VTE Therapy Flashcards
1
Q
What are the goals of VTE therapy?
A
- Relieve symptoms
- Arrest the thrombus
- Prevent embolization
- Prevent recurrence
- Prevent complications (PTS, Pulmonary HTN)
- Prevent death
2
Q
What is the acute treatment for VTE?
A
Bridge therapy or non-bridge therapy
3
Q
What is bridge therapy?
A
Starting a parenteral agent with warfarin for at least five days AND until the INR is greater than or equal to 2
4
Q
What is the benefit of parenteral agents?
A
They provide immediate anticoagulant activity
5
Q
What are the three anticoagulant parenteral agents?
A
UFH, LMWH, and Fondaparinux
6
Q
Which two parenterals anticoagulants are recommended?
A
LMWH and Fondaparinux
7
Q
What guideline established the recommendation of LMWH and Fondaparinux over UFH?
A
The CHEST guidelines
8
Q
What is the common oral anticoagulant that gets bridged with parenteral products?
A
Warfarin
9
Q
What is considered “non-bridge therapy”?
A
Using novel oral anticoagulants (NOAC)
10
Q
What are the common NOACs?
A
rivaroxaban, dabigatran, apixaban, and edoxaban
11
Q
What is the mechanism of action for UFH?
A
Binds to antithrombin and and accelerates its interaction and inactivation of thrombin and factor Xa by 1000-fold
12
Q
What other factors does UFH inactivate?
A
Factors IXa, XIa, and XIIa
13
Q
What is the minimum amount of heparin chains needed to inactivate thrombin?
A
18
14
Q
What happens when antithrombin complexes inactivate thrombin and factor Xa?
A
Heparin is released and available to bind again to antithrombin
15
Q
Since UFH is not absorbed orally, what are the two routes of administration used?
A
Continuous infusion for treatment of VTE and subcutaneous injections for prophylaxis of VTE
16
Q
What is a negative aspect to UFH and intravascular binding?
A
The variability/unpredictability is high; therefore, the pt has to be monitored with aPTT tests for dose adjustments
17
Q
How is UFH cleared from the body?
A
Mainly through a rapid saturable process, but also through a slower, nonsaturable clearance through the kidneys
18
Q
What rate order is UFH?
A
1st order rate (non-linear, dose-dependent)
19
Q
What is the 1/2 life of UFH?
A
30-60 minutes
20
Q
What are the monitoring parameters for UFH?
A
- aPTT
- Platelet counts, hemoglobin/hematocrit
- Signs/symptoms of bleeding
21
Q
What is the dosing for UFH in VTE treatment?
A
IV bolus of 80 units/kg followed by 18 units/kg/hr continuous IV infusion
22
Q
What is the dosing for UFH in VTE prophylaxis?
A
5000 units SC every 8 hours
23
Q
What are the common adverse effects of UFH?
A
- bleeding
- heparin-induced thrombocytopenia
- heparin-induced osteoporosis
24
Q
How do you stop bleeding in patients on UFH?
A
An IV bolus of protamine sulfate will bind to heparin and form a stable salt
25
How many mg of protamine sulfate will neutralize 100 units of UFH?
1 mg
26
What is type 1 heparin-induced thrombocytopenia?
A transient fall in platelet count due to heparin
27
What is type 2 heparin-induced thrombocytopenia?
an immune-mediated reaction where IgG antibodies are directed at heparin-platelet factor 4 complexes
28
How can you diagnose type 2 heparin-induced thrombocytopenia?
The onset is 5-14 days and the platelet count will fall greater than 50%
29
How do you treat type 2 heparin-induced thrombocytopenia?
Direct thrombin inhibitors: argatroban or bivalirudin
30
What drug can you use if a patient has a history of heparin-induced thrombocytopenia?
Fondaparinux
31
When does heparin-induced osteoporosis occur?
It's rare, but occurs in infusions lasting greater than 6 months
32
What is the mechanism of action of LMWH?
It binds to antithrombin with a unique pentasaccharide sequence and accelerates the inactivation of factor Xa
33
What is LMWH's effect on thrombin?
Only 25-50% of LMWH molecules inactivate thrombin
34
How is LMWH administered?
via subcutaneous injections
35
How does the intravascular binding of LMWH compare to UFH?
It's much less than UFH; therefore, there is a more predictable dose-response relationship
36
What are the two LMWH products available in the US?
Enoxaparin (Lovenox) and Dalteparin
37
What are the monitoring parameters for LMWH?
1. Baseline renal function
2. Platelet counts and hemoglobin/hematocrit
3. Signs and symptoms of bleeding
4. Antifactor Xa levels in pt's > 150kg or BMI >50 kg/m2
38
What are the factor Xa target ranges?
0. 6 - 1.0 IU/mL (twice daily)
| 1. 0-2.0 IU/ml (once daily)
39
What is the dosing of enoxaparin in the treatment of VTE?
1 mg/kg SC q12h or 1.5 mg/kg SC q24h
40
What is the dosing adjustment of enoxaparin for VTE treatment in patients with a CrCl of less than 30 mL/min?
1 mg/kg SC q24h
41
What is the dosing of enoxaparin in VTE prophylaxis?
40 mg SC q 24h
42
What is the dosing of enoxaparin in VTE prophylaxis in pt with CrCl less than 30 mL/min?
30 mg SC q 24h
43
What medication is preferred in an obese (>190kg) patient with a CrCl less than 30 mL/min?
UFH
44
How do you reverse bleeding associated with LMWH?
administer 1 mg of protamine sulfate per 1 mg (100 units) of enoxaparin. A second dose of 0.5 mg of protamine sulfate per 1 mg (100 units) of enoxaparin can be used of bleeding persists
45
How does the chance of heparin-induced thrombocytopenia compare with UFH?
It's much lower in LMWH due to less intravascular binding
46
When do you run the risk of a perispinal hematoma?
When administering antithrombotic medications with neuraxial blockade
47
What is the mechanism of action for Fondaparinux?
It's a synthetic analog of the pentasaccharide structure that binds to antithrombin; therefore, it selectively inhibits factor Xa.
48
What is the half-life of fondaparinux?
12 hours
49
What is the route of administration for Fondaparinux?
Subcutaneous injection
50
What monitoring parameters are needed for Fondaparinux?
1. CrCl can't be less than 30
2. Signs and symptoms of bleeding
3. Platelet counts and hemoglobin/hematocrit
51
What is the dosing of Fondaparinux for patients less than 50 kg?
5 mg SC q 24h
52
What is the dosing of Fondaparinux for patients 50-100 kg?
7.5 mg SC 1 24h
53
What is the dosing of Fondaparinux for patients greater than 100 kg?
10 mg SC q 24h
54
What is the dosing of Fondaparinux for VTE prophylaxis?
2.5 mg SC q 24h
55
What are the adverse events associated with Fondaparinux?
Bleeding and heparin-induced thrombocytopenia
56
Why is it important to monitor signs and symptoms of bleeding with Fondaparinux?
There is no antidote for reversal
57
In what population is Fondaparinux contraindicated?
In prophylaxis patients weighing less than 50 kg
58
What is the mechanism of action of Warfarin?
It inhibits the vitamin k oxide reductase enzyme from activating vitamin k which is a cofactor for vitamin k-dependent carboxylation of factors II, VII, IX, and X.
59
Why is the onset of action for warfarin 5-6 days?
Because it depends on the half-life of factors II, VII, IX, and X
60
What is the half-life of factor VII?
6 hours
61
What is the half-life of factor IX?
21-30 hours
62
What is the half-life of factor X?
27-48 hours
63
What is the half-life of factor II?
60-72 hours
64
What is the half-life of protein C?
9 hours
65
What is the half-life of protein S?
60 hours
66
What type of mixture is warfarin?
A racemic mixture of the R and S enantiomers, with the S enantiomer being 2.7 to 3.8 times stronger
67
What is the half-life of warfarin?
36-42 hours, and it takes 3-5 days to reach steady state
68
What enzyme metabolizes the S enantiomer, and what effect does this have on drug interactions?
CYP4502C9. Since this is the stronger enantiomer, any drug that is also metabolized by this enzyme will increase the drug interactions
69
What two factors are most common in interindividual variability of warfarin response?
single nucleotide polymorphisms in VKORC1 and CYP4502C9
70
What effect does a polymorphism in CYP450*2C9 have on a patient?
It leads to poor metabolism of warfarin (use lower doses) and increases the risk of bleeding
71
What effect does a polymorphism in VKORC1 have on patients?
The genotype determines the sensitivity to warfarin. AA is sensitive and needs a low dose, GG is resistant and needs a high dose, AG is normal
72
What are the monitoring parameters for warfarin?
1. Prothrombin time
2. INR
3. Management of non-therapeutic INRS
4. S/Sx of bleeding
73
What is the goal INR range?
2-3
74
What is the goal INR for a patient with mechanical heart valves?
2.5-3.5
75
How often do you monitor hospital patients on warfarin?
Daily
76
How often do you monitor outpatients?
Within three days of hospital discharge and then weekly
77
Once a stable response is achieved with warfarin, how often do you monitor?
every 4 weeks and some patients every 12 weeks
78
What adverse event is associated with warfarin?
Bleeding
79
What can reverse the bleeding in patients on warfarin?
Vitamin K
80
What is the new reversal agent for warfarin?
Kcentra
81
When should Kcentra be used?
In acute major bleeding or when a patient needs urgent surgery or invasive procedure
82
What patient population is Kcentra contraindicated in?
In patients with a history of HIT because the antidote contains heparin
83
What are the 4 non-bridge therapies?
Rivaroxaban (Xarelto), Dabigatran (Pradaxa), Apixiban (Eliquis), and Edoxaban (Savaysa)
84
What is the mechanism of action of Rivaroxaban
It inhibits the active site of factor Xa without requiring a cofactor like antithrombin
85
Why should rivaroxaban be taken with food?
To increase the bioavailability
86
What are the monitoring parameters for rivaroxaban?
1. Baseline kidney and liver function
2. S/Sx of bleeding
3. Platelet count and hemoglobin/hematocrit
87
What are the strong drug-drug interactions with rivaroxaban?
strong 3A4 and P-glycoprotein inhibitors
88
What is the dosing of rivaroxaban for VTE treatment?
15 mg twice daily w/ food for 21 days, then 20 mg once daily w/ food
89
In what patients should you avoid the use of rivaroxaban?
In patients with a CrCl less than 30 or if they are on a P-pg and CYP3A4 inhibitor
90
How do you convert from warfarin to rivaroxaban?
Discontinue warfarin and start rivaroxaban when the INR is less than 3
91
How do you convert from other anticoagulants and rivaroxaban?
Discontinue other anticoagulants and take rivaroxaban 0-2 hours before next scheduled dose
92
What is the antidote for rivaroxaban?
ANDEXXA
93
What is the low dose of ANDEXXA?
400 mg IV bolus at 30 mg/min followed by 4 mg/min for up to 120 minutes
94
What is a high dose of ANDEXXA?
800 mg IV bolus at 30 mg/min followed by 8 mg/min for up to 120 minutes
95
What trial proved that rivaroxaban was noninferior to warfarin for the treatment of DVT and PE, and had no major difference in major or non-major bleeding?
EINSTEIN
96
What is the mechanism of action for Dabigatran?
It is a direct thrombin inhibitor that inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation
97
What is special about dabigatran and it's structure?
Because it is highly polar, it is not orally bioavailable and is actually a pro-drug
98
What are the monitoring parameters for Dabigatran?
1. Renal function
2. Platelet count and hemoglobin/hematocrit
3. S/Sx of bleeding
99
When should dabigatran be used?
5-10 days after treatment with a parenteral anticoagulant
100
What is the dosing for VTE treatment with dabigatran?
150 mg twice daily (no dosing for CrCl less than 30)
101
How do you convert from warfarin to dabigatran?
Stop warfarin and start dabigatran when INR is less than 2
102
What is the reversal agent for dabigatran?
Idarucizumab
103
What is the dosing for idarucizumab?
5 gram infusion
104
What is the adverse effects of dabigatran?
dose-dependent GI bleed and dyspepsia
105
What did the RECOVER I and RECOVER II trials prove?
That dabigatran is noninferior to warfarin for VTE treatment, and that there was no major difference in bleeding
106
What did the RE-MEDY and RE-SONATE trials prove?
They proved the extended use of dabigatran after completion of a 3 month trials
107
What is the mechanism of action for Apixiban?
It's a direct factor Xa inhibitor that inhibits both free and clot-bound factor Xa
108
What are the monitoring parameters for Apixiban?
1. Hemoglobin/hematocrit and platelet counts
2. S/Sx of bleeding
3. Renal function/body weight
109
What dose of Apixiban is used to treat VTE?
10 mg twice daily for 7 days (no dose adjustments)
110
What is the antidote for Apixiban?
ANDEXXA
111
What is the mechanism of action for Edoxaban?
It's a factor Xa inhibitor
112
What are the monitoring parameters for Edoxaban?
1. Hemoglobin/hematocrit and platelet counts
2. S/Sx of bleeding
3. Renal function and body weight
113
What is the dosing of Edoxaban used for VTE treatment?
60 mg once daily after 5-10 days of treatment with a parenteral anticoagulant
114
When do you adjust the dose of edoxaban down to 30 mg daily?
When the patient has a CrCl of 15-50, or weighs less than 60 kg, or is taking verapamil or azithromycin.
115
How do you convert warfarin to Edoxaban?
Discontinue warfarin and initiate edoxaban when the INR is less than 2.5
116
How do you convert UFH to edoxaban?
Discontinue UFH and start edoxaban 4 hours later
117
When are NOACs recommended over warfarin?
In the treatment of VTE in patients without active cancer
118
What should active cancer patients receive to treat VTE?
LMWH monotherapy
119
According to ISTH, what medications are not recommended for use in patients with a BMI greater than 40 kg/m^2 or with a weight greater than 120 kg?
NOACs
120
How long do you treat a patient with 1st episode of DVT or PE secondary to a provoking transient event?
3 months
121
How long do you treat a patient with 1st episode of unprovoked DVT or PE?
3 months and then evaluate risk-benefit ratio for extended therapy
122
How long do you treat a patient with second episode of unprovoked DVT or PE?
Indefinitely, unless patient is at a high risk of bleeding
123
According to the 2016 CHEST update, what defines a high risk for bleeding?
2 or more bleeding risk factors
124
What are the risk factors for bleeding, according to CHEST?
1. greater than 65
2. previous bleeding
3. cancer
4. renal failure
5. liver failure
6. thrombocytopenia
7. diabetes
8. previous stroke
9. anemia
10. recent surgery
11. frequent falls
12. alcohol abuse
13. antiplatelet therapy
14. poor anticoagulant control
15. NSAID use
125
What drugs should not be combined with rivaroxaban?
carbamazepine, phenytoin, or rifampin
126
What are the drug-drug interactions of dabigatran?
A patient with CrCl less than 50 taking dronedarone, amiodarone, or verapamil. Also, do not use with rifampin, no matter the CrCl.
127
When should the dose of apixiban be reduced to 2.5 mg twice daily?
When patient is taking ketoconazole, itraconazole, ritonavir, or clarithromycin (If already on 2.5 mg then do not take).
128
When should patients avoid the use of apixiban?
When taking rifampin, carbamazepine, or phenytoin
129
How can a patient reduce the risk of recurrent DVT or PE with apixiban?
By taking 2.5 mg twice daily after completing VTE treatment dosing, according to AMPLIFY-EXT
130
How do you convert warfarin to apixiban?
Start apixiban when INR is less than 2
131
What did the AMPLIFY trial prove?
Apixiban was noninferior to warfarin for primary endpoint of recurrent VTE, and it was superior to warfarin for the safety outcome of major bleeding
132
What is the one drug-drug interaction for edoxaban?
rifampin
133
When do you avoid the use of edoxaban?
If CrCl is less than 15
134
What are the transient risk factors for VTE, according to CHEST?
1. major or minor surgery
2. estrogen therapy
3. pregnancy or puerperium
4. trauma
5. immobility
6. active cancer
135
When should you use thrombolysis?
When there is a risk of limb gangrene or massive PE
136
How can thrombolytic agents be administered?
Systemically or locally via catheter
137
What are the thrombolytic agents?
streptokinase, urokinase, and Rt-PA
138
When should you use an inferior vena cava filter?
When the patient has contraindications to anticoagulation, according to 2016 CHEST guidelines
139
What drug regimen do you use for total hip replacement surgery?
Enoxaparin 40 mg SC q 24 hours or enoxaparin 30 mg SC q 12 hours. If CrCl is less than 30 use enoxaparin 30 mg SC q 24 hours.
