Noacs

newer oral anticoagulants

1. NEWER ORAL ANTI COAGULANTS Dr . k . nagendra prasad NEWER ORAL ANTICOAGULANTS

2. TOPIC OUTLINE Introduction Types of NOAC s and their properties Advantages of NOAC s over VKA Start-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 regimens. NEWER ORAL ANTICOAGULANTS

3. SPECIAL SITUATIONS patients undergoing a planned surgical intervention or ablation. patients undergoing an urgent surgical intervention. patients with AF and coronary artery disease. NOACs vs. VKAs in AF patients with a malignancy. NEWER ORAL ANTICOAGULANTS

4. Introduction Vitamin K antagonists (VKAs) are the mainstay of management of thromboembolic events for > 5decades. Despite its unquestionable impact to prevent strokes, they have significant limitations, such us common drug or food interactions, and the necessity of regular monitoring to adjust doses, inter personal variation in response. NEWER ORAL ANTICOAGULANTS

5. NEWER ORAL ANTICOAGULANTS

6. NEWER ORAL ANTICOAGULANTS

7. NEWER ORAL ANTICOAGULANTS

8. NEWER ORAL ANTICOAGULANTS

9. NEWER ORAL ANTICOAGULANTS

10. NEWER ORAL ANTICOAGULANTS

11. NEWER ORAL ANTICOAGULANTS

12. NEWER ORAL ANTICOAGULANTS

13. NEWER ORAL ANTICOAGULANTS

14. Indications for NOAC s Prevention of arterial thromboembolic events in non- valvular atrial fibrillation and VTE prophylaxis following hip and knee-replacement surgery – DABIGATRAN ,RIVAROXABAN, APIXABAN. Treatment of deep vein thrombosis - RIVAROXABAN NEWER ORAL ANTICOAGULANTS

15. Dabigatran Etexilate Dabigatran etexilate , a prodrug of dabigatran , which reversibly inhibits both free and clot bound thrombin, It has an oral bioavailability of 6%. After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran by esterases . Plasma levels of dabigatran peak 2 hours after drug administration. Dabigatran has a half-life of 14 to 17 hours, which permits once- or twice-daily administration, and 80% of the drug is excreted unchanged by the kidneys. NEWER ORAL ANTICOAGULANTS

16. Coadministration of dabigatran etexilate and amiodarone,verapamil , quinidine,dronedarone - strong P- gp inhibitors, increases dabigatran levels. It shouls be taken with food or water to minimise dyspepsia. If a dose is missed it should be taken within 6 hours. NEWER ORAL ANTICOAGULANTS

17. NEWER ORAL ANTICOAGULANTS

18. DOSE REGIMEN for acute VTE: 150 mgBID ; for VTE prevention after knee or hip replacement surgery (14 or 30 days, respectively): 110 mg (initial dose) then 220 mg daily. COMMON SIDE EFFECTS – Indigestion, upset stomach, or burning ,stomach pain Allergic reaction, including hives, rash, and itching Bleeding NEWER ORAL ANTICOAGULANTS

19. The RE-LY (Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ) phase III trial was a prospective, randomized, open-label trial comparing two blinded doses of dabigatran etexilate (110 or 150 mg BID) with warfarin in 18,113 patients with AF and at least one additional risk factor (a mean CHADS score of 2.1). NEWER ORAL ANTICOAGULANTS

20. RESULTS 150 mg BID dose – superior to warfarin for reduction of stroke and systemic embolism with similar major bleeding. 110 mg BID dose – non inferior to warfarin for SSE but with significant lower bleeding rates. ICH is significantly low with both doses . NEWER ORAL ANTICOAGULANTS

21. RELY-ABLE Assessed the Additional information on the long-term effects of the two doses of dabigatran in patients completing RE-LY by extending the follow-up of patients on dabigatran from a mean of 2 years at the end of RE-LY by an additional 2.3 years. RELY-ABLE confirmed the results reported in RE-LY. Conclusions— During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. NEWER ORAL ANTICOAGULANTS

22. VTE trials RECOVER and REMEDY – Non inferior to warfarin in VTE prevention (2.4% vs 2.1%) No diffrerences in major bleeding. NEWER ORAL ANTICOAGULANTS

23. RIVAROXABAN It has an oral bioavailability of 80%. Rivaroxaban has a rapid onset of action and a half-life of 7 to 11 hours. Rivaroxaban has a dual mode of elimination; one third is cleared as unchanged drug via the kidneys, one third is metabolized by the liver via CYP3A4-dependent and -independent pathways with the metabolites then excreted in the feces, and one third is metabolized in the liver with the inactive metabolites then eliminated via the kidneys. NEWER ORAL ANTICOAGULANTS

24. 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 levels. There is only a minor interaction between Rivaroxiban and verapamil unlike dabigatran and edoxaban . Co adminstration of FLUVASTATIN or ROSUVASTATIN with this drug does not need dose reduction of rivaroxiban . NEWER ORAL ANTICOAGULANTS

25. NEWER ORAL ANTICOAGULANTS

26. NEWER ORAL ANTICOAGULANTS

27. DOSE REGIMEN- for acute VTE: 20 mg daily (15 mg twice daily for initial 21 days); for VTE prevention after knee or hip replacement surgery (14 or 30 days, respectively): 10 mg daily NEWER ORAL ANTICOAGULANTS

28. ROCKET AF The ROCKET AF was a double-blinded study in which 14,264 patients with non- valvular AF and CHADS2 scores ≥2 (mean 3.5) were studied. After a median follow-up of 1.93 years, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There were no differences in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Gastrointestinal bleeding and transfusion requirements were greater with rivaroxaban . Total mortality was not significantly different between groups. NEWER ORAL ANTICOAGULANTS

29. ATLAS : Background - Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. NEWER ORAL ANTICOAGULANTS

30. ATLAS ACS 2-TIMI 51 trial compared rivaroxaban 2.5 mg or 5 mg twice daily (unlike the 20 mg once-daily dose for atrial fibrillation) with placebo in 15 526 patients following ACS. At a 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 and 8.8% with rivaroxaban 5mg with no interaction by ACS subtype. Rates of definite, probable or possible stent thrombosis were 2.2% and 2.3% with 2.5 and 5 mg rivaroxaban , respectively, vs. 2.9% with placebo . Rates of CV death were signifi cantly lower with rivaroxaban 2.5 mg compared with placebo but not with rivaroxaban 5 mg (4.0%). NEWER ORAL ANTICOAGULANTS

31. 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. Intracranial haemorrhage rates were 0.4% with 2.5 mg and 0.7% with 5 mg rivaroxaban 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 ischaemic and low bleeding risks NEWER ORAL ANTICOAGULANTS

32. CONCLUSION - In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. NEWER ORAL ANTICOAGULANTS

33. VTE trials 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 loer bleeding risk than warfarin . EINSTEIN EXTENSION – similar results. NEWER ORAL ANTICOAGULANTS

34. 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 non- valvular AF. It is well absorbed achieving peak plasma concentration in 1–4 h. It is predominantly metabolized in liver. It is a mild P- glycoprotein inhibitor. Compared to other NOACS it has least bleeding complications and greater efficacy. NEWER ORAL ANTICOAGULANTS

35. NEWER ORAL ANTICOAGULANTS

36. NEWER ORAL ANTICOAGULANTS

37. ARISTOTLE The Apixaban for Reduction In STroke and Other ThromboemboLic Events in AF (ARISTOTLE) compared apixaban (5 mg BID) with dose-adjusted warfarin in 18,201 patients with non- valvular AF (a mean CHADS2 scoreof2.1). After amean followup of 1.8 years, apixaban was significantly better than warfarin , with fewer primary outcomes (overall strokes and systemic emboli), but with no significant differences in rates of ischaemic strokes. Patients treated with apixaban had significantly fewer intracranial bleeds, but GI bleedings were similar between both groups. All-cause mortality was found to be significantly lower in the apixaban group. NEWER ORAL ANTICOAGULANTS

38. Apixaban was also compared with aspirin alone in the AVERROES study, a double-blinded study of 5599 patients who were not suitable candidates for VKA treatment (mean CHADS2 score of 2). After a mean follow-up of 1.1 years, the study was prematurely stopped due to a clear benefit in favour of apixaban . Patients with severe renal impairment (serum creatinine.2.5 mg/ dL or CrCl ,25 mL /min) were excluded from the ARISTOTLE and AVERROES trials. NEWER ORAL ANTICOAGULANTS

39. APPRAISE The Apixaban for Prevention of Acute Ischaemic Events ( APPRAISE ) 2 study assessed the effects of the oral factor Xa inhibitor apixaban 5 mg twice daily compared with placebo, in addition to standard-of-care antiplatelet therapy following ACS; It was terminated early (median 8 months) due to a markedly increased risk of severe bleeds, including intracranial haemorrhage , without any apparent benefit in terms of ischaemic events NEWER ORAL ANTICOAGULANTS

40. Edoxaban Edoxaban is another reversible factorXainhibitor , recently approved by theFDA but not yet by the EMA. It is rapidly absorbed and reaches peak plasma concentration within 1–2 h. Up to 50% of edoxaban is eliminated by the kidneys and rest through multiple pathways. It is also a substrate for P-glycoprotein-concomitant administration with quinidine , amiodarone , and verapamil will result in a significant increase of plasma levels of edoxaban . Therefore, in patients under concomitant use of potent glycoprotein inhibitors , body weight < 60 kg, or moderate–severe renal impairment ( CrCl < 50 mL /min), edoxaban dose should be reduced by 50%. NEWER ORAL ANTICOAGULANTS

41. NEWER ORAL ANTICOAGULANTS

42. NEWER ORAL ANTICOAGULANTS

43. ENGAGE AF-TIMI The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation– Thrombolysis in Myocardial Infarction (ENGAGE AF-TIMI 48) compared the two dose regimens of edoxaban (30 and 60 mg once daily) with warfarin in a total of 21,026 patients with non- valvular AF. After a follow-up of 2.8 years, both regimens of edoxaban were non-inferior to warfarin with respect to the prevention of stroke or systemic embolism. NEWER ORAL ANTICOAGULANTS

44. Edoxaban was associated with lower, dose-related rates of bleeding, including major bleeding, intracranial bleeding, and life-threatening bleeding. GI bleeding - occurred more frequently with high-dose edoxaban but less frequently with low-dose edoxaban compared with warfarin . NEWER ORAL ANTICOAGULANTS

45. Finally, the incidence rate of haemorrhagic stroke and the rate of death from cardiovascular causes were significantly lower with both edoxaban regimens. Patients with severe renal dysfunction ( CrCl < 30 mL /min), high risk of bleeding, use of dual antiplatelet , acute coronary syndromes or coronary revascularization, and strokes within 30 days were excluded. NEWER ORAL ANTICOAGULANTS

46. HOKUSAI VTE – in DVT it is non inferior to warfarin and in PE it is superior to warfarin with similar bleeding risk in both conditions . NEWER ORAL ANTICOAGULANTS

47. OTHER fXa inhibitors These are betrixaban , YM150, and TAK442. Betrixaban has the unique features of a 15-hour half-life and extrarenal clearance. Betrixaban and YM150 are undergoing phase II evaluation for stroke prevention in AF, whereas TAK442 is undergoing phase II evaluation for prevention of recurrent ischemia in ACS patients. NEWER ORAL ANTICOAGULANTS

48. CONCOMITANT USE OF NOAC and DIGOXIN Digoxin is a P-glycoprotein inhibitor and commonly used drug in AF. But there is clinically relavent interaction between digoxin and NOACS. NEWER ORAL ANTICOAGULANTS

49. Comparison between new oral anticoagulants There no direct head-to-head comparisons between these drugs. NOACs have been made in randomized, controlled trials, and extrapolation from primary trial data is the best available strategy for medical prescription. However, due to differences in trial design, in the estimated risk for stroke in the study population, comparator uniformity, and definitions of efficacy and safety endpoints make complex direct comparisons. NEWER ORAL ANTICOAGULANTS

50. Comparative analysis of the four NOACs confirmed that NOACs significantly reduced the composite of stroke or systemic embolic events by 19% compared with warfarin , which very much depended on large reduction in haemorrhagic strokes. Data for all four NOACS showed that they were associated with a 14% non-significant reduction in major bleedings. NEWER ORAL ANTICOAGULANTS

51. NEWER ORAL ANTICOAGULANTS

52. General recommendations NEWER ORAL ANTICOAGULANTS

53. How to measure effect NEWER ORAL ANTICOAGULANTS

54. The activated partial thromboplastin time ( aPTT ) may provide a qualitative assessment of the presence of dabigatran . The prothrombin time (PT) may provide a qualitative assessment of the presence of factor Xa inhibitors. Quantitative tests for DTI and FXa inhibitors - diluted thrombin-time and chromogenic assays, respectively, But they may not (yet) be routinely available in most hospitals. Moreover, there are no data on a cut-off of these specific tests below which elective or urgent surgery is ‘safe’, and therefore their use in this respect cannot be recommended at this time. NEWER ORAL ANTICOAGULANTS

55. When interpreting these results, consider when the last dose of NOAC was administered patient characteristics, and renal function – determinants of elimination half-life NEWER ORAL ANTICOAGULANTS

56. DABIGATRAN – aPTT level (i.e. 12–24 h after ingestion) of ≥2 the upper limit of normal or ECT ≥3 times and a dTT ( Hemoclot ) - .200 ng / mL after 12 h of the last dose is associated with a higher risk of bleeding. NEWER ORAL ANTICOAGULANTS

57. ‘ What if’ scenarios NEWER ORAL ANTICOAGULANTS

58. Patient has a bleeding complication Specific antidotes for NOACs are still lacking and the strategies to reverse anticoagulant effect are limited. Time is the best advantage of NOACs, in view of their relatively short elimination half-lives. If a major bleeding complication occurs, standard supportive measurements must be started. These include mechanical compression, surgical haemostasis , fluid replacement, and additional haemodynamic support. NEWER ORAL ANTICOAGULANTS

59. Haemodialysis can accelerate drug removal in those patients receiving dabigatran ; however, its benefit in life-threatening bleeding has not been established. In contrast, dialysis is not effective for factor Xa inhibitors due to their high plasma binding and lower renal clearance. The administration of prothrombin complex concentrate (PCC) or activated prothrombin complex ( aPCC ) concentrates can be considered in life-threatening bleeding, despite the scarce evidence. Administration of PCC could start at a dose of 25 U/kg and can be repeated if clinically indicated. NEWER ORAL ANTICOAGULANTS

60. NEWER ORAL ANTICOAGULANTS

61. Novel reversal agents in clinical development There are currently 3 NOAC-specific reversal agents in clinical development: (1) andexanet alfa , (2) idarucizumab , and (3) PER977 NEWER ORAL ANTICOAGULANTS

62. “ Andexanet alfa ” is a recombinant, modified human factor Xa that is being developed as a direct factor Xa reversal agent. It has been shown to rapidly attenuate the anti- FXa activity of apixaban , rivaroxaban , edoxaban , and enoxaparin and to restore thrombin generation in phase 2 studies in healthy human volunteers. Andexanet alfa has been generally well tolerated and is currently in phase 3 clinical trials (ANNEXA-A [ apixaban ] and ANNEXA-R [ rivaroxaban ]). NEWER ORAL ANTICOAGULANTS

63. Idarucizumab ” is a fully humanized antibody fragment ( Fab ) that binds dabigatran with high affinity and specificity. Idarucizumab rapidly reverses the anticoagulant effect of a 220 mg twice daily dose of dabigatran in healthy human volunteers and is currently being evaluated in phase 3 trials. Idarucizumab has been generally well tolerated in healthy human volunteers and is currently in clinical trials in the RE-VERSE AD study. NEWER ORAL ANTICOAGULANTS

64. PER977 ( ciraparantag )” is a water-soluble small-molecule nonspecific reversal agent. In preclinical testing and during testing with edoxaban in healthy male volunteers, it rapidly reversed the effect of multiple anticoagulants, purportedly via hydrogen bonding. It is currently in phase 1 to 2 clinical testing in healthy human volunteers. NEWER ORAL ANTICOAGULANTS

65. Patient undergoes intervention The most appropriate management should be individualized depending on the NOAC used, the type of surgery, the required anaesthetic regimen, and the patients’ characteristics, particularly, on their renal function. For patients undergoing minor interventions,NOACs can be continued around the time of the procedure, similar to VKA-treated patients. Some examples include skin cancer removal, joint injection, cataract removal, or tooth extraction in which an adequate local haemostasis is commonly possible. Intervention should not be performed at peak concentrations but 12 or 24 h after the last intake, depending on their specific regimen dosing. NEWER ORAL ANTICOAGULANTS

66. NEWER ORAL ANTICOAGULANTS

67. Managing oral antiplatelet agents in patients requiring long-term oral anticoagulants Approximately 6 – 8% of patients undergoing PCI have an indication for long-term OAC with VKA or NOACs due to various conditions such as atrial fibrillation, mechanical heart valves or venous thromboembolism . In the absence of safety and efficacy data, the use of prasugrel or ticagrelor as part of triple therapy should be avoided. Gastric protection with a proton pump inhibitor is recommended. The dose intensity of OAC should be carefully monitored with a target INR of 2.0 – 2.5 in patients treated with VKA & in patients treated with NOACs, the lowest tested dose for stroke prevention should be applied (i.e. dabigatran 110 mg twice a day, rivaroxaban 15 mg once a day, apixaban 2.5 mg twice a day) NEWER ORAL ANTICOAGULANTS

68. new-generation DESs are recommended over BMSs in patients requiring OAC at low bleeding risk (HAS-BLED ≤2). For patients at high bleeding risk (HAS-BLED ≥3) undergoing PCI who require OAC, the choice between a BMS and a new-generation DES needs to be individualised . it is not known whether there are differences according to the type of OAC (NOACs versus VKA) or stent platform. NEWER ORAL ANTICOAGULANTS

69. NEWER ORAL ANTICOAGULANTS

70. Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting ( REDUAL-PCI) The main objective of this study is to compare a Dual Antithrombotic Therapy (DAT) regimen of 110mg dabigatran etexilate b.i.d . plus clopidogrel or ticagrelor (110mg DE DAT) and 150mg dabigatran etexilate b.i.d . plus clopidogrel or ticagrelor (150mg DE-DAT) with a Triple Antithrombotic Therapy (TAT) combination of warfarin plus clopidogrel or ticagrelor plus ASA <= 100mg once daily ( warfarin -TAT) in patients with Atrial Fibrillation that undergo a PCI with stenting (elective or due to an Acute Coronary Syndrome). The study aims to show non-inferiority of each dose of DE-DAT when compared to Warfarin -TAT in terms of safety. Safety will be determined by comparing the rates of bleeding events and Clinically Relevant Non Major Bleeding Events. NEWER ORAL ANTICOAGULANTS

71. New oral anticoagulants vs.vitamin K antagonists in atrial fibrillation patients with a malignancy – Active malignancy usually was an exclusion criterion in NOAC trials. When anticoagulant therapy needs to be initiated in a patient with malignancy, therapy with VKAs or heparins should be considered over NOACs, because of the clinical experience with these substances, the possibility of close monitoring (for VKAs and unfractionated heparin, UFH), and reversal options (for VKAs and UFH). NEWER ORAL ANTICOAGULANTS

72. Patient need to switch between anticoagulant regimens NEWER ORAL ANTICOAGULANTS

73. Conclusion New oral anticoagulants have shown to have a favourable balance between efficacy and safety compared with VKA s. Advantages Of NOACs include 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 patients’ age, renal function, and concomitant treatments. Further research is underway to develop reliable and accessible measures to monitor the anticoagulant effects of the new agents, as well as antidotes with the ability to effectively reverse anticoagulation effect. NEWER ORAL ANTICOAGULANTS

74. NEWER ORAL ANTICOAGULANTS