venous thromboembolism

DVT presentation

sx: unilateral and localized to area, swelling, pain, redness, tenderness

s: superficial veins dilated (palpable cord), unilateral leg edema (2 cm difference in diameter), homan’s sign (calf pain during dorsiflexion (backward bending) of foot

PE presentation

sx: SOB + fatigue, chest pain, palpitations, hemoptysis, syncope

s: tachypnea, tachycardia, diaphoresis, hypoxia; lungs sound clear

dx tests for dvt

d-dimer (rule out), ultrasound (non-invasive), venography (invasive)

dx tests for pe

d-dimer (rule out), computed tomographic pulmonary angiography (CTPA) [minimally invasive], ventilation-perfusion (V/Q) scan [minimally invasive], echocardiography [non-invasive]

d-dimer

measures plasma levels of d-dimers, generated when the endogenous fibrinolytic system degrades fibrin

97% sensitivity, 35-45% specificity (useful as exclusionary test for VTE

compression ultrasound

highly sensitive + specific modallity for recognition of lower extremity DVTs w/o need for radiation or contrast exposure non-invasive

computed tomographic pulmonary angiography (CTPA)

1st line testing for PE, high sensitivity and specificity

contrast dye used to visualize thrombus in lungs

ventilation perfusion (V/Q) scan

2nd line dx test for PE (esp for pts who can take contrast dye)

pt breathes in isotope nebulizing solution used to assess air flow (ventilation)

isotope inj then used to assess blood flow (perfusion)

dx: blood flow defects in presence of normal air flow

tx goals of VTE

prevent development of PE

prevent recurrence of dvt/pe

reduce post-thrombotic syndrome, chronic thromboembolic pulmonary HTN

prevent complications, mortality + morbidity

tx w/ minimal AE and cost

direct oral anticoags (DOACs)

apixaban, rivaroxaban, edoxaban, dabigatran

which DOACs are factor Xa inhibitors

apixaban, rivaroxaban, edoxaban

which DOAC is a factor IIa (thrombin) inhibitor

dabigatran

vitamin K antagonist (indirect)

warfarin

which parenteral anticoags work indirectly

UFH, LMWH (enoxaparin, deltaparin), factor Xa inhibitor (fondaparinux)

which parenteral anticoags work directly on thrombin

argatroban, bivalludin, desirudin

how does warfarin work in the clotting cascade

prevents factor 2, 7, 9, 10 production from the liver! and adds anticoag proteins C and S (→ early procoagulant effect)

which factors does unfractionated heparin inhibit indirectly

Xa and IIa equally

which factors dose LMWH inhibit indirectly

more Xa than IIa

which parenteral anticoags are given SC

fondaparinux, desirudin, UFH, LMWH (both)

which parenteral anticoags are given IV

argatroban, bivalirudin, UFH, enoxaparin

true or false: are DOACs less effective than warfarin

false they are non-inferior!

which DOACs are dosed BID

apixaban, dabigatran

which DOACs are dosed QD

rivaroxaban, edoxaban

which DOAC is more renally cleared (in order)

dabigatran » edoxaban » rivaroxaban » apixaban

are DOACs recommended in pregnancy

no! avoid!

apixaban: category B

rivaroxaban, edoxaban, dabigatran: category C

contraindications for DOACs

active bleeding, mechanical heart valves, severe hepatic impairment

adrs for apixaban, rivaroxaban, edoxaban

bleeding

adrs for dabigatran

bleeding, dyspepsia, gi upset (gastritis)

what should you monitor for when pt is on DOAC

no efficacy lab monitoring

monitor renal fxn (for dosing adjustment), hgb, hct for safety

what antidote/reversal agent is used for apixaban, rivaroxaban, and edoxaban

factor 4-PCC (Kcentra)

what antidote/reversal agent is used for dabigatran

idarucizumab (Praxbind)

DOAC black box warning

increased risk of thrombotic events when discontinued prematurely

risk of epidural or spinal hematoma if receiving neuraxial anesthesia or undergoing spinal puncture

edoxaban specific black box warning

reduced efficacy in nonvalvular a-fib if crcl is >95 ml/min

apixaban tx for dvt/pe

10 mg BID x 7 days then 5 mg BID

rivaroxaban tx for dvt/pe

15 mg BID x 21 days then 20 mg daily with food

avoid use if crcl <30

edoxaban tx for dvt/pe

60 mg daily, start after 5-10d of parenteral anticoag
reduce to 30 mg if crcl 15-50, wt ≤ 60 kg, or on certain P-gp inhibitors

not recommended if crcl <15

dabigatran tx for dvt/pe

150 mg BID, start after 5-10d of parenteral anticoag

avoid if crcl <30

apixaban ppx for dvt (after knee/hip replacement)

2.5 mg BID x 12 d after knee or x 35d after hip surgery

1st dose 12-24h after surgery

rivaroxaban ppx for dvt (after knee/hip replacement surgery)

10 mg QD x 12d after knee or x 35d after hip surgery

1st dose 6-10h after surgery

avoid if crcl <30

is edoxaban used for ppx of dvt

no

dabigatran ppx for dvt (after knee/hip replacement surgery)

110 mg on day 1, then 220 mg QD

avoid if crcl <30

when should pt take rivaroxaban if taking it for nonvalvular afib stroke prevention

with their evening meal

avoid if crcl<15

15 mg qd if crcl 15-50

30 mg qd if crcl >50

which DOACs need renal adjustment

rivaroxaban, edoxaban, dabigatran

which DOAC does not need renal adjustment

apixaban, but dose adjust for afib! (reduce to 2.5mg bid if they have ≥2 of age≥80y, wt ≤60kg, or scr ≥ 1.5 mg/dl)

which DOAC has less bleeding than the other DOACs

apixaban

which DOAC has the least DDIs

dabigatran

which DOAC do you keep in the original bottle/blister pack/dont add to pill box (d/t humidity)

dabigatran

DOAC DDIs that should generally be avoided

p-gp inhibitors + cyp3a4 inhibitors

p-gp inducers + cyp3a4 inducers

which cyp3a4 inhibitors should be avoided w/ DOACs

azole antifungals, macrolides, protease inhibitors, non-dhp ccbs, amiodarone etc (g-pacman)

what cyp3a4 inducers should be avoided

rifampin, phenytoin, smoking, phenobarbital, carbamazepine, oxcarbamazepine, st.johns wort

initial management tx duration

5-21d

primary tx duration

3-6 months

extended tx (2ndary prevention) duration

beyond 3-6 months

apixaban initial tx

10 mg bid x 7 days

rivaroxaban initial tx

15 mg bid x 21 d

avoid if crcl <30

which anticoags are not used in initial treatment?

edoxaban and dabigatran

warfarin initial tx

combo!

warfarin + UFH/LMWH

heparin (UFH) initial tx

80 units/kg iv bolus

18 units/kg/hr infusion

or

5000 units iv bolus

1000 units/hr infusion

enoxaparin initial tx

1 mg/kg SC bid

1.5 mg/kg SC qd only for inpt vte tx

if crcl <30 : 1mg/kg SC qd

apixaban primary tx

5 mg bid

rivaroxaban primary tx

20 mg qd

avoid if crcl <30

edoxaban primary tx

60 mg qd

if crcl 15-50 or wt ≤ 60 kg: reduce to 30 mg qd

dabigatran primary tx

150 mg bid

avoid if crcl <30

warfarin primary tx

monotherapy! target INR 2-3

is heparin used for primary tx

no!

is enoxaparin used for primary tx

not usually, some pts w/ cancer may use it for 3-6 months

apixaban extended tx

2.5 mg (or 5mg) bid

rivaroxaban extended tx

10mg (or 20 mg) qd

avoid if crcl <30

is edoxaban used for extended tx?

no!

dabigatran extended tx

150 mg bid

avoid if crcl <30

is heparin or enoxaparin used for extended treatment?

no!

apixaban ppx (primary prevention)

2.5mg bid

rivaroxaban ppx (primary prevention)

10 mg qd

avoid if crcl <30

is edoxaban used for ppx (primary prevention)

no!

dabigatran ppx tx (primary prevention)

110 mg on day 1 then 220 QD

avoid if crcl <30

warfarin ppx tx (primary prevention)

monotherapy, target INR 2-3 (less evidence)

heparin ppx tx (primary prevention)

5000 units SC q8-q12

enoxaparin ppx tx (primary prevention)

30 mg SC bid (or 40 mg SC daily)

if crcl <30 → 30 mg SC daily

how is warfarin dosed

daily

indications of warfarin

vte tx and ppx

ppx of stroke in afib

ppx of acute MI in pts w/ pad

ppx of stroke, recurrent infxn

how many days of warfarin therapy is necessary before a pt is completely anticoagulated?

4-5 days

how is warfarin metabolized and what does that mean

hepatic metabolism meansssss → NO renal adjustment!

can you use warfarin in pregnancy

no! contraindicated (crosses placenta but not secreted in breast milk)

adrs of warfarin

purple toe syndrome: dark blue-tinged discoloration of the feet that occurs rarely 3-8 wks after warfarin initiation

warfarin-induced skin necrosis rare but serious adverse effect (begins within 10 days of initiation)

what do you monitor for warfarin

PT, INR (shows reduction in clotting factors II, VII, and X)

antidote/reversal agents for warfarin

vitamin K and 4-factor PCC (Kcentra)

which genes are tested with warfarin

VKORC1 and CYP2C9

VKORC1

vitamin K epoxide reductase complex subunit 1 gene

AA genotype : sensitive to warfarin

GG genotype : resistant to warfarin

CYP2C9

presence of variant alleles cyp2c9*2 and *3 results in slower clearance of warfarin

mneumonic for warfarin tablet colors

Please → pink → 1

Let → lavender → 2

Granny → green → 2.5

Brown → brown → 3

Bring → blue → 4

Peaches → peach → 5

To → teal → 6

Your → yellow → 7.5

Wedding → white → 10

what initial dose of warfarin will bring INR to around 2.0 in 4-5 days for most pts

5 mg QD

initiating warfarin with UFH/LMWH

take both together, stop UFH/LMWH when ≥5 days of combo therapy AND INR ≥ 2.0 for ≥ 24h

target INR of 2.5 and therapeutic range of 2-3 is indicated for

pts treated for VTE, afib, mechanical aortic valve, bioprosthetic valve, or antiphospholipid syndrome

target INR of 3.0 and therapeutic range of 2.5-3.5 is indicated for

pts treated for mechanical mitral valve or both mechanical aortic and mitral valves

what is used to monitor heparin

efficacy: aPTT (activated thromboplastin time), ACT (activated clotting time), anti Xa levels

safety: platelet, hgb, hct, s/sx of bleeding

warfarin maintenance dosing

when is IV vitamin K used

only for pts with serious bleeding

warfarin DDIs

has NTI so must monitor INR

many DDIs ☹

drugs that inhibit or induce cyp2c9 or 3a4 can potentiate or reduce anticoag effect

S-isomer is more active!

which drugs increase PT/INR

metronidazole, bactrim, cimetidine, omeprazole, fluconazole, voriconazole, ciprofloxacin, erythromycin, miconazole, simvastatin, amiodarone, cephalosporins w/ NMTT side chains, aspirin + nsaids

which drugs decrease PT/INR

cholestyramine, barbiturates, rifampin, carbamazepine