VTE Part 2 Flashcards
Rivaroxaban (Xarelto™)
• Oral tablet
Metabolized by CYP 3A4, 2J2
& CYP-independent ways Larger doses (15mg & 20mg) should be taken with food / largest meal of the day (if not only 2/3 absorbed)
MOA: Competitive, direct (antithrombin independent) Factor-Xa Inhibitor (both free and clot-associated Xa)
Side Effects:
– Bleeding
Rivaroxaban-drug interactions?
– Strong inhibitors of both CYP
450 3A4 and P-glycoprotein
– Caution with Inducers
– Increase risk of bleeding
Rivaroxaban Dosing
Treatment of acute VTE* 15mg BID x 3 weeks, then
20mg daily
(take with food)
As per VTE assessment, 3 months to lifelong
Apixaban (Eliquis™)
Oral tablet
Metabolized by CYP
3A4/5, minor from 1A2,
2C8, 2C9, 2C19, 2J2
MOA: Competitive, direct (antithrombin independent) Factor-Xa Inhibitor (both free and clot-associated Xa) • Side Effects: – Bleeding
Apixaban-drug interactions
– Strong inhibitors of both
CYP 450 3A4 and Pglycoprotein
– Caution with Inducers
– Increase risk of bleeding
Apixaban Dosing
Treatment of acute
VTE*
10mg BID x 7 days, then 5mg BID
As per VTE assessment, 3 months to lifelong†
Edoxaban (Lixiana™)
• Oral tablet • Peaks in 1-2 hours MOA: Competitive, direct (antithrombin independent) Factor-Xa Inhibitor (both free and clot-associated Xa) • Side Effects: – Bleeding
Edoxaban Dosing
Treatment of acute VTE* After 5-10 days treatment with a parenteral anticoagulant, edoxaban dosing as per AF As per VTE assessment, 3 months to lifelong
AF: 60 mg once daily if CrCL >50
30mg once daily if CrCL 30-50, body wt <60kg
Edoxaban -drug interactions?
see table 49
Drug Interactions:
– Strong inhibitors or inducers
of P-glycoprotein
– Increase risk of bleeding
DOAC Dosing for the Acute Treatment of VTE
Apixaban
10 mg BID (1 week) –> 5 mg BID
Dabigatran
Parenteral Anticoagulant 5-10 Days -> 150 mg BID or 110 mg BID*
Edoxaban
Parenteral Anticoagulant 5-10 Days -> 60 mg daily or
30 mg daily
Rivaroxaban
15 mg BID (3 weeks) -> 20 mg QD
Which of the following is correct?
1. The D-dimer is helpful to rule out VTE if it is
positive
2. Dabigatran and Rivaroxaban require a parenteral
anticoagulant lead in for the acute treatment of
VTE
3. Both dabigatran and edoxaban are subject to
drug interactions with P-glycoprotien inhibition.
4. For apixaban, edoxaban and rivaroxaban,
routine PT/INR monitoring should occur as well
as the creatinine clearance.
3
we don’t do routing monitoring for any of them
DOAC: Contraindications
• 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:
– Dabigatran: strong P-gp inhibitors/inducers
– Edoxaban: strong P-gp inducers
– Rivaroxaban & Apixaban: strong inhibitors / inducers of both CYP 3A4 & P-gp
• Severe renal impairment cut offs:
– Dabigatran: CrCl < 30mL/min
– Apixaban: CrCl < 25 mL/min
– Rivaroxaban < 15 mL/min
– Edoxaban < 15 mL/min
DOAC impact on Coagulation Tests
see slide 52
ok
dont need routine coag monitoring
Treatment Options for Acute VTE
Must Act Quickly
Indirect Acting Anticoagulants • Heparins (subcutaneous) – Low molecular weight heparin (LMWH) - subcutaneious – Unfractionated heparin (UFH) – intravenous or subcutaneous • Fondaparinux (subcutaneous)
Initial – Long-Term Treatment Phase: Options
VTE Parenteral Anticoagulant (LMWH,
fondaparinux) + Warfarin to an INR of 2.0-
3.0, then warfarin (INR 2.0-3.0) alone
Overlap with parenteral agent at least 5 days or until
INRs > 2.0 for at least 2 days (whichever is longer)
Mechanisms of Action:
UFH, LMWH, Fondaparinux
• LMWH vs UFH – size of molecule
• Both contain pentasaccharide
sequence binding to antithrombin
→ accelerates interaction with Xa
• LMWH (smaller), primarily Xa
• UFH, larger, requires chain to wrap around factor II = thrombin hence both Xa and IIa
• Fondaparinux – synthetic pentasaccharide sequence
• ALL require antithrombin = not direct acting anticoagulants
small ones only impact Xa
unfractionated hep impacts Xa and IIa depending on size
inactivating thrombin and activated factor X (factor Xa) through an antithrombin (AT)-dependent mechanism.
which one needs antithrombin?
Direct Xa Inhibitors (PO): Rivaroxaban, Apixaban – Do not require antithrombin – Act directly on Factor Xa
• Direct IIa Inhibitor
(PO): Dabigatran
– Acts directly on
Factor IIa
UFH dosing
Weight based, then guided
based on aPTT or anti-Xa
need to routinely monitor coag activity
not needed for LMWH and Fonda
UFH for Initial VTE Treatment
• Place in Therapy:
– 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)
Thrombolytic Therapy for PE
Lysis accelerates resolution of PE BUT increases risk of
major bleeding (harm outweighs benefit for majority)
- lots of intracranial hemorrhage
Reserved for those at greatest risk of dying from PE –
with “massive” PE or PE with cardiopulmonary
compromise
LMWH: Coagulation Assessment?
only do it for uncertain dosing or• Anit-Xa Levels (akin to LMWH Levels –
pharmacodynamic effect)
– Recommend against routine monitoring of Anti-Xa
levels
– Anti-Xa levels have never been correlated with clinical outcomes tx failure
Consider assessing if potentially unsure of dosing:
• Extremes of weight
• Renal dysfunction
• Failure of therapy (clot or bleed)
• Renal dysfunction
• Obesity
LMWH
Pre-filled syringes: operationally looking for syringe strength that best matches
weight; can round to higher strength (if high clot risk) or lower strength (if higher
bleed risk); ideal to stay within 10% of body weight dose
• 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
• 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)
• Pretty much exclusively use pre-filled syringes
Heparin Adverse Effects
• Bleeding – Less with LMWH vs UFH – Protamine can be used to neutralize UFH, partially neutralizes LMWH • Osteoporosis – Risk increases with duration of use – Lower risk with LMWH vs UFH • Hematoma at injection site • Hypersensitivity • Alopecia • Heparin Induced Thrombocytopenia (HIT) *** – UFH >>> LMWH
Heparin-Induced Thrombocytopenia
which 2 types
More common in unfractionated hep than LMWH
Type I – Non-immune mediated – Transient, mild thrombocytopenia – Early onset (< 4 days) – Reversible, asymptomatic – Commonly seen, especially in the post-operative patient
Type II – Immunologic drug reaction – Severe thrombocytopenia – Late onset (day 5 –14) but can develop within 24hrs if heparin exposure in last 100 days – Clotting disorder – Life threatening
neoantigen tht is recognized by the FC receptor of the platelets and then we have intense platelet activation and then the platelets form clots.
They recruit their colleagues and release pro coagulate micro particles which further amplifies this and the end result is thrombosis, we see a dramatic drop in the platelets.
HIT Type II:
Consequences, Monitoring & Diagnosis
Potential Consequences:
• Thrombotic complications occur in 20 –50% of patients
• Thrombosis may be arterial or venous
• Results in limb amputation in 10% of patients
• Fatal in 8 –20% of patients
Monitoring 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
Diagnosis:
• Based upon clinical sequlea (above) plus presence of HIT antibodies
• Result of antibody testing is delayed
True or False?
• UFH, LMWH and fondaparinux are indirect
anticoagulants because they bind to
antithrombin to then go onto reduce the
activity of clotting factors in the circulation;
they act quickly because they affect clotting
factors in the circulation.
True
ndirect again because they require that co factor
don’t act directly on the clotting factors they require that antithrombin to bind to to undergo that conformation change and then exert effects on clotting factors and they do act quickly because they act on the clotting factors that are fleet free floating in the circulation okay.
Initial Treatment of VTE:
Warfarin
Warfarin has a delayed effect – must “cross cover” using a rapid acting anticoagulant, namely a parenteral one (LMWH, fondaparinux or UFH)
– Overlap at least 5 days and until the INR is at least 2.0 for 24 hours (=2 consecutive days)
– Initiate warfarin on day 1 or 2 that parenteral is used
Those at high risk of clot (or embolism) for the 1st month of therapy, if INR falls sub-therapeutic (<2.0), “cross coverage” should be implemented with a rapid acting anticoagulant (e.g., LMWH)
– Consideration for cross coverage for sub-therapeutic INRs should be done within the 1st 3 months of therapy
minimum 5 days
Warfarin Mechanism of Action
interferes with interal recylcing of vit K
prevent Vit K being reduced
carboxyl groups necessary for activation
impacts half life of clotting factors
factor II is the last step, needed to make a clot
don’t use loading doses with warfarin
Monitoring of Warfarin Therapy
Prothrombin time (PT) measures an individual patient’s response to warfarin therapy • International Normalized Ratio (INR) standardizes the PT to allow universal interpretation INR = pt PT/mean normal PT
INR measures (crudely speaking) the time it takes for a blood clot to form – INR without warfarin =1.0 (0.8-1.2) – INR while taking warfarin either 2.0-3.0 (or 2 – 3 times as long) or 2.5 -3.5 (2.5-3.5 times as long) to form a clot
Warfarin Side Effects and antidote
– Clinical Practice Challenges for antidotes: • Time to treatment • Using right antidote, right dose, etc… • Lack data of improved outcomes with use of antidote
• Bleeding (details later) – Major & minor bleeding • Teratogenic – Hypoplastic nose, stippled epiphyses, skeletal and ocular abnormalities – 6-12 weeks gestation • Much less common (rare) – Skin necrosis – Purple Toe Syndrome
• Antidote for Warfarin – Vitamin K • Intravenous or oral (urgencydependent) – Prothrombin Complex Concentrate (PCC) • Factors II, VII, IX & X = blood product • Intravenous
Warfarin Dosing: 2 Phases
1. Initiation Phase – Establishing INR target – Hospitalized vs Ambulatory – Stability of Warfarin Dosing Achieved 2. Maintenance Phase – Ongoing achievement of target INR
• 2 questions to ask yourself:
– Clot vs Bleed risk, with next INR would you prefer it above or below the target range?
– Knowing what you know now, can you justify your actions to your peers?
Warfarin Initiation
– Important practice elements
• Initiation Phase typically lasts 2-4 weeks
– Dose changes in response to INRs
– Clotting factors are not at “steady state”
– “map out the patient” and appreciate the delayed impact of warfarin
- Warfarin Initiation – Important practice elements
- INRs should be assessed regularly (2-3 times/week)
- Must consider the delay of warfarin’s impact and that large variation in dosing is difficult to interpret
- Take average doses in context
LMWH/fonda
doses for VTE Tx
once dai;y dosing suggested over twice dialy tx for DVT/PE
often use twice daily dosing for extensive VTEs
warfarin considerations
- Changes to Health - assess first
– Acute changes (fever, flu, diarrhea, etc.)
– Chronic Medical Condition Changes:
• Exacerbation of heart failure
• Alterations in thyroid function - Changes to Medications*
– Prescription, non-prescription, herbals
Drug Interactions:
1. Induction / Inhibition of
Cytochrome P450
• Major 2C9 –> know that inhibitors of 2C9 should not be used
• Minor 3A4, 1A2
2. Displacement of binding plasma proteins
3. Alterations in Vitamin K Status
4. Contributing to bleeding / clotting risk
- Changes to Lifestyle
– Vitamin K intake - impact INR, normal diet and if there is issue, then monitor diet
– Alcohol Consumption - drunk, INR get high, drink in moderation (1-2 drinks a day)
– Level of Activity - the more active, the more warfarin needed, significant changes
