Pharmacotherapy of Anticoagulants for VTE Flashcards
The MOA of heparin (UFH) is…
Catalyzation of antithrombin, which inactivates factor 2a, 9a, 10a, 11a, and 12a
Heparin affects this lab value…
aPTT - prolongation
Heparin has unpredictable PK and PD, because…
It binds to other cells and other plasma proteins
Onset of effect with heparin is…
Immediate with IV
30-60 minutes with Subcut
Duration of effect with heparin is…
Half-life? How often is it given?
Half-life of 1-2 hours;
IV is given continuously, SC is given q8h
Cannot have anticoag free period during clot treatment
Some indications that may warrant caution/monitoring with heparin use include…
Active bleeding, or conditions that increase risk of bleeding
Injuries + operations to brain, spinal cord, eyes/ears
Severe thrombocytopenia
Prior occurrence of HIT
No absolute CI since PE mortality is high
Dosing of heparin differs based on…
Body weight
Use for prophylaxis or treatment, IV or SC
Response to heparin treatment dose may be variable because of…
Narrow therapeutic window
Heparin will usually be given for ____ days, simultaneously with _____
<7 days, with warfarin (THIS was before DOAC’s existed)
Common adverse effects resulting from heparin include…
Minor bleeds
If SC, injection site reactions
Transient, mild liver enzyme increase
Serious adverse effects that may result from heparin include…
Major bleeds
Heparin induced thrombocytopenia (HIT)
Hyperkalemia, skin necrosis, BMD decrease with LONG duration of usage
In the case of a major bleed with heparin usage, what could be given as an antidote?
IV protamine sulfate
What kind of reaction is HIT? What happens to the platelets?
Immune-mediated platelet aggregation reaction - platelets activate and stick together
HIT is a severe risk, because it results in increase to…
Both thrombotic AND bleed risk
Onset of HIT usually occurs ____ after heparin initiation
5-10 days
May depend on prior heparin exposure
A good way to judge likelihood of HIT is…
The 4Ts score for HIT
Criteria that tells probability of HIT
The 4Ts criteria of measuring HIT likelihood are…
Degree of thrombocytopenia
Timing of decrease in platelet count
Thrombosis
Other causes of thrombocytopenia
If HIT occurs, the following needs to be done…
Discontinuation of ALL sources of heparin
Begin alternate anticoagulation
Alternate anticoagulation when HIT occurs include…
DOAC’s in stable patients with medium bleed risk - rivaroxaban preferred
Argatroban, fondaparinux, danaparoid, bivalirudin
Warfarin initially unsuitable, but can transition to once platelets OK
Drug interactions to note with heparin usage include…
Anything that may increase anti-coagulation or incrase thrombotic risk
Antiplatelets, NSAID’s, estrogens, herbals
This lab value shows the effectiveness of heparin VTE treatment:
Used for dosage adjustments, so is MANDATORY
aPTT for VTE treatment - use of validated nomograms
The following should be monitored during heparin treatment:
Platelet count - baseline if possible, and every other day
Hgb and hematocrit
Potassium if high risk of hyperkalemia
The low-molecular weight heparin (LMWH) most commonly used in SHA is…
Tinzaparin
Which LMWH is best to use?
ALL appear equal, clinically in safety and efficacy - just not interchangeable due to different dosing regimens
Enoxaparin is unique in that it can be used…
In acute ACS
The MOA of a LMWH is…
Similar to heparin, but higher affinity for 10a
Can affect aPTT, and can be monitored with Anti-10a if needed
A benefit of LMWH compared to heparin in terms of PK is…
More predictable PK properties, so it can be administered in fixed doses without need for dose adjustment based on lab monitoring
CONVENIENCE
Cautions with LMWH include…
Identical to heparin
Again, not absolute CI, except for previous occurrence of HIT; PE severe
Active bleeding, or conditions that may increase bleed risk
Injuries/operations to brain, spinal cord, eyes/ears
Severe thrombocytopenia
LMWH’s are given…
Route of admin?
Subcut
Dosing of tinzaparin for VTE prophylaxis is…
75 units/kg
Dosing of tinzaparin for VTE treatment is…
175 units/kg
In impaired kidney function, tinzaparin is okay to use down to…
CrCl?
20mL/min for prophylaxis
~25-30 mL/min for treatment
Can we dose adjust tinzaparin in renal impairment?
No - we CAN or CANNOT use.
Does tinzaparin dosing change in obese patients?
Yes, dose increases; >30 000 units subcut daily and above
Does tinzaparin dosing change in pregnancy?
Yes - metabolism of LMWH is altered throughout the course of pregnancy, especially in the 3rd trimester
Onset of effect of tinzaparin is…
When is peak?
~1 hour - peak anti-coagulation response in 3-5 hours
The adverse profile of LMWH’s compared to UFH is…
Similar, but much lower incidence of common AE’s, as well as MUCH lower risk of HIT
Drug interactions are also similar, just watch antiplatelets, anticoags
Duration of effect of tinzaparin is…
12-24 hours of anti-10a activity; half-life of 3-6 hours
Do we need to monitor for LMWH efficacy? If so, how?
Monitoring is not indicated, unless patient is obese, pregnant, or has renal issues. Cannot use aPTT, so we need to use Anti-10a, 4 hours post-dose
For safety monitoring of LMWH, what should be measured?
Platelet count; baseline, and every other day (if 4+ days)
Hgb and hematocrit, baseline and q3d
Potassium if high risk of hyperkalemia
Renal function
Fondaparinux and danaparoid share the same MOA by…
Inhibiting Factor Xa
Similar to LMWH
Argatroban’s MOA is to…
Directly inhibit thrombin (II)
Advantages of fondaparinux compared to LMWH include…
Safety? Adherence?
No cases of HIT reported, may be superior in preventing recurrent events
Fixed dosing, studied in obesity
No monitoring
Advantages of danaparoid and argatroban compared to LMWH include…
Safety? Adhrerence?
Specifically studied to treat HIT
No dose adjustments needed in obesity
CAN be used in severe renal impairment
Some disadvantages of using fondaparinux compared to LMWH include…
Safety? PK?
Possible increase in major bleeds with high doses
No antidote
Longer half-life
Can only use up to CrCl of 30 mL/min
Some disadvantages of using danaparoid or argatroban instead of LMWH include…
Safety?
No antidone available
Limited pregnancy experience
Warfarin MOA is…
Vitamin K antagonist - interferes with production of clotting factors, dependant on vitamin K
What clotting factors are dependant on vitamin K?
10, 9, 7, 2
Protein C&S
Onset of effect of warfarin is important to note, because…
Also how long?
It is not immediate since vitamin K clotting factors need to be cleared from circulation
Takes 2-7 days (avg 3-5)
Offset will also take a similar time
While on warfarin, any changes in dose, diet, or drug-interactions will have a ____ effect
Delayed
Remember that vitamin K clotting factors take 2-7 days to clear
CI’s to warfarin usage include…
Pregnancy
High risk of bleed where benefit of anticoagulation > risk of bleeding
Previous skin reaction to warfarin
High risk = active bleed, recent surgery, inadequate lab facilities, etc
When initiating warfarin dosing, the following needs to be considered:
Age/Frailty
Risk of bleeding
Urgency to reach therapeutic INR
Medications/Drug-interactions
A good method to adjust warfarin dosing is…
To follow validated nomograms
Lots of other factors can influence INR, such as…
Liver disease
Diet; Vitamin K
Drug interactions
Acute illnesses, physical activity
When dealing with sub-therapeutic or supra-therapeutic INR’s what is the thought process?
Determine indication and target INR - any symptoms of high/low INR?
Is there a TREND? Time since last INR?
Any risk of having issues develop?
Transient or permanent cause?
What are symptoms of high or low INR?
High - signs of bleeding
Low - signs of stroke or VTE
If a patient has no physical symptoms with a high/low INR, when is the patient at risk of having issues develop
Pt. risk factors: Antiplatelet usage, fall risk, frailty, bleed history
Extreme highs and lows in INR
Extremely high warrants vitamin K; extremely low may warrant LMWH
If a sub/supra-therapeutic INR is from a transient cause (foods, acute drug usage), what should be done?
Consider dose correction. and increase frequency of INR monitoring
If a sub/supra-therapeutic INR is from a permanent cause (addition of chronic drug, or medical condition), what should be done?
Weekly dose change, and increase INR monitoring
When would we have to bridge TO warfarin therapy?
If we are using warfarin and not other DOAC
During initial treatment of VTE
Prevention of VTE after high-risk procedure
Patient at hish risk of VTE undergoing surgery
Essentially higher risk for clots
A downside of bridging to warfarin therapy is…
Consider need for rapid anticoagulation
Delayed onset, and may be prothrombotic when started
When briding to warfarin is needed, the following should be done:
Initiate warfarin and UFH/LMWH simultaneously
Overlap for at least 5 days AND until INR is 2+ for 2 days
When bridging OFF warfarin therapy, we must assess…
Risks of?
Risk of thrombosis for stopping anticoagulation, vs. bleed risk for continuing (during surgery)
When bridging off warfarin therapy, the following steps are recommended:
Steps involved? INR levels involved? Time management?
Stop warfarin 3-5 days prior to surgery, and wait until INR drops <1.5
Begin UFH or LMWH once INR <2, stop UFH 4-5 hours pre surgery and LMWH 24 hours pre surgery
Resume UFH or LMWH 24+ hours after surgery with warfarin
Common adverse effects of warfarin include…
Minor bleeds
Abdominal cramps
Diarrhea + Nausea
Skin reactions/hives are rare but not serious
Minor bleeds = bruises, cuts, gums, nosebleeds, etc.
Serious adverse effects of warfarin include…
Major bleeds
Purple toe syndrome
Skin necrosis
Major bleeds = blood where blood should not be
Drug interactions with warfarin work via two mechanisms:
Change in INR due to enzyme induction/inhibition
Synergistic increase in bleeding risk without affecting INR
8 major classes of interacting drugs with warfarin are…
All but one start with A
Antibiotics
Antifungals
Antidepressants
Antiplatelets
Anti-inflammatories
Acetaminophen
Alternative remedies (herbals)
Corticosteroids
Any 2C9 inhibitor/inducer will have a strong effect
Addition of acute drugs onto warfarin therapy is most risky, because…
Can be difficult to manage lots of fluctuations compared to chronic dosing
When managing warfarin DI’s, the best thing to do is…
Check INR again in 4-6 days and adjust dose in response for those that can be monitored
Balance risk of bleed/clot with benefit of therapy for those that cannot be monitored (ex: NSAID, antiplatelet, hormones)
Empiric dose adjustment to warfarin is more risk and unpredictable - don’t do unless its well documented
How often should INR be monitored?
Day 3&5
then twice weekly F1W
then weekly until stable for 2 weeks. Then every 2 weeks until stable for a month
then monthly.
If really stable, can extend up to Q3months
Check in 4-6 days after dose changes, or other issues
It is important to inform patients to monitor for signs of major bleeds, such as…
Bright red blood in stool
Darkened, foul-smelling stools
“Coffee ground” vomit
Cuts that do not clot within 5 minutes
The best piece of advice to give to patients about warfarin therapy is…
Do not start any new meds/OTC’s/Herbals, or make drastic changes in diet without talking to pharmacist +/- physician
In case of a bleed, or extremely elevated INR (>10), what can be given as an antidote?
Vitamin K
2.5 - 5mg orally will reduce INR in 24-48 hours
If a serious bleed occurs with warfarin regardless of INR, what should be done?
HOLD warfarin
GIVE vitamin K 5-10mg IV q12h
Give factor IV prothrombin complex or FFP
The four DOAC’s are…
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
MOA of DOAC’s is…
Rivaroxaban, apixaban, and edoxaban inhibit Factor 10a
Dabigatran directly inhibits thrombin
10a is Xa which is in the name
Onset of effect for DOAC’s is…
Reaching peak anti-coagulation in about 2 hours
Makes bridging from different anti-coags easy, but makes adherence key
Duration of effect for DOAC’s relies on their half-life, which is…
Rivaroxaban: 9h
Apixaban: 8-14h
Edoxaban: 14h
Dabigatran: 13h, up to 18h with renal impairment
Duration is important for when to d/c prior to surgery
When do DOAC’s need to be avoided in renal impairment?
Dabigatran <30 mL/min
Apixaban, edoxaban, and rivaroxaban <15 mL/min
Can DOAC’s be used in hepatic disease?
No, except for dabigatran which is cautioned
CI of ALL DOAC’s include:
Active or high risk of bleeding
Pregnancy + lactation
Which enzymes are involved in metabolism of DOAC’s?
D-GP and 3A4
Both inducers and inhibitors
Therefore DOAC’s have a lot of DI’s
Weak/moderate inhibitors may not be significant enough
Which DOAC’s may have less drug interactions?
Dabigatran and edoxaban
Not affected by 3A4 inhibitor + inducers
Dabigatran has unique DI in that it is affected by anything that _____
Raises pH
PPI’s
These DOAC’s are usually dosed BID:
Apixaban, Dabigatran,
These DOAC’s are usually dosed once daily
Edoxaban, rivaroxaban
Dose of rivaroxaban for VTE prevention, after TKR/THR, is…
TKR = total knee replacement; THR = total hip replacement
10mg once daily; 35 days for hip, 14 days for knee
Dose of rivaroxaban for VTE treatment is…
15mg BID cc for 3 weeks, then 20 mg once daily for 3-6 months
WITH FOOD
Dose of rivaroxaban for prevention of recurrent VTE is…
10-20mg daily cc, 6 months after treatment dose
WITH FOOD
These two DOAC’s need bridging for VTE treatment:
Dabigatran and edoxaban
Dose of apixaban for VTE prevention after TKR/THR is…
2.5 mg BID; 35 days for hip and 14 days for knee
Dose of apixaban for VTE treatment is…
10mg BID for 7 days, then 5mg BID for 3-6 months
Dose of apixaban for recurrent VTE prevention is…
2.5mg BID, 6 months after treatment dose
Dose of dabigatran for VTE prevention after TKR/THR is…
Differs on age!
110mg stat, then 220mg daily; 35 days for hip and 14 days for knee
Reduced to 150mg once daily if 75+
Dose of dabigatran for treatment of VTE is…
This is special
5-10 days of SC anti-coag, then prevention dose of 150mg BID (or 110mg BID if bleeding risk is high)
Dose of dabigatran for preventing recurrent VTE is…
150mg BID; 110mg BID if bleeding risk is high
Edoxaban dosing for treatment of VTE/prevention of recurrent VTE is…
After bridging for 5-10 days with SC anti-coag, 60mg once daily
30mg if under 60kg
DOAC’s relationship with obesity is…
Which DOAC’s should be avoided?
Can use, but potential unknown risks… Avoid dabigatran and edoxaban, or just use warfarin
Common side effects of DOAC’s include…
Minor bleeding (similar to warfarin)
GI upset, dyspepsia, diarrhea, constipation
Itch
Serious side effects of DOAC’s include…
Major bleeds
But mostly better, or same risk as warfarin
What should we monitor with DOAC usage?
ABCDE
A: Adherence
B: Bleeding
C: CrCl (baseline, and more frequent depending on fx)
D: Drug interactions
E: Exam for LFT’s, plasma, etc.
No really direct monitoring like warfarin and INR
How long should anticoagulant therapy be if used for VTE provoked by a transient risk factor
Meaning that we know what caused it
3 months, 6 months if symptoms persist or very large DVT/PE
Or just low risk of bleed
How long should anticoagulant therapy be, if used for unprovoked VTE?
Differs based on bleed risk
Minimum of 3 months, then reassess:
Low/moderate bleed risk: indefinite with periodic reviews
High bleed risk: 3 months
Having a second unprovoked VTE strongly suggests indefinite therapy
How long should anticoagulant therapy be, if used for VTE associated with ongoing risk factors?
Indefinitely with periodic reviews, or as long as the risk factor persists
How long should anticoagulant therapy be, if used for cancer associated VTE?
Minimum of 3 months, then reassess and continue if active therapy/continuing to receive anticancer therapy
