CLINICAMP 2015 CASE DISCUSSION ON NOACs. Stephane Steurbaut Anne-Sophie Larock

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1 CLINICAMP 2015 CASE DISCUSSION ON NOACs Stephane Steurbaut Anne-Sophie Larock

2 Background During 60 years, VKAs = the only anticoagulants available for oral use in prevention and treatment of TE. Highly effective but have some limitations: many food and drug interactions a regular therapeutic monitoring and dose adjustment an unpredictable anticoagulant response Mantha S., 2013 Non anti-vitamin K Oral Anticoagulants (NOACs) no drug monitoring fewer drug interactions no food interactions a predictable therapeutic effect fixed dose recommended for majority of the patients

3 Background AG Turpie; C Esmon. Thromb Haemost 2011; 105:

4 Indication & posology Indication VTE prophylaxis in joint replacement Non-valvular atrial fibrillation VTE treatment and secondary prevention Acute coronary syndrome Pradaxa dabigatran etexialte R (10/2009) 220 mg/d (2 caps 110 mg 1 x/d) 150mg/d (2 caps 75 mg 1 x/d) if Cr Cl 30-50ml/min, if >75 y, if verapamil, amiodarone and quinidine THR: 28-35d TKA: 10d R (08/2012) 300 mg/d (1caps 150 mg 2x/d) 220 mg/d (1 caps 110 mg 2x/d) if >80 years or verapamil NR Tt: LMWH therapeutic dose 5 d P2: 300 mg/d (1 caps 150 mg 2x/d) OR 220 mg/d (1 caps 110 mg 2x/d) if >80 years or high bleeding risk Min 3 months Xarelto rivaroxban R (09/2009) 10mg/d (1 tab 10 mg 1x/d) THR: 5w TKA: 2w R (09/2012) 20 mg/d (1 tab 20 mg 1x/d) 15mg/d (1 tab15 mg 1x/d) if Cr Cl CG 15-49ml/min R (01/2013) Tt: 30 mg/d 21 d (1tab 15 mg 2x/d) P2: 20 mg/d (1 tab 20 mg 1x/d) 15 mg/d (1 tab 15 mg 1x/d) if Cr Cl CG 15-49ml/min) Min 3 months, max 12 months NR 5mg/d + aspirin 100mg +/- clopidogrel 75 mg (1tab 2,5 mg 2x/d) Max 24 months Eliquis apixaban R (02/2012) 5mg/d (1 tab 2,5 mg 2x/d) THR: 32-38d TKA: 10d R (09/2013) 10 mg/d (1 tab 5 mg 2x/d) 5mg/d (1 tab 2,5 mg 2xdj) if at least 2 criteria : 80 years, 60 kg or serum creatinine 1,5mg/dl; or if Cr Cl CG ml/min NR Tt: 20 mg/d 7 d (1 tab 10 mg 2x/d) THEN 10 mg/d (1 tab 5 mg 2x/d) Min 3 months P2: 5 mg/d (1 tab 2,5mg 2x/d) From 6 months to Off-label, Label, Cr Cl CG: creatinine clearance, Cockcroft and Gault equation, d: days, R: reimbursement, NR: no reimbursement, P2: secondary prevention, TKA: total knee arthroplasty, THR: total hip replacement, Tt: treatment, w: weeks

5 Atrial fibrillation (AF)

6 Atrial fibrillation (AF) Normal AF

7 Atrial fibrillation (AF)

8 Atrial fibrillation (AF) Eur Heart J 2010;31:

9 Atrial fibrillation (AF) Eur Heart J 2010;31:

10 Pharmacokinetics (1)

11 Pharmacokinetics (2) Dabigatran Apixaban Rivaroxaban Bioavailability 3-7% 50% 66% (w/o food) ~100% with food Prodrug yes no no Clearance: non-renal/renal of adsorbed dose if normal renal function 20%/80% 73%/27% 65%/35% Liver metabolism: CYP3A4 no yes (elimination; minor CYP3A4) yes (elimination) P-gp substrate yes yes yes Absorption with food no effect no effect +39% Intake with food? no no mandatory Absorption with H2B/PPI plasma level -12 to - 30% no effect no effect Asian ethnicity plasma level +25% no effect no effect GI tolerability dyspepsia 5-10% no problem no problem Elimination half-life 12-17h 12h 5-9h (young)/11-13h (elderly)

12 Pharmacokinetics (3) Renal elimination Use of Cockcroft and Gault formula! (140-age) x weight (kg) x 0,85 (if woman) = CrCl (ml/min) 72 x creatinin (mg/dl) Cr Cl Pradaxa Xarelto Eliquis < 15 ml/min CONTRAINDICATION TO AVOID ml/min Use with caution 15 mg/d ml/min 220 mg/d (110 mg bid) if risk of bleeding ++ TO AVOID Use with caution 5 mg/d (2,5mg bid) 15 mg/d 5 mg/d if at least 2 criteria : 80 years, 60 kg or serum creatinine 1,5mg/dl General recommendation : avoid NOACs in severe renal impairment (ClCr < 30 ml/min) J. Stangier,Clin Pharmacokinet,2010;49:259-68; J Clin Pharm Ther 2013;93:68-77

13 Pharmacokinetics (4)

14 Pharmacokinetics (5) Dabigatran Apixaban Rivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect Digoxin P-gp no effect no data yet no effect Verapamil P-gp/ wk CYP3A % no data yet minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% minor effect Quinidine P-gp +50% no data yet +50% Amiodarone P-gp % no data yet minor effect Dronedarone P-gp/CYP3A % no data yet no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A % +100% up to +160% Dabigatran contraindicated with ketoconazole, itraconazole, ciclosporine and dronedarone Dabigatran: dose adjustment with verapamil, quinidine and amiodarone

15 Pharmacokinetics (6) Interaction Dabigatran Apixaban Rivaroxaban Fluconazole CYP3A4 no data no data +42% Cyclosporin; tacrolimus Clarithromycin; erythromycin HIV protease inhibitors Rifampicin; St John s wort; carbamezepine; phenytoin; phenobarbital P-gp no data no data +50% P-gp/ CYP3A % no data % P-gp and BCRP/ CYP3A4 P-gp and BCRP/ CYP3A4/CYP2J2 no data strong increase up to +153% -66% -54% up to -50% Antacids GI absorption % no data no effect

16 Pharmacokinetics (7) Dabigatran Apixaban Edoxaban Rivaroxaban Aged 80 years Increased plasma level no data Aged 75 years Increased plasma level no data Weight 60 kg Renal function Increased plasma level Increased plasma level Other increased bleeding risk Pharmacodynamic interactions antiplatelet drugs, NSAIDs Systemic steroid therapy Other anticoagulants Recent surgery on critical organ (brain, eye) Thrombocytopenia (e.g. chemotherapy) HAS-BLED 3

17 Which one to choose? Weitz JI et al. Hematology, Am soc hematol educ program 2012;2012:536-40

18 Case 1: François François, 83 years old, is hospitalized for a transient ischemic attack. His medical history is atrial fibrillation, PCMK, high blood pressure, diabetes and adenocarcinoma of prostate. He is living alone at home. He refused to take VKA that is why he takes Pradaxa for prevention of stroke in atrial fibrillation. Hb 13,1 g/dl; INR 1,3; glycemia 125 mg/dl; serum creatinine 0,99 mg/dl, Cl Cr Cockcroft&Gault 64 ml/min; weight 80 kg

19 Case 1: François During his hospital stay, François explains he sometimes forgets to take his drugs. Medication 8 AM 12 AM 4 PM 8 PM Bedtime Commentary Pradaxa 110 mg caps 2 He takes 2 caps of Pradaxa once a day at noon because of a dyspepsia Bisoprolol Sandoz 2,5 mg 1 Uni Diamicron 60 mg 1 Belsar plus 20/12,5 mg 1 Lasix 40 mg x ½ or 1 tab if systolic blood presure > 150/160 mmhg Befact forte 1 Inneov 1 Zocor 20 mg 1 Stilnoct 10 mg 1 Lysanxia 10 mg Dafalgan 1 g Brexine 20 mg If necessary If necessary If necessary Venoruton gel 20 mg If necessary Linseed ground 3x per week

20 Case 1: François What about the indication for Pradaxa? (LVEF 52%) What about the dosage and posology? What can we say about the INR in the present case? 1. Nothing, INR is not influenced by dabigatran 2. INR reflects a subtherapeutic level of anticoagulant 3. INR reflects a poor compliance Is Pradaxa the best choice for this patient? if No, Why? What alternative could be proposed? Which clinical pharmacist s intervention could be suggested?

21 Case 2: André André, 69 years old, is referred to the emergency department (ER) by his GP because of difficulties with walking and a rash that presents as a red, warm discoloration on his right calf. André returned a day ago from a holiday to South Africa. You work as a clinical pharmacist on the ER and are the first health care professional to see the patient. What problem do you suspect with this patient?

22 Case 2: André What is the chance of pulmonary embolism (PE) if André has a deep vein thrombosis (DVT) and is left untreated? 1. About 1 in 3 2. About 1 in About 1 in About 1 in 100

23 Case 2: Background DVT Incidence ± 1-2 cases per persons annually About ⅓ of untreated DVT result in potentially fatal pulmonary embolism (PE) About ⅓ will suffer from post-thrombotic syndrome (chronic lower leg edema, pain, pigment changes and skin breakdown) About ⅓ will have a DVT recurrence within 10 years DVT risk factors Although most cases of DVT are unprovoked (idiopathic), certain conditions and provoking factors play a role in about half of DVT cases: Active malignancy Surgery Immobilization > 8 hours Estrogen uses / pregnancy

24 Case 2: André When documenting his preadmission medication you get the following list: Medication 8 AM 12 AM 4 PM 8 PM Bedtime Commentary Amlor 10 mg 1 Brufen 400 mg caps Osteoarthritis with chronic back pain Cordarone 200 mg 1 Relvar 92 µg/22 µg 1 puff Sintrom 1 mg 1 According to INR Ventolin 100 µg 1 If necessary

25 Case 2: André The ER physicians confirms your suspicion of a DVT and asks for your advice regarding pharmacotherapy. What is your recommendation? 1. Start with LMWH 2. Increase dose of Sintrom 3. Start with NOAC 4. No pharmacotherapeutic approach but compression stockings only Does your choice has an impact on the preadmission medication?

26 Case 2: André André is about to be discharged at 2 PM after 3 days of hospitalization. The treating physician decided to start with Xarelto but is not sure when to start and at what dose. The patient received his last dose of LMWH (Fraxodi ) at 11 AM. What is your recommendation concerning the administration time? 1. Start immediately with Xarelto 2. Start Xarelto after 12h 3. Start Xarelto after 24h 4. Start Xarelto after 48h What is your recommendation concerning the dose?

27 Case 2: André Which of the following lists agents that EACH should be avoided in combination with rivaroxaban? 1. grapefruit juice, ketoconazole, ritonavir 2. atorvastatin, rifampicin, ketoconazole 3. midazolam, naproxen, ritonavir 4. St. John s Wort, colchicine, rifampicin

28 Case 2: Background Bridging rules FROM From NOAC To NOAC VKA The NOAC can be begun when INR < 2 LMWH UFH Start NOAC at the same time or up to 2 hours before the next LMWH dose. start NOAC at the time of discontinuation of UFH. TO VKA Concomitant administration until INR > 2 Because NOAC may influence INR, the INR will be monitored just before the next NOAC dose. For dabigatran: bridging depends of renal function!! LMWH UFH Start LMWH 12 h (if bid) / 24 h (if od) after last dose of NOAC Start UFH 12 h (if bid) / 24 h (if od) after last dose of NOAC Menno V. Huisman et al., Thromb Haemost, 2012;107:838-47, Rivaroxaban: A Practical Guide V1.0, BSTH 2012 NO OVERLAP LMWH WITH NOAC!

29 Case 3: Jeanine Jeanine, 86 years old, was admitted at the emergency department for severe epistaxis. Medical history: atrial fibrillation, peripheral artery disease, prosthetic aortic valve, heart failure, high blood pressure Hb 9,4 g/dl; serum creatinine 1,53 mg/dl; Cl Cr Cockcroft&Gault 21 ml/min; weight 50 kg

30 Case 3: Jeanine Medication history Medication 8 AM 12 AM 4 PM 8 PM Bedtime Commentary Asaflow 80 mg Burinex 5 mg Emconcor 2,5 mg Spironolactone EG 25 mg Perindopril 4 mg Myocholine 10 mg Tamsulosine Teva 0,4 mg 1 tab ½ tab 1 tab 1 tab 1 tab 1 tab 1 tab Xarelto 20 mg ½ tab dose reduction 2 months ago because of recurrent epistaxis Calcium carbonate 1,25 g Temesta 1 mg 1 caps 1 tab She jumps some Xarelto doses and splits tablets of Xarelto because of bleeding

31 Case 3: Jeanine What are the risk factor for bleeding in this patient? Which antidote could be used in this case? 1. Vitamin K 2. No antidote necessary because of short half time 3. Protamin 4. A specific antidote of rivaroxaban What about the dose of rivaroxaban? Which is the best anticoagulant alternative for this patient? 1. Another NOAC 2. UFH 3. LMWH 4. VKA

32 Case 3: Background Interpreting the relative risk of strokes versus bleeds Important points about interpreting the HAS-BLED score: The score can aid in comparing the relative risks of stroke vs major bleeding with antithrombotic therapy Stroke risk is usually higher than risk of major bleeding Strokes with AF are more likely to be fatal or disabling than major bleeds Increased risk of major bleeding does not contraindicate antithrombotic therapy Increased risk of major bleeding warrants extra caution and closer monitoring of antithrombotic therapy Only a very high risk/benefit ratio favours no antithrombotic therapy (e.g., a young patient with AF and few or no stroke risk factors, but a high risk of major hemorrhage because of malignancy, prior major hemorrhage, or participation in contact sports) Skanes AC et al. Can J Cardiol 2012; 28(2):

33 Case 3: Background

34 Appropriateness of prescribing of NOACs

35 Appropriateness of prescribing of NOACs NOACs = an important step in the field of anticoagulation This study suboptimal quality of prescribing NOACs Inappropriate use: thrombotic and hemorrhagic risk Main problems associated with prescribing NOACs: Strengthening education of health care professionals choice of anticoagulant dose adjustment modalities of administration guidance compliance Future: clinical pharmacy

36 Take home messages (1) Complexity of NOAC prescribing Multiple drug/dose regimen Renal insufficiency Drug interactions No routine monitoring No specific antidote (yet) No consensus on anticoagulant choice Poor compliance Inappropriate use: thrombotic and hemorrhagic risk Role of pharmacist to optimize Drug prescribing Patient education Health care professionals education

37 Take home messages (2)

38 Take home messages (3) FAST 100/112

39 Thank You for your ATTENTION

40 Appendices

41 Appendices

42 Appendices

43 Take home messages Patients : information leaflets

44 Appendices