MEDICAMENTE ANTIAGREGANTE

Grupe de medicamente:
a. Inhibitori Tromboxan A2
b. Antagoniști a receptorilor ADP

INHIBITOR TROMBOXAN A2 – ASPIRINA

MECANISM DE ACȚIUNE: Tromboxanul A2 este agonistul/substanța

eliberată de plachetele activate, care determină recrutarea și activarea de noi
plachete. Tromboxanul A2 este sintetizat de către plachete – enzima cheie în
sinteza acestuia – COX1. Aspirina blochează enzima COX1, ceea ce duce la
reducerea de TXA2, cu atenuarea activării și recrutării de noi plachete. ! la o
doză mare – 1 g – aspirina inhibă și COX2 – care se găsește predominant în
celulele endoteliale și cele inflamatorii – și care are rol de a sintetiza
prostaciclina – vasodilatator potent și inhibitor a agregării plachetare.

INDICAȚII: prevenția secundară a evenimentelor cardiovasculare la pacienții

cu boală arterială coronară, cerebrală sau periferică prestabilită.

! comparativ cu placebo – aspirina scade riscul cu 25% de moarte CV, IM,

AVC.
Nu se recomandă aspirină pentru profilaxia primară – deoarece riscul de
sângerare gastrointestinală și intracerebrală depășește beneficiul. Totuși, se
poate lua în considerare în profilaxia primară atunci când riscul CV este cel
puțin 1%/an sau 10%/ la 10 ani și care au un risc redus de sângerare.

DOZA: 75 – 325 mg / o doză pe zi

RA sunt doza-dependente și respectiv, se recomandă o doză de 75-100 mg/zi la
majoritatea pacienților.
În caz de inhibiție rapidă necesară – o doză inițială de aspirină de cel puțin 160
mg trebuie administrată.

RA: cele mai comune – gastrointestinale- de la dispepsie la gastrite erozive,

ulcere peptice cu sângerare, perforare. – sunt dependente de doză
Riscul major de sângerare sub tratament cu aspirină este de 1-3% pe an. Riscul
crește de 2-3 ori atunci când se aplică terapie antiagregantă duală/combinată sau
anticoagulantă- warfarina.
Pentru cei cu ulcere peptice = poate scădera riscul de sângerare eradicarea H.
pylori și administrarea de IPP.
Nu se administrează la cei cu alergie la aspirină caracterizată anterior prin
bronhospasm. Este mai des întâlnită la cei cu teren atopic.
In caz de supradozare – poate determina hepatotoxicitate si toxicitate renală.
Rezistența la aspirină: poate fi determinată de o complianță scăzută,
interacțiunea cu ibuprofen sau o overexpresie de COX2.

ANTAGONIȘTI AI RECEPTORULUI ADP

Tienopiridine:
 Clopidogrel
 Prasugrel
Ticagrelor
Cangrelor
Aceste medicamente țintesc P2Y12 – receptorul cheie a ADP-ului plachetar.

TIENOPIRIDINE:
Mecanism de acțiune: inhibă selectiv ADP-ul indus de plachete prin blocarea
ireversibilă a P2Y12 – nu mai are loc activarea și recrutarea de noi plachete
Aceste medicamente sunt prodrugs ce necesită activare metabolică – se produce
prin intermediul sistemului enzimatic citocromul P450(CYP).
CLOPIDOGREL PRASUGREL
Este de 10 ori mai potent decât
clopidogrel – acțiunea sa se instalează
mai rapid din cauza unei absorbții
mai rapide și a unei activări
metabolice mai intense.
Este considerat mai eficient ca Deși este considerat superior
aspirina, dar și mai scump clopidogrelului, riscul de sângerare
Comparativ cu aspirina reduce riscul este mai mare
de moarte CV, IM, AVC cu 8,7% Se evită a fi folosit la cei peste 75 ani
sau care au în antecedente AVC sau
atac ischemic tranzitor – au risc mare
de sângerare; la cei < 60 kg sau la cei
cu afectare renală
Clopidogrel + aspirina = combinate
pentru efectul complimentar de
inhibare a activării plachetare
INDICAȚII: Percutaneous coronary intervention
Implantare de stent metalic – terapie Se admnistrează în asociere cu
duală clopidogrel + aspirina = cel aspirina în doză < =100 mg
puțin 4 sp
Angină instabilă
La cei cu AVC noncardiembolic sau
cu risc înalt de AVC ischemic
tranzitor = clopidogrel/ ticagrelor +
aspirina timp de 21-30 zile, urmată de
administrare de aspirină
 Clopidogrel + aspirină = crește riscul Contraindicații: istoric de boală
de hemoragie la 2% pe an, risc care cerebrovasculară
persistă chiar dacă doza de aspirină
este sub/= 100 mg
Doza: 75 mg Doza: inițial o doză de încărcare de
Doza de încărcare: 300-600 mg (ex – 60 mg, urmată de o doză zilnică unică
pentru cei care sunt supusi stentării de 10 mg
coronare) – reduce agregarea în 4-6 p> 75 ani sau < 60 kg = 5 mg
ore
RA: sângerare Sângerare
Pentru a scădea riscul de sângerare Pentru a scădea riscul de sângerare
majoră, se oprește cu 5-7 zile înainte majoră, se oprește cu 5-7 zile înainte
de o intervenție chirurgicală majoră de o intervenție chirurgicală majoră
RARE: Hematologice: neutropenie RARE: Hematologice: neutropenie
Trombocitopenie Trombocitopenie
Purpură trombotică prombocitopenică Purpură trombotică prombocitopenică
Rezistența la clopidogrel este Polimorfismul CYP2C19 nu este
influențată de isoenzima CYP important în acțiunea prasugrelului.
La cei cu funcția pierdută a alelei
CYP2C19*2 se constată o reducere a
inhibării plachetelor – crește riscul de
evenimente CV.
Este important deoarece se atestă
prezența alelei defecte la:
25% rasa albă
30% americani africani
50% asiatici
Administrarea concomitentă a IPP –
reduce într-un grad mic efectul
clopidogrelului – deoarece IPP inhibă
CYP2C19 – dar rămâne contravesat
dacă această interacțiune crește riscul
de evenimente CV adverse.

În caz de sângerare acută/masivă se poate de administrat transfuzie de

trombocite (deoarece preparatul este legat irevesibil cu plachetele, respectiv
noile trombocite nu vor fi afectate)

TICAGRELOR
Inhibitor al P2Y12, care diferă de tienopiridine, prin faptul că nu necesită
activare metabolică și produce o inhibare reversibilă a receptorului ADP.
Deoarece nu necesită activare metabolică – are o acțiune mai rapidă și produce
o inhibare mai puternică și mai predictibilă decât clopidogrel.
INDICAȚII:

Profilaxia secundară a evenimentelor aterotrombotice la cei cu sindrom

coronarian acut tratat medicamentos sau prin PCI cu/fără implantare de stent
sau cu CABG intervenție – coronary artery bypass graft.
Profilaxie secundară timp de 3 ani la cei cu risc crescut de evenimente CV care
au suferit un IM cu cel puțin 1 an în urmă
Pentru cei care urmează PCI pentru SCA se preferă ticagrelor în loc de
clopidogrel, mai ales la pacieții cu risc înalt.

DOZA:
Doza de încărcare de 180 mg, urmată de o doză de întreținere de 90 mg de 2 ori
pe zi.
De obicei, este administrat sub terapie duală : + aspirină < 100 mg
Pacienții cu insuficiență renală nu necesită ajustare
ATENȚIE! La cei cu afectare hepatică care primesc inhibitori/inducotir de
CYP3A4- ticagrelor este metabolizat hepatic via CYP3A4.

RA: sângerare
Dispnee – cel mai comun – dar este autolimitată și ușoară ca manifestare.
Pauze ventriculare asimptomatice
Pentru a reduce riscul de sângerare se stopează cu 5 zile înainte de o intervenție
chirurgicală majoră.
În caz de sângerare majoră/acută transfuzia de sânge nu este eficientă –
deoarece cuplarea cu P2Y12 este reversibilă, respectiv se vor cupla cu receptorii
de pe trombocitelor nou transfuzate.
!! antidot: BENTRACIMAB – fragment de anticorp care leagă ticagrelor și
metaboliții săi cu afinitate crescută și care rapid inversează efectul inhibitor
asupra plachetelor = este în dezvoltare

DIPIRIDAMOLE = este un antiagregant slab, care nu este recomandat pentru

utilizare; în asociere cu aspirina = Aggrenox – uneori utilizat în profilaxia
secundară cu AVC ischemic sau ischemic tranzitor.
Mecanism de acțiune: inhibă fosfodiesteraza, care este responsabilă de
degradarea AMPc. Respectiv, nivelul crescut de AMPc reduce Ca intracelular și
inhibă activarea plachetor; mai blochează și preluarea de adenozină de către cel

Se preferă clopidogrel în detrimentul dipiridamolului.

Doza: aggrenox de 2 ori/zi – 200 mg dipiridamol cu acțiune prelungită / 25 mg
aspirină.
RA: dipiridamol este și vasodilatator: cu precauție la cei cu boală arterială
coronară.
GI, dureri de cap, facial flushing, amețeli, hipotensiune. Acestea de multe ori
determină oprirea administrării de medicament.

ANTAGONIȘTI AI RECEPTORULUI GP IIB/IIIA – parenteral

Abciximab
Aptifibatide
Tirofiban
Gp IIb/IIIa – este cel mai abundent receptor de pe suprafața plachetelor – 80
000 de copii se găsesc pe un trombocit, la fel și la nivelul megakariocitelor. El
este inactiv, însă o dată cu activarea plachetelor are loc o activare
conformațională care determină capacitatea de a lega diferite molecule de
suprafața plachetară prin anumite secvențe: se leagă fibrinogenul prin secvența
RGD (Arg-Gly-Asp) de pe lanțul alfa a fibrinogenului sau a factorului von
Willebrand și secvența KGD(Lys-Gly-Asp) localizată pe domeniul
dodecapeptidă a lanțului gamma a fibrinogenului. O dată legate se produce
agregarea plachetară.

Abicximab și eptifibatide este utilizat la cei care vor urma PCI, mai ales acei
care nu au fost supuși tratamentului cu inhibitori ADP.
Tirofiban se utilizează la pacienți cu angină instabilă cu risc înalt; la fel și
eptifibatide.

All of the Gp IIb/IIIa antagonists are given as an IV bolus followed by an

infusion.

The recommended dose of abciximab is a bolus of 0.25 mg/kg followed by

an infusion of 0.125 μg/kg pe minute to a maximum of 10 μg/kg for 12 h.

In patients undergoing percutaneous coronary intervention, eptifibatide is

given as two 180 μg/kg boluses given 10 min apart, followed by an
infusion of 2.0 μg/kg per minute for 18–24 h. For patients with acute
coronary syndrome, the second eptifibatide bolus is withheld.

Tirofiban is started at a rate of 0.4 μg/kg per minute for 30 min; the drug is
then continued at a rate of 0.1 μg/kg per minute for up to 18 h.

Because eptifibatide and tirofiban are cleared by the kidneys, the doses
must be reduced in patients with renal insufficiency. Thus, the
eptifibatide infusion is reduced to 1 μg/kg per minute in patients with a
creatinine clearance below 50 mL/min, whereas the dose of tirofiban is cut
in half for patients with a creatinine clearance below 30 mL/min.

RA: sângerare, trombocitopenie – cea mai serioară- imun indusă

Thrombocytopenia is immune-mediated and is caused by antibodies
directed against neoantigens on Gp IIb/IIIa that are exposed upon
antagonist binding. With abciximab, thrombocytopenia occurs in up to 5%
of patients. Thrombocytopenia is severe in ∼1% of these individuals.
Thrombocytopenia is less common with the other two agents, occurring in
∼1% of patients.

MEDICAMENTE ANTICOAGULANTE

LOW – MOLECULAR- WEIGHT – HEPARIN LMWH

Masa moleculară medie = 5000
Exemplu: CLEXANE = ENOXOPARINA
Avantaje față de heparină:

Biodisponibilitate mai bună după injectarea sc (90%) și T1/2 mai mare

Clereance dose- independent
Predictabilitatea raspunsului anticoagulant – nu necesită monitorizarea
INR
Risc mai mic de HIT
Risc mai mic de osteoporoză

MECANISM: activarea antitrombinei – din cauza masei moleculare de

5000, care corespunde cu aprox 17 unități zaharidice, cel puțin ½ din
lanțuri sunt prea scurte pentru a lega trombina de antitrombină. Dar, aceste
lanțuri scurte au capacitatea de a accelerea inhibarea factorului Xa de către
antitrombina. Respectiv ratio anti Xa: anti IIa = 2:1 to 4:1

LMWH has pharmacokinetic advantages over heparin. These advantages

reflect the fact that shorter heparin chains bind less avidly to endothelial
cells, macrophages, and heparin-binding plasma proteins. Reduced binding
to endothelial cells and macrophages eliminates the rapid, dose-dependent,
and saturable mechanism of clearance that is a characteristic of
unfractionated heparin. Instead, the clearance of LMWH is dose-
independent and its plasma half-life is longer.

Prin măsurarea nivelului de anti-factor Xa s-a determinat că T1/2 a

LMWH este de aproximativ 4 ore.
Because LMWH binds less avidly to heparin-binding proteins in plasma
than heparin, LMWH produces a more predictable dose response, and
resistance to LMWH is rare. With a longer half-life and more predictable
anticoagulant response, LMWH can be given SC once or twice daily
without coagulation monitoring, even when the drug is given in treatment
doses.

Indications for LMWH monitoring include renal impairment and obesity.

LMWH monitoring in patients with a creatinine clearance of ≤30 mL/min
is advisable to ensure that there is no drug accumulation.

It may also be advisable to monitor the anticoagulant activity of LMWH

during pregnancy because dose requirements can change, particularly in
the third trimester.

Monitoring should also be considered in high-risk settings, such as in

pregnant women with mechanical heart valves who are given LMWH for
prevention of valve thrombosis, and when LMWH is used in treatment
doses in infants or children.

DOSING The doses of LMWH recommended for prophylaxis or treatment

vary depending on the LMWH preparation. For prophylaxis, once-daily
SC doses of 4000–5000 units are often used, whereas doses of 2500–3000
units are given when the drug is administered twice daily.

For treatment of venous thromboembolism, a dose of 150–200 units/kg is

given if the drug is administered once daily. If a twice-daily regimen is
used, a dose of 100 units/kg is given.

In patients with unstable angina, LMWH is given SC on a twice-daily

basis at a dose of 100–120 units/kg.

¡¡ LMWH should not be used to treat HIT patients because most HIT
antibodies exhibit cross-reactivity with LMWH.

Fondaparinux A synthetic analogue of the antithrombin-binding

pentasaccharide sequence, fondaparinux differs from LMWH in several
ways (Table 118-6). Fondaparinux is licensed for thromboprophylaxis in
general medical or surgical patients and in high-risk orthopedic patients
and as an alternative to heparin or LMWH for initial treatment of patients
with established venous thromboembolism. Although fondaparinux is used
in Europe as an alternative to heparin or LMWH in patients with acute
coronary syndrome, the drug is not licensed for this indication in the
United States.

MECHANISM OF ACTION As a synthetic analogue of the antithrombin-

binding pentasaccharide sequence found in heparin and LMWH,
fondaparinux has a molecular weight of 1728. Fondaparinux binds only to
antithrombin (Fig. 118-5) and is too short to bridge thrombin to
antithrombin. Consequently, fondaparinux catalyzes factor Xa inhibition
by antithrombin and does not enhance the rate of thrombin inhibition.

PHARMACOLOGY Fondaparinux exhibits complete bioavailability after SC

injection. With no binding to endothelial cells or plasma proteins, the
clearance of fondaparinux is dose independent, and its plasma half-life is
17 h. The drug is given SC once daily. Because fondaparinux is cleared
unchanged via the kidneys, it is contraindicated in patients with a
creatinine clearance <30 mL/min and should be used with caution in those
with a creatinine clearance <50 mL/min.

Dosing Fondaparinux produces a predictable anticoagulant response after

administration in fixed doses because it does not bind to plasma proteins.
The drug is given at a dose of 2.5 mg once daily for prevention of venous
thromboembolism. For initial treatment of established venous
thromboembolism, fondaparinux is given at a dose of 7.5 mg once daily.
The dose can be reduced to 5 mg once daily for those weighing <50 kg and
increased to 10 mg for those >100 kg. When given in these doses,
fondaparinux is as effective as heparin or LMWH for initial treatment of
patients with DVT or PE and produces similar rates of bleeding.

SIDE EFFECTS Fondaparinux does not cause HIT because it does not bind
to PF4. In contrast to LMWH, there is no cross-reactivity of fondaparinux
with HIT antibodies. Consequently, fondaparinux appears to be effective
for treatment of HIT patients, although large clinical trials supporting its
use are lacking.

The major side effect of fondaparinux is bleeding. Fondaparinux has no

antidote. Protamine sulfate has no effect on the anticoagulant activity of
fondaparinux because it fails to bind to the drug. Recombinant activated
factor VII reverses the anticoagulant effects of fondaparinux in volunteers,
but it is unknown whether this agent controls fondaparinux-induced
bleeding.

ANTICOAGULANTE ORALE

WARFARINA
Antagonist hidrosolubil al vitaminei K – interferă cu sinteza factorilor de
coagulare vitamina K- dependenți: factor II (protrombina), factorul VII,
IX, X. La fel are loc și reducerea de sinteză a proteinelor anticoagulante C
și S, care sunt la fel K-dependente.

Warfarina inhibă vitamina K reductaza, ceea ce blochează procesul de

gamma- carboxilare a factorilor de coagulare. Factorii de coagulare parțial
sau deloc carboxilați au puțină/deloc activitate biologică.

!!! instalarea acțiunii warfarinei este întârziată până când se produc noi
factori de coagulare cu puțină/fără activitate biologică, fiind dependentă de
reducerea nivelului funcțional al factorului X și a protrombinei, care au un
T1/2 de 24 și 72 de ore. De aceea, cei cu tromboză instalată sau cu risc
crescut de tromboză necesită un tratament concomitent cu un anticoagulant
parenteral ca heparina, LMWH sau fondaparinux pentru cel puțin 5 zile.
Warfarin is a racemic mixture of R and S isomers. Warfarin is rapidly and
almost completely absorbed from the gastrointestinal tract. Levels of
warfarin in the blood peak about 90 min after drug administration.
Racemic warfarin has a plasma half- life of 36–42 h, and >97% of
circulating warfarin is bound to albumin. Only the small fraction of
unbound warfarin is biologically active.

Warfarin accumulates in the liver where the two isomers are metabolized
via distinct pathways. CYP2C9- isomerul S;

the anticoagulant effect of warfarin is influenced by diet, drugs, and

various disease states. Fluctuations in dietary vitamin K intake affect the
activity of warfarin. A wide variety of drugs can alter absorption,
clearance, or metabolism of warfarin. Because of the variability in the
anticoagulant response to warfarin, coagulation monitoring is essential to
ensure that a therapeutic response is obtained.
Monitorizare: timpul de protrombină
INR – țintă – cel mai des între 2.0-3.0
Cei cu valve mecanice – 2,5 – 3,5 în special valva mitrală, aortică

DOZARE: de obicei se inițiază cu 5-10 mg, apoi se titrează în funcție de INR

În caz de risc înalt de tromboză sau tromboză prezentă, anticoagularea cu warfarină se
inițiază concomitent cu un anticoagulant parenteral ca heparina, LMWH sau fondaparinux
până când INR se află în intervalul țintă pentru cel puțin 2 zile consecutive – minim 5 zile
anticoagulare duală se recomandă.
De obicei, se recomadă, ulterior monitorizarea INR la fiecare 3-4 sp, din cauza ferestrei
terapeutice înguste a warfarinei. Se monitorizează mai des atunci când se introduc noi
medicamente, din cauza interacțiunilor multiple care cresc/scad efectul anticoagulant al
warfarinei.
RA: sângerare
Necroză cutanată
Anomalii fetale – traversează placenta – NU SE UTILIZEAZĂ LA ÎNSĂRCINATE

Sângerare: Tominimize the risk of bleeding, the INR should be maintained

in the therapeutic range.

In asymptomatic patients whose INR is between 3.5 and 10, warfarin

should be withheld until the INR returns to the therapeutic range. If the
INR is over 10, oral vitamin K can be administered at a dose of 2.5–5
mg, although there is no evidence that doing so reduces the bleeding risk.
Higher doses of oral vitamin K (5–10 mg) produce more rapid reversal of
the INR but may render patients temporarily resistant to warfarin when the
drug is restarted.

Patients with serious bleeding need more aggressive treatment. These

patients should be given 5–10 mg of vitamin K by slow IV infusion.
Additional vitamin K should be given until the INR is in the normal range.
Treatment with vitamin K should be supplemented with four-factor
prothrombin complex concentrate, which contains all four vitamin K–
dependent clotting proteins. Prothrombin complex concentrate
normalizes the INR more rapidly than transfusion of fresh frozen
plasma.

Warfarin-treated patients who experience bleeding when their INR is in

the therapeutic range require investigation into the cause of the bleeding.
Those with gastrointestinal or genitourinary bleeding often have an
underlying lesion.
NECROZA PIELII:

A rare complication of warfarin, skin necrosis usually is seen 2–5 days

after initiation of therapy. Well-demarcated erythematous lesions form on
the thighs, buttocks, breasts, or toes. Typically, the center of the lesion
becomes progressively necrotic. Examination of skin biopsies taken from
the border of these lesions reveals thrombi in the microvasculature.

Warfarin-induced skin necrosis is seen in patients with congenital or

acquired deficiencies of protein C or protein S. Initiation of warfarin
therapy in these patients produces a precipitous fall in plasma levels of
proteins C or S, thereby eliminating this important anticoagulant pathway
before warfarin exerts an antithrombotic effect through lowering of the
functional levels of factor X and prothrombin. The resultant procoagulant
state triggers thrombosis. Why the thrombosis is localized to the
microvasculature of fatty tissues is unclear.

Treatment involves discontinuation of warfarin and reversal with vitamin

K, if needed. An alternative anticoagulant, such as heparin or LMWH,
should be given in patients with thrombosis. Protein C concentrate can be
given to protein C–deficient patients to accelerate healing of the skin
lesions; fresh-frozen plasma may be of value if protein C concentrate is
unavailable and for those with protein S deficiency. Occasionally, skin
grafting is necessary when there is extensive skin loss.
Because of the potential for skin necrosis, patients with known protein C
or protein S deficiency require overlapping treatment with a parenteral
anticoagulant when initiating warfarin therapy. Warfarin should be started
in low doses in these patients, and the parenteral anticoagulant should be
continued until the INR is therapeutic for at least 2–3 consecutive days.
Alternatively, treatment with rivaroxaban or apixaban could be given,
although there is limited information about their efficacy and safety in
patients with severe protein C or S deficiency.

Pregnancy Warfarin crosses the placenta and can cause fetal abnormalities
or bleeding. The fetal abnormalities include a

characteristic embryopathy, which consists of nasal hypoplasia and

stippled epiphyses. The risk of embryopathy is highest if warfarin is given
in the first trimester of pregnancy. Central nervous system abnormalities
can also occur with exposure to warfarin at any time during pregnancy.
Finally, maternal administration of warfarin produces an anticoagulant
effect in the fetus that can cause bleeding. This is of particular concern at
delivery when trauma to the head during passage through the birth canal
can lead to intracranial bleeding. Because of these potential problems,
warfarin is contraindicated in pregnancy, particularly in the first and third
trimesters. Instead, heparin, LMWH, or fondaparinux can be given during
pregnancy for prevention or treatment of thrombosis.

Warfarin does not pass into the breast milk. Consequently, warfarin can
safely be given to nursing mothers.

There is no need to stop warfarin before procedures associated with a low

risk of bleeding; these include dental cleaning, simple dental extraction,
cataract surgery, or skin biopsy. For procedures associated with a
moderate or high risk of bleeding, warfarin should be stopped 5 days
before the procedure to allow the INR to return to normal levels. Patients
at high risk for thrombosis, such as those with mechanical heart valves,
can be bridged with once- or twice- daily SC injections of LMWH when
the INR falls to <2.0. The last dose of LMWH should be given 12–24 h
before the procedure, depending on whether LMWH is administered twice
or once daily. After the procedure, treatment with warfarin can be
restarted.
DOAC – ANTICOAGULANTE DIRECTE ORALE

Inhibitori de trombină : dabigatran

Inhibitori de factor Xa: rivaroxoban, apixaban (ELIQUIS), edoxaban
Prezintă o instalare rapidă a efectului, T1/2 permite administrarea 1-2/zi, nu necesită
monitorizarea INR comparativ cu warfarina.

MECANISM DE ACȚIUNE: se leagă direct reversibil cu site-urile active ale enzimelor țintă:
factor Xa sau Trombina

Indicații: All four DOACs are licensed for stroke prevention in patients
with nonvalvular atrial fibrillation, which encompasses patients without
mechanical heart valves or severe rheumatic mitral valve disease, and for
treatment of venous thromboembolism (VTE).

Dabigatran, rivaroxaban, and apixaban are licensed for

thromboprophylaxis after elective hip or knee arthroplasty; edoxaban
is only licensed for this indication in Japan.

Finally, low-dose rivaroxaban is licensed for use with aspirin for

secondary prevention in patients with coronary or peripheral artery
disease.

Doza:

For prevention of stroke in patients with nonvalvular atrial

fibrillation,

rivaroxaban is given at a dosage of 20 mg once daily, with a reduction to

15 mg once daily in patients with a creatinine clearance of 15–49 mL/min;
At doses of 15 or 20 mg once daily, rivaroxaban must be administered
with food to enhance absorption

dabigatran is given at a dosage of 150 mg twice daily, with a reduction to

75 mg twice daily in those with a creatinine clearance of 15–30 mL/min;
Administration of dabigatran with food may reduce dyspepsia.
apixaban is given at a dosage of 5 mg twice daily, with a reduction to 2.5
mg twice daily for patients with at least two of the “ABC” criteria (i.e.,
age >80 years, body weight <60 kg, and creatinine >1.5 g/dL);

edoxaban is given at a dosage of 60 mg once daily for patients with a

creatinine clearance of 50–95 mL/min and with a reduction to 30 mg once
daily for patients with any one of the following criteria: creatinine
clearance of 15–50 mL/min, body weight of 60 kg or less, or use of potent
P- glycoprotein inhibitors, such as verapamil or quinidine.

Apixaban and edoxaban can be given with or without food.

For treatment of VTE,

dabigatran and edoxaban are started after patients have received at least a
5-day course of treatment with a parenteral anticoagulant such as LMWH;

dabigatran is given at a dose of 150 mg twice daily provided the creatinine

clearance is >30 mL/min,

and the dosage regimen for edoxaban is identical to that used in patients
with atrial fibrillation.

In contrast, rivaroxaban and apixaban can be given in all-oral regimens;

rivaroxaban is started at a dose of 15 mg twice daily for 21 days and is

then reduced to 20 mg once daily thereafter, whereas apixaban is started at
a dose of 10 mg twice daily for 7 days and is then reduced to 5 mg twice
daily thereafter.

For secondary VTE prevention, the dosage of apixaban can be lowered

to 2.5 mg twice daily while the dose of rivaroxaban can be lowered to 10
mg once daily, doses that have safety profiles like those of placebo and
aspirin, respectively.

Thromboprophylaxis after elective hip or knee replacement surgery is

started after surgery and is often continued for 30 days in patients
undergoing hip replacement and for 10–14 days in patients undergoing
knee replacement. Dabigatran is given at a dose of 220 mg once daily,
whereas rivaroxaban and apixaban are given at doses of 10 mg once daily
and 2.5 mg twice daily, respectively. In lower risk patients undergoing hip
or knee replacement surgery, a 5- day course of rivaroxaban followed by a
30-day course of aspirin at a dose of 81 mg daily appears to be as effective
and safe as extended thromboprophylaxis with rivaroxaban.

For secondary prevention of adverse cardiac or limb events in patients

with coronary or peripheral artery disease, rivaroxaban is given at a dose
of 2.5 mg twice daily on top of aspirin (81 or 100 mg once daily).
MONITORIZARE:

Although designed to be administered without routine monitoring, there

are situations where determination of the anticoagulant activity of the new
oral anticoagulants can be helpful. These include assessment of adherence,
detection of accumulation or overdose, identification of bleeding
mechanisms, and determination of activity prior to surgery, intervention,
or reversal. For qualitative assessment of anticoagulant activity, the
prothrombin time can be used for factor Xa inhibitors and the aPTT for
dabigatran. Rivaroxaban and edoxaban prolong the prothrombin time more
than apixaban. In fact, because apixaban has such a limited effect on the
prothrombin time, anti–factor Xa assays are needed to assess its activity.
The effect of the drugs on tests of coagulation varies depending on the
time that the blood is drawn relative to the timing of the last dose of the
drug and the reagents used to perform the tests

SIDE EFFECTS Like all anticoagulants, bleeding is the most common side
effect of the DOACs. The DOACS are associated with less intracranial
bleeding than warfarin, but the higher dose regimens of dabigatran,
rivaroxaban, and edoxaban are associated with more gastrointestinal
bleeding.

Dyspepsia occurs in up to 10% of patients treated with dabigatran; this

problem improves with time and can be minimized by administering the
drug with food. Dyspepsia is rare with rivaroxaban, apixaban, and
edoxaban.

PERIPROCEDURAL MANAGEMENT Like warfarin, the DOACs must be

stopped before procedures associated with a moderate or high risk of
bleeding. The drugs should be held for 1–2 days, or longer if renal

function is impaired. Assessment of residual anticoagulant activity before

procedures associated with a high bleeding risk is prudent.
MANAGEMENT OF BLEEDING With minor bleeding, withholding one or two
doses of drug is usually sufficient. With more serious bleeding, the
approach is similar to that with warfarin, except that vitamin K
administration is of no benefit; the anticoagulant and any antiplatelet drugs
should be withheld, the patient should be resuscitated with fluids and
blood products as necessary, and the bleeding site should be identified and
managed. Coagulation testing or measurement of DOAC level will
determine the extent of anticoagulation, and renal function should be
assessed so that the half-life of the drug can be calculated. Timing of the
last dose of anticoagulant is important; oral activated charcoal may help
prevent absorption of drug administered in the past 4 h, particularly in
cases of overdose. If >24 h have elapsed since the last intake, the DOAC is
unlikely to be responsible for the bleeding unless there is marked
impairment of renal function.

Anticoagulant reversal should be considered if bleeding continues despite

supportive measures or if the bleeding is life- threatening or occurs in a
critical organ (e.g., intracranial) or in a closed space (e.g., the pericardium
or retroperitoneum). Idarucizumab is licensed for dabigatran reversal in
such patients or in those requiring urgent surgery or intervention. A
humanized antibody fragment, idarucizumab, binds dabigatran with high
affinity to form an essentially irreversible complex that is cleared by the
kidneys. Idarucizumab is given intravenously as a 5-g bolus and is
supplied in a box containing two 50-mL vials, each containing 2.5 g of
idarucizumab. Idarucizumab rapidly reverses the anticoagulant effects of
dabigatran and normalizes the aPTT, diluted thrombin time, or ecarin clot
time.

Andexanet alfa is available for reversal of rivaroxaban, apixaban, and

edoxaban. A recombinant variant of factor Xa without catalytic activity,
andexanet serves as a decoy to sequester oral factor Xa inhibitors until
they are cleared from the circulation. Low- or high- dose IV andexanet
regimens are used. The low-dose regimen starts with a bolus of 400 mg
followed by an infusion of 4 mg/min for up to 120 min, whereas the high-
dose regimen starts with a bolus of 800

mg followed by an infusion of 8 mg/min for up to 120 min. The low- dose

regimen is used for reversal of doses of rivaroxaban or apixaban of 10 mg
or 5 mg or less, respectively, or for any dose of rivaroxaban or apixaban if
the last dose was taken >8 h prior to presentation. The high-dose regimen
is used to reverse rivaroxaban or apixaban doses over 10 and 5 mg,
respectively, if the last dose was taken <8 h since presentation, or for
reversal if the dose of rivaroxaban or apixaban or the timing of the last
dose is unknown.

Andexanet alfa is expensive and is not available in all hospitals. Because

of its cost, andexanet alfa is often reserved for reversal in patients with
life-threatening bleeds such intracranial hemorrhage or bleeds into a closed
space such as retroperitoneal or pericardial bleeds. If andexanet is
unavailable, the results of prospective cohort studies suggest that four-
factor prothrombin complex concentrate (25–50 units/kg) also is effective
at restoring hemostasis. If there is continued bleeding, activated
prothrombin complex concentrate (50 units/kg) or recombinant factor VIIa
(90 μg/kg) can be considered.

Neither andexanet alfa nor four-factor prothrombin complex concentrate

has been evaluated for reversal in patients requiring urgent surgery or
intervention. Furthermore, andexanet alfa not only reverses oral factor Xa
inhibitors but also reverses heparin and LMWH. This could be problematic
in patients who require cardiac surgery or vascular surgery, procedures
where heparin is used routinely. To circumvent this problem, most surgical
procedures and interventions can be undertaken without reversal, and four-
factor prothrombin complex concentrate can be given if necessary. For
patients requiring surgery to stop bleeding such as those with a ruptured
aortic aneurysm or with bleeding secondary to polytrauma, upfront four-
factor prothrombin concentrate administration can be considered.

PREGNANCY As small molecules, the DOACs pass through the placenta.

Consequently, these agents are contraindicated in pregnancy, and when
used by women of childbearing potential, appropriate contraception is
important. The DOACs should be avoided in nursing mothers.