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![Renal function should be evaluated prior to
initiation of direct thrombin or factor Xa
inhibitorsand should be re-evaluated when
clinically indicated and at least annually IB
For patients with nonvalvular AF unable to maintain a
therapeutic INR level with warfarin, use of a direct thrombin
or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban)
is recommended. IC
For patientwith a CHA2DS2-VASc score of 2 and who have
endstage CKD (creatinine clearance [CrCl] <15 mL/min) or
are on hemodialysis, it is reasonable to prescribe warfarin
(INR 2.0 to 3.0) for oral anticoagulation IIaB
The direct thrombin inhibitor, dabigatran, and the factor Xa
inhibitor, rivaroxaban, are not recommended in patients with
AF and end-stage CKD or on hemodialysis because of the lack
of evidence from clinical trials regarding the balance of risks
and benefits IIIC](https://image.slidesharecdn.com/presentation1-151204172337-lva1-app6891/75/Oral-anticoagulation-in-AF-42-2048.jpg)
Uploaded byPavan Rasalkar
Oral anticoagulation in AF
This document discusses atrial fibrillation (AF) and its treatment with oral anticoagulants (OACs). It provides information on: - The prevalence and risks of AF, including increased risk of stroke, heart failure, dementia and mortality. - Guidelines on assessing stroke risk and recommendations for anticoagulation. - A comparison of the efficacy and safety of novel oral anticoagulants (NOACs) like dabigatran, rivaroxaban, apixaban and edoxaban compared to warfarin based on major clinical trials. - Pharmacokinetic profiles, drug interactions and precautions for NOACs.
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Similar to Oral anticoagulation in AF
Oral anticoagulation in AF
- 1. Dr. Pavankumar PRasalkar
- 2. Atrial fibrillation(AF) is the most common sustained cardiac arrhythmia. The estimated number of individuals with AF globally in 2010 was 33∙5 million 20∙9 million males and 12∙6 million females . Prevalence: 596.7/100000 in males 373.1/100000 in females Incidence: 77.5/100000 in males 59.5/100000 in females Sumeet S.Chugh etal CIRCULATIONAHA.113.005119 December 17, 2013,
- 3. AF isassociated with a 5-fold increased risk of stroke AF is also associated with a 3-fold risk of HF 2-fold increased risk of both dementia and mortality HF : Heart Failure
- 4. First diagnosed episodeof AF Paroxysmal (<7 days) Persistent (>7 days to 12m) Long standing persistent (>1year) Permanent (accepted)
- 5. Atrial fibrillation Anticoagulation AssessTE risk NOAC OAC Aspirin or none Rate and rhythm control AF type symptoms Rate control +/- Rhythm control Ablation
- 7. CHADS2 C congestive cardiac failure H Hypertension A Age more than 75 D Diabetes S2 Previous Strokeor TIA Gage BF, Waterman AD et. al. JAMA 2001;285:2864–2870
- 8.
- 9. Risk Profile Class/ Level CHA2DS2-VASc = 0 No antithrombotic therapy Class IIa CHA2DS2-VASc = 1 No antithrombotic therapy Or Asprin Or Oral anticoagulation Class IIb CHA2DS2-VASc ≥ 2 Oral anticoagulation Class I
- 10. INR . internationalnormalized ratio
- 13. Kinetics Absorption Oral: Rapid,complete Distribution 0.14 L/kg Metabolism Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4 Excretion Urine (92%, primarily as metabolites) Half-life 20-60 hours
- 14. Onset ofaction: ◦ 5-7 days ◦ May requiring bridging Antidote: ◦ Vitamin K, FFP, PRBC Interactions: ◦ Foods with high vitamin K content
- 15. Medications ◦ Amiodarone ◦Antiplatelets ◦ Azole antifungals (fluconazole) ◦ 2nd/3rd-gen Cephalosporins ◦ Fluoroquinolones (ciprofloxacin) ◦ Griseofulvin ◦ Isoniazid ◦ Macrolides (clarithromycin) ◦ Metronidazole ◦ NSAIDs ◦ Penicillins (nafcillin) ◦ Prednisone ◦ Rifampin ◦ SSRIs ◦ Sulfonamides (Bactrim) ◦ Tetracyclines (Doxycycline ) Herbals ◦ Ginger ◦ Gingko ◦ Fenugreek ◦ Chamomile ◦ St. John’s Wort
- 16. ADRs ◦ Bleeding/Hemorrhage/Hematuria ◦Vasculitis ◦ Dermatitis, pruritus, urticaria ◦ Abdominal pain, N/V/D ◦ Anemia ◦ Skin necrosis, gangrene, “purple toes” syndrome
- 17. Hart R, etal. Ann Intern Med 1999;131:4 Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate
- 18. VKA Similarto Warfarin Lesser pharmacogenimic interaction (VKORC1 and CYP2C9) Lesser food and drug interactions Higher potency and longer half life
- 19. Requires monitoring Numerous drug and diet interactions Narrow therapeutic range Difficult to control – takes time to get in or out of the system Role for new anticoagulants?
- 20.
- 21. Ideal anticoagulant: ◦Equally efficacious ◦ Equally safe ◦ No monitoring ◦ Fewer interactions ◦ Oral ◦ Reversible
- 22. Direct thrombininhibitors ◦ Dabigatran Factor Xa inhibitors ◦ Rivaroxaban ◦ Apixaban ◦ Edoxaban
- 23. Dabigatran Apixaban Rivaroxaban Bioavailability3-7% 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) 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) 16 www.escardio.org/EHRA
- 24. P-glycoprotein transporterinvolved in absorption and renal clearance – plasma levels may be affected by P-gp inducers or inhibitors1 Cytochrome P450 CYP3A4 involved in hepatic clearance of rivaroxaban and apixaban – plasma levels may be affected by CYP3A4 inducers of inhibitors2 17 1. Gnoth et al, J Pharmacol Exp Ther 2011;338:372-80 2. Mueck et al, Br J Clin Pharmacol 2013
- 25. Three levels ofalert: Red – contraindicated/not recommended for use Orange – adapt NOAC dose ◦ dabigatran: 150 mg to 110 mg BID ◦ rivaroxaban: 20 mg to 15 mg QD ◦ apixaban: 5 mg to 2.5 mg BID Yellow – consider dose reduction if two concomitant yellow interactions Where no data available, NOACs not recommended yet 18 www.escardio.org/EHRA
- 26. Dabigatran Apixaban EdoxabanRivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect Digoxin P-gp no effect no data yet no effect no effect Verapamil P-gp/ wk CYP3A4 +12–180% no data yet + 53% (slow release) minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect Quinidine P-gp +50% no data yet +80% +50% Amiodarone P-gp +12–60% no data yet no effect minor effect Dronedarone P-gp/CYP3A4 +70–100% no data yet +85% no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 +140–150% +100% no data yet up to +160% 19 www.escardio.org/EHRA Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
- 27. Dabigatran Apixaban EdoxabanRivaroxaban Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect Digoxin P-gp no effect no data yet no effect no effect Verapamil P-gp/ wk CYP3A4 +12–180% no data yet + 53% (slow release) minor effect Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect Quinidine P-gp +50% no data yet +80% +50% Amiodarone P-gp +12–60% no data yet no effect minor effect Dronedarone P-gp/CYP3A4 +70–100% no data yet +85% no data yet Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 +140–150% +100% no data yet up to +160% 19 www.escardio.org/EHRA Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
- 28. Interaction Dabigatran ApixabanRivaroxaban Fluconazole CYP3A4 no data no data +42% Cyclosporin; tacrolimus P-gp no data no data +50% Clarithromycin; erythromycin P-gp/ CYP3A4 +15–20% no data +30–54% HIV protease inhibitors P-gp and BCRP/ CYP3A4 no data strong increase up to +153% Rifampicin; St John’s wort; carbamezepine; phenytoin; phenobarbital P-gp and BCRP/ CYP3A4/CYP2J2 -66% -54% up to -50% Antacids GI absorption -12-30% no data no effect 20 www.escardio.org/EHRA Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
- 29. Dabigatran Apixaban Rivaroxaban Aged≥ 80 years Increased plasma level Aged ≥ 75 years Increased plasma level Weight ≤ 60 kg Increased plasma level Renal function Increased plasma level 21 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 Orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
- 31. RE-LY ROCKET-AF ARISTOTLE Dabigatran150mg BID vs. warfarin Rivaroxaban 20mg daily vs. warfarin Apixaban5mg BID vs. warfarin Study Design Trial design RCT Open blinded assessment RCT DB DD RCT DB DD Sample size (n) 18,000+ 14,000+ 18,000+ Inclusion criteria AF and selected risk factor(s) for embolization AF and CHADS2 ≥2 AF or flutter and CHADS2 ≥1 Key exclusion criteria Valvular AF Use of ASA ≥100 mg/day CrCl <30 ml/min Valvular AF; Use of ASA >100 mg/day CrCl <30 ml/min Valvular AF Need for ASA >165 mg/day SCr >2.5mg/dL or CrCl <25ml/min Follow-up (mean) 2 yr 1.9 yr 1.8 yr Outcome Definitions Primary Efficacy Composite of systemic embolism and stroke (ischemic or hemorrhagic) Major Bleeding ISTH: fatal/critical organ bleed; decrease ≥2g/dL Hbg or transfusion of ≥2U blood Mortality All causes Baseline Characteristics Age (years) 71 (mean) 73 (median) 70 (median) Female (%) 36.4% 39.7% 35.2 % CHADS2 (mean) 2.1 3.5 2.1 Previous embolic episode (%) 20% (stroke or TIA only) 55% (stroke,TIA, systemic embolism) 19% (stroke, TIA, systemic embolism) TTR (%) (Standard 60-65%) 64% 55% 62%
- 32. Comparison of EfficacyResults RE-LY ROCKETAF ARISTOTLE Outcome (%/year) Dabigatran 150mg BID vs. warfarin p Value Rivaroxaba n 20mg daily vs. warfarin p Value Apixaban 5mg BID vs. warfarin p Value Primary Outcome Stroke or systemic embolism 1.1 vs. 1.7% p<0.001 NNT 88 2.1 vs. 2.4% p=0.12 1.3 vs. 1.6% p=0.01 NNT 167 Stroke 1.0 vs. 1.6% p<0.001 NNT 88 1.65 vs. 1.96% p=0.09 1.2 vs. 1.5% p=0.01 NNT 175 Ischemic stroke 0.9 vs. 1.3% p=0.03 NNT 132 1.3 vs. 1.4 p=0.58 0.97 vs. 1.05% p=0.42 Hemorrhagic stroke 0.1vs0.4% p<0.001 NNT 182 0.26 vs. 0.44% p=0.02 NNT 333 0.24 vs. 0.47% p<0.00 1 NNT 238 All cause death 3.6 vs. 4.1% p=0.051 4.5 vs. 4.9% p=0.15 3.5 vs. 3.9 p=0.04 7 NNT 132 MI/ACS 0.7 vs. 0.5% p=0.048 NNH 0.9 vs. 1.1% p=0.12 0.5 vs. 0.6% p=0.37
- 33. Comparison of SafetyResults RE-LY ROCKETAF ARISTOTLE Major bleed 3.1 vs. 3.36% p=0.31 3.6 vs. 3.4% p=0.58 2.1 vs. 3.1% p<0.001 NNT 67 Intracranial bleed 0.3 vs. 0.74% p<0.00 1 NNT 116 0.5 vs. 0.7% p=0.02 NNT 250 0.3 vs. 0.8% p<0.001 NNT 128 GI bleed 1.5 vs. 1.0% p<0.00 1 NNH 100 3.2 vs. 2.2%** p=0.001 NNH 100 0.76 vs. 0.86% 0.37
- 34. Factor Xainhibitor Doses 60mg and 30mg OD Engage AF trial(November 2013, NEJM) ◦ Versus Warfarin, RCT DD ◦ More than 20000 subjects ◦ Non inferior ◦ Less major bleed
- 35. Boxed warning:Less effective in pateints with CrCl >95ml/min, as it was associated with more thromboembolic complications compared to warfarin. Also contraindicated if CrCl < 15ml/mim Was FDA approved in January 2015 Approved by European union in June 2015 Savaysa (USA), Lixiana(Europe)
- 36. All majortrials excluded Valvular AF Re-Align AF ◦ RCT, Nejm 2013 ◦ Dabigatran vs Warfarin in prosthetic heart valve ◦ Significantly increased bleeding ◦ Significantly increased thromboembolism ◦ Stopped prematurely
- 38. Advantages Disadvantages Cheap:2rs/5mg Antidote available Robust data(Class IA) Time tested Narrow TI/Non target INR Frequent INR monitoring Numerous drug-drug and drug-food interactions Slow onset and offset of action/ Requires bridging
- 39. Advantages Disadvantages Quickonset/offset of action Few drug-drug and drug-food interactions No need of monitoring Cost ◦ Dabigatran (Pradaxa:71.8rs/150 or 110mg) ◦ Apixaban (Equilis: 72.5 rs) ◦ Rivaroxaban (Xarelto: 240rs) No antidote Less robust data (Class IB)
- 40. Patient notwilling for regular INR Patient preferance Target INR not achieved with warfarin
- 41. 1In patients withAF, antithrombotic therapy should be individualized based on shared decision making after discussion of the absolute and RRs of stroke and bleeding, and the patient’s values and preferences. IC 2. Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, or permanent IB. Among patients treated with warfarin, the INR should be determined at least weekly during initiation of antithrombotic therapy and at least monthly when anticoagulation (INR in range) is stable IABridging therapy with unfractionated heparin (UFH) or low-molecular- weight heparin (LMWH) is recommended for patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions regarding bridging therapy should balance the risks of stroke and bleeding. IC The direct thrombin inhibitor, dabigatran, should not be used in patients with AF and a mechanical heart valve IIIB
- 42. Renal function shouldbe evaluated prior to initiation of direct thrombin or factor Xa inhibitorsand should be re-evaluated when clinically indicated and at least annually IB For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban) is recommended. IC For patientwith a CHA2DS2-VASc score of 2 and who have endstage CKD (creatinine clearance [CrCl] <15 mL/min) or are on hemodialysis, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral anticoagulation IIaB The direct thrombin inhibitor, dabigatran, and the factor Xa inhibitor, rivaroxaban, are not recommended in patients with AF and end-stage CKD or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits IIIC
- 47. Warfarin ◦ Givevitamin K 5-10 mg ◦ Fresh frozen plasma ◦ Octaplex Prothrombin complex concentrate Works within 1 hour More effective than plasma at reversing INR Small volume 40 ml usually enough for most patients $$$$$
- 48. No specificmonitoring test available No reversal agents for new anticoagulants
- 49. Dabigatran Apixaban Rivaroxaban Plasmapeak 2h after ingestion 1-4h post ingestion 2-4h after ingestion Plasma trough 12-24h after ingestion 12-24h after ingestion 16-24h after ingestion PT cannot be used cannot be used prolonged: may indicate excess bleeding risk but local calibration required INR cannot be used cannot be used cannot be used aPTT at trough >2x ULN suggests excess bleeding risk cannot be used cannot be used dTT At trough >200ng/ml ≥ 65s: excess bleeding risk cannot be used cannot be used Anti-FXa assays n/a no data yet quantitative; no data on threshold values for bleeding or thrombosis Ecarin clotting time at trough >2x ULN: excess bleeding risk not affected; cannot be used not affected; cannot be used12
- 50.
- 51. Randomized, double-blind,placebo controlled study 12 healthy male volunteers received rivaroxaban 20mg BID or dabigatran 150 mg BID for 2.5 days Followed by bolus of 50IU/kg PCC (Cofact) or saline Procedure then repeated with the other anticoagulant treatment
- 52. Rivaroxaban: ◦ Prolongedthe PT ◦ Immediately reversed by PCC completely ◦ Endogenous thrombin potential inhibited ◦ Also completely normalized with PC Dabigatran: ◦ Affected PTT, ecarin clotting time, and thrombin time ◦ Not reversed by PCC
- 55. Antidote toDabigatran NEJM 6th august 2015 (REVERSE AD TRIAL) IV 5g dose Rapidly reversed anticoagulant effecs in minutes Pending approval
- 56. 37 Van Ryn etal Am J Med 2012;125:417
- 57. VKA to NOACINR <2.0: immediate INR 2.0–2.5: immediate or next day INR >2.5: use INR and VKA half-life to estimate time to INR <2.5 Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) Low molecular weight heparin (LMWH) Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment Start when next dose would have been given NOAC to VKA Administer concomitantly until INR in appropriate range Measure INR just before next intake of NOAC Re-test 24h after last dose of NOAC Monitor INR in first month until stable values (2.0–3.0) achieved NOAC to parenteral anticoagulant Initiate when next dose of NOAC is due NOAC to NOAC Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Aspirin or clodiprogel to NOAC Switch immediately, unless combination therapy needed22 www.escardio.org/EHRA
- 58. Missed dose: BID:take missed dose up to 6 h after scheduled intake. If not possible skip dose and take next scheduled dose. QD: take missed dose up to 12 h after scheduled intake. If not possible skip dose and take next scheduled dose. Double dose: BID: skip next planned dose and restart BID after 24 h. QD: continue normal regimen. Uncertainty about intake: BID: continue normal regimen. QD: take another dose then continue normal regimen. Overdose: Hospitalization advised. 25
- 59. Dabigatran Apixaban Edoxaban* Rivaroxaban No important bleeding risk and/or local haemostasis possible: perform at trough level (i.e. ≥12h or 24h after last intake) Low risk High risk Low risk High risk Low risk High risk Low risk High risk CrCl ≥80 ml/min ≥24h ≥48h ≥24h ≥48h no data yet no data yet ≥24h ≥48h CrCl 50–80 ml/min ≥36h ≥72h ≥24h ≥48h no data yet no data yet ≥24h ≥48h CrCl 30–50 ml/min § ≥48h ≥96h ≥24h ≥48h no data yet no data yet ≥24h ≥48h CrCl 15–30 ml/min § not indicated not indicated ≥36h ≥48h no data yet no data yet ≥36h ≥48h CrCl <15 ml/min no official indication for use 40 www.escardio.org/EHR A Last intake of drug before elective surgical intervention *no EMA approval yet.; Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding § many of these patients may be on the lower dose of dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d).
- 60. Procedures with immediateand complete haemostasis: Atraumatic spinal/epidural anethesia Clean lumbar puncture Resume 6–8 h after surgery Procedures associated with immobilization: Procedures with post-operative risk of bleeding: Initiate reduced venous or intermediate dose of LMWH 6–8 h after surgery if haemostasis achieved. Restart NOACs 48–72h after surgery upon complete haemostasis Thromboprophylaxis (e.g. with LMWH) can be initiated 6-8 h after surgery 41 www.escardio.org/EHR A
- 61. Discontinue NOAC. Try to defer surgery at least 12 h and ideally 24 h after last dose. Urgent surgery associated with much higher rates of bleeding than elective procedures, but lower than VKA-treated patients. 1 Coagulation tests can be considered (classical test or specific tests) but strategy based on these results has never been evaluated. Therefore such strategy cannot be recommended and should not be used routinely. 43 1. Healey et al, Circulation 2012:126;343-8
- 62. No data Currently contraindicated
- 63. Warfarin hasbeen the benchmark since long But, limitations with warfarin have paved way for NOAC’S NOAC’S have their own limitations One not superior over other Decide case to case basis
- 65.