Dr. Ganasani

Sreeni Gangasani, M.D.• Cardiologist at Gwinnett Heart

Specialists

• American Board of Internal Medicine Cardiovascular Disease

• American Board of Internal MedicineInternal Medicine

• AOA Board of Internal MedicineCardiology

• Special interests include general Cardiology, Echocardiography, Nuclear, Preventive Cardiology

Medical School:Kurnool Medical College

Residency:William Beaumont

Hospital

Fellowship:William Beaumont

Hospital

Tailoring NOAC’s for your individual patient

Sreeni Gangasani MD, FACC

04/18/2023 Gwinnett Heart Specialists

• 1. We hate sleeping.2. We have enjoyed our life in childhood.3. We can't live without tension.4. We want to have a disturbed life.5. We want to take revenge on ourselves.6. We love dreaming about diseases .7. We love to work on holidays.8. We can't live without mobile hooked on our ears even in the bathroom .9.When we make money its already too late

9 reasons why we chose Medicine as a profession:


• Which one is the newest of direct Factor X inhibitors ?

• A) Darbigatran• B) Edoxaban• C) Rivaraxoban• D) Epixaban• E) Betrixaban

Question 1

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Newer Anti-coagulants(NOAC)(Dabigatran/Rivaroxaban/Apix

aban/Edoxaban)

Practical Issues


• Prevention and treatment of venous thromboembolism (VTE)

• Stroke prophylaxis in non-valvular atrial fibrillation (AF),

Newer Oral Anticoagulants


• Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) is used initially in the treatment of acute VTE or A fib, followed by long-term vitamin K antagonist (VKA) therapy.

• For stroke prophylaxis in AF, long-term anticoagulation with the VKA warfarin is the standard of care

Traditional care


• Inter patient variability with regard to clinical response because of genetic polymorphisms, particularly upon initiating therapy.

• Drug-drug and drug-food interactions necessitate more frequent monitoring of international normalized ratio (INR) and may complicate management.

• Major and non–major bleeding events,• Supra and Sub therapeutic INRs management• In older patients, warfarin is the most common

cause of drug-related emergency hospitalization

Problems with Warfarin



Edoxoban


• Dabigatran and Rivaroxaban and Apixaban Edoxaban have successfully completed phase III trials for acute VTE treatment, Prophylaxis and are currently approved for the reduction of risk of stroke and systemic embolism in patients with non-valvular AF

Newer Anticoagulants


• Direct thrombin inhibitors

- dabigatran( Pradaxa)

Factor IIa Inhibitors


• The pro-drug dabigatran etexilate is converted

completely to active dabigatran

• Terminal elimination t½ of 14–17 hours

• Bioavailability of 3.5–6.5%

• No food interactions

• Eliminated mainly by renal excretion (80%)

Dabigatran (Pradaxa)

Stangier et al. J Clin Pharmacol 2005; Liesenfeld et al. Br J Clin Pharmacol 2006;

Stangier et al. Br J Clin Pharmacol 2007


• Must be stored in the original blister pack with desiccant and not crushed.

Dabigatran


VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionTissue factor

Fibrinogen Fibrin clot

Factor II(prothrombin)

RivaroxabanApixaban

YM150Edoxaban Betrixaban

TAK 442

×


Direct Factor Xa Inhibitors

Rivaroxaban (Xarelto)

Apixaban (Eliquis)

Edoxaban( Savaysa)

Rivaroxaban: oral direct Factor Xa inhibitor (Xarelto)

• Predictable pharmacology

• High bioavailability • Low risk of drug–

drug interactions• Fixed dose• No requirement for

monitoringPerzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

SCl

O

O

O

Gwinnett Heart Specialists 04/18/2023

Apixaban(Eliquis)• Oral, direct, selective factor Xa inhibitor• Produces concentration-dependent

anticoagulation• No formation of reactive intermediates• No organ toxicity or LFT abnormalities in

chronic toxicology studies • Low likelihood of drug interactions or QTc

prolongation• Good oral bioavailability • No food effect • Balanced elimination (~25% renal) • Half-life ~12 hrs

He et al., ASH, 2006, Lassen, et al ASH, 2006

N

N

NO

N O

NH2

O

O

Gwinnett Heart Specialists04/18/2023

Edoxaban( Savaysa)

• Half-life:6-11 hrs• Dosing 30 or 60 mg orally once daily• Absorption is unaffected by food• Renally excreted• Substrate for P glycoprotein• Reduced efficacy in nonvalvular atrial

fibrillation in patients with a high creatinine clearance

(CrCL >95 mL/minute)04/18/2023 Gwinnett Heart Specialists


• Laboratory testing should include • Prothrombin time (PT) • Activated partial thromboplastin time

(aPTT),

• Serum creatinine, as a baseline and for potential dose adjustment in the event of renal insufficiency.

Testing before starting NOAC


• NOAC are contraindicated in what valvular heart disease conditions ?

• A) Moderate mitral regurgitation• B) Mild Aortic stenosis• C) Moderate to severe tricuspid

regurgitation• D) Prosthetic mechanical aortic valve• E)Bicuspid aortic valve with minimal aortic

regurgitation

Question 2



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• Many of the major clinical trials subsequent meta-analyses have excluded patients with

• prosthetic heart valves, • with mitral stenosis, • with decompensated valvular heart

disease who were likely to require valve replacement in the near future.

• Based on these studies, the newer anticoagulants should not be prescribed for these patients

Valvular heart disease and NAC


• Which of the NOAC is approved for use in ESRD?

• A) Epixaban• B) rivaroxoban• C) Edoxaban• D) None of the above

Question 3



https://www.polleverywhere.com/multiple_choice_polls/YSCYWgQplHqJ3T3?preview=true


Renal Insufficiency


Time to fully active: 5 days vs 2-3 hrs

Time to being out of system :5-7 days vs 24-48hrs

Cost : NOAC more expensive(About $200/month)

Safety:• Same risk of major bleeding, but lower risk of

bleeds into the head with NOAC

Differences between VKA vs NOAC


Factor WarfarinEnoxaparin (LMWH)

Dabigatran etexilate

Rivaroxaban Apixaban

Routine laboratory monitoring required

X

Antidote available

X X

Dose adjustment for renal insufficiency

X X X X

Rapid onset and offset of action

X X X

Comparison of key considerations for new oral anticoagulants

FactorWarfarin

Enoxaparin (LMWH) Dabigatran Rivaroxaban Apixaban

Routine laboratory monitoring required

X

Antidote available X X

Dose adjustment for renal insufficiency

X X X X

Rapid onset and offset of action

X X X


Comparison of the NOAC for DVT and PE Apixaban Dabigatran Rivaroxaban

Started immediately with Dx DVT or PE yes no yes Dosing BID BID QD

Excreted through the kidney 25% 80% 33%

Efficacy c/w warfarin (recurrent DVT or PE) same same same

Safety c/w warfarin in respect to bleeding better same same/better

Reversal agent available for major bleeding none none none

FDA approved for DVT/PE treatment yes yes yes


• 68% relative risk (RR) reduction of ischemic stroke compared with placebo;

• Aspirin has a less-robust RR reduction of 21% compared with placebo

Warfarin

Gwinnett Heart Specialists

04/18/2023




• Difficult achieving stable anti-coagulation

• Drugs proven to cause INR fluctuations

• Better compliance with once a day than bid (rivaroxiban vs dabigatran/apixaban)

Who should switch?


• GI bleeds (increased risk with dabigatran and rivaroxiban) either stay on VKA or apixaban

• Previous acute coronary syndromes??? Conflicting data with dabigatran

• Populations excluded from trials: pediatric, pregnant patients, prosthetic valves (Re-ALIGN a negative trial)

Who should NOT switch?


• When to stop NOACs?• Risk of stroke when off ACs• Duration off vs CHADS2 score

How to deal with Surgery?


How to deal with Surgery?


• Depends on CHADS2

• For CHADS2 of ≥3 use bridge with lovenox or IV Heparin

Risk of stroke off Anticoagulants


Risk Scores


Stroke Risk


• NOACs discontinued and procedure schedules 1-2 days later….if possible

• Risk of bleeding vs risk of delaying surgery

How to deal with Urgent Surgery?


• Which of the NOAC is class B in Pregnancy?

• A) Endoxaban• B) Epixaban• C) Darbigatran• D)Rivaraxoban

Question 4


• Eliquis: Class B ( No adverse effects demonstrated but not enough data)

• Xarelto: Class C ( Use with caution)• Pradaxa : Class C

• Lactation: Not indicated(safety unknown)

Pregnancy and Lactation


• Ecarin clotting time has shown to be a reliable assay to assess coagulation in patients taking dabigatran etexilate

• Availability of this assay is limited . • Prothrombin time assays may be useful for

assessing coagulation in patients receiving rivaroxaban or apixaban (dilute prothrombin time), but because of a lack of standardization, as is the case with INR, results may be difficult to interpret.

• Anti–factor Xa assays used for nonroutine monitoring of LMWHs may prove to be the best method to monitor rivaroxaban or apixaban

Laboratory monitoring


• The new oral anticoagulants do not have specific antidotes

• For non–major bleeding events, temporary cessation

• Activated prothrombin complex concentrates (PCCs) and recombinant factor VII have been explored in early studies as reversal agents for the new anticoagulants, but data are limited

Management of bleeding events


• A study in healthy human subjects demonstrated that 4-factor PCCs that are available in Europe immediately and completely reverse the effect of rivaroxaban, but they did not have any influence on dabigatran at the dose studied.

• Recombinant factor Xa is currently being explored as a reversal agent for factor Xa inhibitors

Management of bleeding events


• Emergency dialysis may be considered

• Partially dialyzable,

• Maintain renal perfusion with intravenous fluids.

• Need to develop protocols for institution for major bleeds

Darbitrigan



• Name: Husband Symbol: Hb

• Atomic Weight:-Light when first found...-tends to get heavier over the years with time.

•Physical Properties :- Boils at any time with inlaws- Melts if sees other women- Very Bitter if questioned

• Chemical Properties :- Very Reactive- Highly Unstable- Possess Strong resistance to Gold, Silver,Diamond, Platinum, Credit cards&Cheque books

• Occurrence :- Mostly found in front of the TV

A new metal is added to chemistry:


• Which NOAC should not be used when Cr Cl is over 95?

• A) Endoxoban• B) Epixaban• C) rivaraxoban• D) Darbigatran

Question 5:


• No data head to head between agents

• Insurance

• Familiarity with agent

• Availability of samples

• Side effect profile

• Compliance issues: Qd vs BID

NOAC Agent of choice



Thank You for your attention

Health & Medicine

Dr. Ganasani