1
Q
venous thrombi are composed of ___
A
RBCs, fibrin, few platelets
“red thrombi”
2
Q
symptoms result when:
A
flow is obstructed, vascular tissue wall becomes inflamed, thrombus occurs and affects venous blood flow, or emboli occur and enter pulmonary circulation
3
Q
virchow’s triad
A
hypercoaguable state - abnormalities of clotting components
endothelial injury - abnormality of surfaces in contact with blood flow
circulatory stasis - abnormalities in blood flow
4
Q
activators of clotting system
A
von willebrand factor, tissue factor, VIIa, Xa, XIIa, thrombin (II), XIIIa, tissue plasminogen activator
5
Q
inhibitors of clotting system
A
heparin, thrombomodulin, antithrombin, protein C, protein S, tissue factor pathway inhibitor, plasminogen activator inhibitor-1
6
Q
postthrombotic syndrome
A
- long term complications of DVT caused by damage to venous valves: chronic venous obstruction, caused by venous HTN, chronic pain and swelling, stasis ulcers, development of infection
- rule out recurrent thrombosis before diagnosis
7
Q
DVT risk factors
A
age over 40, FH, HF, immobilization over 10 days, malignancy, MI, obesity, orthopedic injury, OC/estrogen, paralysis, postoperative state, pregnancy, prior DVT, varicose veins
8
Q
idiopathic DVT
A
we don’t know what caused it; unprovoked
9
Q
NonPCOL treatment
A
- baseline monitoring
- DVT: bed rest, elevation of feet, pain management, compression stockings
- PE: oxygen, mechanical ventilation, compression stockings
10
Q
UFH overview
A
- rapid anticoag
- parenteral
- non-specific binding
- Non-linear kinetics: variable dose response (i.e. need for aPTT monitoring)
- Decreased bioavailability: plasma protein binding
- Pregnancy Category B
11
Q
UFH uses
A
- prophylaxis and treatment of thromboembolic disorders
- anticoagulant for extracorporeal and dialysis procedures
12
Q
UFH MOA
A
-Interacts with ATIII which catalyzes the formation of thrombin:antithrombin
complexes
-Binds to heparin co-factor and catalyzes inactivation of factor IIa -Binds to platelets
13
Q
UFH lab monitoring
A
- Close monitoring required
- activated Partial Thromboplastin Test (aPTT) is utilized
- Commercial test vary therefore follow institution specific range
- 1.5 – 2.5 times normal control = therapeutic range
14
Q
UFH dosing
A
- Dosing protocols
- IV or SubQ (NOT IM)
- Old standard: 5000 unit IV bolus; 1000 – 1200 units per hour
- Subcutaneous: 5000 units subQ every 8-12 hours (proph)(8 hours if crcl above 50; 12 if below); 17500 units every 12 hours (treatment)
- Weight based (actual body weight)(recommended): 80 units/kg IV bolus; 18 units/kg/hr infusion
- Given for at least 5 days with warfarin
- concern for incompatibility
15
Q
UFH dosing adjustments
A
- check aPTT at baseline
- Check 6 hours after dose or with each dosage change (for first 24 hours)
- Check daily after first day – unless out of range
- Adjust dose based on results
- aPTT less than 1.2x normal: 80 U/kg bolus, then increase rate by 4 U/kg/h
- aPTT 1.2-1.5x normal: 40 U/kg bolus, then increase rate by 2 U/kg/h
- aPTT 2.3-3x normal: Decrease infusion rate by 2 U/kg/h
- aPTT over 3x normal: Hold infusion 1 h, then decrease infusion rate by 3 U/kg/h
16
Q
UFH PK
A
- Subcutaneous dosing: Bioavailability 30-70%, Onset 1-2 hours; peak 3 hours
- IV dosing: Half life: 30-90 minutes (dose dependent), Continuous infusion preferred
3. Elimination
a. Inactivation via heparinases and desulfatases (rapid, saturable)
b. Renal (slower, non-saturable)
17
Q
UFH AE
A
- Bleeding: Major bleeding 0-2% (without other concomitant risks), Thrombocytopenia
- Osteoporosis: Doses > 20,000 units/day, Duration > 6 months (i.e. during pregnancy)
- Hypersensitivity
18
Q
thrombocytopenia
A
- HAT: heparin associated thrombocytopenia
- HIT: heparin induced thrombocytopenia
- Check platelet counts every other day until day 14
19
Q
why get CBC if pt is bleeding?
A
we want to know Hgb and Hct
20
Q
minor bleeding
A
- Superficial bruising
- Nosebleeds that resolve
- Gum bleeding that resolves
- Blood on tissue when blowing nose
21
Q
major bleeding
A
- IF PATIENT IS UNCOMFORTABLE W AMOUNT OF BLOOD
- Unresolved epistaxis
- Hematuria
- BRBPR
- Spontaneous hematomas
- Hemoptysis
- Hematemesis
- Hematuria
22
Q
treatment related bleeding risk factors
A
dose, duration, route
23
Q
patient related bleeding risk factors
A
- Age > 65
- h/o GI bleed or PUD
- Comorbid diseases
- Concurrent medications
- EtOH use
- Renal failure
- Malignancy
- Cerebrovascular disease
- Surgery/major trauma
24
Q
bleeding management
A
1-Monitor: HGB, HCT, & blood pressure
2. If occurs: Discontinue heparin, may require blood transfusion, Protamine sulfate administration
25
protamine sulfate
- MOA: cationic protein binds to anionic heparin
- Neutralizes heparin in 5 min; persists for 2 hours
- Half-life: 7 min
- Repeat aPTT 30 minutes after administration of protamine
26
protamine sulfate dosing
immediate: 1-1.5 (mg per 100 units UFH)
30-120 minutes: 0.5-0.75
over 2 hours: 0.25-0.375
27
protamine sulfate adverse reactions
-Hypotension, bradycardia: Slow IV infusion (over 1-3 minutes), Max 50 mg over 10 minutes
-Anaphylaxis: Received protamine-containing insulin, h/o vasectomy, fish
sensitivity
28
HAT
- Also known as HIT-Type I
- Non-immune mediated
- Mild decrease in platelets (>100,000/mm3)
- Occurs around 48-72 hours after administration of heparin
- Transient
- Do not need to d/c heparin
29
HIT
- Immune mediated
- Thrombotic complications
- Occurs between: 7-14 days
- Can occur up to 9 days after stopping therapy
- Platelets drop >50% from baseline or
30
HIT clinical presentation
- Thrombocytopenia: Platelets decrease by >50% OR Decrease to less than 100,000/mm3
- Venous thromboembolic complications
- Heparin-induced skin lesions
D/C all heparin products
31
when d/c heparin in suspected HIT, start ___
argatroban, danaparoid, or fondaparniux
32
duration of therapy
if had previous thrombi - continue as directed by guidelines
| if develop thromosis during HIT continue for at least 3 months
33
LMWH
- Fragments of UFH
- Heterogeneous mixture of sulfated glycosaminoglycans
- Approximately 1/3rd the molecular weight of UFH
34
LMWH labeled uses
-ACS (UA, NSTEMI, STEMI)
-DVT treatment
-Prophylaxis following TKA, THA, abdominal surgery, acute medical
patients
35
advantages of LMWH
good bioavailability, predictable dose response, resistance not encountered, fixed or weight-based dosing, no monitoring required, QD or BID, improved SQ abs, reduced incidence of HIT and bleeding
36
LMWH MOA
- Activates ATIII
- Reduced ability to bind thrombin
- Retains ability of inactivate factor Xa
- 3-4X more affinity for X over II
37
LMWH PK
- Subcutaneous dosing: 90% bioavailability, Peak effect 3-5 hours
- Eliminated renally: Plasma half-life 2-4 x longer than UFH
38
LMWH examples
enoxaparin, dalteparin, tinzaparin
39
enoxaparin dosing
Prophylaxis: 30 mg SQ BID, 40 mg SQ QD
treatment: 1mg/kg SQ BID, 1.5 mg/kg SQ QD
renal dysfunction: 30 mg SQ QD (prophylaxis), 1 mg/kg SQ QD (treatment)
40
dalteparin dosing
prophylaxis: 2500-5000 IU SQ QD
treatment: 200 IU/kg SQ QD (max 18000 IU)
renal dysfunction: monitor Xa levels; goal: 0.5-1.5 4-6 hours post)
41
tinzaparin dosing
treatment: 175 anti-Xa IU/kg SQ QD
42
LWMH special population
- Obesity: Enoxaparin up to 144 kg, Dalteparin up to 190 kg, Tinzaparin up to 165 kg
- Pregnancy category B
- Consider anti-factor Xa levels
43
LMWH monitoring
Adverse Effects/Toxicity: CBC with platelet, Serum creatinine, Fecal occult blood
44
anti Xa monitoring
- Consider for children, severe kidney failure, obesity, long courses, pregnancy
- Treatment: Twice daily dosing: 0.6-1.0 units/mL obtained 4 hours post dose, Once daily dosing: 0.1-0.3 units/mL obtained as trough (can consider peak of 1-2 units/mL obtained 4 hours post dose)
- Routine monitoring not recommended
45
LMWH black box warning
-All LMWH products have the same warning
-Use with neural anesthesia or spinal puncture can lead to increased risk of spinal
hematoma leading to paralysis
46
LMWH AE
- Bleeding: Major/minor
- Thrombocytopenia: Less than UFH, Monitor platelets
- Delayed hypersensitivity skin reactions
47
LMWH bleeding management
- D/C LMWH
- Best neutralization method not as clear
- Protamine sulfate administration: Within 8 hours of last LMWH dose( 1 mg per 100 anti-factor Xa units; 1 mg per 1 mg enoxaparin), over 8 hours (0.5 mg per 100 anti-factor Xa units; 0.5 mg per 1 mg enoxaparin)
48
factor Xa inhibitors
- Indirect agents: binds to antithrombin (like heparin): Fondaparinux (Arixtra®)
- Drect agents: binds to factor Xa: Rivaroxaban (Xarelto), Apixaban (Eliquis®), Edoxaban, Betrixaban (not approved for use in US)
49
fondaparinux labeled uses
- usually acute, can be maintenance in specific patients
- Prophylaxis following THA, TKA, hip replacement, or abdominal surgery
- Treatment of DVT or PE
50
fondaparinux dosing
- prophylaxis: 2.5 mg subQ once daily (hip, knee, or abdominal surgery)
- Treatment:
51
fondaparinux PK
- Peak plasma activity: 2-3 hours
- Eliminated in urine: Half-life 17-21 hours, Anticoagulation effects lasts 2-4 days post discontinuation
- No binding to other proteins, including platelets or PF4: No risk of HIT
52
fondaparinux special considerations
-Do not use if have renal dysfunction (CrCl
53
fondaparinux BBW
Use with neural anesthesia or spinal puncture can lead to increased risk of spinal
hematoma leading to paralysis
54
fondaparinux monitoring
- No routine monitoring for therapeutic efficacy: Can monitor anti-Xa levels (similar to LMWH)
- Serum creatinine
55
fondaparinux AE
bleeding
56
rivaroxaban uses
```
NOAC
acute and maintenance
-DVT prophylaxis
-DVT treatment
-NV Afib
-PE treatment
-reduction in the risk (secondary prevention) of recurrent DVT and/or PE
```
57
rivaroxaban dosing
- DVT prophylaxis: 10 mg daily - 6-10 hours post surgery (confirmed hemostasis); THA: continue for 35 days; TKA: continue for 12 days
- DVT/PE treatment: 15 mg BID x 3 weeks, then 20 mg daily with food
- Non-valvular atrial fibrillation: 20 mg daily (CrCl > 50 mL/min)
- CrCl 15-50 mL/min: 15 mg once daily
- Secondary prevention: 20 mg daily - Duration: 6-12 months, following initial treatment of 6-12 months
58
rivaroxaban antidote
No antidote for reversal (not dialyzable)
- PCC has been shown to be beneficial in trials
- Andexanet alfa: directed factor Xa antidote (Phase III trials)
59
rivaroxaban PK
-Metabolized by CYA 3A4/5: Caution: strong CYP3A4 inhibitors, PGP inhibitors, other products
affecting hemostasis
-Time to peak: 2-4 hours
-Half life: adults 5-9 hours; elderly 11-13 hours
60
rivaroxaban DI
-P-gp and CYP3A4 inducers: Carbamazepine, phenytoin, rifampin, St. John’s wort
61
rivaroxaban AE
- bleeding
| - Avoid: CrCl
62
warfarin to rivaroxaban
stop warfarin and start rivaroxaban when INR less than 3
63
rivaroxaban to warfarin
Start warfarin and stop rivaroxaban 3 days
later
OR IF continuous, uninterruped
anticoagulation is necessary:
stop rivaroxaban, begin both parenteral anticoagulation (LMWH or UFH) and warfarin at the time the next dose of rivaroxaban would have
been given and stop the parenteral anticoagulant when
INR reaches an acceptable range
64
LMWH/ fondaparinux to rivaroxaban
Stop parenteral anticoagulant and administer rivaroxaban 0-2 hours before the next dose of parenteral drug would have been given
65
IV heparin to rivaroxaban
Administer first dose of rivaroxaban at the same time as discontinuation of IV heparin infusion
66
rivaroxaban to parenteral anticoagulant
Stop rivaroxaban and administer first dose of parenteral anticoagulant at the time the next dose of rivaroxaban would have been given
67
rivaroxaban to oral anticoagulant other than warfarin
Stop rivaroxaban and begin the other anticoagulant at the time that the next scheduled dose of rivaroxaban would have been given
68
rivaroxaban black box warning
- spinal/epidural hematomas
| - premature d/c increases risk of thrombotic event
69
apixaban uses
```
NOAC
acute and maintenance
-DVT prophylaxis
-DVT treatment
-NV Afib
-PE treatment
```
70
apixaban dosing
-DVT prophylaxis: 2.5 mg PO BID: Start 12-24 hours postoperatively (hemostasis confirmed); THA: continue for 35 days; TKA: continue for 12 days
-DVT/PE treatment: 10 mg PO BID x 7 days, then 5 mg BID: Can continue 2.5 mg PO BID ≥ 6 months (following initial 6-12 months) for reduction in risk recurrence
-Non-valvular atrial fibrillation: 5 mg PO BID: 2.5 mg PO BID (2 of the following): age ≥ 80 years, weight under 60
kg, SCr ≥ 1.5 mg/dL; Dialysis: 5 mg PO BID; 2.5 mg PO BID if age over 80 years OR
weight under 60 kg
71
apixaban antidote
No antidote for reversal currently approved (not dialyzable)
- PCC or rFVIIa can be considered
- Andexanet alfa: directed factor Xa antidote (Phase III trials)
72
apixaban PK
- Metabolized by CYA 3A4/5: Caution: strong CYP3A4 inhibitors, PGP inhibitors, other products affecting hemostasis
- Time to peak: 3-4 hours
- Half life: 5 mg dose = 15 hours; 2.5 mg dose = 8 hours
73
apixaban cautions
-avoid use with Strong 3A4 inhibitors and inducers, dabigatran etexilate,
rivaroxaban, and St. Johns Wort
-Adverse reactions: bleeding
-Caution: Patients with CrCl
74
warfarin to apixaban
stop warfarin and start apixaban when INR less than 2
75
apixaban to warfarin
start warfarin and stop apixaban 3 days later OR IF continuous, uninterrupted anticoagulation is
necessary: Stop apixaban, Begin both a parenteral anticoagulant (LMWH/fondaparinux or UFH) and warfarin at the same time that the next dose of apixaban would have been given, Stop the parenteral anticoagulant when INR is over 2.
76
LMWH/fondaparinux to apixaban
stop LMWH/fondaparinux and start apixaban at the same time that the next dose of LMWH/fondaparinux would have been given
77
IV heparin to apixaban
Stop IV heparin and start apixaban simultaneously
78
apixaban to parenteral anticoagulant
stop apixaban and administer first dose of parenteral anticoagulant at the time that the next dose of apixaban would have been given
79
apixaban to oral anticoagulant other than warfarin
stop apixaban and begin the other anticoagulant at the time that the next scheduled dose of apixaban would have been given
80
apixaban BBW
spinal/epidural hematomas
| premature discontinuation increases the risk of thrombotic event
81
edoxaban uses
NOAC
acute or maintenance
-DVT/PE treatment
-NVAF
82
edoxaban dosing
- Non-valvular atrial fibrillation: CrCl 50 - 95 mL/min: 60 mg once daily; CrCl 15 - 50 mL/min: 30 mg once daily
- DVT/PE Treatment: Following 5-10 days of initial parenteral anticoagulant therapy; CrCl greater than 50 mL/min: 60 mg once daily; 30 mg once daily: with 1 or more of the following: CrCl 15 to 50 mL/min, Body weight less than 60 kg, OR Use of P-gp inhibitors
83
edoxaban antidote
No antidote for reversal (not dialyzable): PCC or rFVIIa can be considered, Andexanet alfa: directed factor Xa antidote (Phase III trials)
84
edoxaban PK
-Metabolism: Minimal via hydrolysis, conjugation, and oxidation by CYP3A4;
PGP substrate, Predominant metabolite (M-4) is active (
85
edoxaban caustions
- Caution: other products affecting hemostasis
- Adverse reactions: bleeding
- Avoid: Child-Pugh Class B or C
- Pregnancy category C
86
warfarin to edoxaban
Stop warfarin and start edoxaban with INR less than 2
87
Edoxaban to warfarin
Start warfarin and stop edoxaban 3 days later Manufacturer recommends: for patients taking 60mg, reduce edoxaban to 30mg and start warfarin concomitantly. Stop edoxaban when INR > 2, for patients taking 30mg, reduce edoxaban to 15mg and start warfarin concomitantly. Stop edoxaban when INR > 2
OR if continuous , uninterrupted anticoagulation is necessary: stop edoxaban, begin both a parenteral anticoagulant
(LMWH/fondaparinux or UFH) and warfarin at the same time
that the next dose of edoxaban would have been givenc) stop the parenteral anticoagulant when the INR is > 2
88
LMWH/Fondaparinux to
| edoxaban
Stop LMWH/Fondaparinux and start edoxaban at the same time that the next dose of LMWH/fondaparinux would have been given
89
IV heparin to edoxaban
Stop IV heparin and start edoxaban simultaneously
(manufacturer recommends starting edoxaban 4 hrs after
stopping IV heparin)
90
Edoxaban to parenteral
| anticoagulant
Stop edoxaban and start the parenteral anticoagulant at the same time that the next dose of edoxaban would have been given
91
Edoxaban to oral anticoagulant other than warfarin
Stop edoxaban and start the other anticoagulant at the same time that the next scheduled dose of edoxaban would have been given
92
edoxaban BBW
- Reduced efficacy in nonvalvular atrial fibrillation patients with CrCl >95 mL/minute
- Spinal/epiduarl hematomas
- Prematue discontinuation increases the risk of thrombotic event
93
direct thrombin inhibitors
direct agents: prevent thrombin generation by binding to circulating and clot-bound fibrin
IV: lepirudin, bivalirudin, argatroban
NOAC: dabigatran
-Mechanism of action: Interact directly with thrombin molecule, Do not require antithrombin
-No antidote for reversal: lepirudin, bivalirudin, argatroban
-Useful in HIT treatment
94
lepirudin
dose: 0.15 mg/kg/h (± 0.4
mg/kg bolus)
Use: HIT -Goal aPTT 1.5-2.5 normal
notes: Reduce dose CrCl
95
bivalirudin
Dose: 0.7 mg/kg, then 1.75
mg/kg/h
Use: HIT, UFH alternative
during PCI
96
argatroban
```
dose:
Normal: 2 mcg/kg/min
Hepatic: 0.5 mcg/kg/min
Use: HIT
Notes: Elevates INR, overlap with warfarin until INR ≥ 4; Caution hepatic dysfunction
```
97
dabigratran uses
NOAC
- DV/PE treatment
- NVAF
98
dabigratran dosing
-DVT/PE Treatment: 150 mg PO BID (after 5-10 days of parenteral anticoagulation); Patients with CrCl
99
dabigratran cautions
- Recommend alternate agent: age over 75 years
- Must be kept in manufacturer bottle (expires 4 months after opening)
- Adverse reactions: dyspepsia, bleeding
100
dabigratran PK
- Time to peak: 1 hour (2 hours with food)
- Half-life: 12-17 hours; 15-28 hours mild – severe renal impairment
- metabolism: Dabigatran etexilate: plasma & hepatic esterases to active form; Dabigatran: hepatic glucuronidation
101
Warfarin to dabigatran
Stop warfarin and start dabigatran when INR less than 2
102
Dabigatran to warfarin
-Clcr over 50 mL/min: start warfarin and stop dabigatran 3 days later
-Clcr 31-50 mL/min: start warfarin and stop dabigatran 2 days later
-Clcr 15-30 mL/min: start warfarin and stop dabigatran 1 day later
(dabigatran may alter INR results; therefore, using INR to guide when to stop dabigatran is not reliable)
103
LMWH/ fondaparinux to dabigatran
Stop parenteral anticoagulant and administer dabigatran 0-2 hours before next parenteral dose would have been given
104
IV heparin to dabigatran
Administer first dose of dabigatran at time of discontinuation of IV heparin infusion
105
Dabigatran to parenteral
| anticoagulant
Clcr over 30 mL/min: Start parenteral anticoagulant 12 hours after the last dose of dabigatran
Clcr under 30 mL/min: Start parenteral anticoagulant 24 hours after the last dose of dabigatran
106
dabigatran to oral anticoagulant other than warfarin
stop dabigatran and begin the other anticoagulant at the time that the next dose of dabigatran would have been given
107
dabigratran CI
mechanical heart valve
| active bleeding
108
dabigratran BBW
thrombotic events
| spinal/epidural hematomas
109
idarucizumab (praxbind) use
-Reversal of dabigatran anticoagulant effects
110
idarucizumab dose
5 g intravenous (administered as 2 separate 2.5 g doses no more than 15 minutes apart)
111
idarucizumab ADR
delirium (7%), HA (5%), hypokalemia (7%), constipation (7%), pneumonia (6%), fever (6%)
112
idarucizumab monitoring
Baseline aPTT (at presentation), repeat at 2 hours postexposure (if exposure time is known) or post-presentation (if exposure time is unknown) and every 12 hours thereafter until aPTT returns to normal
113
idarucizumab onset
Effects observed within minutes and hemostasis is restored at a median of 11.4 hours
duration: 24 hours
half-life elimination: 47 minutes (initial); 10.3 hours (terminal)
-excreted in the urine
114
3 goals of anticoags:
- stabilize clot
- prevent propagation of clot
- minimize risk of embolism
NOT to get rid of clot - body has mechanisms to do so
115
thrombolytics
- "clot busting drug"
- NOT recommended for routine use for VTE
- If used, suspend anticoagulant use during thrombolytic: Following use: restart anticoagulant when aPTT is less than 80 seconds
116
thrombolytics absolute CI
- Any prior ICH
- Structural cerebral vascular lesion
- Malignant IC neoplasm
- Ischemic stroke within 3 months
- Suspected aortic dissection
- Active bleeding or bleeding diathesis (excluding menses)
- Significant closed-head or facial trauma within 3 months
117
thrombolytics cautions/relative CIs
- Severe HTN (SBP>180 mmHg)
- Ischemic stroke > 3 months
- Major surgery
118
thrombolytic examples
- tpa, alteplase (activase) - only one we use to dissolve clot
- reteplase
- tenecteplase
- urokinase
119
alteplase dosing and considerations
```
Bolus: 10 mg
Infusion: 90 mg over 2
hours
-Total dose = 100 mg over 2 hours
-Not weight based
-Most commonly used for PE
```
120
reteplase considerations
only used for ACS
121
tenecteplase considerations
only used for ACS
122
urokinase dosing and considerations
Bolus: 4400 units/kg x 10 min
Infusion: 4400 units/kg/hour over 12 hours
123
warfarin
- Most widely prescribed anticoagulant
- Warfarin is available as brand and generic products
- Available in 1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10mg tablets
124
warfarin labeled uses
- Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement
- Adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction
125
challenges of warfarin
- Narrow therapeutic window
- Considerable inter-subject variability
- Drug and diet interactions
- Labs difficult to standardize
- Good PK/PD understanding by both patient/provider
126
warfarin MOA
- Does not effect circulating factors or previously formed thrombi
- Inhibits enzymes responsible for cyclic conversion of vitamin K
- Inhibit synthesis of vitamin K dependent clotting factors: Factors II, VII, IX, and X; Protein C and S
127
half life of proteins
- Prothrombin (factor II): 60-100 hours
- Factor VII: 4-6 hours
- Factor IX: 20-30 hours
- Factor X: 24-40 hours
important when bridging to warfarin - need to get rid of existing clotting factors since warfarin won't directly inhibit them
128
warfarin PK
- Anticoagulant effect within 24 hours: Peak effect 72-96 hours, Duration of action from single dose: 2-5 days
- Mixture of S and R isomers: S isomer 5 times more potent
- Rapid absorption from GI tract: Maximal concentrations in ≈ 90 minutes
- Hepatically metabolized: CYP P450 (S: 2C9, 2C19, 2C18; R: 1A2, and 3A4); DRUG INTERACTIONS!!!!; Genetic Variances
- Pregnancy Category X
129
warfarin dosing algorithms
```
CYP2C9*1/*1:
GG: 5-7, GA: 5-7, AA: 3-4
CYP2C9*1/*2:
GG: 5-7, GA: 3-4, AA: 3-4
CYP2C9*1/*3:
GG: 3-4, GA: 3-4, AA: 0.5-2
CYP2C9*2/*2:
GG: 3-4, GA: 3-4, AA: 0.5-2
CYP2C9*2/*3:
GG: 3-4, GA: 0.5-2, AA: 0.5-2
CYP2C9*3/*3:
GG: 0.5-2, GA: 0.5-2, AA: 0.5-2
```
130
who should be tested?
patient is warfarin naive, genetic tests are available before the 6th dose, patient is at a high risk of bleeding if INR is elevated
131
warfarin monitoring
- PT: reduction of factors II, VII, and X: Monitoring NOT standardized
- INR= (patient PT/mean normal PT)ISI - ISI: international sensitivity index
- Narrow therapeutic window
132
INR: higher the number the ___ it takes to clot
LONGER
133
normal INR
1
134
goal INR
usually 2-3
135
indications for goal INR 2-3
```
prophylaxis of VTE
treatment of VTE or PE
prevention of systemic embolism: tissue heart valves, AMI (2.5-3.5), valvular heart disease, afib
antiphospholipid antibody syndrome
mechanical heart valve (aortic)
```
mechanical heart valve (MITRAL): 2.5-3.5
136
warfarin dosing
- Variable over time
- Variable between patients
- Initial dose: 5 mg by mouth once daily; Healthy outpatients: 10 mg daily x 2 days
- Overlap with UFH/LMWH/Xa for at least 5 days AANNNDDDD until INR is therapeutic
- Adjust weekly dose to achieve therapeutic INR
137
warfarin dosing exceptions
may need
138
dose alterations for INR 2-3
INR less than 2: increase 5-15%
INR 3.1-3.5: decrease 5-15%
INR 3.5-4: hold 0-1 dose and decrease by 10-15%
INR over 4: hold 0-2 doses and decrease by 10-15%
for goal 2.5-3.5: all the same but +0.5
139
initiation of warfarin therapy - frequency of INR monitoring
- Flexible initiation method: Daily through day 4, then within 3-5 days
- Average daily dosing method: Within 3-5 days, then within 1 week
- After hospital discharge : If stable, within 3-5 days; If unstable, within 1-3 days
- First month of therapy: Weekly
140
maintenance therapy of warfarin - frequency of INR monitoring
- Dose held today:Within 1-2 days
- Dose change today:Within 1-2 weeks
- Dosage change less than 2 wks ago:Within 2-4 weeks
- Routine follow-up stable pt: Every 4-6 weeks
- Routine follow-up unstable pt: Every 1-2 weeks
- Consistently stable (i.e. no change in 6 months): Every 12 weeks
141
point of care warfarin monitoring
1-Self-testing: send result to healthcare provider
- Self-managed: self-adjust warfarin
- Appropriately selected and trained patients; Anticoagulated over 3 months, Good cognitive skills, dexterity, and communication
- Mechanical heart valves, atrial fibrillation, VTE
142
warfarin patient interview
The 5 D’s
- Drugs (any changes in medications)
- Diseases (any changes in overall medical condition and/or treatment)
- Doses (any missed doses)
- Diet (any changes in diet, specifically green leafy vegetables)
- Drink (any EtOH consumption)
Bruising/bleeding
143
warfarin dose adjustments
- Signs/symptoms of bleeding
- Thromboembolic complications
- Prescription medication changes
- Diet
- Activity
- EtOH use
- Adverse effects
- OTC drug use
- Drug interaction screening
144
duration of therapy (minimums)
- Reversible risk factor: 3 months
- Idiopathic DVT: at least 3 months, then re-evaluate; Consider extended therapy up to 1 year
- DVT + cancer: LMWH for 3-6 months, then warfarin or LMWH indefinitely or cancer resolves
- Multiple events: lifelong therapy; consider at least 3 months if at high bleeding risk
145
warfarin drug interaction risks
- Hepatic metabolism
- Plasma protein binding
- Increased risk of bleeding
146
increase INR drug interactions with warfarin
- Erythromycin
- Metronidazole*
- Amiodarone*
- Alcohol (acute ingestion)
- Cimetidine
- Anabolic steroids
- Fluconazole*
- Isoniazid
- Liver disease
- Ciprofloxacin*
- Bactrim*
- Propafenone
*=adjust dose
147
aspirin and warfarin
increase risk of bleeding without increasing INR
148
decrease INR drug interactions with warfarin
- Rifampin*
- Cholestyramine
- Carbamazepine
- Alcohol (chronic ingestion)
- Vit K foods
*=adjust dose
149
food-drug warfarin interaction
- Role of vitamin K; Reverses warfarin activity, Contained in several foods, Need patient education
- Consistency is key
- Monitoring
150
alcohol and warfarin
- Acute EtOH: Increase anticoagulant effect of warfarin by inhibiting its metabolism
- Chronic EtOH w/o liver damage: Enhances warfarin metabolism by inducing hepatic enzymes decreases the effect of warfarin
- Chronic EtOH w/ liver damage: Due to lack of hepatic enzymes, increased anticoagulant effect (dose reduction often needed)
151
warfarin AE
bleeding
| pregnancy category X
152
bleeding management with warfarin
- Dependent on INR and presence/absence of bleeding: Vitamin K (Oral: 5 mg tablets, Parenteral: do NOT exceed 1 mg/min (anaphylaxis)); Fresh Frozen Plasma (FFP) (10-15 mL/kg); Prothrombin Complex Concentrate (PCC) (30 IU/kg (check INR before, 30-60 minutes after))
- INR 4.5-10.0 NO evidence of bleeding: avoid vitamin K
- INR > 10.0 NO evidence of bleeding: PO vitamin K
- Major bleeding while on warfarin: PCC preferred over FFP: May add vitamin K 5-10 mg as well
153
warfarin reversal
- rapid (10-15 min): Prothrombin complex concentrate (immediate replacement of vitamin K-dependent coagulation factors) plus intravenous vitamin K (to switch on endogenous synthesis of vitamin K-dependent coagulation factors within a few hours)
- fast (partial): Fresh frozen plasma (immediate replacement of vitamin K dependent coagulation factors – but the correction of coagulopathy is partial)
- prompt (4-6 hours): IV Vit K
- slow (24 hours): PO Vit K
- very slow (3-5 days): omit warfarin
154
VTE prophylaxis
- Without prophylaxis: VTE incidence 5-15% in medical patients (EVERY PATIENT MUST BE EVALUATED FOR ANTICOAG NEED)
- Without prophylaxis: VTA incidence 40-80% in surgical patients
- Up to 40% qualified medical patients don’t receive appropriate prophylaxis
155
VTE propylaxis options
- Unfractionated heparin (UFH)
- Low-molecular weight heparin (LMWH)
- Factor Xa Inhibitors
- Vitamin K antagonists
156
low risk VTE
VTE risk
157
moderate risk VTE
VTE risk 10-40%
- Most non-orthopedic surgery patients
- Acutely ill medical patients (limited mobility)
- General surgery patients: UFH, LMWH, and Factor Xa inhibitor (fondaparinux) all recommended, VTE risk continues post hospital discharge (40% of events > 21 days after surgery), Continue prophylaxis up to 28 days after hospital discharge
- Acutely ill medical patients: UFH, LMWH, and fondaparinux all appropriate, Increased VTE risk due to early discharge/immobility at home, No specific recommendations for post-discharge VTE prophylaxis duration
158
high risk VTE
VTE risk 40-80%
- Most orthopedic surgery
- Major trauma
- Spinal cord injury
- Orthopedic surgery (TKA or THA): LMWH, fondaparinux, rivaroxaban, apixaban, UFH, or vitamin K antagonist – FDA approved, Dabigatran possibility – non-FDA approved, Continue ≥ 10-14 days postop (consider up to 35 days)
159
high bleeding risk ___ prophylaxis preferred
Mechanical prophylaxis preferred
- Intermittent pneumatic compression devices
- Venous foot pumps
- Graduated compression stockings
160
VTE treatment (initial DVT or PE treatment)
- SubQ LMWH, IV or subQ UFH, fondaparinux: Initiate warfarin Day 1-2 of treatment, Overlap warfarin + injectable anticoagulant (At least 5 days AND INR > 2.0 for 24 hours, Warfarin 5-10 mg usual starting dose)
- Rivaroxaban or apixaban: DOES NOT need warfarin overlap, continue medication for treatment duration
- Edoxaban: DOES NOT need warfain overlap, continue parenteral anticoagulant for 5-10 days
- Dabigatran: DOES NOT need warfain overlap, continue parenteral anticoagulant for 5-10 days
161
VTE treatment (thrombolytic use)
- Preferred VTE treatments on previous slides
- Majority of VTE patients don’t require thrombolytics
IF NEEDED:
- DVT: extensive proximal DVT (i.e. risk of losing the limb), low bleeding risk: Catheter directed or systemic
- PE: associated with hypotension (SBP
162
Afib
- has not had a clot, but use whats considered "treatment level" anticoag
- Mechanical heart valve: warfarin recommended (INR 2.0-3.0 or 2.5-3.5)
- Non-valvular afib: CHA2DS2-VASc recommended to assess risk
- Non-valvular afib with prior stroke, TIA, or CHA2DS2-VASc at least: oral anticoagulants: Warfarin, rivaroxaban, apixaban, edoxaban, dabigatran
- CHA2DS2-VASc = 1: no antithrombotic therapy OR oral anticoagulant OR ASA considered
- CHA2DS2-VASc = 0: omit antithrombotic therapy
163
CHADS2VASc is only used ___
to determine the need the need for anticoag in AFib patients
164
CHA2DS2VASc acronym and score
```
CHF - 1
HTN - 1
Age over 75 -2
DM - 1
Stroke/TIA/TE - 2
Vascular disease - 1
Age 65-74 - 1
sex (female) - 1
```
165
AFib rivoroxaban dosing
- 20 mg daily with the evening meal
| - CrCl 15-50 mL/min: 15 mg daily
166
AFib apixaban dosing
- . 5 mg BID
| - at least 80 yrs, wt under 60 kg, sCr at least 1.5 mg/dL (any 2): 2.5 mg BID
167
AFib edoxaban dosing
- CrCl 50-95 mL/min: 60 mg daily
| - CrCl 15-50 mL/min: 30 mg daily
168
AFib dabigratran dosing
- 150 mg BID
- CrCl 30-50 w/ dronedarone or ketoconazole: 75 mg BID
- CrCl 15-30: 75 mg BID
169
AFib warfarin dosing
5 mg daily (bridging with parenteral anticoagulant not recommended)
170
invasive prodecures
- “Bridging therapy” may be needed if on warfarin
- Typically not needed for dental, dermatologic, or cataract procedures
- If bridging is needed: Stop warfarin 5 days before surgery, Give LMWH or UFH until the procedure (Stop LMWH 24 hours before procedure; Stop IV UFH 4-6 hours before procedure), Resume warfarin 12-24 hours after surgery (assuming adequate hemostasis)
171
D/C dabigatran before procedure
```
CrCl 30-49
-low risk: over 48 hours
-high risk: over 96 hours
CrCl 50-79
-low risk: over 36 hours
-high risk: over 72 hours
CrCl above 80
-low risk: over 24 hours
-high risk: over 48 hours
```
172
D/C Xa inhibitors before procedure
```
CrCl 15-29
-low risk: over 36 hours
-high risk: over 48 hours
CrCl above 30
-low risk: 24 hours
-high risk: over 48 hours
```
173
VKORC
1639A: inc sens
1639G: inc resistance
module 2b
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