Apixaban - for post-cardiac surgery children

Apixaban

(Eliquiss®)

General principles of use in children (post-cardiac surgery)

Dose is weight-based.

For an adult size person, 5 mg BID may be used.

Under some circumstances 7.5 mg BID may be used.

Dose is adjusted for renal and hepatic dysfunction.

Monitoring: 

Check peak level, about 3-4 hrs after morning dose, after 4 doses.

For post-cardiac surgery children, Anti-Xa (Apixaban-specific) level is kept at 100-300 ng/ml.

For a 3-mo course (short course), repeat peak level once about 2-3 weeks later.

After that, repeat peak level is done if the dose is changed or bleeding occurs.

Andexxa - Recombinant Factor Xa - Antidote for Apixaban and Rivaroxaban

 Andexxa (Recombinant Factor Xa) - Adnexa net alfa: Received accelerated FDA approval in (?2018)

Mechanism of Action:

Andexanet Alfa - genetically modified variant of human factor Xa (alanine substituted for serine).

Acts by binding to Factor Xa inhibitors and neutralizes their anticoagulant effect.

This is useful to reverse the anticoagulant effect caused by Apixaban (Eliquis) and Rivaroxaban (Xarelto).

This is the second antidote approved by FDA for Factor Xa inhibitors:

First one, approved in 2015, was Idarucizumab (Praxbind) - for reversal of direct thrombin inhibitor - Dabigatran etexilate (Pradaxa).

Above information was taken from this JAMA review article: JAMA 2018;320(4):399-400.

Rivaroxaban (Xarelto) for Post-Fontan children

Source: Manufacturer webpage

UNIVERSE clinical trial

• n = 112 (Final n = 98, 64 Rivaroxaban, 34 Aspirin)
• Randomized 2:1 (Rivaroxaban : Aspirin) 
• Open label Rivaroxaban vs. Usual Aspirin.
• Age 2-8 yrs
• Follow up for 12 months.

 

Reversal agent for Dabigatran (Pradaxa)

The US Food and Drug Administration (FDA) has granted accelerated approval to Praxbind (idarucizumab, Boehringer Ingelheim) to rapidly reverse the blood-thinning effects of the anticoagulant Pradaxa (dabigatran, Boehringer Ingelheim).

Link to Medscape news

Antiplatelet activity measurement at bedside

For P2Y12 inhibitors such as Clopidogrel & Ticagrelor (Platelet aggregation inhibitors).
More information at this website: http://www.accumetrics.com/en/products/verifynow-p2y12
VerifyNow Brochure: http://www.accumetrics.com/dmdocuments/system/VN-SystemOverview.pdf
VerifyNow Pocket Guide: http://www.accumetrics.com/dmdocuments/VN-PocketGuide-Interventional_OUS.pdf

"Kcentra" approved for Reversing Coumadin

FDA approved "Kcentra" for reversing Coumadin in adults with acute major bleeding. Plasma is the only agent approved thus far.

It is a human prothrombin complex concentrate prepared from pooled donors.

Link to FDA announcement.

Enoxaparin (Lovenox) - Subcutaneous injection

From Lexi-Comp:

Neonates (<>
Prophylactic use: 0.75 mg/kg q12hrs
Therapeutic use: 1.5 mg/kg q12hrs

Infants (> 2 mo):
Prophylactic use: 0.5 mg/kg q12hrs
Therapeutic use: 1 mg/kg q12hrs

Then, check Antifactor Xa level and adjust to set maintenance dose:
< 0.35 U/ml → Increase by 20% - Check dose 4 hr after next dose
0.35-0.49 U/ml → Increase by 10% - Check dose 4 hr after next dose
0.5 - 1.0 U/ml → No change - Check level next day, 1 week later and monthly
1.1 - 1.5 U/ml → Decrease by 20% - Check level before next dose
1.6 - 2.0 U/ml → Hold dose for 3 hrs and Decrease by 30% - Check level before next dose and 4 hr after
? 2.0 U/ml → Hold doses until level is 0.5 U/ml, Resume with decreased dose by 40% - Check every 12 hrs until level < 0.5 U/ml. Then, before next dose.

Anticoagulation: Warfarin

From Lexi-Comp
To maintain INR 2-3:
Loading:
Day 1: 0.2 mg/kg/day (0.1 mg/kg/day if liver dysfunction is present)
Day 2-4: Depends on daily INR
1.1 - 1.3 → Repeat same dose
1.4 - 3.0 → 50% of loading dose
3.1 - 3.5 → 25% of loading dose
> 3.5 → Hold until INR < 3.5. Then, start 50% of loading dose.

Maintenance (Day 5 & beyond): Depends on INR
1.1 -1.4 → Increase 20%
1.5 - 1.9 → Increase 10%
2-3 → No change
3.1 - 3.5 → Decrease 10%
> 3.5 → Hold until INR < 3.5. Then, start 20% lower than prior dose

PICOLO Trial: Dosing of Clopidogrel in Infants and Young Children

Li, J. et al. Circulation 2008;117:553-9.

Conlcusion: Clopidogrel 0.2 mg/kg/day in children 0-24 months of age achieves a platelet inhibition similar to that of adults with 75 mg/day.

Method:
Prospective, multicenter, randomized, placebo-controlled trial.
n=73 (50% neonates, 50% rest)
Randomized to Clopidogrel vs. Placebo in 3:1 in sequential groups.
Doses used were: 0.01 mg/kg, 0.1 mg/kg, 0.2 mg/kg, and 0.15 mg/kg. Given for 7-28 days.
Platelet aggregation was assessed by Light-Transmission Aggregometry (Maximal extent of platelet aggregation and rate of aggregation were calculated). 30-50% inhibition of 5-microMol/L ADP-induced platelet aggregation is taken as therapeutic range (similar to adults on 75 mg/day).

0.20 mg/kg daily achieved a mean of 49.3% inhibition of maximum extent of aggregation & 43.9% inhibition of rate of aggregation. Marked interpatient variability in inhibition achieved was noted within each group.

Aspirin resistance

Ref: Khaled Mansour et al. Advances in Hematology Vol 2009; Article ID 937352. 10 pages.

Tests for Platelet function &/or Aspirin resistance:

1) LTA (Light Transmission Aggregometry)

2) Point of care testing: PFA-100 device (Dade Behring, Germany)

3) Point of care testing: VerifyNow-Aspirin (Accumetrics, USA)
Aspirin reaction units > 550 is taken as evidence of Aspirin resistance.

4) Serum Thromboxane B2

5) Urinary 11-dehydro Thromboxane B2

Dabigatran - Alternative for Warfarin

RE-LY trial in patients with Atrial fibrillation.
Dabigatran was approved by FDA on 10/20/10.
See the posting on Journal Club.

Anti-platelet agents...to be expanded further.

Antiplatelet drugs alter the platelet activation at the site of vascular damage crucial to the development of arterial thrombosis.

Aspirin
irreversibly inhibits the enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane - powerful vasoconstrictor which lowers cyclic AMP and initiates the platelet release reaction).

Dipyridamole
inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2

Clopidogrel
affects the ADP-dependent activation of IIb/IIIa complex

Glycoprotein IIb/IIIa receptor antagonists block a receptor on the platelet for fibrinogen and von Willebrand factor. 3 classes:
Murine-human chimeric antibodies (e.g. abciximab)
Synthetic peptides (e.g. eptifibatide)
Synthetic non-peptides (e.g. tirofiban)

ICU: Antiplatelet agents

Cangrelor - ADP P2Y12 receptor inhibitor, 6-min half life. Immediately reversible inhibition of platelet aggregation. Continuous IV Infusion. CHAMPION trials.

Ref: NEJM Dec 2009;361(24):2382-4

Clopidogrel - ATP analogue/inhibitor, irreversible inhibition of platelet aggregation. Onset of action 1 hour. Oral administration.

Eptifibatide (Integrillin) - Gp IIb-IIIa inhibitor

Abciximab (ReoPro) - Fab fraction agains Gp IIb-IIIa receptors. Platelet inhibition lasts for 96-120 hrs (theoretically reversible)