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Newer oral Anticoagulants

(NOACs)

DisclaimerAny views or opinions expressed in this presentation are solely those of the author and do not necessarily

represent those of company

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Need of NOACs over Vitamin K antagonists

• Drug or food interactions

• Necessity of regular monitoring to adjust doses

• Slow onset

• Need for monitoring

• Narrow therapeutic window

• Polymorphism, Age, perioperative management

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• Oral direct thrombin inhibitors(DTIs): Dabigatran

• Oral direct factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban.

Classification of NOACs

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Pharmacology of NOACsDabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Direct thrombin inhibitor

Direct factor Xa inhibitor

Prodrug Yes NoBA 6% 66% NF

100% F50% 62%

Renal excretion

80% 35% 25% 50%

Liver metabolism

No Yes Minimal

GI tolerability

Dyspepsia -

Dosing BD OD BD OD

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Dabigatran

• 1 st NOACs, (150mg) EMA & USFDA approved (RE-LY)

• (RE-LY) Primary efficacy endpoint (stroke and systemic embolism): Dabigatran 150 mg BID superior to warfarin with no significant differences in major bleedings.

• (Cf: warfarin) Reduced risk of ischaemic stroke, intracranial haemorrhage and mortality,

Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA.Cardiovascular, bleeding, andmortality risks in elderlymedicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation 2015;131:157–164.

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Rivaroxaban

• Approved: USFDA and EMA (ROCKET AF)• non inferior to warfarin for the prevention of stroke or

systemic embolism• Black box warnings:

Premature discontinuation increases the risk of thrombotic events, Spinal/Epidural hematomas Monitor: S/S neurological impairment

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Apixaban• (ARISTOTLE): significantly better than warfarin (overall

strokes—both ischaemic and haemorrhagic—and systemic emboli)• (AVERROES2): prematurely stopped = clear benefit in favour

of apixaban (Cf: Aspirin)

2. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–817.

1. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTL Committees and Investigators. Apixaban vs. warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992.

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Edoxaban• Edoxaban non-inferior to warfarin: Prevention of stroke or

systemic embolism (ENGAGE AF-TIMI);

03/05/2023 Dr Anup Petare. 10Wassef A, Butcher K. Novel oral anticoagulant management issues for the stroke clinician. Int J Stroke. 2016 Jul 27. pii: 1747493016660100.

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Comparison between NOACs

Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM.Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955–962.

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High risk of stroke(high CHADS-VASC score)

Dabigatran 150 mg BID

Previous stroke Rivaroxaban 20 mg QDHigh risk of bleeding or previous

life-threatening bleedingsDabigatran 110 mg BID

Apixaban 5 mg BIDDyspepsia Rivaroxaban 20 mg QD

Apixaban 5 mg BID

GI bleeding Apixaban 5 mg BIDMedication compliance problems Rivaroxaban 20 mg QDElderly (≥80 years) and impaired

renal functionApixaban 2.5 mg BID

Choice of NOACs

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Advantage of NOACs • Fixed-dosing

• Rapid onset

• No need for monitoring,

• Few interactions, no interaction with food

• Wider therapeutic window

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Limitations of NOACs

• Lack of an effective antidote

• Cost

• Vitamin K Antagonists 1st line anticoagulant: Mechanical

heart valves or RHD and with severe renal insufficiency,

• ESC guidelines doesn’t recommend rivaroxaban and apixaban ( RHD, Mechanical heart valve, Severe renal insufficiency)

Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al. Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14:1385–1413.

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Conclusion• NOACs have a favourable balance between efficacy and

safety compared with VKAs• Individualized anticoagulant treatment: Age, RFT,

concomitant treatment• NOACs future depends upon clinical experience, patients’

tolerance to these drugs, novel data from further studies, reimbursement policies, and other market forces.• Further research is underway: Monitor anticoagulant effect,

antidote.