Peter Thomson. Clinical Resource Pharmacist, WRHA Medicine Program Clinical Asst Professor, Faculty of Pharmacy, University of Manitoba

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1 Rivaroxaban Expanding Beyond Orthopedics Peter Thomson Clinical Resource Pharmacist, WRHA Medicine Program Clinical Asst Professor, Faculty of Pharmacy, University of Manitoba Objectives Compare key pharmacologic factors with the new oral anticoagulants Discuss recent regulatory changes with the new oral agents and their potential impact on practice Identify key factors to assess with patients regarding the use of rivaroxaban in AF prophylaxis and VTE treatment Review resources for information on the dynamically changing are of oral anticoagulation 1

2 Disclosures In the past 2 yrs I have either been sponsored to speak at education event, introduced speakers or attended advisory meeting provided advice to the following pharmaceutical companies: AstraZeneca Canada Bayer Canada Boehringer Ingelheim Canada Paladin Labs Inc. Pfizer Canada Sanofi Aventis Canada New Oral Agents Are all small molecules targeted at specific sites in the coagulation system Primary target is either Thrombin; i.e. activated factor II (F IIa) Activated factor X (F Xa) 2

3 New Oral Anticoagulants Direct Thrombin Inhibitors: Dabigatran (Pradax, Pradaxa in other countries) Direct F Xa Inhibitors: Rivaroxaban (Xarelto ) Apixaban (Eliquis ) New Oral Anticoagulants Benefits of new oral agents include: Predictable pharmacokinetics with low interpatient variability: LMW Heparin like Much lower rate of drug interactions than warfarin Much faster onset of action than warfarin - few hrs versus days Generally, much shorter duration of action than warfarin 3

4 New Oral Anticoagulants Benefits of new oral agents also include a flatter dose response curve than warfarin. Should translate into a lower risk of major bleeding with overshooting the therapeutic range With warfarin increased bleeding incidence becomes exponential once INR > 4.5 Palareti G Thromb Haemost 2009 New Orals: Indications Approved for use in Canada Hip and knee orthopedic surgery prophylaxis (all 3). WRHA lists rivaroxaban for this Atrial fibrillation (dabigatran, rivaroxaban). Only dabigartran approved on WRHA formulary right now Deep Vein Thrombosis treatment (rivaroxaban) 4

5 Rivaroxaban in Orthopedics RECORD 1 4 (~ 2,000 3,000 pts) total hip or knee arthroplasty. All given Rivaroxaban 10 mg starting 6 8 hr post op vs enoxaparin Surg Enoxaparin Composite Endpt (%) Major VT (%) Riva Enox Signf Riva Enox Signf THA 40 mg/d start preop (35 d) THA 40 mg/d start preop (14 vs d) TKA 40 mg/d 12 hr preop (14 d) TKA 30 mg q12h start hr postop (11-12d) < < ns 5

6 Rivaroxaban in Orthopedics Surg Enoxaparin Major (%) Clinically Relevant Non- Major Bleed (%) Minor (%) Riva Enox Riva Enox Riva Enox 1 THA 40 mg/d start preop 2 THA 40 mg/d start preop 3 TKA 40 mg/d 12 hr preop 4 TKA 30 mg q12h start hr postop , Rivavoxaban Indication & Dose Prevention of VTE in elective total hip or knee replacement (THA, TKA) 10 mg daily starting 6 10 hr post op for 14 d (knees), 35 d (hips) 6

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8 Case TT is a 70 yr old female with hypertension and peripheral vascular disease Just discharged from the HSC with Rx: Levofloxacin 500 mg daily X 4 days Metoprolol 50 mg bid Warfarin 5 mg take as directed Meds on profile: ASA 81 mg once daily Ramipril 5 mg bid Common for people to develop following any stress Many times on medicine wards people come in with something else and leave with A Fib People usually forget what they were told in the hospital about AF because so much going on, being discussed with them and family 8

9 Atrial Fibrillation The most common arrhythmia of the heart that is sustained Risk of stroke is the same for either persistent or paroxysmal Very common, roughly 25% of those over 40 yrs will have it in their life You JJ Chest 2012; 141 Albers GW Chest 2008; 133 Atrial Fibrillation Strong predictor of stroke, increases risk 5 fold A Fib strokes are more devastating than most other sources of stroke 50,000 new strokes each year in Canada average system cost for 1 st 6 months $50,000 Total Cost $ 2.5 billion CAN per year Cost per family up to $200,000 per yr for most severely affected Can Stroke Network

10 Atrial Fibrillation Atrial Fibrillation Many people are asymptomatic no heart skipped a beat or racing 10

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12 Atrial Fibrillation Major treatment approaches are either to restore normal sinus rhythm or to leave in atrial fibrillation and control ventricular rate In both, anticoagulation is essential Rhythm Control Does Not Replace Anticoagulation No evidence that AF reduction via antiarrhythmic therapy reduces the risk of stroke/thromboembolism Patients must continue on appropriate anticoagulation according to their individual embolic risk (CHADS 2 score) 12

13 Predictive Index for Stroke Risk Factor CHADS 2 Congestive Heart Failure Score Hypertension 1 Age 75 1 Diabetes Mellitus 1 Stroke/TIA/ Thromboembolism Maximum Score Patients (n = 1733) Adjusted Stroke Rate (%/yr) CHADS 2 Score CHA 2 DS 2 -VASc Risk Factor Score Congestive Heart Failure 1 Hypertension 1 Age 75 2 Diabetes Mellitus 1 Stroke/TIA/Thrombo-embolism 2 Vascular Disease 1 Age Female 1 Maximum Score 9 13

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16 Overview of Thromboembolic Management Assess Thromboembolic Risk (CHADS 2 ) and Bleeding Risk (HAS-BLED) CHADS 2 = 0 CHADS 2 = 1 CHADS 2 2 aspirin OAC* OAC No antithrombotic may be appropriate in selected young patients with no stroke risk factors *Aspirin is a reasonable alternative in some as indicated by risk/benefit Dabigatran is preferred OAC over warfarin in most patients. Can Cardiovasc Soc: 2012 A Fib Update New guidelines expected in next couple of months Anticipate changes include: Predicting Risk CHADS2 with score of 0 apply the CHADSVASC factors Incorporate other new oral anticoagulants: rivaroxaban and apixaban Rewording of new oral anticoagulants in coronary artery disease ACC Rockies

17 Atrial Fibrillation Trials Re-LY (n=18,113) ROCKET-AF (n = 14,266) ARISTOTLE (n = 18,206) Drug Dabigatran Rivaroxaban Apixaban Dose 150, 110 mg BID 20 mg OD 5 mg BID Entry Criteria CHADS > 1 (avg CHADS ~ 2) CHADS > 2 (avg CHADS > 3) CHADS > 1 (avg CHADS ~ 2) Follow Up qs > 2 yrs qs > 2 yrs qs > 2 yrs Comment Exclude Clcr < mg OD Clcr Exclude Clcr < mg bid if > 80yr, Wt < 60 kg. Scr > 133 Exclude Scr > 221 Connelly SJ N Engl J Med 2010; 361: Patel MR N N Engl J Med : Granger CB N Engl J Med 2011; 365: Rivaroxaban Warfarin ASA + Clopidogrel Dabigatran ASA Dabigatran Warfarin WHAT ONE TO USE? Warfarin Rivaroxaban ASA + Clopidogrel ASA Rivaroxaban ASA + Clopidogrel Dabigatran 17

18 What About Guidelines? Great news! They May not agree! 18

19 Google: dabigatran manitoba 19

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21 Atrial Fib Trials: Bleeding Major bleeding Re-LY (n=18,113) % Events Dabi 110/ Intracranial Lifethreatening Gastrointestinal ROCKET (n = 14,236) % Events ARISTOTLE (n = 18,160) % Events/yr Warf Riva Warf Apix Warf

22 Case TT is a 70 yr old female with hypertension and peripheral vascular disease Just discharged from the HSC with Rx: Levofloxacin 500 mg daily X 4 days Metoprolol 50 mg bid Warfarin 5 mg take as directed Meds on profile: ASA 81 mg once daily Ramipril 5 mg daily Case TT still lives at home Not terribly mobile. Cognition borderline Home care comes in daily in daily in AM to help with pills, ADLs Daughter in law will now have to come over daily to help with pm meds Trainer labs will be coming in to draw blood work 22

23 A Fib Summary Very commone cause of stroke, especially disabiling ones Patients, other health professionals should screen for it New guidelines coming expect more encouragement for OCs in lower risk stroke pts and use of new approvals Some will have strong opinions on which drugs are better than others 23

24 Case BB is a 65 yr old male who presents to ER with a painful swollen right leg Back of leg has been sore for a number of days, now that it is swelling up thought he better come in and get checked out DM 2, Hypertension, Hypercholesterolemia Meds on profile: Ramipril 10 mg od, Atorvastatin 10 mg od, EC ASA 81 mg od, Glyburide 5 mg bid 24

25 Pathogenesis of Venous Thromboembolism Clots arise due to defects of three basic mechanisms (Virchrow s triad): Blood and its forming elements Injury to vessel walls Stasis of blood Spectrum of VT DVT Proximal vs. Distal PE Fatal Both maybe asymptomatic 25

26 Clinical Risk Factors for VT Age Cancer Chemotherapy CHF Central Lines Estrogen Use Hypercoaguable States IBD Immobility Major Surgery Nephrotic Syndrome Obesity Paralysis Pregnancy Previous VT Stroke Trauma Varicose Veins Geerts, WH et al. Chest, 2001: 119: 132 S How should he be treated? 26

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29 EINSTEIN: Efficacy: Acute DVT 29

30 EINSTEIN: Safety Acute DVT Rivaroxaban Price 15 and 20 mg tabs $ 2.84 ea 30

31 Pt Issues Don t need bed rest Important factor for recurrent VTE is therapeutic anticoagulation in first 3 months Risk esp high if not therapeutic in first month Drops off to lower level for 2 nd and 3 rd month I m going to threaten people I will call their MD to put them on warfarin if they fall behind on their refill If going on warfarin, ask when not if blood being checked next and who and where to find out result Coagulation Cascade Intrinsic Pathway (surface contact) Extrinsic Pathway (tissue factor) Warfarin: F II, VII, IX, X XIIa IX XIa Fondaparinux (AT-III dependent Pure Anti-Xa) IXa VIIa Heparin / LMWH (AT-III dependent) TF Pathway Inhibitor Apixaban Rivaroxaban X II Xa Thrombin (IIa) Ximelagatran Dabigatran (direct antithrombin) Thrombin-Fibrin Clot 31

32 Why warfarin rocks Strong evidence base for its use approved for rats in 1948, humans in 1954 Highly effective anticoagulant in a broad range of indications atrial fibrillation venous thromboembolism mechanical heart valves No significant off-target toxicities Cheap Why warfarin sucks Narrow therapeutic index Inhibits sequential enzymes (VII, IX, X, and prothrombin) in a cascade reaction Hence extremely steep dose-response curve Works by antagonizing Vitamin K, a trace nutrient present in only a few foods Moving target Common genetic polymorphisms (CYP2C9; VKORC1) influence its activity Many drug interactions (713 by one source, 193 major ) 32

33 More problems with warfarin For aforementioned reasons, incessant monitoring is essential Nonetheless, even in good hands, only ~2/3 of INRs will be in target range Delayed onset and reversal of anticoagulant effect long half-life of drug (~2d) and of circulating procoagulant proteins (~2.5d for prothrombin) New oral anticoagulants: Dabigatran (Pradax) Oral direct thrombin inhibitor little food interaction Half life hrs AFib (approved): 110 or 150mg bid (75 mg in US Scr) Rivaroxaban (Xarelto) Oral direct Factor Xa inhibitor little food interaction Half-life 9 hrs AFib: 20mg o.d. (15 mg od Scr) DVT: 15 mg bid then 20 mg daily Apixaban (Eliquis) Oral direct Factor Xa inhibitor little food interaction Half-life 12 hrs AFib (not approved): 5mg bid (2.5 mg bid Scr) 33

34 New Orals: Other Indications Other indications likely to see in use: Pulmonary Embolism (rivaroxaban probably 1st) Venous thromboembolism (VTE) treatment (other agents) New Orals: Other Indications Possibly see in the future: Acute Coronary Syndromes Venous thromboembolism prophylaxis Valves 34

35 Pharmacokinetics / dynamics Dabigatran Rivaroxaban Apixaban Target Site Absorption Hrs to Cmax (i.e full effect) IIa (thrombin) Low, but consistent ~ 2 as a prodrug Xa ~ 70 % but dose dependent Xa ~ 60 % 2-4 ~ 2 Pradax Product Monograph 35

36 PK/PD Apixaban Dabigatran Rivaroxaban Liver (CYP) Metabolism Yes, multiple pathways None CYP 3A4 Renal Elimination ~ 1/3 80% ~ 1/3 (active drug) Apixaban Dabigatran Rivaroxaban Drug Interactions CYP 3A4 & P-gp Strong P-gp CYP 3A4 & P-gp Wt Extremes (Δ exposure) < 50 kg ~ 30% > 120kg ~30% ~ 48 kg: 25% ~ 120 kg 20 % < 50 kg 24% > 120 kg < 24% Product Monograph Rivaroxaban Contraindications Recent bleeding Contraindicated in moderate and severe liver with coagulopathy and severe renal impairment (Clcr < 30 ml/min) Contraindicated with agents that are both strong CYP 3A4 and P-gp inhibitors Contraindicated in pregnancy and nursing women Dosage adjustments for Clcr ml/min 36

37 Just not a good idea: NSAIDs 37

38 PT (X-fold change from baseline) Rivaroxaban Monitoring? anti Xa test coming. I think If want to ensure out of system (e.g. going to surgery) a normal INR is probably ok. NOT an aptt (that s for dabi) Concern with major drug interaction or multiple moderate DIs +/- renal dysfunction Rivaroxaban: effect on Prothrombin time Healthy human subjects Rivaroxaban 80 mg (n=6) Rivaroxaban 40 mg (n=8) Rivaroxaban 20 mg (n=7) Rivaroxaban 10 mg (n=8) Rivaroxaban 5 mg (n=6) Rivaroxaban 1.25 mg (n=8) Placebo (n=25) Time (hours) Kubitza et al., Clin Pharmacol Ther

39 Monitoring Enoxaparin Dalteparin Anti Xa Dabigatran aptt more sensitive Rivaroxaban Apixaban INR more sensitive Anti-Xa (potential) Anti-Xa (potential) Note: the new oral drugs are NOT conventionally monitored INR and aptt are NOT adjusted to a target range Caveats with New Drugs New agents should not be assumed to be interchangeable with warfarin; each needs to be tested in specific situations mechanical heart valves antiphospholipid syndrome cancer associated thrombosis acute coronary syndromes thrombosis in pregnancy Only loose guidelines available for perioperative management on these agents No antidote exists for any of them 39

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41 Patient Counselling Can t miss doses otherwise back to warfarin (or stroke/ PE) for you! Take with food at 15 and 20 mg doses Tell everyone who touches you I am on a blood thinner Know Thy Dose! 10 mg 15 mg 20 mg Orthopedics Bid for DVT (Clcr > 30) Daily for AF or DVT with Clcr Daily for AF or DVT and good renal fn Not indicated for Clcr < 30 ml/min 41

42 Questions Reversal Call Hematology at HSC or St B Timing around surgeries and procedures 42

43 Questions Use with clopidogrel/asa or both? Doubles the bleeding time with clopidogrel Both antiplatlets increase bleeding risk with riva 43

44 Questions Can I crush the pills? Can I split the pills? 44

45 Summary A Fib requires anticoagulation. First thing is to find it Role of the new oral anticoagulants continues to expand. Now have another agent for A Fib. First one for DVT treatment Pharmacists have an important role to ensure patient safety Questions 45