1. DR.RAJEEV RANJAN

2. TOPIC OUTLINE Introduction Types of NOACs and their properties Advantages of NOACs over VKA Star-up and follow-up scheme for patients on NOACs How to measure the anticoagulant effect of NOACs How to deal with dosing errors and management of bleeding complications when it occurs How to switch between various anticoagulant regimen

3. SPECIAL SITUATIONS Patient with AF and coronary artery disease Patient undergoing planned surgical interventions and urgent surgical intervention NOACs vs. VKA in AF patients with a malignancy NOACs in CKD

4. INTRODUCTION Vitamin K antagonists (VKA) are the mainstay of the management of thromboembolic events for >5 decades Despite it impact to prevent strokes, they have significant limitations, such as common drug or food interactions, necessity of regular monitoring to adjust doses, inter personal variation in response.

11. Indication of NOACs

12. Dabigatran Etexilate Dabigatran Etexilate, a prodrug of Dabigatran, which reversibly inhibit both free and clot bound thrombin Oral bioavailability of 6% After oral administration it is rapidly and completely converted to Dabigatran by estrases Plasma level peak by 2 hrs Half life of 14-17 hrs, permits once or twice daily administration, 80% of the drug is excreted unchanged by the kidneys.

13. Co administration of Dabigatran Etexilate and Verapamil, quinidine, Amiodarone, dronendarone – strong P-gp inhibitor increases dabigatran level It should be taken with food or water to minimize dyspepsia If a dose is missed it should be taken within 6 hours

15. Dose regimen For acute VTE : 150 mg BID For VTE prophylaxis after knee/ hip replacemnet surgery (14 or 30 days respectively) : 110 mg initial dose then 220 mg daily. Common Side Effect : indigestion, dyspepsia, allergic reactions (hives, rash, itching), bleeding.

16. The RE-LY (Randomized Evaluation of long-term anticoagulant therapy with Dabigatran Etexilate) phase III trial was prospective randomized open label trial comparing two blinded doses of dabigatran (110 mg or 150mg) with warfarin in 18,113 patients with AF with at least one risk factor (mean CHADS score of 2.1)

17. Results 150 mg BID dose was superior to warfarin for reduction of stroke and systemic embolism with similar major bleeding 110 mg dose non inferior to warfarin for SSE but with significant lower bleeding rates ICH is significant low with both doses

18. RELY-ABLE Assessed the additional information on the long term effect of the two doses of dabigatran in patients completing RE-LY by extending the follow up of the patients from mean of 2 yrs to additional 2.3 yrs. RELY-ABLE confirmed the results reported in RE-LY CONCLUSIONS : during 2.3 yrs of continued treatment with dabigatran after RE-LY, there was higher rate of major bleeding with higher dose but similar rate of stroke and death.

19. VTE trials RECOVER and REMEDY Non inferior to warfarin in VTE prevention (2.4% vs. 2.1%) No differences in major bleeding

20. Rivaroxaban Oral bioavailability of 80% Rapid onset of action and half life of 7-11 hours Has dual mode of elimination; one third cleared as unchanged drug via the kidneys, one third metabolized by the liver via CYP3A4-dependent pathway then excreted in feces and one third metabolized in the liver with the inactive metabolite then eliminated via the kidneys.

21. Rivaroxaban is a substrate for P-gp and concomitant administration of potent inhibitors of both P-gp and CYP3A4 such as Ketoconazole or Ritonavir is contraindicated because they increase plasma drug level Minor interaction with Verapamil unlike dabigatran and edoxaban Co administration of Fluvastatin or Rosuvastatin need no dose reduction of Rivaroxaban

23. Dose regimen For acute VTE : 20mg daily (15 mg bid for initial 21 days) For VTE prevention after knee/ hip replacement : 10 mg daily (14 or 30 days respectively)

24. Rocket AF The ROCKET-AF was a double blinded study in which 14,264 patient with nonvalvular AF and CHADS2 scores ≥2 (mean 3.5) were studied After a median follow-up of 1.93 yrs Rivaroxaban was non-inferior to warfarin for the prevention of strokes or systemic embolism There was no difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the Rivaroxaban group Gastrointestinal and transfusion requirements were greater with Rivaroxaban. Total mortality was not significantly different between the groups

26. ATLAS ACS 2- TIMI 51 trial compared Rivaroxaban 2.5 mg or 5 mg twice daily ( unlike 20 mg OD dose for AF) With placebo in 15526 patients following ACS At the mean follow-up of 13 months the primary efficacy endpoint of CV death, MI or stroke was 10.7% with placebo, 9.1% with rivaroxaban 2.5 mg, 8.8% with rivaroxaban 5 mg with no interaction with ACS subtype Rate of definite, probable or possible stent thrombosis were 2.2% and 2.3% with 2.5 mg and 5 mg doses respectively vs. 2.9% with placebo Rate of CV death were significantly lower with rivaroxaban 2.5 mg than placebo but not with rivaroxaban 5 mg (4.0%)

27. Non –CABG major bleeds occurred in 1.8% and 2.4% with 2.5 and 5 mg rivaroxaban respectively compared with 0.6% with placebo ICH rates were 0.4% with 2.5 mg and 0.7% with 5 mg dose vs. 0.2% with placebo The use of rivaroxaban 2.5 mg twice daily, might be considered in combination with aspirin and clopidogrel if Ticagrelor and Prasugrel are not available for NSTEMI patients who have high ischemic and low bleeding risks

28. Conclusion In patient with recent ACS rivaroxaban reduces the risk of the composite end point of death from cardiovascular cause, MI or strokes Rivaroxaban increases the risk of major bleeding and ICH.

29. VTE trial EINSTEIN DVT – non-inferior to warfarin for DVT (2.1% vs. 3%) with similar bleeding risk EINSTEIN PE – non-inferior to warfarin for PE with lower bleeding risk. EINSTEIN EXTNSION – similar results

30. Apixaban Apixaban is a direct, reversible, competitive and selective inhibitor of factor Xa and the last NOAC approved by the FDA and EMA for the prevention of stroke and embolism in nonvalvular AF Well absorbed and peak plasma concentration in1-4 h. Predominantly metabolized by liver It is a mild P-glycoprotein inhibitor Compared to other NOAC it has least bleeding complication and greatest efficacy

32. Aristotle The Apixaban for the reduction in stroke and other thromboembolic events in AF ( ARISTOTLE) compared Apixaban (5 mg BID) with dose adjusted warfarin in 18,201 patients with nonvalvular AF (a mean CHADS2 score of 2.1) After mean follow-up of 1.8 yrs Apixaban was significantly better than warfarin with fewer primary outcomes (overall strokes and systemic emboli) but with no significant difference in rates of ischemic strokes Patients treated with Apixaban had significant fewer intracranial bleed but GI bleed were similar in both groups All cause mortality was significantly lower in the Apixaban group

33. Apixaban was also compared with aspirin alone in the AVERROES study, a double blinded study of5,599 patients who were not suitable candidate for VKA treatment ( mean CHADS2 score of 2) After a mean follow-up of 1.1 yrs the study was prematurely stopped due to a clear benefit in favor of Apixaban Patient with severe renal impairment (sr.cr. > 2.5 mg/dl or Cr.Cl. < 15 ml/min) were excluded from the ARISTOTLE and AVERROES trial.

34. Appraise The Apixaban for the prevention of Acute Ischemic Events (APPRAISE) 2 study assessed the effect of Apixaban 5 mg twice daily compared with placebo in addition to antiplatelet therapy following ACS It was prematurely terminated (in 8 months) due to markedly increase risk of severe bleeds, including ICH without apparent benefit of ischemic events

35. Edoxaban Another reversible factor Xa inhibitor, recently approved by FDA but not yet by the EMA. Rapidly absorbed and peal plasma level within 1-2 h Up to 50% eliminated by the kidneys, rest through multiple pathways It is a substrate for P-glycoprotein – concomitant administration with quinidine, Amiodarone, Verapamil will result in increase in plasma level of edoxaban With use of potent P-glycoprotein inhibitor, body wt<60kg, moderate to severe renal impairment (CrCI <50 ml/min) dose should be reduced by 50%.

37. ENGAGE AF-TIMI The Effective Anticoagulation with Factor Xa Next Generation in AF- Thrombolysis in myocardial infarction compared two dose regimen of edoxaban (30 and 60 mg once daily) with warfarin in total 21,026 patients with nonvalvular AF After follow-up of 2.8 yrs both regimen of Edoxaban were non-inferior to warfarin in prevention of stroke and systemic embolism

38. Edoxaban was associated with lower, dose related rate of bleeding including major and intracranial bleed. GI bleed was more frequent with high dose of edoxaban. Patient with severe renal impairment (CrCl < 30 ml/min), use of dual antiplatelet, ACS, stroke within 30 days were excluded. HOKUSAI VTE – in DVT it is non-inferior to warfarin and in PE it is superior to warfarin with similar bleeding conditions.

39. Other factor Xa inhibitors BETRIXABAN, YM150, TAK442. Betrixaban- has unique feature of 15 hrs of half life and extra-renal clearance. Betrixaban and YM150 are undergoing phase II evaluation for stroke in AF, TAK442 in phase II for prevention of recurrent ischemia in ACS patients.

40. Absorption and metabolism of NOAC DabigatranApixabanEdoxaban *Rivaroxaban Bioavailability3-7%50%62% 66% (w/o food) ~100% with food Prodrugyesno Clearance: non-renal/renal of adsorbed dose if normal renal function 20%/80%73%/27%50%/50%65%/35% Liver metabolism: CYP3A4 no yes (elimination; minor CYP3A4) minimal (<4% of elimination) yes (elimination) Absorption with foodno effect 6-22% more+39% Intake with food?no no official recommendation yet mandatory Absorption with H2B/PPI plasma level -12 to - 30% no effect Asian ethnicityplasma level +25%no effect GI tolerabilitydyspepsia 5-10%no problem Elimination half-life12-17h12h9-11h 5-9h (young)/11-13h (elderly)

41. Possible drug-drug interactions : Effect on NOAC DabigatranApixabanEdoxabanRivaroxaban AtorvastatinP-gp/ CYP3A4+18%no data yetno effect DigoxinP-gpno effectno data yetno 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 dataminor effect QuinidineP-gp+50%no data yet+80%+50% AmiodaroneP-gp+12–60%no data yetno effectminor effect DronedaroneP-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 yetup to +160%

42. Factors associated with raised plasma levels of NOACs Age≥80 years Weight≤60 kg Renal impairment Pharmacodynamic interactions – antiplatelet drugs, NSAIDs Systemic steroid therapy Other anticoagulants Recent surgery on critical organ (brain, eye) Thrombocytopenia (e.g. chemotherapy) HAS-BLED ≥ 3

43. Switching between anticoagulant regimens 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 VKAAdminister 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 anticoagulantInitiate when next dose of NOAC is due NOAC to NOACInitiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Aspirin or clodiprogel to NOACSwitch immediately, unless combination therapy needed

44. How to deal with dosing errors 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.

46. Suggested structured follow-up

47. Checklist during follow-up of AF patients on NOACs IntervalComments ComplianceEach visit Inspect remaining medication Stress importance of compliance Thrombo-embolismEach visit Cerebral, systemic and pulmonary circulation BleedingEach visit “Nuisance” bleeding – prevention possible? Bleeding with risk or impact on QoL – prevention possible? Need to revise dose? Side effectsEach visit Continuation? Temporary cessation with bridging? Change of anticoagulant drug? Co-medicationsEach visit Prescription or over-the counter drugs? Even temporary use can be risky Blood sampling Yearly 6-monthly 3-monthly on indication Haemoglobin, renal, liver function Renal function if CrCl 30-60 ml/min or if on dabigatran and aged >75 years or fragile If CrCl 15-30 ml/min If intercurring condition may impact renal or hepatic function.

49. DABIGATRAN aPTT level (i.e. 12-24 h after ingestion )of ≥2 the upper normal limit or ECT ≥3 times and adTT ( Hemoclot) ≥0.200ng/ml after 12 h of the last dose is associated with high bleeding risks Haemodialysis can accelerate drug removal in those receiving dabigatran but no benefit established in life threatening bleeding In contrast dialysis is not effective for factor Xa inhibitors

50. Management of bleeding complications

51. NOAC specific reversal agents IDARUCIZUMAB (REVERSE-AD study) fully humanized antibody fragment (Fab) that binds dabigatran with high affinity and specificity. It rapidly reverses the anticoagulant effect of dabigatran Its binding affinity to dabigatran is 350 times higher than dabigatran to thrombin resulting in irreversible binding No indigenous target and the complex is eliminated rapidly Approved by FDA in OCT 2015 and by EMA in NOV 2015

52. ANDEXANET ALFA :(ANNEXA-A [Apixaban]) and (ANNEXA-R[Rivaroxaban]) study Recombinant modified human direct fXa reversal agent Shown to rapidly attenuate anti fXa activity in healthy volunteers in phase II trial PER977 (CIRAPARANTAG) : Water soluble small molecule nonspecific reversal agent reverses the effect by hydrogen bonding Is currently in phase 1 to 2 trial.

53. Pre-and postoperative management of patients taking NOACs

54. Managing oral antiplatelet agent in patient requiring long term oral anticoagulant Approximately 6-8% of patients undergoing PCI have an indication for long term OAC with VKA or NOACs due to various conditions as AF, mechanical heart valves or venous thromboembolism In the absence of safety and efficacy data, the use of Ticagrelor or Prasugrel as a part of triple therapy should be avoided Gastric protection with a proton pump inhibitor is recommended The dose intensity of OAC should be monitored with target INR of 2- 2.5 in patient treated with VKA and with NOACS the lowest tested dose of stroke prevention should be used (110 mg twice daily – dabigatran, 15 mg once daily rivaroxaban, 2.5 mg twice daily apixaban)

55. Newer generation DESs are recommended over BMSs in patient requiring OAC at lower bleeding risk ( HAS-BLED ≤2) For patient at high bleeding risk ( HAS-BLED ≥3) undergoing PCI who require OAC, the choice between BMS and new gen. DES need to be individualised

56. Recommendations concerning management of AF patients on NOACs who present with an acute coronary syndrome (ACS) Temporarily discontinue NOACs upon presentation Initiate DAPT therapy unless frail with high bleeding risk Administer low-dose aspirin (150–300 mg loading; 75–100 mg later) on admission, preferably combined with ADP receptor inhibitor (ticagrelor or Prasugrel preferred over clopidogrel) Initiate Parenteral anticoagulation (fondaparinux preferred) In case of STEMI: use primary PCI (radial approach) over fibrinolysis avoid UFH or enoxaparin until NOAC effect disappeared In case of NSTE-ACS: if not urgent, delay coronary angiography until waning of NOAC effect peri-procedural anticoagulation (UFH or bivalirudin preferred)

57. ESC Guidelines for the Management of AF and PCI: ‘Minimize Triple Therapy Duration ’

58. STUDIES EVALUATING COMBINATION OF NOACs or VKA + antiplatelets post PCI & Stenting The WOEST trial: Is ASA Necessary in Triple Therapy? Small-scale, open-label WOEST study (N=573) compared safety outcomes with triple therapy (VKA plus clopidogrel plus ASA) vs dual therapy (VKA plus clopidogrel): 69% of WOEST patients had AF. Use of dual therapy was associated with significantly lower rates of bleeding and overall mortality vs triple therapy, with similar rates of thrombotic events

59. RE-DUAL PCI – Dabigatran In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual- therapy groups) Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.

60. PIONEER AF PCI – Rivaroxaban In PIONEER AF-PCI, both rivaroxaban 15 mg OD plus single antiplatelet therapy and rivaroxaban 2.5 mg BID plus DAPT demonstrated significantly improved safety vs VKA plus DAPT. Comparable efficacy vs VKA plus DAPT was observed, however, the trial was not powered to definitively demonstrate either superiority or non-inferiority for efficacy, Considering both safety and practical use, the reduced dose of rivaroxaban 15 mg OD plus single antiplatelet therapy could become the approach of choice once approved. AUGUSTUS – Apixaban EVOLVE-AF-PCI – Edoxaban

61. NOACs vs. VKA in AF patients with a malignancy Active malignancy was an exclusion criteria in NOAC trials. When anticoagulant therapy is needs to be initiated in patients with malignancy, therapy with VKA or heparin should be considered over NOACs, because of the clinical experience with these substances, the possibility of close monitoring and reversal options.

62. Stroke patients-Management of post-acute phase Ischemic stroke If infarct size not expected to increase risk of secondary intracerebral bleeding, re-initiate: - in patients with TIA after 1 day - small, non-disabling infarct after 3 days - large infarcts not before 2 weeks TIA of cardioembolic origin (Re)start NOACs as soon as possible. Bridging with LMWH not required. In AF patients not suitable for VKAs, apixaban is superior to aspirin in stroke prevention Patients with AF and significant carotid stenosis Carotid endarterectomy and not stenting recommended to avoid triple therapy

63. NOACs and Cardioversion Cardioversion in patients with NOACs have similar thromboembolic risk as under warfarin X-VeRT trial confirmed the low pericardioversion stroke risk in patient with Rivaroxaban compared to warfarin. Ongoing studies: ENMATE- Rivaroxaban ENSURE-Edoxaban NOACS & Cardioversion

64. NOACs in renal dysfunction – Practical recommendations for dosing in chronic kidney disease DabigatranApixabanEdoxaban *Rivaroxaban When CrCl 30-49 ml/min, 150 mg BID is possible but 110 mg BID if ‘high risk of bleeding’ or ‘recommended’ Note: 75 mg BID approved in US only ** -if CrCl 15-30 ml/min - if CrCl 30-49 ml/min -and other factor (e.g. verapamil) CrCl 15-29 ml/min: 2.5 mg BID is possible Serum creatinine ≥ 1.5 mg/dl in combination with age ≥80 years or weight ≤60 kg or with other drug factor: 2.5 mg BID not available15 mg OD when CrCl 15-49 ml/min

65. Conclusion NOACs shown to have favorable balance between efficacy and safety compared with VKAs. Advantages of NOACs included fewer interactions with medications and no interaction with food, rapid onset, fast clearance and no need for laboratory monitoring. Individualized anticoagulant treatment should be based on patient’s age, renal function, and concomitant treatment. Further research is underway to develop reliable and accessible measures to monitor the anticoagulant effect of the new agents, as well as antidotes with the ability to effectively reverse anticoagulation effect.