Lecture 24 - Venous Thromboembolism Part 3

how does the half life of fondaparinux compare to UFH/LMWF

significantly longer

what are qualities of fondaparinux (SC)

high/predictable bioavailability

elimination: renal, dose independent

no routine monitoring (calibrated anti-Xa)

what is the place of UFH in initial VTE treatment

Situations wherein reversal of anticoagulant effect may be anticipated (extensive clot, circulatory compromise=massive PE) → IV drip is typically used

Renal dysfunction (CrCl < 20mL/min)

what are the 3 most common LMWH used in Alberta

Dalteparin

Enoxaparin

Tinzaparin

what is the treatment dose of Dalteparin

(weight-based dosing - with pre-filled syringes, use one closest to weight-based dosing)

100 IU/kg SC q12h

200 IU/kg SC q24h

what is the treatment dose of Enoxaparin

(weight-based dosing - with pre-filled syringes, use one closest to weight-based dosing)

1 mg/kg SC q12h

1.5 mg/kg SC q24h

what is the treatment dose of Tinzaparin

(weight-based dosing - with pre-filled syringes, use one closest to weight-based dosing)

175 IU/kg SC q24h

what is the treatment dose of Fondaparinux

< 50 Kg, 5 mg SC Q24H

50-100 Kg, 7.5 mg SC Q24H

> 100 Kg, 10 mg SC Q24H

what are considerations for LMWH in renal dysfunction

LMWH are primarily renally eliminated

• Enoxaparin >> dalteparin > tinzaparin

<20 mL/min – use UFH

20-30 mL/min – tinzaparin

> 30 mL/min –dalteparin, enoxaparin or tinzaparin

what are considerations for LMWH in obesity

Dosing based on total body weight (TBW) is recommended when using LMWH

Don’t dose cap (contradicts Canadian product monographs)

Will administer it Q12H (often so only one syringe is injected at once)

although anti-Xa is not usually recommended for LMWH, what are situations where you could consider testing

Extremes of weight

Renal dysfunction

Failure of therapy (clot or bleed)

how should anti-Xa levels be checked

Patient should have received at least 72 hours of LMWH dosing (steady state) and peaks at 4 hours (draw 4-6 hours post-dose)

Q12H dosing = 0.5 – 1 IU/mL*

Q24H dosing = 1 – 1.5 IU/mL*

*variability in targets may exist depending on indication and drug

what are adverse effects of heparin

Bleeding (more with UFH)

Osteoporosis (more with UFH)

Alopecia

Heparin Induced Thrombocytopenia (HIT) – Type I

HIT Type II

what is HIT type 1

Non-immune mediated, transient & mild

Early onset (<4 days) & reversible

what is HIT type 2

Immunologic drug reaction, severe

More common with UFH vs LMWH

Delayed (day 5-14), can be within 24 hours if exposure in last 100 days

Thrombotic disorder in 20- 50%, can be arterial or venous

Limb amputation in 10%, fatal in 8-20%

how is HIT type 2 monitored for

Platelet count typically falls below 150 X 109 /L, however decrease from baseline platelets of 40-50% is hallmark

With heparin administration, clinical signs/symptoms of:

• clot (venous or arterial)

• skin necrosis/lesions at injection site

• systemic reactions (fever/chills) after IV heparin bolus

how is HIT type 2 diagnosed

clinical symptoms and presence of HIT antibodies (result of antibody testing is delayed)

what can be given is a patient has a HIT type 2 reaction

fondaparinux, DOAC

what are monitoring recommendations for low risk HIT patients (Medical & obstetrical getting LMWH LMWH after minor surgery or trauma)

No monitoring required

what are monitoring recommendations for intermediate risk HIT patients (Medical & obstetrical getting UFH LMWH after major surgery or trauma)

Platelet counts every 2-3 days for 4-14 days or until heparin stopped

what are monitoring recommendations for high risk HIT patients (Surgical & trauma patients getting UFH)

Platelet counts at least every 2nd day for 4-14 days or until heparin stopped

when are DOACs contraindicated

Mechanical heart valves

Active bleeding or risk of bleeding deemed too high

Pregnancy or breastfeeding (no data)

Moderate to severe hepatic impairment (limited, if any data)

Drug Interactions:

Severe renal impairment

what are drug interactions with dabigatran

strong P-gp inhibitors/inducers

what are drug interactions with endoxaban

strong P-gp inducers

what are drug interactions with rivaroxaban/apixaban

strong inhibitors / inducers of both CYP 3A4 & P-gp

what is the renal impairment cutoff for dabigatran

CrCl < 30mL/min

what is the renal impairment cutoff for apixaban

CrCl < 25 mL/min

(caution if CrCl 15-29mL/min)

what is the renal impairment cutoff for rivaroxaban

< 15 mL/min

what is the renal impairment cutoff for edoxaban

< 15 mL/min

what are considerations for DOACs in obesity

often preferred to use traditional therapy instead, but some observational data suggests that it’s okay

in practice → LMWH at full dose for 1 month then transition to DOAC (not really evidence behind this, just what people do)

what are recommendations for DOACs with thrombophilias

ideal to use traditional therapy for most (except antiphospholipid antibody syndrome)

what are monitoring parameters for VTE

Ensure appropriate DOAC drug / dose sequence, as applicable

Assessment of clinical improvement - ongoing

• Encourage ambulation, active lifestyle

Adherence, Reinforce Education, Labs (Renal Assessment, CBC- platelets if heparin)

what are signs of clinical improvement of DVT

leg swelling, color, pain/tenderness, use/limitations – recommend leg elevation & compression stockings

what are signs of clinical improvement in PE

pain, breathing (SOB), right heart pressure, activity limitations

how long is the treatment phase of anticoagulation in In patients with acute VTE who do not have a contraindications

3 months

On completion of the 3-month treatment phase of therapy, all patients should be assessed for extended phase therapy

Elective procedures should be avoided until after 3 months

Clinical progress is crucial prior to therapy modification

how long is the anticoagulation treatment phase usually in practive

often do 6 months

Judgement based on extent / location of thrombosis

should therapy be extended for proximal DVT or PE if VTE provoked by a major transient risk factor (Surgery with general anesthesia > 30 min, hospital bed confinement (only bathroom privileges) >/= 3 days with acute illness, caesarean section)

Recommend against extending therapy

overall risk of recurrence is very low

should therapy be extended for proximal DVT or PE if VTE provoked by a minor transient risk factor

(Surgery with general anesthesia < 30 min, hospitalized <3 days with acute illness, estrogen therapy, pregnancy or puerperium, confinement to bed out of hospital for at least 3 days with an acute illness, leg injury with reduced mobility for at least 3 days)

Panel favoured suggestion against offering extended therapy

moderate risk of recurrence, guidelines differ

Closest balance between recurrence without therapy extension & risk of bleeding with therapy extension

should therapy be extended for proximal DVT or PE if Absence of transient provocation (Unprovoked VTE (or persistent risk factor))

Recommend offering extended therapy

high risk of recurrence

what increases the risk of clot recurrence

unprovoked VTE

active cancer

VTE was 2nd episode

males (1.75x higher than females)

Measured 1 month after therapy discontinuation, positive D-dimer (vs negative) have a 50% increased risk of recurrence

what is the association between Covid-19 and VTE

General trend – saw higher VTE rates in hospitalized patients earlier in the pandemic compared to later in the pandemic

higher risk in more severely ill patients

risk with disease itself, NOT the vaccine

believe risk is akin to non-surgical (transient minor) risk factor

what is the dose of apixaban for extension (secondary prevention) phase

2.5mg BID

what is the dose of rivaroxaban for extension (secondary prevention) phase

10mg once daily

what are the recommendations for ASA for extended phase (secondary prevention)

risk of bleeding of low dose ASA is very similar to rivaroxaban BUT it is significantly less effective in reducing the risk of recurrent VTE

can be used in certain circumstances if DOAC is contraindicated