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![Rates of Major GI Bleeding from the pivotal NOAC trials
Dabigatran 150 mg BD
(n=6,076)
Rivaroxaban 20 mg OD
(n=7,131)
Apixaban 5 mg BD
(n=9,088)
0
0.5
1
1.5
2
2.5
1.9
2.0
0.8
Major GI bleeding (%/year)1,2
%/year
1. Desai et al. Thromb Hemost 2013;110:205-212;
2. Giugliano et al. N Engl J Med 2013;369:2093–2104.
Hazard ratio for
major GI bleeding
vs warfarin
1.49
[CI 1.21–1.84],
p=0.002
1.61
[CI 1.30–1.99]
0.89
[CI 0.70–1.15]
Dabigatran 110 mg does not increase GI bleeding vs warfarin
• Adjusted-dose warfarin increases the risk of major GI bleeding approximately three-fold compared with placebo.
• The addition of aspirin or other anti-platelet agents to warfarin increases the risk of major GI bleeding approximately two-fold (compared
with warfarin alone).
There are no head-to-head trials comparing NOACs, direct
comparisons cannot be made](https://image.slidesharecdn.com/udaipur03-240807114621-0e2a0a9a/75/NOVEL-ANTI-COAGULANTS-DABIGATRON-RIVOROXABAN-APIXABAN-30-2048.jpg)
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NOVEL ANTI COAGULANTS DABIGATRON RIVOROXABAN APIXABAN
The document discusses stroke risk management in patients with atrial fibrillation (AF), focusing on balancing the reduction of thromboembolic events with the risk of bleeding. It highlights the CHA2DS2-VASc and HAS-BLED scoring systems for risk stratification and outlines the benefits of non-vitamin K antagonist oral anticoagulants (NOACs) as the standard treatment over warfarin, especially in elderly and renal-compromised patients. The document also emphasizes the need for careful monitoring and individualized treatment decisions based on patient-specific factors, including prior bleeding history and gastrointestinal bleeding risks.
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- 1.
- 3. Managing Stroke Risk: ClinicalEvidence
- 4. Stroke prevention inAF is about finding the balance Risk for thromboembolic events Risk for bleeding Fang. Ann Intern Med 2011;155:636-7. Aim: Reduce the risk of thromboembolic events with a minimal risk of bleeding complications
- 5. Stroke risk stratification:CHA2DS2-VASc 1. Lip et al. Chest 2010;137:263–272. 2. Lip et al. Stroke 2010; 41:2731–2738. Risk factor CHA2DS2- VASc score1 Congestive heart failure/LV dysfunction 1 Hypertension 1 Aged ≥75 years 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease (prior MI, PAD or aortic plaque) 1 Aged 65–74 years 1 Sex category (i.e. female gender) 1 Maximum score 9 Risk of stroke stratified by CHA2DS2-VASc score CHA2DS2-VASc score1 Adjusted stroke rate (%/year)*2 0 0% 1 1.3% 2 2.2% 3 3.2% 4 4.0% 5 6.7% 6 9.8% 7 9.6% 8 6.7% 9 15.2% *TE rate during 1 year, adjusted for warfarin use. Theoretical TE rates without therapy: assuming that warfarin provides a 64% reduction in TE risk. Hypertension: systolic BP >140 mmHg and/or diastolic BP >90 mmHg on at least two occasions, or on antihypertensive medication; Diabetes: Fasting plasma glucose level ≥7.0 mmol/L (126 mg/dL), or treatment with oral hypoglycemic agent and/or insulin.
- 6. Bleeding risk stratification:HAS-BLED Risk factor HAS-BLED score1 Hypertension 1 Abnormal renal / liver function (1 point each) 1 or 2 Stroke 1 Bleeding 1 Labile INRs 1 Elderly (>65 years) 1 Drugs or alcohol (1 point each) 1 or 2 Maximum score 9 1. Pisters et al. Chest. 2010;138:1093–1100. 2. Kirchhof et al. Eur Heart J 2016;37:2893–962. • Several CHA2DS2-VASc and HAS-BLED risk factors overlap (age, hypertension, stroke)2 • A high bleeding risk score should generally not result in withholding OAC therapy. Rather, bleeding risk factors should be identified and treatable factors corrected2 Hypertension: systolic BP >160 mmHg; Abnormal renal function: Dialysis, transplant, Cr >2.26 mg/dL or >200 µmol/L; Abnormal liver function: Cirrhosis or bilirubin >2x normal or AST/ALT/AP >3x normal; Bleeding: Prior major bleeding or predisposition to bleeding; Labile INR: TTR <60%; Drugs: antiplatelets or NSAIDs.
- 7. Managing stroke riskin AF: European Society of Cardiology 2020 Guidelines Hindricks G et al. Eur Heart J. 2021 Feb 1;42(5):373-498.
- 8. Managing Stroke Risk: ClinicalEvidence
- 9. Stroke prevention inatrial fibrillation: Oral anticoagulation is the standard of care1 9 ESC, European Society of Cardiology; NOAC, non-vitamin K antagonist oral anticoagulant; RRR, relative risk reduction; VKA, vitamin K antagonist. 1. Kirchhof et al. Eur Heart J 2016;37:2893–962; 2. Hart et al. Ann Intern Med 2007;146:857-67; 3. Ruff et al. Lancet 2014;383:955-62. 22% RRR vs placebo Aspirin2 38% RRR vs aspirin VKA2 19% RRR vs VKA NOACs3 Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk (ESC 2016)1
- 10. VKA (warfarin) therapy:Overview Long established, effective stroke prevention in patients with AF (RRR, 64% vs placebo/control)1 However, warfarin has several limitations: 1. Hart et al. Ann Intern Med 2007;146:857–867; 2. Weitz. Eur J Haematol 2010;85 (Suppl 72);1-28; 3. Camm et al. Eur Heart J 2010;31:2369-429. Genetic variations in metabolism2 Long half-life3 Slow onset and offset of action2,3 Interactions with drugs and diet2 Narrow therapeutic window (INR range)2 Dose adjustments2 Risk of stroke2 Risk of bleeding2 Frequent coagulation monitoring2 Frequent dose adjustments2 Issue in perioperative anticoagulation (bridging)3
- 11. Management considerations inAF patients receiving warfarin Kirchhof et al. Eur Heart J 2016;37:2893–2962. Warfarin is an effective treatment for managing stroke risk in AF patients, but is limited by its narrow therapeutic window Frequent INR monitoring and dose adjustments are required to maintain patients in the therapeutic window (INR 2.0–3.0) Patients’ time in therapeutic range (TTR) should be kept as high as possible (≥70%) and closely monitored High TTR If a patient’s TTR cannot be sustained above 70%, switching to a NOAC should be considered
- 12. • Oral directthrombin inhibitors(DTIs): Dabigatran • Oral direct factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban. Classification of NOACs 08/09/201 6 DrAnup Petare. 4
- 14. NOACs: Advantages overwarfarin1-5 Established criteria for dose- adjustment in elderly patients and in cases of renal impairment2-5 1. Steffel et al. Eur Heart J 2018;39:1330–1393; 2. Dabigatran SmPC Available at http://www.ema.europa.eu last accessed on 30th April 2021 3. Rivaroxaban SmPC Available at http://www.ema.europa.eu last accessed on 30th April 2021 4. Apixaban LPDELI052021 (Version no. 13), dated 17th June 2021 5. Edoxaban SmPC. SmPCs Available at http://www.ema.europa.eu last accessed on 30th April 2021 6. Yeh et al. Arterioscler Thromb Vasc Biol. 2015; 35: 1056-1054. Adapted from Yeh et al. Arterioscler Thromb Vasc Biol. 2015; 35: 1056-1054.
- 15. Dabigatran Etexilate Dabigatran etexilate,a prodrug of dabigatran, which reversibly inhibits both free and clot bound thrombin. 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. Coadministration of dabigatran etexilate and amiodarone, verapamil, quinidine, dronedarone - strong P- gp inhibitors, increases dabigatran levels. It should be taken with food or water to minimise dyspepsia.
- 16. RIVAROXABAN It hasan oral bioavailability of 80%. Rivaroxaban has a rapid onset of action and a half-life of 7to 11 hours. There is only a minor interaction between Rivaroxiban and verapamil unlike dabigatran and Edoxaban. Rivaroxaban is a substrate for P-gp and concomitant administration of both P-gp and potent inhibitors of CYP3A4, such as ketoconazole or ritonavir is contraindicated because they increase plasma drug levels.
- 17. Apixaba n Apixaban isa direct, reversible, competitive, and selective inhibitor of factor Xa 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.
- 19. Dosing –Non-valvular Atrial Fibrillation DagibatranRivaroxaban Apixaban Crcl > 50ml / min 150mg twice daily 20mg once daily Crcl 30-50ml / min 110mg twice daily 15mg once daily 5mg twice daily Crcl 15-30ml / min Contraindicated Contraindicated Special Older than 75 populations years old 110mg twice daily Not applicable At least two of following: -older than 80 yo -Weight less than 60kg -Scr > 1.5 mg/dl -2.5mg twice daily
- 20. How to manage NOACsin Clinical Practice for SPAF • Elderly • Renal compromised • High Risk of GI Bleeding
- 21. NOACs in ElderlyPatients
- 22. Efficacy and safetyof NOACs vs Warfarin in patients ≥75 years of age There are no head-to-head RCTs comparing the NOACs. Comparisons cannot be made between individual NOACs based Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959–7 *Reduced to 15 mg if CrCl 30–49 mL/min; **Reduced to 2.5 mg twice-daily if at least two of the following criteria were present: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dl. † P<0.001 vs warfarin. ‡ Reduced dose as per the SmPC. BID, twice daily; ICH, intracranial haemorrhage; QD, once daily
- 23. NOACs in theElderly Population Expert Recommendation >75 years Diener, et al. Eur Heart J 2017;38:860-868. Apixaban 5 mg twice daily First Choice Dabigatran 110 mg BID Rivaroxaban 20 mg daily Edoxaban 60 mg daily Second Choice Edoxaban is not approved for use in India
- 24. NOACs in RenalCompromised Patients
- 25. Dabiga Edoxa RivaApixa 0% 20% 40% 60% 80% 100% 80 50 33 27 % eliminated in the kidneys NOACs in Renal Failure Renal Excretion of NOACs Diener, et al. Eur Heart J 2017;38:860-868. Edoxaban is not approved for use in India
- 26. NOACs in RenalFailure Dose Adjustment of NOACs based on Renal Excretion Steffel et al. Eur Heart J 2018 LPDELI122020 (Version no. 10), dated 28th January 2021 * Dosing regimen of 2.5 mg BID in patients with 2 or more of the following criteria: –Serum Cr ≥1.5 mg/dL –Age ≥80 years –Body weight ≤60 kg Edoxaban is not approved for use in India #2 x 110 mg in patients at high risk of bleeding (per SmPc). #Other dose reduction criteria may apply (weight <_60 kg, concomitant potent P-Gp inhibitor therapy). CrCl Rivaroxaban Dabigatran Edoxaban Apixaban 95 mL/min 50 mL/min 40 mL/min 30 mL/min 15 mL/min Dialysis 2 x 150 mg 2 x 150 mg or 2 x 110 mg# 20 mg 15 mg 15 mg 30 mg 30 mg 60 mg 60 mg 2 x 5 mg 2 x 2.5 mg* Apixaban 2x 5 mg 2x 2.5 mg* Update
- 27. A systematic review andmeta-analysis: Apixaban vs Warfarin (After 2017) Abdullah et al. Cardiovascular Revascularization Medicine 2020. Conclusion: Apixaban may serve as a potential alternative to warfarin as an anticoagulation agent in patients with ESRD and AF due to a significantly lower risk of major bleeding, without increased risk of stroke. ESRD: End Stage Renal Disease
- 28. NOACs in patientswith High Risk of GI Bleeding
- 29. Mechanisms of NOAC-relatedGI Bleeding Pathogenesis of novel oral anticoagulant-related gastrointestinal bleeding. NOAC: Novel oral anticoagulant; GIB: Gastrointestinal bleeding. Cheung et al_World J Gastroenterol 2017 March 21; 23(11): 1954-1963
- 30. Rates of MajorGI Bleeding from the pivotal NOAC trials Dabigatran 150 mg BD (n=6,076) Rivaroxaban 20 mg OD (n=7,131) Apixaban 5 mg BD (n=9,088) 0 0.5 1 1.5 2 2.5 1.9 2.0 0.8 Major GI bleeding (%/year)1,2 %/year 1. Desai et al. Thromb Hemost 2013;110:205-212; 2. Giugliano et al. N Engl J Med 2013;369:2093–2104. Hazard ratio for major GI bleeding vs warfarin 1.49 [CI 1.21–1.84], p=0.002 1.61 [CI 1.30–1.99] 0.89 [CI 0.70–1.15] Dabigatran 110 mg does not increase GI bleeding vs warfarin • Adjusted-dose warfarin increases the risk of major GI bleeding approximately three-fold compared with placebo. • The addition of aspirin or other anti-platelet agents to warfarin increases the risk of major GI bleeding approximately two-fold (compared with warfarin alone). There are no head-to-head trials comparing NOACs, direct comparisons cannot be made
- 31. Conclusion: The riskof GI bleeding significantly varies among different NOAC regimens, and evidence shows that Apixaban and Edoxaban had the most favorable MGI bleeding safety profile, while rivaroxaban and dabigatran etexilate were the least safe. MGI- Major Gastrointestinal Bleeds Edoxaban is not approved for use in India
- 32. Patient scenario 1stchoice 2nd choice Comments Age ≥ 75 years Apixaban 5 mg BID (2.5 mg BID if ≥ 2 of the following: age ≥ 80 years, body weight ≤ 60 kg, or creatinine ≥ 1.5 mg/dL) • Dabigatran 110 mg BID; OR • Rivaroxaban 20 mg QD; OR • Edoxaban 60 mg QD - High risk of GI bleeding • Apixaban 5 mg BID; OR • Dabigatran 110 mg BID • Dabigatran 150 mg BID; OR • Edoxaban 60 mg QD; OR • Rivaroxaban 20 mg QD • GI bleeding risk associated with any anticoagulant is increased by concurrent use of antiplatelet agents, including aspirin • NOAC agents should be restarted as soon as deemed safe to do so once GI bleeding has been controlled • The increased GI bleeding risk of dabigatran and rivaroxaban are most evident in patients ≥ 75 years old 1. Diener HC, et al. Eur Heart J 2017;38:852-9. 2. Diener HC, et al. Eur Heart J 2017;38:860-8. GI, gastrointestinal; CrCl, creatinine clearance; BID, twice daily; QD, once daily; NOAC, non-vitamin K antagonist oral anticoagulant; AF, Atrial Fibrillation 2017 Expert Consensus Recommendations Antithrombotic therapy for AF: 2018 CHEST Guideline and Expert Panel Report Patient scenario Comments Patients with prior unprovoked bleeding, warfarin-associated bleeding, or at high risk of bleeding It suggests using Apixaban, Edoxaban, or Dabigatran 110 mg (where available) as all demonstrate significantly less major bleeding compared with warfarin Patients with prior GI bleeding Apixaban or Dabigatran 110 mg BID may be preferable as they are the only NOACs associated without an increased risk of GI bleeding compared with warfarin Lip GYH, et al. Chest 2018;154:1121-201.
- 33.
- 34. Kirchhof, Europace 2016:18,1609–1678 Managementof AF Detected After Stroke All patients with ischemic stroke & AFDAS should be anticoagulated C: III LoE: B 1 for Males 2 for Females ≥2 for Males ≥3 for Females 0 for Males 1 for Females C: I LoE: A C: IIa LoE: B VKA NOAC NOAC VKA ⊖ CHA2DS2-VASc Score Weight of evidence/opinion is in favor of usefulness or efficacy = should be considered Evidence and/or general agreement that treatment is beneficial, useful, and effective = is indicated Evidence and/or general agreement that treatment is not useful or effective; and in some cases can be harmful = is not recommended
- 35. Stroke/SE ICH DeathMajor bleed Dabigatran 110 mg BID Better Better Dabigatran 150 mg BID Better Better Rivaroxaban 20/15 mg QD Better Apixaban 5/2.5 mg BID Better Better Better Better NOACs vs. Warfarin Summary of Major Efficacy & Safety Outcomes Created from capstone papers of each trial: 1. Connolly et al. N Engl J Med 2009;361:1139–51; 2. Patel et al. N Engl J Med 2011;365:883–91; 3. Granger et al. N Engl J Med 2011;365:981–92; 4. Giugliano et al. N Engl J Med 2013;369:2093–104. Head-to-head studies do not exist, and direct comparisons between agents may not be made. Edoxaban is not approved for use in India
- 36. Choice of NOACs High riskof stroke (high CHADS-V ASC score) Dabigatran 150 mg BID High risk of bleeding or previous life-threatening bleedings Dabigatran 110 mg BID Apixaban 5 mg BID GI bleeding Apixaban 5 mg BID Medication compliance problems Rivaroxaban 20 mg QD Elderly (≥80 years) and impaired 08/09/2016renal function Apixaban 2.5 mg BID p Petare. 13
- 37. Benefits of VKAover direct acting oral anticoagulants In cases with lack of adherence, regular INR monitoring with VKA encourages regular physician–patient contact Zirlik A, Bode C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis. 2017;43(3):365-379. doi:10.1007/s11239-016-1446-0 Applicable in patients with AF and who have creatinine clearance (CrCl) <15 mL/min In the case of a missed VKA dose, patients are at less immediate risk of a thrombotic event than patients missing a dose of DOAC Oral VKA therapy is recommended throughout pregnancy in patients with daily warfarin dose requirement of ≤5mg (or equivalent Acenocoumarol dose) with target INR of 3
- 38. SUMMARY RCTs data: Apixaban5 mg BID showed Superior Efficacy and Safety at the same dose and Dabigatran 150 mg BID showed Superior Efficacy & Dabigatran 110 mg showed superior Safety against warfarin 1 Guidelines: NOACs are recommended as the first choice for patients with CHA2DS2-VASc Score ≥1 in men or ≥2 in women. 2 Elderly Population: Apixaban: best safety profile of all NOACs (major bleeding and ICH) Apixaban: recommended first option in this population. 3 Renal failure: NOACs are better than ASA and warfarin. First choice: Apixaban 5 mg BID (2.5 mg for ABC criteria), Rivaroxaban 15 mg daily or Edoxaban 30 mg daily. 4 Secondary stroke prevention: For now, Diener’s law. Wait for ongoing RCTs. NOACs: preferred to VKAs or aspirin. Apixaban reduces risk of stroke by 24% relative to warfarin. 5 Bleeding risk: NOACs better safety profile than warfarin in terms of major bleed and intracranial hemorrhage. Bleeding risk scores, use them only for identifying patients at the highest risk only. 6 Edoxaban is not approved for use in India
- 41. Switching anticoagulants Switching fromSwitching to Instructions LMW Heparin NOACs When next dose of LMW Heparin is due Heparin NOACs Immediately when heparin ceased Warfarin NOACs Start once INR < 2 Dagibatran LMW heparin / UFH No bolus required. Start 12 hrs after last dose Rivaroxaban / Apixaban LMW heparin / UFH No bolus required. Start 24 hrs after last dose NOACs Warfarin Continue NOAC and give warfarin ≤5 mg Stop NOAC once INR ≥2 on 2 consecutive days
- 42. Transitioning from VKAto NOAC 2018 EHRA practical guide on the use of NOACs in NVAF patients Steffel et al. Eur Heart J 2018;39:1330–1393. Daily VKA Therapeutic INR INR ≥3.0: postpone NOAC Stop INR INR INR INR INR ≤2.0: Start NOAC immediately INR 2.0–2.5: Start NOAC immediately or next day INR 2.5–3.0: Re-check INR in 1–3 days ↑ thromboembolism risk ↑ bleeding risk In patients with INR >2.5, the actual INR value and half-life of the VKA should be taken into account to estimate when the INR will likely drop to below the threshold and a NOAC can be initiated
- 43. The most appropriatemanagement 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. What do we do when patient undergoes surgical intervention
- 45. • GI Bleeding:Apixaban has shown numerically lower GI Bleeding events as compared to Warfarin • 2017 Expert Consensus: Apixaban is the 1st choice of drugs for elderly and in patients with high risk of GI bleeds. • Apixaban has consistent benefits with respect to lower bleeding risk in high-risk subgroups
- 47.
Editor's Notes
- #22 In tutti i trial si osserva una diminuzione delle ICH anche nella popolazione over 75 Please mention verbally: Not head to head comparisons: these comparisons have not been made in a head to head study