Tim Brown, PharmD, BCACP, FASHP Director of Clinical Pharmacotherapy, Akron General Medical Center for Family Medicine Professor, Northeast Ohio

Transcription

1 Tim Brown, PharmD, BCACP, FASHP Director of Clinical Pharmacotherapy, Akron General Medical Center for Family Medicine Professor, Northeast Ohio Medical University

2 Objectives Review and discuss current changes in anticoagulation guidelines in relation to NOACs. Discuss stratification of risk using the CHADS2 and CHA2DS2Vasc scoring system for atrial fibrillation patients Review and discuss NOACs with regard to mechanism of action, drug interactions, side effects, and indication as compared to warfarin Identify the appropriate protocol to transition to and from NOACs in relation to warfarin, LMWHs, unfractionated heparin, and surgical procedures.

3 Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9 th Edition published in 2012 CHEST supplement.

4 CHEST Guideline Review Updated recommendations in All NOACs were not addressed Guidelines were updated based perception of the future therapies Warfarin remained the gold standard LMWH took center stage Bridging therapy VTE prevention pre/post CA treatment

5 True or False

6 True or False 20s In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C). True

7 True or False 24s In patients with a first VTE that is an unprovoked PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy. True

8 True or False 10s 9.1 a For patients taking VKAs with INRs between 4.5 and 10 and with no evidence of bleeding, we suggest against the routine use of vitamin K True

9 True of False 9s 3.1 For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 8 weeks rather than every 4 weeks False the suggestion is 12 weeks

10 True of False 9s 3.2 For patients taking VKAs with previously stable therapeutic INRs who present with a single out-of-range INR of 0.5 below or above therapeutic, we suggest continuing the current dose and testing the INR within 1 to 2 weeks True

11 True or False 14s 2.1 In patients who require temporary interruption of a VKA before surgery, we recommend stopping VKAs approximately 3 days before surgery. False- 5 days is recommended

12 True or False 15s (sic)in patients who require a minor dental procedure, a minor dermatologic procedure, and/or cataract surgery, we suggest to continue VKAs instead of other therapies. True

13 True or False 15s 2.4 In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we suggest no bridging anticoagulation during interruption of VKA therapy False-Always bridge VKA therapy

14 True or False 15s 3.6 In patients who are receiving ASA and require CABG, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C), as well as those on dual therapy should continue ASA but clopidogrel/ prasugrel should be stopped 5 days before surgery True

15 AHA/ACC/HRS Guideline for Management of Patients with Atrial Fibrillation, Executive Summary published in JACC in 2014.

16 Who Receives Anticoagulation? Individualized based on: CVA risk Bleeding risk Patient's preference All types of A Fib are treated the same with stratification of risk for thromboembolism Some patients in borderline risk categories may prefer no anticoagulation Some patients may be at a high risk for bleeds and not be candidates for therapy

17 Who Receives Anticoagulation? CHADS2 Validated - 2% increase in CVA rate for each 1 point increase However a score of 1 is considered intermediate risk Lowest risk may not be well identified Score of 2 from CVA/TIA is not equal risk as the score from other risk factors CHA2DS2-VASc is PREFERRED Broader score (0 to 9) Women cannot achieve a score of 0 Better discrimination of stroke risk More predictably with the lower risk category

18 Who Receives Anticoagulation?

19 Who Receives Anticoagulation? Considered for: CHA2DS2-VASc score of 1 Duration of <48h and low risk Recommended for: Nonvalvular A Fib Prior CVA or TIA CHA2DS2-VASc score of 2 or greater Hypertrophic cardiomyopathy Mechanical heart valves Cardioversion candidates

20 Who Receives Anticoagulation? Bleeding Risk Assessment: RIETE and HEMORR2HAGES HAS-BLED Score of 3 potential high risk HTN (SBP>160) Abnormal Liver or Renal Function History of Stroke or Bleeding Labile INRs Elderly (>65yo) Use Drugs that Promote Bleeding or ETOH abuse

21 Review of Warfarin Therapy

22 Warfarin Gold standard for comparison Numerous clinical trials showing efficacy and adverse outcomes DOC in valvular issues including AF Remains the inexpensive option Numerous drug and food interactions Only one where compliance can be assessed Narrow therapeutic window (INR 2-3) Does not begin to work immediately Half life of Vitamin K factors are reason II, VII, IX, X

23 Warfarin

24 Warfarin Cursory review of literature 64% RR reduction for ischemic and hemorrhage CVAs ARR 2.7%/yr Cochrane Collaboration review ARR 2.6%/yr or about 25 CVAs prevented annually per 1000 subjects treated BAFTA Head to Head with ASA in older pts Warfarin was superior to ASA No significant increase in bleeding

25 Warfarin

26 Warfarin Maintenance Dosing Suggested MD Adjustment Takes 5 days to see dosing adjustment effect on INR Adjust WEEKLY dose by 5-25% Check INR every 1-2 weeks until stable Can extend INR check interval as comfortable Maximum is 3 mos per Chest Home INR monitoring exists

27 Warfarin Bridging Therapy Certain procedures do not require interruption Dental extraction(s) Cataract surgery Colonoscopy Pacer, ICDs, ablations, angiography Risk stratification when interruption required Based on CHA2DS2-Vasc Score 2 Timing of VTE within last 3-12 months Valve replacement with prosthesis and type TIA and/or CVA within last 6 mos

28 Bridging Therapy in A. Fib. Low Risk: CHADS2 score 0-2 with no previous CVA and/or TIA No bridge or consider low dose LMWH Moderate Risk: CHADS2 score of 3-4 Bridge with full dose LMWH High Risk: CHADS2 score of 5-6 Bridge with full dose LMWH Chest 2008;133:S

29 Warfarin-Bridging Therapy If INR is 2-3 Start holding warfarin 5 days prior to procedure Initiate LMWH 3 days prior to procedure (INR should be < 2.5) Last dose of LMWH 24 h prior to procedure Resume BOTH Warfarin and LMWH h post BUT If high risk for bleed resume LMWH h post INR and CBC Day 3, then on Day 5 start daily INRs until therapeutic If INR >4 Same as above but if INR >1.5 on Day 2 consider oral vitamin K 2.5mg

30 Dabigatran Rivaroxaban Apixaban

31 Dabigatran (Pradaxa): Mechanism of Action Univalent, competitive, reversible direct thrombin inhibitor Binds to active site inactivates fibrin-bound & unbound thrombin Thrombin Inhibition Prevents Fibrinogen fibrin conversion Positive feedback amplification Platelet activation Fibrinolysis Circulation 2005; 112: Thromb Haemost 2010; 103: Thromb Haemost. 2011; 105:371-8.

32 Dabigatran: Mechanism of Action Ann Pharmacother 2011; 45:990-9.

33 Circulation 2005; 112: Thromb Haemost 2010; 103: Thromb Haemost. 2011; 105: Dabigatran: Pharmacokinetics Dabigatran etexilate (prodrug) + esterases dabigatran (active) Rapidly absorbed & hydrolyzed = peak plasma levels within 1.5 hrs NOT metabolism by the cytochrome P450 enzymes Dabigatran etexilate = p-glycoprotein substrate Plasma protein binding: ~35% Few displacement interactions & dialyzable Predominant elimination pathway: RENAL (80%) Creatinine clearance most important factor for drug exposure Terminal half-life: hrs

34 Dabigatran: Dosing Nonvalvular afib (NVAF) 150mg BID Prevents 5 more CVAs per 1000 pts/yr than warfarin (RELY Trial) Postoperative thromboprophylaxis Knee and Hip 110mg post op then 220mg/d x d up to 35 d Treatment of DVT and PE Treat with a parenteral anticoagulant for 5-10 days then 150mg BID Reduce the risk of recurrence of DVT and PE 150 mg BID Caution >75yo Poor renal function Underweight H/O GI bleed

35 Dabigatran: Conversion Manufacturer Recommendations Warfarin to dabigatran Stop warfarin and start dabigatran when INR < 2 Dabigatran to warfarin LMWH/Fondaparinux to dabigatran IV heparin to dabigatran Dabigatran to parenteral anticoagulant DC dabigatran 3 d after starting warfarin. CLcr ml/min: DC dabigatran 2 d after starting warfarin. CL ml/min: DC dabigatran 1 d after starting warfarin. DC parenteral anticoagulant and give dabigatran 0-2 h before next parenteral dose would have been given Administer 1 st dose of dabigatran at time of discontinuation of IV infusion CLcr > 30 ml/min: Start parenteral anticoagulant 12 h after the last dose of dabigatran CLcr < 30 ml/min: Start parenteral anticoagulant 24 h after the last dose of dabigatran

36 Dabigatran: Perioperative Management Calculated creatinine clearance ml/min Standard risk of bleeding High risk of bleeding >50 1 day 2 days days 4 days 30 4 days 6 days Blood 2012;119:

37 Dabigatran Drug Interactions Increased Effect G-glycoprotein Inhibitors Amiodarone Dronedarone Verapamil Clarithromycin Ketoconazole Antiplatelet Salicylates Plavix Effient Brillinta Decreased Effect Decrease Gastric ph Antacids PPIs H2 Antagonists Hepatic Inducers Rifampin Carbamazepine St. John s Wort Pradaxa package insert. FDA.

38 m a Rivaroxaban (Xarelto): Mechanism of Action

39 Rivaroxaban: Pharmacokinetics Rivaroxaban is rapidly absorbed after administration Peak plasma levels within 2-4 hrs Maximal Factor Xa inhibition = 1-4 hours Metabolized by hepatic oxidation CYP3A4/5 & CYP2J2 Avoid concomitant use with strong CYP3A4 inhibitors/inducers Plasma protein binding: ~93% NOT dialyzable Bioavailability % Terminal half-life: 5-13 hrs Eliminated via renal (66%) AND fecal/biliary (33%) route Renal dose adjustment required for CrCl <50 ml/min

40 Rivaroxaban: Indications Dosing Should be taken with food, preferably dinner Indication Atrial fibrillation DVT/PE VTE prophylaxis Dose 20 mg daily 15 mg daily (CrCl ml/min) 15 mg BID x 21 days, then 20 mg daily 10 mg daily Proved to be noninferior to warfarin in CVA prevention and VTE management (Rocket AF and EINSTEIN-DVT trials) Avoid Use CrCl< 15 ml/min Significant hepatic disease (Child-Pugh B or C)

41 Rivaroxaban: Drug interactions Increased Effect Azoles Fluconzaole, Itraconazole, Voriconazole Macrolides Clarithromycin Calcium Channel Blockers Verapamil Protease inhibitors Ritonavir Decreased Effect Hepatic Inducers St. John s Wort Carbamazepine, Phenytoin Xarelto package insert. FDA.

42 Rivaroxaban: Conversion From Warfarin Initiate Rivaroxaban when INR <3 To Warfarin Initiate warfarin and LMWH 24 h after last dose of Rivaroxaban From LMWH Initiate 2h prior to the next regularly scheduled dose of LMWH To LMWH Initiate 24h after the last dose of Rivaroxaban

43 Rivaroxaban: Perioperative Management Calculated creatinine clearance ml/min Standard risk of bleeding High risk of bleeding >50 1 day 3 days < 50 2 days 5 days Blood 2012;119:

44 m a Apixaban (Eliquis): Mechanism of Action

45 Apixaban: Pharmacokinetics Apixaban is rapidly absorbed after administration Peak plasma levels within 3-4 hrs Take with or without food and can crush Metabolized by hepatic oxidation CYP3A4/5 & CYP2J2 Avoid concomitant use with strong CYP3A4 inhibitors/inducers Plasma protein binding: ~87% NOT dialyzable Bioavailability 50% Terminal half-life: 12 hrs Eliminated via renal (27%) AND fecal/biliary (73%) route Renal dose adjustment if SCr 1.5mg/dl

46 . Apixaban: Indications NVAF 5 mg BID 2.5 mg BID if 2 or more of the following met: Age > 80 years old Weight < 60 kg Scr > 1.5 mg/dl Treatment and prevention of VTE Initial 10mg BID x 7 d then 5mg BID x 3-6 mos Extended timeline reduce to 2.5mg BID Hip and Knee post op 2.5mg BID 12 days post knee but 35 days post hip Renal dosing Mild-to-moderate: No dosage adjustment required SCr 1.5 mg/dl: 2.5 mg BID if patient has 1 additional characteristic of age 80 years or weight 60 kg ESRD on HD: 5 mg BID; decrease dose to 2.5 mg BID if 1 additional characteristic of age 80 years or weight 60 kg is present

47 Apixaban: Indications AMPLIFY and AMPLIFY-EXT Approval 8/21/14 Non-inferior to traditional management Superior with adverse effects like major bleeding ARISTOTLE results 3 more CVAs prevented, ten major bleed avoided, and 4 deaths prevented for every 1000 pts/yr compared to warfarin Demonstrated superiority against Warfarin Seeing an increase in use due to the study results Less bleeding noted vs. Dabigatran

48 Apixaban: Drug Interactions Increased Effect Azole antifungals Fluconazole, ketoconazole Calcium channel blockers Verapamil Anti Seizure Antiplatelet NSAIDs ASA Decreased Effect Beta Blocker Atenolol Hepatic Inducers Rifampin Cambamazepine Phenytoin St Johns Wort Eliquis package insert. FDA.

49 Apixaban: Conversion From Warfarin Initiate when INR <2 To Warfarin Initiate LMWH and warfarin when next dose of Apixaban is scheduled From LMWH Start Apixaban at the next regularly scheduled LMWH dose To LMWH Start LMWH at the next regularly scheduled Apixaban dose

50 Apixaban: Perioperative Management Calculated creatinine clearance ml/min Standard risk of bleeding High risk of bleeding Not a factor unless SCr 1.5mg/dl 1 day 2 days

51 Pharmacokinetic Comparison Dabigatran Rivaroxaban Apixaban MOA Diract Thrombin (IIA) inhibitor Direct Xa inhibitor Direct Xa inhibitor Bioavailability 6-7% 80% 50% T max 1.5h 2-4h 2-3h T 1/ h 9-13h 8-15h Hepatic metabolism Prodrug, glucuronidation CYP enzymes CYP enzymes Drug Interactions P-gp CYP3A4, Pg-p CYP3A4, P-gp Protein binding 35% 90% 87% Dialyzable Yes No No Renal elimination 80% 66% 27% 5 1

52 Reversal of NOACs Am J Hematol 2012:87:S141-S145.

53 A. Spinal injections B. Open cholecystectomy C. Colonoscopy D. Root Canal E. None of the above

54 A. Dabigatran B. Rivaroxaban C. Apixaban D. All the above

55 A. True B. False

56 Questions? Go with the flow and don t be a drip!!