU and discharged home on anticoagulation and appropriate control therapy ED Observation Atrial Fibrillation Inclusion Criteria Stable vital signs Normal oxygenation Heart Rate consistently below for one hour after control No comorbidities requiring inpatient treatment No evidence of Congestive heart failure Normal initial troponins No evidence of Ischemia on ECG No evidence of active bleeding or bleeding disorder ED Observation Atrial Fibrillation Exclusion Criteria Unstable vital signs Acute comorbidities requiring hospitalization Positive initial troponins Ischemic ECG Changes Pulse oximeter less than 94 % Signs of Acute Congestive Heart Failure Active bleeding or bleeding disorder 6

7 EDOU Care of Atrial Fibrillation Oral Diltiazem (Cardizem) or Beta Blockers(Lopressor) Oral or injection anticoagulation Serial Troponins Monitoring 2 D ECHO Cardiology Electrophysiology Consult In consult with Cardiology can arrange for TEE So back to our Clinical Case This patient is a perfect patient to go to the EDOU, get started on anticoagulation with a NOAC be further evaluated, connected to cardiology and go home! Apixaban Dosing in NVAF Apixaban NVAF Dosing 5 mg Twice Daily 50% dose, 2.5 mg BID if 2 of the following: 80 yo, 60 kg Creatinine 1.5 mg/dl Avoid in moderate to severe liver failure (Child-Pugh B, C) Avoid with antiplatelets ESRD dialysis patients, 5mg BID (based on pharmacokinetics only) Metabolized primarily through CYP3A4 and P-gp Apixaban Drug interactions/ NVAF 2.5 mg BID (decrease 50%): if given with strong dual CYP3A4 and P-gp inhibitors (ketoconazole, clarithromycin, ritonavir) Avoid with Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors(SNRIs) - increased bleeding risk- avoid Avoid use in strong dual inducers of CYP3A4 and P-gp (rifampin, carbamazepine phenytoin, ST Johns Wart) decreases apixaban availability Dabigatran dosing in NVAF 150 mg BID for Creatinine Clearance (CrCl) > 30 ml/min 75 mg BID For CrCl ml/min Not recommended CrCl < 15mL/min or on dialysis Consider lower dosing in > 75 y.o. low BMI Important to not break or chew capsule Common side effect dyspepsia 7

8 Dabigatran Dosing NVAF Edoxaban Dosing for NVAF Evaluate drug-drug interactions: P-gP inhibitors (Ketoconazole, Dronedarone) + CrCl ml/min lower dose to 75 mg BID Avoid if P-gp and CrCl <30 ml/min Avoid if P-gp inducers(rifampin), NSAIDS, antiplatelets Liver Impairment: Wide variability Child-Pugh B? 60 mg daily in Normal renal function CrCl > 95 Do not use, increased stroke risk, Black box warning Only one where you have to worry the renal function is too good! Edoxaban Dosing For NVAF CrCl ml/min, 30 mg daily No dose reduction for P-gp inhibitors Avoid in Liver impairment (Child-Pugh B,C) Avoid with antiplatelets other anticoagulants Rivaroxaban Dosing in NVAF CrCl > 50 ml/min,20 mg daily with food CrCl mi/min, 15 mg daily Avoid CrCl < 15 ml/min Studies underway in ESRD and dialysis patients Metabolized primarily through CYP3A4/3A5 system Avoid with ketoconazole (CYP3A4/3A5 Inhibitor) Avoid with rifampin (CYP3A4/3A5 Inducer) Rivaroxaban Dosing NVAF Avoid in moderate to severe liver failure (Child-Pugh B, C) Avoid with antiplatelets Avoid with other anticoagulants Dabigatran Rivaroxaban Apixaban Edoxaban Ketoconazoles Avoid Avoid Avoid Avoid Clarithromycin No adjustment Precaution* Avoid Avoid Erythromycin Precaution* Precaution* *Precaution* Avoid Fluconazole Avoid Precaution* Avoid Avoid Rifampin Avoid Avoid Avoid Safe NSAIDs/ASA Caution Caution Caution Caution Clopidogrel/anti Caution platelet agents Caution Caution Caution Diltiazem UNK Caution Caution UNK Verapamil Avoid Caution Caution Avoid Heparin/anticoa gulants/ticagrel Avoid Avoid Avoid Avoid or Medscape, Mookadam M et al 8

9 Reversal Agents Studies underway Being fast tracked by FDA Dabigatran: Idarucizumab Factor Xa Inhibitors: Andexanet Alpha All: Arapazine, Phase 1 All: KCentra, being studied Currently reversal until previous trials finished 4 Factor PCCs (Kcentra, FEIBA) Charcoal if dose within 2 hours, repeat dose in 6 hours Dialysis for Dabigatran (only) Best Reversal Agent is time and supportive care VTE THERAPY WITH NOACS All four current NOACS now approved for VTE treatment CAVEAT: Only Apixaban and Rivaroxiban are approved DeNovo Dabigatran and Edoxaban are approved after 5-10 days of injectable, or intravenous therapy Make ED and discharge or ED to EDOU and discharge an attractive proposition of treatment of VTE Apixaban Dosing VTE 10 mg BID times 7 days, then 5 mg BID No dosing reduction suggested for decrease CrCl higher than 25 ml/min CrCl < 25 ml/min were excluded, no dosing suggestions Avoid in moderate to severe liver failure (Child-Pugh B, C) Avoid in pregnancy/ breastfeeding Apixaban Dosing VTE Based on pharmacokinetic data (only) has been approved for dialysis patients on stable dialysis May start as DeNovo therapy No bridging 9

10 Apixaban Drug interactions Decrease dose 50% if given with strong dual CYP3A4 and P-gP inhibitors (ketoconazole, clarithromycin, ritonavir) Avoid with Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors(SNRIs) - increased bleeding risk- avoid Avoid use in strong dual inducers of CYP3A4 and P-gp (rifampin, carbamazepine phenytoin, ST Johns Wart) decreases apixaban Rivaroxaban Dosing VTE 15 mg Bid for 21 days then 20 mg daily for rest of therapy Starter Pack available Avoid use in CrCl < 30 ml/min May start DeNovo therapy No bridging necessary Rivaroxiban Dosing VTE Avoid in liver failure (Child-Pugh B,C) Avoid in Combined P-gp and strong CYP3A4 Inhibitors or Inducers Avoid pregnancy or breast feeding Dabigatran VTE Dosing 150 mg twice daily, CrCl > 30 ml/min Dosing adjustments, CrCl < 30 ml/min or on dialysis not provided Dosing is recommended after 5-10 days of parenteral/injectable treatment Start dose immediately on discontinuation of parenteral or two hours before next scheduled dose of injectable Edoxaban Dosing VTE All dosing after 5-10 days of parenteral or injectable therapy > 60 kg 60 mg daily < 60 kg 30 mg daily P-gp inhibitors, 30 mg daily (ketoconazole) Avoid with P-gp Inducers (rifampin) CrCl ml/min, 30mg daily CrCl ml/min, 60 mg daily CrCl > 95 Do not use, increased stroke risk So VTE Practicality in ED/EDOU Dr. K Sawyer to cover thoroughly Rivaroxiban or Apixaban and out Know idiosyncrasies of chosen medication Arrange close follow-up Coupons and Starter packs are available Further Studies on specifically Pulmonary Embolus ongoing Start dose immediately on discontinuation of parenteral or at next scheduled dose of injectable 10

11 THE END Thank you for having me! Any Questions? 11