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PHAR 253 Final > Venous Thromboembolism > Flashcards

Venous Thromboembolism Flashcards

1
Q

Why is it important for pharmacists to understand VTE?

A

VTE is a major cause of morbidity & mortality
Causes more death than breast cancer, HIV, and motor vehicle accidents combined

50% attributed to hospitalization (esp. surgery)
–> 10% of hospital deaths due to PE

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2
Q

Describe venous circulation

A

Return blood to heart for re-oxygenation

Thinner walled than arteries

Elastic; variably widens as blood passes through

Lower shear rate than arteries

One-way valves close to prevent backflow
–> Damage here means static or pooling blood

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3
Q

What is a VTE? Where does it form commonly? Exception?

A

VTE is a formation of a blood clot that most often occurs as a deep vein thrombosis of lower extremities, or as a pulmonary embolism.

VTEs can less often occur in the upper extremities (UEDVT), the portal vein, the cerebral vein of the brain, and other venous locations.

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4
Q

What is the difference between a venous and arterial thrombus?

A

Venous thrombus (red clot):
Formed without damaging vessel wall
Held together by mostly fibrin, less platelet
Leads to VTE (DVT/PE)

Arterial thrombus (white clot):
Formed from rupture of atherosclerotic plaque
Held together by mostly platelets, less fibrin
Leads to ACS, stroke, or peripheral arterial disease (PAD)

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5
Q

What is a DVT and PE? What is the rates of the total VTE?

A

Deep vein thrombosis (DVT)
–> Formation of a clot in a deep vein
~2/3 of VTEs

Pulmonary embolism (PE)
–> is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream
–> a possible consequence of DVT
~1/3 of VTEs

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6
Q

Cause of VTE (simple)

A

Results from clot formation within venous circulation

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7
Q

Where does VTE usually develop?

A

Mainly develops in lower extremities
Majority in calf veins
Minority in arm, brain, GI tract, liver (rare often malignanacy or other cause)

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8
Q

One a venous clot has formed, the clot may then…..

A

Lyse
Obstruct venous circulation
Embolize
Combination

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9
Q

What is the central portion of the coagulation cascade?

A

Central to the coagulation cascade is the generation of thrombin (factor IIa)

Thrombin is made from prothrombin by factor Xa

Prothrombin => thrombin => fibrinogen => fibrin clot

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10
Q

Describe the coagulation cascade and where the drugs work?

A

Antithrombin (AT or AT-III) is a small protein molecule that inactivates several enzymes of the coagulation system.

It is one of the most important coagulation inhibitors; it controls the activities of thrombin, and factors IXa, Xa, XIa and XIIa

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11
Q

What is virchows triad?

A
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12
Q

What are some risk factor categories for VTE?

A

Circulatory Stasis
Vascular Damage
Hypercoagulability
Preganancy/Post-partum
Medications
Birth Control

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13
Q

The risk factor of circulatory stasis examples include:

A

Bed rest/immobility (prolonged)
–> Hospitalization
Heart failure (Class III-IV)
Varicose veins (controversy)
Atrial fibrillation

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14
Q

The risk factor of vascular damage examples include:

A

Previous VTE
Bacterial infection (sepsis)
Prosthetic implants
Peripheral vascular disease
Trauma
Surgery – watch those hips and knee’s

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15
Q

The risk factor of hypercoagulability examples include:

A

Medications (chemotx)
Use of oral contraceptives
Malignancy
Inherited thrombophilias
Advanced age >60 (>75)
Obesity – BMI >30? (>50)
Protein C or S deficiency
Smoking

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16
Q

The risk factor of pregnancy stats:

A

5-10x increase during pregnancy
15-35x risk during the early postpartum (6-12 weeks)

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17
Q

What medications are risk fcators for VTE?

A

Estrogen
SERMS (Tamoxifen/raloxifen)
Chemotherapy
Older antipsychotics
Erythropoietin

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18
Q

When should birth control be stopped in VTE?

A

Consider stopping OCP during a life threatening clot. But, no evidence to stop in acute clot because:

1) About to put her on a DOAC/warfarin that isn’t studied in pregnancy and could be unsafe

2) She may get heavy menstruation as on a blood thinner and OCP may be used to regulate heavy periods.

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19
Q

VTE often presents as….

A

ASYMPTOMATIC

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20
Q

What are some difficulties associated with VTE (simple)?

A

Symptoms are often non-specific
–> Diagnosis is difficult
–> Requires assessment of risk factors and lab / imaging tests

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21
Q

What are some sx of DVT?

A

Leg pain
Tenderness
Ankle edema
Calf swelling
Dilated veins
Dusky discolouration

Let Tony Ask Can Daddy D***

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22
Q

What are some symptoms of a PE?

A

Sudden, unexplained SoB
Tachypnea
Tachycardia
Unexplained chest pain / discomfort
Cough
Hemoptysis
Fever
Cyanosis
Syncope
Sense of impending doom

someonetell tony cole can hurt feelings, cole slays skies

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23
Q

What are some complications of a VTE?

A

Recurrence rates are high

Post-thrombotic syndrome

Venous ulcers

Chronic thromboembolic pulmonary hypertension (CTEPH)

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24
Q

What is the tx of post-thrombotic syndrome (PTS)?

A

Post-thrombotic syndrome (PTS)
–> Chronic pain, swelling (edema), fatigue, and leg ulcers

Possible treatment: –> compression stockings

Ankle to knee (increase venous return)

30-40mmHG at ankle at onset of DVT

May decreases incidence of PTS

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25
Q

What is the result of venous skin ulcers complications?

A

Results from venous insufficiency, leading to pooling of blood

Major cause of chronic wounds

Lack of proper blood flow

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26
Q

What is the effect of the complication of chronic thromboembolic pulmonary htn? TX?

A

Can occur after a PE

Causes scarring in the lungs, which narrows the arteries and leads to a permanent increase in pulmonary blood pressure, and may lead to right-sided heart failure.

Must be anti-coagulated for life after treatment

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27
Q

How is VTE diagnosed?

A

Lab tests​
- D-dimer increase​ (If high, may have a clot – cant rule in VTE but can rule it out)
- ESR and WBC count increase​ (WBC increase –> Inflammation, acute phase reactant)

Clinical prediction score
- Wells criteria (DVT & PE)

Imaging​
–> Compression ultrasonography ​
–> CT scan (lungs)
–> Ventilation/perfusion scan –

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28
Q

How is DVT diagnosed?

A
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29
Q

How is a pulmonary embolism diagnosed?

A
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30
Q

What are the goals of therapy for VTE?

A

Prevent initial VTE​ (primary goal)

Resolution of signs and symptoms of VTE (be specific to the patient)in 7 days

Prevention of extension of VTE – prevention of PE in patients with DVT

Prevention of hemodynamic collapse and/or death

Prevention of recurrence of VTE in select patients

Prevent the development of CTEPH or PTS

Reduce the risk of adverse effects from pharmacologic treatment

Prevent long-term complications of VTE and bleeds from tx

8

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31
Q

What lab tests are used to monitor anticoag?

A

Prothrombin time (PT)​

Partial thromboplastin time (PTT)​

Activated partial thromboplastin time (aPTT)​

Anti-Xa activity​

International normalized ratio (INR)

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32
Q

What does PT measure?What factors?

A

PT measures the extrinsic and common pathway of coagulation (factor X,V, VII, II) – tests heparin (not commonly used, use aPTT)

tests Warfarin ​

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33
Q

What does aPTT measure?

A

aPTT measures the intrinsic and common pathways of coagulation.

Highertime - Longer time to clot – tests heparin. NOT for LMWH.​

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34
Q

WHat is the difference between aPTT and PTT?

A

aPTT and PTT measures intrinstic and common pathways, but aPTT uses an activator to speed up clotting time, creating a narrower reference range to aim for, IE more sensitive

PTT no longer commonly used

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35
Q

What does INR measure?

A

INR standard measure of anticoagulant activity of warfarin.

ONLY VALIDATED FOR WARFARIN. OTHER ANTICOAGS WILL CHANGE IT, BUT DOES NOT ACCURATELY REFLECT IT!

INR calculated with PT (patient) / PT (normal reference), corrected for lab variation​

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36
Q

What are some challenges of preventing and treating VTE’s?

A

Precise dosing of anticoagulants​

Monitoring properly​

Balance bleed risk vs. clotting risk​
–>Bleeding is the predominant adverse event​
– > Tends to increase with the intensity and duration of therapy

Potential drug interactions

Drug/disease interactions​

Patient issues: compliance, administration​

Clinician assessment and appropriate prophylaxis

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37
Q

What are the pharmacotherapy options available for VTE?

A

Heparin (UFH)

Low molecular weight heparin (LMWH)

Heparinoids (danaparoid)

Glycosaminoglycan heparinoid (fondaparinux)

Direct thrombin inhibitor (argatroban)

Vitamin K antagonist (warfarin)

Direct oral anticoagulants (DOACs)

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38
Q

What is the MOA of Heparin (UFH)?

A

Catalyzes antithrombin –> inactivates factor IIa and IXa, Xa, XIa, & XIIa

Prolongs aPTT (measures function of those clotting factors)

Cannot bind to thrombin already in a clot

Also binds to cells and other plasma proteins –> unpredictable pharmacokinetics / dynamics

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39
Q

Onset of effect for IV and Subcut Heparin (UFH)?

A

IV: Begins working immediately
Subcut: 30-60m

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40
Q

UFH Duration of Effect

A

T1/2 = 1-2 hours
IV: continuous infusion to ensure level response
Subcut: 8 hours

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41
Q

What is unique about UFH’s PK?

A

Short Half-Life –> Easy to stop the medication, can stop the infusion

–> person in car accident

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42
Q

What are some C.I. of UFH? Are any absolute C.I.?

A

Active bleeding or conditions that may increase risk of bleeding
–> Hemorrhagic stroke
–> Severe, uncontrolled HTN
–> Active gastric/duodenal ulcer
–> Blood clotting disorders (haemophilia)

Injuries and operations to brain, spinal cord, eyes/ears

Severe thrombocytopenia

Prior occurrence of heparin-induced thrombocytopenia (ACTUAL C.I.)

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43
Q

How is UFH administered and dosed?

A

IV or Subcut only

Initial doses calculated using body weight

Dose depends on if prophylaxis, treatment, IV vs. Subcut.

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44
Q

UFH Doses: Prophylaxis and Treatment of DVT/PE. How long for?

A

Thromboprophylaxis – 5000 units SC q8-12h

Treatment of DVT/PE:

IV: LD 80 units/kg over 10 min; then 18 units/kg/hour

SC: 250 units/kg Q12H
Both: Adjust dose until aPTT is 1.5-2.5x baseline

Usually, heparin will just be used for <7 days
Simultaneously given with warfarin

Discontinued once warfarin reaches target INR for 2 days

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45
Q

What is a caution of using UFH?

A

Narrow therapeutic window!

Variable response to the recommended doses

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46
Q

How long is UFH used for tx of VTE?

A

Usually, heparin will just be used for <7 days

Simultaneously given with warfarin

Discontinued once warfarin reaches target INR for 1-2 days

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47
Q

UFH Common A/E

A

Minor bleeds
Injection site reactions if Subcut
Transient, mild liver enzyme increase

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48
Q

What are some serious a/e of UFH?

A

Heparin induced thrombocytopenia (HIT)
Major bleeds
Hyperkalemia
Skin necrosis
BMD decrease

(Usually not concern as using for less than 7 days)

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49
Q

What is the antidote for UFH induced major bleed?

A

IV Protamine sulfate neutralizes heparin

1 – 1.5 mg protamine neutralizes 100 units of heparin if heparin given in last 29 minutes

0.5 – 0.75mg protamine neutralizes 100 units of heparin if heparin given in last 30-120 minutes

0.25 – 0.375mg of pramine neutralizes 100 units of heparin if heparin give in over 120 minutes ago

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50
Q

What are some adverse effects of protamine sulfate?

A

Allergic reactions, including anaphylaxis (0.6-10.6%)

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51
Q

What is heparin induced thrombocytopenia (HIT)? When does it occur?

A

All stick together –> no platelets to control bleed and higher risk of thrombosis

occurs 5-10 days after heparin initiation

*Depends on prior heparin exposure

Depends on degree of thrombocytopenia and nadir

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52
Q

What is the treatment of HIT?

A

Discontinue ALL sources of heparin

Begin alternate anticoagulation
Warfarin initially unsuitable

Argatroban, fondaparinux, danaparoid, bivalirudin

Transition to warfarin once platelets restored (~150 x 109L) and minimum x 5 days

DOACs in stable patients with medium risk of bleeding (rivaroxaban preferred)

Rivaroxaban 15mg PO BID until platelets platelets restored (~150 x 109L) (No thrombus)

Rivaroxaban 15mg PO BID x 21 days then 20mg daily thereafter (thrombus)

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53
Q

Describe the platelets and antibodies changes after HIT

A

Platelets return to normal in 4-10 days.

Rise within 2-3 days of cessation.

Antibodies can take ~100 days to disappear

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54
Q

What are some drug interactions of UFH?

A

ACE / ARBs: Increased risk of hyperkalemia

Antiplatelets: Increased anti-coagulation

Aspirin / NSAIDs: Increased anticoagulation

Estrogens / progestins: Pro-thrombotic

Herbs: 194 herbs have anti-coagulant properties

Potassium salts / potassium sparing diuretics

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55
Q

What is the monitoring of UFH effectiveness?

A

Must monitor aPTT (VTE treatment, not prophylaxis)

See validated nomograms

Note – reagents differ lab to lab (i.e. cannot use Saskatoon heparin nomogram in Regina)

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56
Q

What is the monitoring of UFH safety?

A

Platelet count
–> Get baseline if possible
–> If on therapy for >4 days, check every other day until finished
–> If previous exposure to heparin, baseline and after 24h (then daily or every other day)

Hgb and hematocrit – baseline and q3d

Potassium – only if high risk of hyperkalemia; baseline & q3d x 2 then weekly thereafter

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57
Q

What are the LMWH’s?

A
  • Enoxaparin
  • Dalteparin
  • Tinzaparin
  • Nadroparin
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58
Q

Are the LMWH’s interchangable?

A

All appear equal clinically in safety and efficacy

  • NOT interchangeable
  • Different dosing regimens
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59
Q

Compare LMWH’s (Chart: DVT prophylaxis, non-ortho surgery, ortho surgery, VTE tx, Dialysis line patency, tx of unstable angina or NSTEMI, and Tx of STEMI)

A
60
Q

Which LMWH’s cane be used for dialysis line patenyc?

A

Dalteparin and Tinzaparin

61
Q

Which LMWH’s can be used for Angina/NSTEMI? STEMI?

A

Angina/NSTEMI - Dalteparin, enoxaparin

STEMI –> ONLY EnOXAPARIN

62
Q

LMWH MOA

A

Same as heparin but higher affinity for Xa

Can affect aPTT

Cannot bind to thrombin already in a clot

Anti Xa levels if monitoring needed (rare)

63
Q

Compare the pharmacokinetics of UFH and LMWH

A

LMWHs have more predictable pharmacokinetic properties compared with UFH

Allows LMWHs to be administered in fixed doses and without the need for dose adjustment based on laboratory monitoring.

64
Q

What is the SHA’s choice of LMWH?

A

SHA uses tinzaparin for the prophylaxis and treatment of VTE

As well as maintaining dialysis line patency

Enoxaparin is only used in acute ACS

65
Q

What are the contraindications of LMWH?

A

Same as UFH

Active bleeding or conditions that may increase risk of bleeding
–> Hemorrhagic stroke
–> Severe, uncontrolled HTN
–> Active gastric/duodenal ulcer
–> Blood clotting disorders (haemophilia)

Injuries and operations to brain, spinal cord, eyes/ears

Severe thrombocytopenia

Prior occurrence of heparin-induced thrombocytopenia (ACTUAL C.I.)

66
Q

What does the dosing of LMWH depend on?

A

Depends on:

Prophylaxis vs. treatment
Agent used
Renal function
Obesity
Indication

Subcut administration

67
Q

Dosing of Tinzaparin VTE tx, prophylaxis and dialysis line patency

A

Tinzaparin 75 units/kg for VTE prophylaxis
Some references recommend tinzaparin 4500 units for all patients regardless of weight

Tinzaparin 175 units/kg for VTE treatment

Tinzaparin 2500 units subcut for dialysis line patency

(rounded to the nearest dosage size)
3500,4500,8000,10000,12000

68
Q

What is the CrCl recommendations for prophylaxis and treatment? Is there renal dose adjustments?

Tinzaparin

A

VTE prophylaxis tinzaparin dosing – okay down to CrCl 20ml/min

VTE treatment tinzaparin dosing – Likely okay down to a CrCl of 30ml/min
Use in CrCl ~25ml/min with caution?

No renal dose adjustment
Can or cannot use

69
Q

Obesity dosing of LMWH

A

Continue to use actual body weight

Each agent differs with recommendation

For Tinzaparin
–> Dose 30,000 units subcut daily and above

Anti Xa levels should be monitored

No evidence for BID dosing though some experts may split the dose

70
Q

Describe the use of LMWH in Pregnancy

A

Alters the metabolism of LMWH throughout course of pregnancy, especially in the 3rd trimester

Opinion differs:
–> Weight at the beginning and go
–> Weigh every trimester and adjust dose?
–> Anti Xa levels
–> Switch to UFH at 36 weeks. Subcut divided Q12H

71
Q

Onset of effect LMWH

A

Starts in one hour

Peak anti-coagulation response in 3-5 hours

72
Q

Duration of effect of LMWH

A

Anti-Xa activity persists for 12-24 hours with a subcut dose

Half-life is only 3-6 hours

73
Q

Come adverse effects of LMWH

A

(Same as UFH, but much lower incidence)

Minor bleeds
Injection site reactions if Subcut
Transient, mild liver enzyme increase

74
Q

Serious adverse effects of LMWH

A

Same as UFH

Heparin induced thrombocytopenia (HIT)
Major bleeds
Hyperkalemia
Skin necrosis
BMD decrease

  • Same as UFH, but…
    Risk of HIT is dramatically lower
75
Q

LMWH Drug Interactions

A

Same as UFH

ACE / ARBs: Increased risk of hyperkalemia

Antiplatelets: Increased anti-coagulation

Aspirin / NSAIDs: Increased anticoagulation

Estrogens / progestins: Pro-thrombotic

Herbs: 194 herbs have anti-coagulant properties

Potassium salts / potassium sparing diuretics

76
Q

How can the efficacy of LMWH be monitored?

A

Cannot use aPTT

Monitoring anti-Xa levels not indicated, unless:
–> Obese
–> Pregnant
–> Renal insufficiency

Measure anti-Xa 4 hours post-dose

77
Q

When is monitoring of anti-xa levels indicated for LMWH?When should it be monitored?

A

Monitoring anti-Xa levels not indicated, unless:

Obese
Pregnant
Renal insufficiency
—> Measure anti-Xa 4 hours post-dose

78
Q

How can the safety of LMWH be monitored?

A

Platelet count
–> Get baseline if possible
–> If on therapy for >4 days, check every other day until finished
–> If previous exposure to heparin, baseline and after 24h (then daily or every other day)

Hgb and hematocrit – baseline and q3d

Potassium – only if high risk of hyperkalemia; baseline & q3d x 2 then weekly thereafter

Renal function

Same as Heparin

79
Q

Compare UFH and LMWH (Onset, Duration of Anticoag, Dosing regimen, Dose adjustments, saftey issues)

A
80
Q

Comapre UFH and LMWH in C.I., Efficacy and Monitoring

A
81
Q

What are the miscellaneous pharmacotx that can be used for VTE? MOA?

A

Heparinoids –Danaparoid

Glycosaminoglycan– fondaparinux

Direct thrombin inhibitor - Argatroban

Inhibits factor Xa (fondaparinux, danaparoid) or directly inhibits thrombin (argatroban)

82
Q

Indications of Danparoid, fondaprinux, and argatroban

A

Danaparoid: Prevention of DVT after surgery, or use in HIT

Fondaparinux: Same as LMWH, plus use in HIT

Argatroban: Anticoagulation in patients with HIT

83
Q

Compare fondaparinux, danaparoid, and argatroban to LMWH

A
84
Q

Warfarin MOA

A

Vitamin K antagonist; interferes with production of clotting factors dependant on vitamin K (X, IX, VII, II)

Protein C & S

Initially puts you into a pro-thrombic state

Canada vs. Soviets 1972

85
Q

Warfarin onset of effect? Exception?

A

Not immediate; must clear vitamin K clotting factors from circulation

Takes 2-7 days (avg 3-5)

Offset also takes a similar time

Any changes in dose, diet, or drug-interactions have delayed effect

86
Q

Warfarin C.I.

A

Pregnancy

High risk of bleed where benefit of anticoagulation is less than risk of bleeding
–> Active bleed
–> Recent CNS or eye surgery
–> Inadequate laboratory facilities
–> Unsupervised patients with senility, alcoholism or psychosis

Previous skin reaction to warfarin

87
Q

Does Warfarin require dose adjustments in renal or hepatic dysfx?

A

No adjustments in renal/liver

88
Q

How can warfarin be initiated? For which pt’s?

A

Option 1: Begin at Warfarin 2-3mg OD for 2 days
–> Elderly, high bleed risk patient, liver disease, medications which increase INR, non-urgent need for therapeutic INR

Option 2: Begin Warfarin 5mg OD for 2 days
–> Most patients

Option 3: Begin Warfarin 10mg OD for 2 days
–> Young, healthy patient with low bleed risk; urgent need for therapeutic INR

89
Q

Describe a high and low INR

A

HIGH INR –> TOO GOOD –> BLEED EASIER (coughing up blood, bleeding form eyes)

LOW INR –> Clot again, VTE and PE sx or asymptomatic

90
Q

How can a pharmacist deal with a sub-therapeutic or supra-therapeutic INR?

A

Step 1: Determine indication and target INR; any symptoms of high or low INR?

Step 2: If no issues above; is the patient at risk of having those issues develop?

Step 3: Determine if sub/supra-therapeutic INR is from a permanent or transient cause

91
Q

INR Values

A

In healthy people an INR of 1.1 or below is considered normal.

An INR range of 2.0 to 3.0 is generally an effective therapeutic range for people taking warfarin for certain disorders.

92
Q

What are some considerations for the interpretation of a patient’s INR?

A

trend & time since last INR, duration of current dose full therapeutic effect may take 5-7 days

  • changes in medications (starting, stopping & changes in doses) of interacting medications,
  • factors that may change INR: acute illnesses e.g. diarrhea, fever, change in alcohol intake
  • factors that may change INR: edema, vitamin K intake (e.g. garden harvest),change physical activity level
  • patients with heart failure, diabetes & acute GI illness may experience INR instability
93
Q

When should bridging onto to warfarin therapy occur?

A

We need to bridge patients onto warfarin if they’re at very high risk and need immediate protection

During initial treatment of VTE (DVT or PE)

For prevention of VTE after high-risk procedure (THR, TKR, abdominal surgery, mechanical valve surgery)

For a patient at high risk of VTE or arterial emboli undergoing surgery

94
Q

Why is bridging onto warfarin required? How should it be done?

A

Delayed onset

Must assess how critical rapid anti-coagulation is needed

Starting Warfarin:

1) Initiate warfarin and UFH or LMWH simultaneously

2) Overlap for at least 5 days AND until INR is >2 for 2 days

95
Q

What is the main consideration when bridging someone off of Warfarin? How is this done?

A

Delayed offset

Must assess risk of thrombosis for stopping anticoagulation vs. bleed risk for continuing during surgeries

1) Stop warfarin 3-5 days prior; wait until INR drops to <1.5

2) Begin UFH or LMWH once INR <2
–> stop UFH 4-5 hours before surgery; LMWH 24 hours

3) Resume UFH or LMWH 24 hours after surgery, alongside warfarin (longer if high-risk surgery)

If patient can’t wait to get surgery done, Vitamin K will be administered to bring it down faster

96
Q

What are some common side-effects of Warfarin?

A

Minor bleeds ~10% (eg. Gums bleeding, shaving cuts, bruises)

Abdominal cramps

Diarrhea

Nausea

Skin reactions, hives (rare but not serious) – not a type-1 IGE mediated rxn

97
Q

What are some serious side-effects of Warfarin?

A

Major bleeds (~1.3-3% per year)

Intracranial hemorrhage (0.33% per year)

Purple toe syndrome (0.01%) –> cholesterol emboli in the toe

Skin necrosis (0.01%)

98
Q

Warfarin Drug Interactions

A

Drug-interactions
648 documented drug and food interactions!

8 major classes of interacting drugs:

Antibiotics
Antifungals
Antidepressants
Antiplatelets
Amiodarone
Anti-inflammatory agents
Acetaminophen
Alternative Remedies
Corticosteroids

Any 2C9 inhibitor/inducer will have strong effect

Acute drugs are most risky

99
Q

What antibiotics interact with warfarin?

A

Antibiotics

ALL impact warfarin by decrease in vitamin K
–> Kills intestinal flora which create Vitamin K

Some also inhibit warfarin metabolism significantly:

Ciprofloxacin
Clarithromycin
Erythromycin
Metronidazole
TMP-SMX

100
Q

How can the drug interactions of warfarin be managed?

A

Empiric dose adjustment to warfarin often more risky and unpredictable than the DI

Check INR again in 4-6 days and adjust dose in response

Some Warfarin DIs cannot be monitored for –> NSAIDs (increase bleeding without increasing INR), antiplatelets, hormone therapy
–> Must balance risk of bleed or clot with benefit of therapy

101
Q

How should the safety and efficacy of Warfarin be monitored?

A

Signs of major bleeds

INR on day 3&5

V

twice weekly x1 wk

V

weekly until stable for 2 wks

V

q2w until stable x1 month

V

Monthly.

Can extend up to q3m if very stable.
Check in 4-6 days after dose change or other issue

102
Q

What is a clinical tip for Warfarin tx?

A

Warfarin thrives on consistency
–> Many DIs
–> Many food interactions

Easiest piece of advice to give patients:

“Don’t start any new meds/OTC/Herbals or make any drastic changes in your diet without talking to the pharmacist and/or physician”

103
Q

What is the anti-dote for warfarin?

A

In case of a bleed or extremely elevated INR (>10), vitamin K IV or oral is given
Vitamin K 2.5-5mg orally will reduce INR in 24-48 hours

If serious bleed, regardless of INR:
Hold warfarin
Give Vitamin K 5-10mg IV q12h
Give factor IV prothrombin complex or FFP

104
Q

What are the available DOAC’s?

A

Rivaroxaban
Apixaban
Edoxaban
Dabigatran

105
Q

What is the MOA of the DOAC’s?

A

Rivaroxaban / Apixaban / Edoxaban:
Inhibits factor Xa

Dabigatran:
Directly inhibits thrombin

106
Q

Onset of Effect DOAC’s

A

All achieve peak anti-coagulation in about 2 hours

107
Q

Duration of effect DOAC’s

A

Rivaroxaban: t ½ 9h
Apixaban: t ½ of 8-14h
Dabigatran: t ½ 13h, up to 18h renal impairment
Edoxaban: t ½ 14h

108
Q

Renal Impairment –> DOAC’s

A

CANNOT RENAL ADJUST –> IF CRCL BELOW< CANNOT USE

109
Q

What is the risk of bleeding with DOAC’s?

A

High risk for all as no antidote

110
Q

Can DOAC’s be used in preganncy?

A

No –> Not well studied and crosses placenta

111
Q

In hepatic disease, which DOAC’s are acceptable?

A

Apixaban, Edoxaban, and Rivaroxaban –>NO
Dabigatran –> Caution

112
Q

DOAC’s and dialysis

A

Dialysis does remove apixaban and dabigatran

113
Q

Rivaroxaban C.I. Drug Interactions

A

Rivaroxaban: only CI with drugs if BOTH p-gp and 3A4. Just p-gp ok. 3A4 is cautioned. Not removed by dialysis

114
Q

Describe the general drug interactions of DOAC’s

A
115
Q

Drug Interactions of DOAC’s –> Specific Drugs

A

Agents with antiplatelet properties (NSAIDs, ASA, antidepressants)

Estrogens / Progestins

Strong 3A4 and P-gp inducers:
Carbamazepine, phenytoin, rifampin, st.john’s wort

Strong p-glycoprotein inducers
Tipranavir

Strong 3A4 inhibitors and P-gp inhibitors:
Ketoconazole, itraconazole, ritonavir, clarithromycin, fluconazole, dronedarone

Strong 3A4 inhibitors
- HIV protease inhibitors

Strong p-glycoprotein inhibitors
Cyclosporine

Dis are even more critical in someone with renal disfunction!

For moderate or weak inhibitors, it does alter levels, but not significantly enough to be clinically relevant and necessitate a dose reduction

116
Q

What is unique about dabigatran and edoxaban ?

A

Dabigatran / edoxaban unaffected by the CYP drug interactions

Dabigatran affected anything that raises pH

117
Q

Dosing of DOAC’s –> Prevention after TKR/THR, Treatment and Prevention of Recurrent VTE

A
118
Q

What is unique about the dosing of Dabi and Edox?

A

Dabi and Edox need a bridge

Edoxaban has simplest dosing

119
Q

Convenience of Dosing DOAC’s

A

Convenience: Apix/dabi = BID; Riva/edox = OD

120
Q

Rivaroxaban IMPORTANT Counselling

A

Any dose >10 mg –> TAKE WITH FOOD

AUC increased 40% with 20mg.

121
Q

DOAC Dosing Adjustments

A

Obesity
BMI <40, or <120kg: Standard dosing

BMI >40, or >120kg: Can use, but patient must understand potential unknown risks

–> Avoid dabigatran & edoxaban
–> Avoid in acute setting after bariatric surgery. Likely use VKA (Warfarin)

122
Q

DOAC Common Side-effects

A

Minor bleeding….
GI upset and dyspepsia ~ same as warfarin (Dabigatran more)
Diarrhea or constipation
Itch (not immune mediated)

123
Q

What is unique about dabigatran in common side effects?

A

Dabigatran causes more G.I. upset and dyspepsia

124
Q

What are the serious risks associated with DOAC’s?

A

Bleeding; but mostly better or same as warfarin

125
Q

What is the benefit and risks associated with thrombolytics?

A

Benefit:
More rapid and complete lysis of DVT, less post-thrombotic syndrome (43% vs 64%)

Risk:
More major bleeding (9% vs. 4%)
Other anticoagulation has similar rates of recurrence and overall mortality

126
Q

What are the thrombolytics available?

A

Alteplase and Tenecteplase

127
Q

What is the indication for thrombolytics in VTE?

A

Only VTE indication:

High risk (Massive) pulmonary embolism

128
Q

Duration of Treatment for VTE

A
129
Q

Switching Warfarin to a DOAC

A

Warfarin to DOAC

To rivaroxaban: Stop warfarin, wait until INR is <2.5

To dabigatran / apixaban / edoxaban: Stop warfarin, wait until INR <2.0

130
Q

Switching from DOAC to Warfarin

A

From rivaroxaban / apixaban:
Use both concurrently. Test INR on day 3, then each day prior to dose. Once INR is >2.0, discontinue NOAC.

From dabigatran / edoxaban:
If CrCl >50ml/min, start warfarin 3 days before d/c
If CrCl 30-50ml/min, start warfarin 2 days before d/c

131
Q

What are the recommendations for VTE prophylaxis in hospital?

A

Every person in hospital gets VTE prophylaxis unless:

132
Q

What are some available mechanical VTE prophylaxis?

A

Graduated compression stockings

Intermittent pneumatic compression device

133
Q

What is the VTE risk associated with air-travel?

A

0.5% for flights > 12 hours
1.5 – 10% for flights > 24 hours
Risk is elevated for up 2-8 weeks post-travel

Almost all who have a VTE during travel had many risk factors for VTE

134
Q

Pharmacological tx for air travel

A

Pharmacologic prophylaxis NOT needed
Highest risk individuals may receive LMWH
Other antiplatelets or anticoagulants have no proven value in this scenario

135
Q

Which pharmacotx agents are not to be used in pregnancy and post-partum?

A

A subset of patients will need anti-coagulation to reduce risk

Warfarin is teratogenic and cannot be used
NOACs have not been studied

136
Q

What conditions require anti-coag tx in preganncy and post-partum?

A
137
Q

What are the therapeutic agents used in pregnancy and post-partum?

A

UFH
LMWH –> DRUG OF CHOICE
Danaparoid / Fondaparinux

Multi-dose heparin preparations have benzyl alcohol as a preservative; must select preservative free options

138
Q

What is the recommendation of intitiating tx, monitoring and dosing in pregnancy and post partum?

A

Initiate treatment as soon as pregnancy occurs

If already on anti-coagulation, switch to safer alternatives

Monitoring same as regular anti-coagulation
More anti-Xa monitoring with tinzaparin

Doses usually increase throughout pregnancy

139
Q

What are the dosing protocols of anti-coag in pregnancy and post-partum?

A

Prophylactic dosing (low, fixed)

Intermediate dosing (adjust upwards based on weight)

Therapeutic dosing (full dose, weight adjusted)

Which dosing to use depends on clot risk

140
Q

Dosing of Tinzaprin in Prehanncy/Post-partum according to dosing protocols?

A
141
Q

Describe the process of pharmacotx in preganncy and post-partum?

A

Start on Tinzaparin (LMWH)

At 36-37 weeks gestation, switch to UFH

4-6 hours after delivery, should begin anti-coagulation

Usual LMWH –> warfarin bridging protocol

Anti-coagulate for at least 6 weeks post-partum
–> If had a VTE during pregnancy, 3-6 months
–> If on-going issues (eg. Afib), possibly indefinite

142
Q

What are the complications of anti-coag pharmacotx in pregnancy and post-partum?

A

Bleeds

HIT
–> Lower incidence in pregnancy
–> Platelets decrease in pregnancy

Bone loss
Counsel to use calcium / vitamin D for sure, weight bearing exercise

143
Q

What is the relationship between cancer-related thrombosis and bleeding?

A

Malignancy and cancer –> More likely to bleed and more likely to clot

Varies from types of cancer and treatment given

144
Q

What are bleeding risks associated with cancer related thrombosis?

A

Increased bleeding risk due to:

Cancer/chemotherapy-associated thrombocytopenia

Disseminated intravascular coagulation

Direct invasion of cancer

Increased fibrinolytic factors

Radiation-induced tissue damage

145
Q

What is the pharmacotx for cancer associated thrombosis?

A

LMWH is the drug of choice historically
Evidence for DOAC usage
DOAC not recommended in GI/GU malignancy

146
Q

What are some considerations for treatment of cancer associated thrombosis?

A

Drug interactions with chemotherapy
Renal impairment
Thrombocytopenia
Dosing in underweight cancer patients
ICH risk in brain cancers

PHAR 253 Final (8 decks)

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