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Oral anticoagulation with vitamin K antagonists or non-vitamin K antagonist oral anticoagulants (NOACs) is the standard of care for reducing thromboembolic risk in patients with atrial fibrillation (AF). Warfarin is effective but has limitations including a narrow therapeutic window requiring frequent monitoring and dose adjustments. NOACs have advantages over warfarin such as rapid onset, fewer drug interactions and no requirement for routine monitoring. Apixaban and edoxaban have been shown to have the lowest risk of gastrointestinal bleeding compared to other NOACs based on data from pivotal clinical trials. Dosing of NOACs requires adjustment based on renal function and bleeding risk.

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STROKE PREVENTION IN AF
Managing Stroke Risk: Clinical Evidence
Stroke prevention in AF 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
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.
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.
Managing stroke risk in AF: European Society of Cardiology 2020 Guidelines Hindricks G et al. Eur Heart J. 2021 Feb 1;42(5):373-498.
Managing Stroke Risk: Clinical Evidence
Stroke prevention in atrial 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. vs placebo Aspirin2 vs aspirin VKA2 vs VKA NOACs3 Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk (ESC 2016)1
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
GARFIELD AF Registry AF patients receiving VKA in Asia spend the majority of time outside of the therapeutic range Oh et al. Int J Cardiol 2016;223:543-7. Less than one third of INR readings in Asia were in the therapeutic range (2.0–3.0)
Warfarin-associated intracranial hemorrhage Incidence of ICH in different ethnic groups on warfarin: 18,867 patients hospitalized with first-time AF Shen et al. J Am Coll Cardiol 2007;50:309-315. White Black Hispanic Asian 0 1 2 3 4 5 6 7 INR 2-3 Hazard ratio (95% CI) p value White 55% 1 - Black 48% 2.05 (1.25-3.36) 0.005 Hispanic 54% 2.06 (1.31-3.24) 0.002 Asian 54% 4.06 (2.48-6.66) <0.0001 Hazard ratio Asian patients were at 4-times the risk of ICH
Management considerations in AF 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
• Oral direct thrombin inhibitors(DTIs):Dabigatran • Oral direct factor Xainhibitors: Rivaroxaban,Apixaban, Edoxaban. ClassificationofNOACs 08/09/2016 DrAnupPetare. 4
NOACs: Advantages over warfarin1-5 Rapid onset of action1 No significant food interactions1 Low potential for drug–drug interactions1 No requirement for close coagulation monitoring1 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.
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.
RIVAROXABAN It has an oral bioavailability of 80%. Rivaroxaban has a rapid onset of action and a half-life of 7to 11hours. 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.
Apixaban Apixaban is a direct, reversible, competitive, and selective inhibitor of factor Xa It is well absorbed achieving peak plasma concentration in 1–4h. It is predominantly metabolized in liver. It is a mild P- glycoprotein inhibitor. Compared to other NOACS it has least bleeding complications and greaterefficacy.
Dosing –Non-valvularAtrial Fibrillation Dagibatran Rivaroxaban 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 twoof following: -older than 80yo -Weight less than 60kg -Scr >1.5 mg/dl -2.5mg twice daily
How to manage NOACs in Clinical Practice for SPAF
NOACs in Elderly Patients
Efficacy and safety of 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 on these data 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
NOACs in the Elderly 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
NOACs in Renal Compromised Patients
CKD, Thrombosis & Hemorrhage A double-edged sword Hohnloser SH et al. Eur Heart J. 2012;33:2821-2830, Steffel et al. Eur Heart J 2018. 1.65 2.52 0.76 1.05 4.8 7.71 1.7 2.39 0 1 2 3 4 5 6 7 8 9 Major bleeding All-cause mortality Ischemic stroke rate Annual stroke rate Stroke, Bleeding & Mortality Increase as Renal Function Deteriorates ≤50 mL/min n=3017 (17%) >80 mL/min n=7518 (41%) Recheck interval (in months) CrCl/10
80 50 33 27 0% 20% 40% 60% 80% 100% Dabiga Edoxa Riva Apixa % 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
NOACs in Renal Failure 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
A systematic review and meta-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
NOACs in patients with High Risk of GI Bleeding
Mechanisms of NOAC-related GI 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
Rates of Major GI Bleeding from the pivotal NOAC trials 1.85 2.0 0.76 0 0.5 1 1.5 2 2.5 Dabigatran 150 mg BD (n=6,076) Rivaroxaban 20 mg OD (n=7,131) Apixaban 5 mg BD (n=9,088) %/year Major GI bleeding (%/year)1,2 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
Conclusion: The risk of 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
European Society of Cardiology (ESC) Guideline 1. Hindricks G, et al. Eur Heart J. 2020;42:373–498. 2. Kirchhof P, et al. Eur J Cardiothorac Surg. 2016;50(5):e1–e88. ESC’2016: In patients at high-risk of GIB, a VKA or another NOAC preparation should be preferred over dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily (Class IIa, level B).2 1 GIB: GI Bleeding
Patient scenario 1st choice 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.
GUIDELINES
Kirchhof, Europace 2016:18,1609–1678 Management of 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
CHA2DS2-VASc Score Warfarin Threshold = 1.7%/year NOAC Threshold = 0.9%/year 0.68 1 0 2 3 0 1 2 1.61 2.49 Use only NOAC, warfarin not beneficial NOAC 1st option Warfarin 2nd choice Annual Risk of Stroke/SE % No anticoagulation Joundi R, Cipriano LE, Sposato LA, Saposnik G. Stroke 2016;47:1364 Eckman MH. Circ Cardiovasc Qual Outcomes 2011;4:14. CAUSES OF DEATH AFTER STROKE Cardiovascular Death is Frequent after Stroke
Management of AF Detected After Stroke 3 Important Class III Recommendations European AF Guidelines Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Anti- platelet agents Class III Class III Mechanical heart valve Moderate to severe mitral stenosis Anti- platelet agents OAC Class III Use warfarin Kirchhof, Europace 2016:18,1609–1678
WHEN SHOULD NOACs BE STARTED? Diener’s Law Now included in the European & Canadian Guidelines Day Huisman et al. Thromb Haemost 2012 | Kirchhof, Europace 2016:18,1609–1678 NIHSS TIA 1 As soon as imaging has excluded a cerebral haemorrhage Mild stroke 3 <8 3–5 days after stroke onset Moderate stroke 6 8-16 5–7 days after stroke onset Severe stroke 12 >16 2 weeks after stroke onset Start OAC AHA: 2 weeks ACCP: 1 to 2 weeks
Stroke/SE ICH Death Major 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
ChoiceofNOACs High risk of stroke (high CHADS-V ASCscore) Dabigatran 150 mgBID Previous stroke Rivaroxaban 20 mg QD High risk of bleeding orprevious life-threatening bleedings Dabigatran 110 mgBID Apixaban 5 mgBID GIbleeding Apixaban 5 mgBID Medication complianceproblems Rivaroxaban 20 mgQD Elderly (≥80 years) andimpaired 08/09/2016renal function DrAnu Apixaban 2.5 mgBID p Petare. 13
Transitioning from VKA to 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
Switchinganticoagulants Switching from Switching to Instructions LMW Heparin NOACs When next dose of LMW Heparin isdue 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 ≤5mg Stop NOAC once INR ≥2 on 2 consecutive days
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. What do we do when patient undergoes surgical intervention
SUMMARY RCTs data: Apixaban 5 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
• 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
New oral anticoagulants have shown to have a favourable balance between efficacy and safety compared with VKAs. Advantages Of NOACs include fewer interactions with medications and no interaction with food, rapid onset, fast clearance, and no need for laboratory monitoring.
THANK YOU

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udaipur 19.11.2022 noac.pptx

  • 1.
  • 3.
  • 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.
  • 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. vs placebo Aspirin2 vs aspirin VKA2 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.
    GARFIELD AF Registry AFpatients receiving VKA in Asia spend the majority of time outside of the therapeutic range Oh et al. Int J Cardiol 2016;223:543-7. Less than one third of INR readings in Asia were in the therapeutic range (2.0–3.0)
  • 12.
    Warfarin-associated intracranial hemorrhage Incidenceof ICH in different ethnic groups on warfarin: 18,867 patients hospitalized with first-time AF Shen et al. J Am Coll Cardiol 2007;50:309-315. White Black Hispanic Asian 0 1 2 3 4 5 6 7 INR 2-3 Hazard ratio (95% CI) p value White 55% 1 - Black 48% 2.05 (1.25-3.36) 0.005 Hispanic 54% 2.06 (1.31-3.24) 0.002 Asian 54% 4.06 (2.48-6.66) <0.0001 Hazard ratio Asian patients were at 4-times the risk of ICH
  • 13.
    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
  • 14.
    • Oral directthrombin inhibitors(DTIs):Dabigatran • Oral direct factor Xainhibitors: Rivaroxaban,Apixaban, Edoxaban. ClassificationofNOACs 08/09/2016 DrAnupPetare. 4
  • 16.
    NOACs: Advantages overwarfarin1-5 Rapid onset of action1 No significant food interactions1 Low potential for drug–drug interactions1 No requirement for close coagulation monitoring1 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.
  • 17.
    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.
  • 18.
    RIVAROXABAN It has anoral bioavailability of 80%. Rivaroxaban has a rapid onset of action and a half-life of 7to 11hours. 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.
  • 19.
    Apixaban Apixaban is adirect, reversible, competitive, and selective inhibitor of factor Xa It is well absorbed achieving peak plasma concentration in 1–4h. It is predominantly metabolized in liver. It is a mild P- glycoprotein inhibitor. Compared to other NOACS it has least bleeding complications and greaterefficacy.
  • 21.
    Dosing –Non-valvularAtrial Fibrillation Dagibatran RivaroxabanApixaban 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 twoof following: -older than 80yo -Weight less than 60kg -Scr >1.5 mg/dl -2.5mg twice daily
  • 22.
    How to manage NOACsin Clinical Practice for SPAF
  • 23.
  • 24.
    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 on these data 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
  • 25.
    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
  • 26.
    NOACs in RenalCompromised Patients
  • 27.
    CKD, Thrombosis &Hemorrhage A double-edged sword Hohnloser SH et al. Eur Heart J. 2012;33:2821-2830, Steffel et al. Eur Heart J 2018. 1.65 2.52 0.76 1.05 4.8 7.71 1.7 2.39 0 1 2 3 4 5 6 7 8 9 Major bleeding All-cause mortality Ischemic stroke rate Annual stroke rate Stroke, Bleeding & Mortality Increase as Renal Function Deteriorates ≤50 mL/min n=3017 (17%) >80 mL/min n=7518 (41%) Recheck interval (in months) CrCl/10
  • 28.
    80 50 3327 0% 20% 40% 60% 80% 100% Dabiga Edoxa Riva Apixa % 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
  • 29.
    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
  • 30.
    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
  • 31.
    NOACs in patientswith High Risk of GI Bleeding
  • 32.
    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
  • 33.
    Rates of MajorGI Bleeding from the pivotal NOAC trials 1.85 2.0 0.76 0 0.5 1 1.5 2 2.5 Dabigatran 150 mg BD (n=6,076) Rivaroxaban 20 mg OD (n=7,131) Apixaban 5 mg BD (n=9,088) %/year Major GI bleeding (%/year)1,2 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
  • 34.
    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
  • 35.
    European Society ofCardiology (ESC) Guideline 1. Hindricks G, et al. Eur Heart J. 2020;42:373–498. 2. Kirchhof P, et al. Eur J Cardiothorac Surg. 2016;50(5):e1–e88. ESC’2016: In patients at high-risk of GIB, a VKA or another NOAC preparation should be preferred over dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily (Class IIa, level B).2 1 GIB: GI Bleeding
  • 36.
    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.
  • 37.
  • 38.
    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
  • 39.
    CHA2DS2-VASc Score Warfarin Threshold= 1.7%/year NOAC Threshold = 0.9%/year 0.68 1 0 2 3 0 1 2 1.61 2.49 Use only NOAC, warfarin not beneficial NOAC 1st option Warfarin 2nd choice Annual Risk of Stroke/SE % No anticoagulation Joundi R, Cipriano LE, Sposato LA, Saposnik G. Stroke 2016;47:1364 Eckman MH. Circ Cardiovasc Qual Outcomes 2011;4:14. CAUSES OF DEATH AFTER STROKE Cardiovascular Death is Frequent after Stroke
  • 40.
    Management of AFDetected After Stroke 3 Important Class III Recommendations European AF Guidelines Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Anti- platelet agents Class III Class III Mechanical heart valve Moderate to severe mitral stenosis Anti- platelet agents OAC Class III Use warfarin Kirchhof, Europace 2016:18,1609–1678
  • 41.
    WHEN SHOULD NOACsBE STARTED? Diener’s Law Now included in the European & Canadian Guidelines Day Huisman et al. Thromb Haemost 2012 | Kirchhof, Europace 2016:18,1609–1678 NIHSS TIA 1 As soon as imaging has excluded a cerebral haemorrhage Mild stroke 3 <8 3–5 days after stroke onset Moderate stroke 6 8-16 5–7 days after stroke onset Severe stroke 12 >16 2 weeks after stroke onset Start OAC AHA: 2 weeks ACCP: 1 to 2 weeks
  • 42.
    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
  • 43.
    ChoiceofNOACs High risk ofstroke (high CHADS-V ASCscore) Dabigatran 150 mgBID Previous stroke Rivaroxaban 20 mg QD High risk of bleeding orprevious life-threatening bleedings Dabigatran 110 mgBID Apixaban 5 mgBID GIbleeding Apixaban 5 mgBID Medication complianceproblems Rivaroxaban 20 mgQD Elderly (≥80 years) andimpaired 08/09/2016renal function DrAnu Apixaban 2.5 mgBID p Petare. 13
  • 44.
    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
  • 45.
    Switchinganticoagulants Switching from Switchingto Instructions LMW Heparin NOACs When next dose of LMW Heparin isdue 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 ≤5mg Stop NOAC once INR ≥2 on 2 consecutive days
  • 46.
    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
  • 48.
    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
  • 49.
    • 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
  • 50.
    New oral anticoagulantshave shown to have a favourable balance between efficacy and safety compared with VKAs. Advantages Of NOACs include fewer interactions with medications and no interaction with food, rapid onset, fast clearance, and no need for laboratory monitoring.
  • 52.