Paradigm Shift In Oral Anticoagulation Non-Vitamin K Oral Anticoagulants(NOACs) -

Transcription

1 Paradigm Shift In Oral Anticoagulation Non-Vitamin K Oral Anticoagulants(NOACs) - Mohammad Taha, MD University of Kansas Medical center, Kansas city, KS Abebe Abebe, MD University of Kansas Medical Center, Kansas city, KS

2 Conflict of Interest No personal or financial interest to declare

3 Outline Presentation of a case Introduction to oral anticoagulants Basic Pharmacology of NOACs Use of Coagulation assays in NOACs Literature review on efficacy and safety of NOACs Role of NOACS in current Practice guidelines Practice pearls in selecting and dosing NOACS

4 Relevance High risk medications Knowledge needed for prescribing & managing complications Update of new anticoagulation guidelines incorporating NOACs Provide updates on NOACs

5 Case presentation A 71 year old white female with history of Hypertension, DM-Type II and Osteoarthritis Shortness of breath for the last three days Long range flight to Paris for a vacation a week ago. Pleuritic right sided chest pain No past history of blood clots or bleeding.

6 Case presentation Complete blood counts, PT/INR & aptt were normal Renal and hepatic function/transaminases normal Left leg US - completely occlusive acute popliteal vein thrombus CT of chest right segmental pulmonary artery filling defect Discussion of anticoagulation options Want to avoid frequent lab draws What will be the anticoagulation of choice?

7

8

9 Warfarin( Vitamin K antagonist) Advantages * Oral * Once daily dosing * Easy to reverse * No adjustment with low GFR * Affordable Pitfalls * Delayed onset of action * Major drug or food interaction * Unpredictable pharmacokinetics * Need for lab monitoring * Narrow therapeutic window Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):

10 Ideal anticoagulant Oral Rapid onset of action No major drug or food interaction Once daily dosing Predictable pharmacokinetics No need for laboratory monitoring Easy to reverse Wide therapeutic window No adjustment with low GFR Affordable Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121(13):

11 NOACs Novel oral anticoagulants Non Vitamin K antagonist oral anticoagulants(noacs) 1 Target specific oral anticoagulants(tsoas) 1 Direct oral anticoagulants(doacs) 2 Oral direct Inhibitors (ODIs) 3 1. Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis. 2013;36(2): Levy JH, Spyropoulos AC, Samama CM, et al. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv. 2014;7(12): Baglin T, Hillarp A, Tripodi A, et al. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost

12 Taha M, Abebe A, Wooldridge D. New options in anticoagulation: a hospitalist s guide to non vitamin K antagonist oral anticoagulants. Hospital Medicine Practice. 2015;3(9):1-34

13 Direct Thrombin Inhibitors(DTIs) Dabigatran ( Pradaxa ) Prodrug Dabigatran etexilate Peak plasma concentration 1-2 hours Half life hours Low plasma protein binding Renal elimination -80%. Can not be crushed. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):

14 Direct Factor Xa Inhibitors Rivaroxaban (Xarelto ) Peak plasma concentration 2-4 hours Half life hours ; hours in elderly High plasma protein binding Renal clearance 66% Needs to be taken with food to improve absorption. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):

15 Direct Factor Xa Inhibitors Apixaban(Eliquis ) Peak plasma level 1-3 hours Half life 8-15 hours High plasma protein binding Renal clearance -25% Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):

16 Direct Factor Xa Inhibitors Edoxaban(Savaysa, Lixiana ) Peak plasma level 1-2 hours Half life hours Intermediate plasma protein binding Renal clearance- 50% Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):

17 Direct Factor Xa Inhibitors Betrixaban(Bevyxxa ) Peak plasma level: 3-4 hours Half life : hours Plasma protein binding: 60%( in Vitro) Excretion : Feces ~ 85% Renal excretion: 6-13% Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):

18 20% Comparative pharmacology of non-vitamin K antagonist oral anticoagulants Abbreviations: Tmax, time to reach peak concentration in plasma after oral dose; h, hours; CYP450, cytochrome 450; T1/2, terminal half-life of drug; PD T1/2, pharmacodynamic half-life. Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:

19 * Retrospective study - Taiwan National Health Insurance database * 91,330 patients with Nonvalvular A.fib( Dabigatran, Rivaroxaban or Apixaban) * 4770 major bleeding occurred * Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with use of NOACs alone, was associated with increased risk of major bleeding. * For example, the bleeding rate with amiodarone plus NOACs was 52 per 1000 person-years of exposure, versus 38 per 1000 with NOACs alone Chang-Fu et al. JAMA October 3, 2017 Volume 318, Number 13, pages

20 Drug interaction Decreased metabolism * Ritonavir * ketoconazole * itraconazole * clarithromycin Increased metabolism * Rifampin * Carbamazepine * phenytoin Dabigatran also should be used in caution with amiodarone and verapamil Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc. 2013;88(5):

21 Coagulation assays & NOACs Indications Life threatening bleeding Prior to invasive procedures Suspected overdose Non compliance

22 Dabigatran Rivaroxaban Apixaban Edoxaban Betrixabban PT Insensitive Prolonged Lower effect aptt TT ECT Anti-Factor xa Chromogenic assay PT:Prothrombin time; aptt:activated Partial Thromboplastin time; TT: Thrombin time; ECT:Ecerin clotting time

23 Coagulation assays & NOACs Prothrombin time(pt) Variable effect None to prolonged time 1 Insensitive to Dabigatran 1 Rivaroxaban - Prolonged PT indicate excess risk of bleeding 1 Apixban significantly lower effect 1 Edoxaban no known relationship between PT elevation and bleeding risk 1 Betrixaban Insensitive, at antithrombotic concentration 2 1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20): Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:

24 Coagulation assays & NOACs Activated Partial Thromboplastin Time( aptt) Dabigatran Variably prolonged -?quantitative assessment of level and activity 1 Rivaroxaban slightly prolonged but no known relation to bleeding risk 1 Apixaban slightly prolonged but no known relation to bleeding risk 1 Edoxaban prolonged but no known relation to bleeding risk 1 Betrixaban Insensitive 2 1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20): Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:

25 Coagulation related studies & NOACs Thrombin time(tt) Dabigatran too sensitive Important parameter when Normal Excludes clinically relevant Dabigatran concentration Factor Xa Inhibitors unaffected Hemoclot - modified ( dilute) TT can be used for dabigatran measurement Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20):

26 Coagulation assays & NOACs Ecarin Clotting Time( ECT) Dabigatran - Direct measurement and monitoring Factor Xa inhibitors not affected Draw back - Lack of access Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003;33(4):

27 Coagulation assays & NOACs Anti-Factor Xa Chromogenic Assay Dabigatran not applicable 1,2 Rivaroxaban and Apixaban Optimal method of measuring their effects 1,2 Edoxaban No threshold values for bleeding or thrombosis 1,2 Betrixaban sensitive and used to measure antithrombotic effect and quantitation 3 1-Tripodi A. The laboratory and the direct oral anticoagulants. Blood. 2013;121(20): Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5): Chan etal. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vascular Health and Risk Management 2015:

28 Summery Coagulation assays & NOACs ØNo FDA approved diagnostic tests ØPT/aPTT- don t reflect NOAC concentration ØUse normal PT to exclude factor Xa inhibitors anticoagulation effects ØUse normal aptt- to exclude factor Xa inhibitors anticoagulation effects ØUse normal TT to exclude any anticoagulation effect for DTIs

29 Summery Coagulation assays & NOACs ØDabigatran measurement Use Hemoclot Ø Dabigatran effect measurement and monitoring - Ecarin clotting time( ECT) ØRivaroxaban, Apixaban, Edoxaban, and Betrixaban activity- Anti Xa chromogenic assay (locally calibrated)

30 Outline Literature review/evidence of efficacy and safety of NOACs. - RCTs of NVAF - RCTs of VTE treatment. - Comparison of different NOACs in real world data. Role of NOACS in current Practice guidelines. Practice pearls in selecting and dosing NOACS.

31 Stroke prevention in A fib * Dabigatran, rivaroxaban, apixaban and edoxaban are currently the only FDA approved NOACs for treatment of NVAF. * 4 large multicenter RCTs comparing VKAs Vs NOACs. * Non Valvular A fib. * Primary endpoint of efficacy is composite of any stroke or systemic embolism. * Major bleeding was defined as bleeding resulting in transfusion of more than 2 units of blood, drop of hemoglobin more than 2 g/dl, or symptomatic bleeding in a critical area or organ Ruff et al., The Lancet, 2013

32 Study NOAC Drug Doses Design Median Age (Y) # of Patients TTR Time in therapeuti c range % Median follow up time (Y) CHADS2 score Primary outcome For Efficacy Safety outcome RE-LY Dabigatran 150 mg or 110 mg twice daily Open label but blinded to endpoint evaluation All Stroke or systemic embolism Major bleeding ROCKET AF Rivaroxaban 20 or 15 mg daily Double blind All Stroke or systemic embolism Major and non major clinically relevant bleeding ARISTOTLE Apixaban 5 or 2.5 mg twice daily Double blind All Stroke or systemic embolism Major bleeding ENGAGE -AFIB TIMI 48 Edoxaban 60 or 30 mg daily Double blind All Stroke or systemic embolism Major bleeding

33 Study NOAC Drug Doses Design Median Age (Y) # of Patients TTR Time in therapeuti c range % Median follow up time (Y) CHADS2 score Primary outcome For Efficacy Safety outcome RE-LY Dabigatran 150 mg or 110 mg twice daily Open label but blinded to endpoint evaluation All Stroke or systemic embolism Major bleeding ROCKET AF Rivaroxaban 20 or 15 mg daily Double blind All Stroke or systemic embolism Major and non major clinically relevant bleeding ARISTOTLE Apixaban 5 or 2.5 mg twice daily Double blind All Stroke or systemic embolism Major bleeding ENGAGE -AFIB TIMI 48 Edoxaban 60 or 30 mg daily Double blind All Stroke or systemic embolism Major bleeding

34 Study NOAC Drug Doses Design Median Age (Y) # of Patients TTR Time in therapeuti c range % Median follow up time (Y) CHADS2 score Primary outcome For Efficacy Safety outcome RE-LY Dabigatran 150 mg or 110 mg twice daily Open label but blinded to endpoint evaluation All Stroke or systemic embolism Major bleeding ROCKET AF Rivaroxaban 20 or 15 mg daily Double blind All Stroke or systemic embolism Major and non major clinically relevant bleeding ARISTOTLE Apixaban 5 or 2.5 mg twice daily Double blind All Stroke or systemic embolism Major bleeding ENGAGE -AFIB TIMI 48 Edoxaban 60 or 30 mg daily Double blind All Stroke or systemic embolism Major bleeding

35 Study NOAC Drug Doses Primary outcome For Efficacy (stroke or systemic embolism ) Safety outcome compared to VKAs RE-LY Dabigatran 150 mg or 110 mg twice daily ROCKET AF Rivaroxaban 20 or 15 mg daily ARISTOTLE Apixaban 5 or 2.5 mg twice daily ENGAGE -AFIB TIMI 48 Edoxaban 60 or 30 mg daily 150 mg dose was superior to VKA 110 mg dose was non-inferior to VKA non-inferior to VKA superior to VKA non-inferior to VKA Similar rates of Major bleeding Lower rate of major bleeding Similar rates of Major and non major clinically relevant bleeding Lower rate of major bleeding Lowerall-cause mortality Lower rate of Major bleeding

36 Study NOAC Drug Doses Primary outcome For Efficacy (stroke or systemic embolism ) Safety outcome compared to VKAs RE-LY Dabigatran 150 mg or 110 mg twice daily ROCKET AF Rivaroxaban 20 or 15 mg daily ARISTOTLE Apixaban 5 or 2.5 mg twice daily ENGAGE -AFIB TIMI 48 Edoxaban 60 or 30 mg daily 150 mg dose was superior to VKA 110 mg dose was non-inferior to VKA non-inferior to VKA superior to VKA non-inferior to VKA Similar rates of Major bleeding Lower rate of major bleeding Similar rates of Major and non major clinically relevant bleeding Lower rate of major bleeding Lowerall-cause mortality Lower rate of Major bleeding

37 Published in the Lancet December Meta-analysis of 4 Randomized controlled studies included patients

38 Stroke or systemic embolic events in large NOAC trials, vs warfarin 19% reduction Ruff et al., The Lancet, 2013

39 Secondary efficacy and safety outcomes in large NOACs trials vs. VKAs 50 % reduction RR (95%CI) p Efficacy Ischaemic stroke Haemorrhagic stroke Myocardial infarction All-cause mortality Safety Intracranial haemorrhage Gastrointestinal bleeding 10% reduction 0 92 ( ) ( ) < ( ) ( ) ( ) < ( ) FavoursNOAC Favourswarfarin Ruff et al., The Lancet, 2013

40 Major bleeding events in large NOAC trials, vs warfarin RE-LY Ruff et al., The Lancet, 2013

41 What else we learn from RTCs of NOACS in NF A Fib * All NOACS has lower incidence IC bleeding. * NOACS has Higher risk of GI bleeding (except Apixaban). * Patient with Cr CL less than 30 were excluded, patients with Cr CL less than 50 % relatively underrepresented. * Patients on dual anti platelet therapy were excluded. * Dabigatran dose 75 mg BID that was approved by FDA for patient Cr CL was not studied in outcome based RCTs. Ruff et al., The Lancet, 2013

42 NOACS RCTS in VTE * RCTs with Non inferiority design compared dabigatran, rivaroxaban, apixaban and edoxaban to standard treatment LMWH/VKAs or UFH/VKA in patients with acute VTE. * The primary efficacy outcome was recurrent symptomatic VTE and/or VTE-related deaths. * The primary safety outcome was major bleeding or combined major and clinically relevant non major bleeding bleeding. der Hulle et all. J Thromb Haemost. 2014;12(3):

43 Study NOAC Drug NOAC Dose Design of RCTs Patients N Average age Parenteral Treatment TTR % Primary Efficacy outcome Primary Safety outcome RE-COVER 1 Dabigatran 150mg BID Double blind Heparin At least 5 days 60 Not inferior to VKA Similar incidence of major bleeding Einstein DVT Rivaroxaban 15mg BID for 21 days then 20mg once daily Open-label, assessor blind None 58 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Einstein PE Rivaroxaban 15mg BID for 21 days then 20 once daily Open-label, assessor blind None 63 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Amplify Apixaban 10 mg BID for 7 days then 5 mg BID Hokusai VTE Edoxaban 60mg Double blind None 61 Not inferior to VKA Significant reduction in major bleeding Double blind Heparin or LMWH at least 5 days 64 Not inferior to VKA Significant reduction in major and clinical relevant bleeding

44 Study NOAC Drug NOAC Dose Design of RCTs Patients N Average age Parenteral Treatment TTR % Primary Efficacy outcome Primary Safety outcome RE-COVER 1 Dabigatran 150mg BID Double -blind Heparin 60 Not inferior to VKA Similar incidence of major bleeding Einstein DVT Rivaroxaban 15mg BID for 21 days then 20mg once daily Open-label, assessor blind None 58 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Einstein PE Rivaroxaban 15mg BID for 21 days then 20 once daily Open-label, assessor blind None 63 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Amplify Apixaban 10 mg BID for 7 days then 5 mg BID Hokusai VTE Edoxaban 60mg (or 30 mg daily if higher risk of bleeding) Double blind None 61 Not inferior to VKA Significant reduction in major bleeding Double blind Heparin 64 Not inferior to VKA Significant reduction in major and clinical relevant bleeding

45 Study NOAC Drug NOAC Dose Design of RCTs Patients N Average age Parenteral Treatment TTR % Primary Efficacy outcome Primary Safety outcome RE-COVER 1 Dabigatran 150mg BID Double -blind Heparin 60 Not inferior to VKA Similar incidence of major bleeding Einstein DVT Rivaroxaban 15mg BID for 21 days then 20mg once daily Open-label, assessor blind None 58 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Einstein PE Rivaroxaban 15mg BID for 21 days then 20 once daily Open-label, assessor blind None 63 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Amplify Apixaban 10 mg BID for 7 days then 5 mg BID Hokusai VTE Edoxaban 60mg (or 30 mg daily if higher risk of bleeding) Double blind None 61 Not inferior to VKA Significant reduction in major bleeding Double blind Heparin 64 Not inferior to VKA Significant reduction in major and clinical relevant bleeding

46 Study NOAC Drug NOAC Dose Design of RCTs Patients N Average age Parenteral Treatment TTR % Primary Efficacy outcome Primary Safety outcome RE-COVER 1 Dabigatran 150mg BID Double -blind Heparin 60 Not inferior to VKA Similar incidence of major bleeding Einstein DVT Rivaroxaban 15mg BID for 21 days then 20mg once daily Open-label, assessor blind None 58 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Einstein PE Rivaroxaban 15mg BID for 21 days then 20 once daily Open-label, assessor blind None 63 Not inferior to VKA Similar incidence of major and clinical relevant bleeding Amplify Apixaban 10 mg BID for 7 days then 5 mg BID Hokusai VTE Edoxaban 60mg (or 30 mg daily if higher risk of bleeding) Double blind None 61 Not inferior to VKA Significant reduction in major bleeding Double blind Heparin 64 Not inferior to VKA Significant reduction in major and clinical relevant bleeding

47 Meta-Analysis of 5 RCTs of NOACs vs VKAs in VTE * NOACs have a comparable efficacy to that of VKAs. * Slight but significantly lower risk of major bleeding. * Needed to treat with NOACs versus VKAs to prevent one major bleed was 149 (relatively high ). * Cancer and CKD patients were underrepresented. der Hulle et all. J Thromb Haemost. 2014;12(3):

48 NOACs in other indications * 4 NOACS are approved for DVT prophylaxis in major orthopedic surgery like THA and TKA. * Only Betrixaban is approved for DVT prophylaxis in medical patients. * Not approved for stroke prevention in valvular Afib. * Not approved for ACS management. * Observational evidence of efficacy in HIT not FDA approved for this indication.

49 APEX trial * Double blinded double dummy RCTs compared Enoxaparin 40 mg for 10 day to days of Betrixaban 80 mg. First dose 160 mg * Patients hospitalized for medical reason (CHF, infection, respiratory failure --). * Reduced mobility. * 75 yo, elevated D dimer, have hx of VTE or hx of cancer.

50 Primary Efficacy Endpoint Cohort 1: D-Dimer 2 x ULN 50 10% 9% 8% 7% Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death 8.49% RRR = 19.4% ARR = 1.59% NNT = % Event rate (%) 6% 5% 4% 3% 2% p= % 0% n=166 Enoxaparin (N=1,956) n=132 Betrixaban (N=1,914) P-values reported using the Mantel-Haenszel test stratified for dosing criteria (ie. No adjustment, renal insufficiency, P-gp inhibitor). Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47. Gibson et. al. ISTH SSC 2016 May 27, 2016

51 Primary Efficacy Endpoint Cohort 3: Overall Efficacy Population 51 10% Composite of Adjudicated Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, non-fatal PE, or VTE-related Death 8% 7.03% NNT = 57.8 Event rate (%) 6% 4% p= % 2% 0% n=223 n=165 Enoxaparin (N=3,174) Betrixaban (N=3,112) P-values reported using the Mantel-Haenszel test stratified for dosing and entry criteria (ie. No adjustment, renal insufficiency, or P-gp inhibitor / DD > 2x ULN or DD < 2x ULN). Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47. Gibson et. al. ISTH SSC 2016 May 27, 2016

52 Comparison to Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients 52 8 ADOPT Apixaban MAGELLAN Rivaroxaban RRR = 22.8% p = 0.02 RRR* = 24.0% p<0.001 p* = % APEX Betrixaban Incidence (%) VTE Events Major Bleeding % RRR = 12.9% 5.3% p = % 3.1% 2.7% 0.2% 0.5% 0.4% 0.57% 0.67% 1.1% p=0.04 p<0.001 p=0.55 Enoxaparin Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban * Overall efficacy population analysis used for comparison purposes Gibson et. al. ISTH SSC 2016 May 27, 2016

53 NOACS in clinical practice Guidelines * 2016 ACCP Guidelines for VTE treatment recommend NOACS over VKAs in patients without cancer (grade 2B). Based on less bleeding with NOACs and greater convenience. * Patients with caner and VTE, LMWH is recommended over NOACs or VKAs. * When using Dabigatran and Edoxaban for VTE treatment, 5-10 days of parenteral anticoagulation should precede the use of NOACS for that indication Kearon ; el all Chest February 2016, Vol 149, No. 2

54 Treating low risk PE as Outpatient ACCP Guidelines * Clinically stable with good cardiopulmonary reserve. * * * * * Low risk for bleeding, No recent bleeding. No severe renal or liver disease, or PLT less than 70 K. Expected to be compliant with treatment. the patient feels well enough to be treated at home. No elevated cardiac markers or R heart strain. Kearon ; el all Chest February 2016, Vol 149, No. 2

55 2014 AHA/ACC guidelines for Afib management * Non valvular A fib and CHA2DS2-VASc score of 2 or greater, oral anticoagulation is recommended with VKAs (level A ) or NOACs (grade B). * In nonvalvular AF patients unable to maintain a therapeutic INR level with warfarin, NOACs is recommended. * Renal function need to be assessed before starting NOACs * Patients on dialysis, CrCl less than 15 or who has prosthetic valve should be treated with VKAs not NOACs. January CT et al AHA/ACC/HRS guideline Circulation. 2014;130(23):

56 Valvular AFIB 2014 AHA/ACC guidelines for Afib management define this population as any patient with : * Rheumatic mitral stenosis, * Prosthetic or bioprosthetic valve replacement * Mitral valve repair. Aortic stenosis, aortic regurgitation and mitral regurgitation are not considered vulvar Afib January CT et al AHA/ACC/HRS guideline Circulation. 2014;130(23):

57 2014 Canadian Cardiovascular society guidelines for A fib management * In NVAF patient older than 65 or CHADS2 more than 1, NOACs is recommended over VKAs (strong recommendations, high quality evidence ). * Exceptions- Patients with a mechanical prosthetic valve, rheumatic mitral stenosis or Cr Cl of * Patient above 75 y should receive lower dose of dabigatran 110 mg (not available in USA ) Verma ;el all Can J Cardiol. 2014;30(10):

58 -Retrospective Analysis Comparing the Safety and Efficacy of NOACs in Afib by creating 3 matched cohorts using administrative data Rivaroxaban versus dabigatran [N=31,574] Apixaban versus dabigatran [N=13,084] Apixaban versus rivaroxaban [N=13,130]

59 Retrospective Analysis Comparing the Safety and Efficacy of NOACs: Results Event Rate per 100 Person-Years Hazard Ratio (95% CI) P Rivaroxaban N=15, vs. Dabigatran N=15, (0.75, 1.32) 0.99 Favor Rivaroxaban Favor Dabigatran Apixaban N=6, vs. Dabigatran N=6, (0.51, 1.31) 0.41 Favor Apixaban Favor Dabigatran Apixaban N=6, vs. Rivaroxaban N=6, (0.64, 1.72) 0.85 Favor Apixaban Favor Rivaroxaban Noseworthy PA et al. Chest doi: /j.chest

60 Direct comparison Dabigatran, apixaban and Rivaroxaban Event Rate per 100 Person-Years Hazard Ratio (95% CI) P Rivaroxaban N=15, vs. Dabigatran N=15, (1.10, 1.53) <0.01 Favor Rivaroxaban Favor Dabigatran Apixaban N=6, vs. Dabigatran N=6, (0.36, 0.70) <0.001 Favor Apixaban Favor Dabigatran Apixaban N=6, vs. Rivaroxaban N=6, (0.28, 0.54) <0.001 Favor Apixaban Favor Rivaroxaban Noseworthy PA et al. Chest doi: /j.chest

61 JAMA Intern Med. 2016;176(11): doi: /jamainternmed

62 2016 ESC guidelines A fib * NOACs or VKs * NOACs are safe in mild to moderate CKDs. * In dialysis No RCT to show benefit in VKAs or NOACS. ESC 2016 guidelines for A fib European Heart Journal, Volume 37, Issue 38, 7 October 2016, Pages ,

63 Practice pearls (choice of anticoagulant ) Favor NOAC Favor VKA Favor LMWH Labile INR despite compliance Severe renal insufficiency (GFR Pregnancy (Poor TTR) <30) Lower intracranial bleeding risk Dual antiplatelet therapy Active cancer No initial parenteral treatment for VTE (rivaroxaban and apixaban only) Preference not to have frequent monitoring Less drug and food interaction Mitral stenosis Prosthetic Valve Cost is a concern Concern about GI bleeding Poor Compliance Established patient with good TTR (>65%) recurrent DVT on oral treatment liver dysfunction with elevated INR

64 Practice pearls (choice of anticoagulant) Favor NOAC Favor VKA Favor LMWH Labile INR despite compliance Severe renal insufficiency (GFR Pregnancy (Poor TTR) <30) or dialysis patients Lower intracranial bleeding risk Dual antiplatelet therapy Active cancer No initial parenteral treatment for VTE (rivaroxaban and apixaban only) Preference not to have frequent monitoring Less drug and food interactions Rheumatic mitral disease, Prosthetic Valve Extreme of weight Cost is a concern Concern about GI bleeding Poor Compliance Established patient with good TTR (>65%) recurrent DVT on oral treatment liver dysfunction with elevated INR

65 Choice of NOACS History of GI bleeding Reversal agent preferred Kidney dysfunction Daily doses preferred Higher risk of bleeding GFR above 90 Dabigatran Rivaroxaban Apixaban Edoxaban?

66 FDA Approved dosing A fib Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; March 1, 2017

67 FDA Approved dosing VTE Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; March 1, 2017

68 Off-Label Dosing of NOACS and Adverse Outcomes 5738 patients in 242 sites in The ORBIT-AF II Registry

69 Idarucizumab, Praxbind * a monoclonal antibody that binds and neutralizes dabigatran.approved by FDA in * (RE-VERSE AD) trial of 90 patients on dabigatran who either were bleeding or needed an urgent procedure. * Idarucizumab was able to normalize coagulation studies in 88-98% of patients within minutes. * it restored hemostasis in all bleeding patients and in 33 out of 36 patients who needed to undergo procedures. * Cost a dose. Pollack ;et all The New England journal of medicine

70 Under review by FDA. Not available currently. Inactive Factor Xa-like protein that binds to NOACS 67 patient with major bleeding from rivaroxaban or apixaban. effective hemostasis occurring in 79% of patients Connolly ; et all. New England Journal of Medicine. 2016;375(12):

71 Andexanet Alfa * Under review by FDA. Not available currently. * Inactive Factor Xa infusion that showed promise in reversing major bleeding from 67 patients taking rivaroxaban or apixaban. * effective hemostasis occurring in 79% of patients * Connolly ; et all. New England Journal of Medicine. 2016;375(12):

72 Prothrombin complex concentrates * 4-factor PCC (II, VII, IX, X) Kcentra (approved for VKAs reversal ) is recommended in life-threatening bleeding related to NOACs by The European Heart Rhythm Association Guidelines * It have shown efficacy in reversing their anticoagulation effect in animal models and studies on normal volunteers. * It is available at KU MC (cost ~ 3200 $ a dose )

73 Controversies in NOACS * In December 2014 point of care INR device that was used in ROCKET AF were withdrawn by FDA due to falsely lower INR results. * Some authors called ROCKET AF results into question as adjusting VKA to higher level may contributed to higher bleeding rate in VKAs arm * FDA reviewed data and determined no change in drug label is needed.

74 Controversies of NOACs post marketing data * 2016 JAMA published Retrospective new-user cohort study of Medicare patients with nonvalvular who started either Rivaroxaban or Dabigatran for stroke prevention. * Study concluded Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

75 Summary * NOACs are at least as effective as VKAs in A fib, VTEs treatment and may be safer. * All NOACs cause less ICH. * Apixaban may have favorable efficacy /safety profile especially in patients with CKD. * Be aware of FDA approved dosing for NOACS. * Be Aware of drug-drug interactions.

76 Case conclusion Compliant Commercial insurance Apixaban 10 mg oral BID for 7 days followed by 5 mg BID was prescribed Duration three months

77 Questions?