Venous Thromboembolism Flashcards
Why is it important for pharmacists to understand VTE?
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
Describe venous circulation
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
What is a VTE? Where does it form commonly? Exception?
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.
What is the difference between a venous and arterial thrombus?
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)
What is a DVT and PE? What is the rates of the total VTE?
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
Cause of VTE (simple)
Results from clot formation within venous circulation
Where does VTE usually develop?
Mainly develops in lower extremities
Majority in calf veins
Minority in arm, brain, GI tract, liver (rare often malignanacy or other cause)
One a venous clot has formed, the clot may then…..
Lyse
Obstruct venous circulation
Embolize
Combination
What is the central portion of the coagulation cascade?
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
Describe the coagulation cascade and where the drugs work?
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
What is virchows triad?
What are some risk factor categories for VTE?
Circulatory Stasis
Vascular Damage
Hypercoagulability
Preganancy/Post-partum
Medications
Birth Control
The risk factor of circulatory stasis examples include:
Bed rest/immobility (prolonged)
–> Hospitalization
Heart failure (Class III-IV)
Varicose veins (controversy)
Atrial fibrillation
The risk factor of vascular damage examples include:
Previous VTE
Bacterial infection (sepsis)
Prosthetic implants
Peripheral vascular disease
Trauma
Surgery – watch those hips and knee’s
The risk factor of hypercoagulability examples include:
Medications (chemotx)
Use of oral contraceptives
Malignancy
Inherited thrombophilias
Advanced age >60 (>75)
Obesity – BMI >30? (>50)
Protein C or S deficiency
Smoking
The risk factor of pregnancy stats:
5-10x increase during pregnancy
15-35x risk during the early postpartum (6-12 weeks)
What medications are risk fcators for VTE?
Estrogen
SERMS (Tamoxifen/raloxifen)
Chemotherapy
Older antipsychotics
Erythropoietin
When should birth control be stopped in VTE?
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.
VTE often presents as….
ASYMPTOMATIC
What are some difficulties associated with VTE (simple)?
Symptoms are often non-specific
–> Diagnosis is difficult
–> Requires assessment of risk factors and lab / imaging tests
What are some sx of DVT?
Leg pain
Tenderness
Ankle edema
Calf swelling
Dilated veins
Dusky discolouration
Let Tony Ask Can Daddy D***
What are some symptoms of a PE?
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
What are some complications of a VTE?
Recurrence rates are high
Post-thrombotic syndrome
Venous ulcers
Chronic thromboembolic pulmonary hypertension (CTEPH)
What is the tx of post-thrombotic syndrome (PTS)?
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
What is the result of venous skin ulcers complications?
Results from venous insufficiency, leading to pooling of blood
Major cause of chronic wounds
Lack of proper blood flow
What is the effect of the complication of chronic thromboembolic pulmonary htn? TX?
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
How is VTE diagnosed?
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 –
How is DVT diagnosed?
How is a pulmonary embolism diagnosed?
What are the goals of therapy for VTE?
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
What lab tests are used to monitor anticoag?
Prothrombin time (PT)
Partial thromboplastin time (PTT)
Activated partial thromboplastin time (aPTT)
Anti-Xa activity
International normalized ratio (INR)
What does PT measure?What factors?
PT measures the extrinsic and common pathway of coagulation (factor X,V, VII, II) – tests heparin (not commonly used, use aPTT)
tests Warfarin
What does aPTT measure?
aPTT measures the intrinsic and common pathways of coagulation.
Highertime - Longer time to clot – tests heparin. NOT for LMWH.
WHat is the difference between aPTT and PTT?
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
What does INR measure?
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
What are some challenges of preventing and treating VTE’s?
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
What are the pharmacotherapy options available for VTE?
Heparin (UFH)
Low molecular weight heparin (LMWH)
Heparinoids (danaparoid)
Glycosaminoglycan heparinoid (fondaparinux)
Direct thrombin inhibitor (argatroban)
Vitamin K antagonist (warfarin)
Direct oral anticoagulants (DOACs)
What is the MOA of Heparin (UFH)?
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
Onset of effect for IV and Subcut Heparin (UFH)?
IV: Begins working immediately
Subcut: 30-60m
UFH Duration of Effect
T1/2 = 1-2 hours
IV: continuous infusion to ensure level response
Subcut: 8 hours
What is unique about UFH’s PK?
Short Half-Life –> Easy to stop the medication, can stop the infusion
–> person in car accident
What are some C.I. of UFH? Are any absolute C.I.?
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.)
How is UFH administered and dosed?
IV or Subcut only
Initial doses calculated using body weight
Dose depends on if prophylaxis, treatment, IV vs. Subcut.
UFH Doses: Prophylaxis and Treatment of DVT/PE. How long for?
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
What is a caution of using UFH?
Narrow therapeutic window!
Variable response to the recommended doses
How long is UFH used for tx of VTE?
Usually, heparin will just be used for <7 days
Simultaneously given with warfarin
Discontinued once warfarin reaches target INR for 1-2 days
UFH Common A/E
Minor bleeds
Injection site reactions if Subcut
Transient, mild liver enzyme increase
What are some serious a/e of UFH?
Heparin induced thrombocytopenia (HIT)
Major bleeds
Hyperkalemia
Skin necrosis
BMD decrease
(Usually not concern as using for less than 7 days)
What is the antidote for UFH induced major bleed?
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
What are some adverse effects of protamine sulfate?
Allergic reactions, including anaphylaxis (0.6-10.6%)
What is heparin induced thrombocytopenia (HIT)? When does it occur?
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
What is the treatment of HIT?
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)
Describe the platelets and antibodies changes after HIT
Platelets return to normal in 4-10 days.
Rise within 2-3 days of cessation.
Antibodies can take ~100 days to disappear
What are some drug interactions of 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
What is the monitoring of UFH effectiveness?
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)
What is the monitoring of UFH safety?
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
What are the LMWH’s?
- Enoxaparin
- Dalteparin
- Tinzaparin
- Nadroparin
Are the LMWH’s interchangable?
All appear equal clinically in safety and efficacy
- NOT interchangeable
- Different dosing regimens
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)
Which LMWH’s cane be used for dialysis line patenyc?
Dalteparin and Tinzaparin
Which LMWH’s can be used for Angina/NSTEMI? STEMI?
Angina/NSTEMI - Dalteparin, enoxaparin
STEMI –> ONLY EnOXAPARIN
LMWH MOA
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)
Compare the pharmacokinetics of UFH and LMWH
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.
What is the SHA’s choice of LMWH?
SHA uses tinzaparin for the prophylaxis and treatment of VTE
As well as maintaining dialysis line patency
Enoxaparin is only used in acute ACS
What are the contraindications of LMWH?
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.)
What does the dosing of LMWH depend on?
Depends on:
Prophylaxis vs. treatment
Agent used
Renal function
Obesity
Indication
Subcut administration
Dosing of Tinzaparin VTE tx, prophylaxis and dialysis line patency
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
What is the CrCl recommendations for prophylaxis and treatment? Is there renal dose adjustments?
Tinzaparin
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
Obesity dosing of LMWH
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
Describe the use of LMWH in Pregnancy
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
Onset of effect LMWH
Starts in one hour
Peak anti-coagulation response in 3-5 hours
Duration of effect of LMWH
Anti-Xa activity persists for 12-24 hours with a subcut dose
Half-life is only 3-6 hours
Come adverse effects of LMWH
(Same as UFH, but much lower incidence)
Minor bleeds
Injection site reactions if Subcut
Transient, mild liver enzyme increase
Serious adverse effects of LMWH
Same as UFH
Heparin induced thrombocytopenia (HIT)
Major bleeds
Hyperkalemia
Skin necrosis
BMD decrease
- Same as UFH, but…
Risk of HIT is dramatically lower
LMWH Drug Interactions
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
How can the efficacy of LMWH be monitored?
Cannot use aPTT
Monitoring anti-Xa levels not indicated, unless:
–> Obese
–> Pregnant
–> Renal insufficiency
Measure anti-Xa 4 hours post-dose
When is monitoring of anti-xa levels indicated for LMWH?When should it be monitored?
Monitoring anti-Xa levels not indicated, unless:
Obese
Pregnant
Renal insufficiency
—> Measure anti-Xa 4 hours post-dose
How can the safety of LMWH be monitored?
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
Compare UFH and LMWH (Onset, Duration of Anticoag, Dosing regimen, Dose adjustments, saftey issues)
Comapre UFH and LMWH in C.I., Efficacy and Monitoring
What are the miscellaneous pharmacotx that can be used for VTE? MOA?
Heparinoids –Danaparoid
Glycosaminoglycan– fondaparinux
Direct thrombin inhibitor - Argatroban
Inhibits factor Xa (fondaparinux, danaparoid) or directly inhibits thrombin (argatroban)
Indications of Danparoid, fondaprinux, and argatroban
Danaparoid: Prevention of DVT after surgery, or use in HIT
Fondaparinux: Same as LMWH, plus use in HIT
Argatroban: Anticoagulation in patients with HIT
Compare fondaparinux, danaparoid, and argatroban to LMWH
Warfarin MOA
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
Warfarin onset of effect? Exception?
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
Warfarin C.I.
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
Does Warfarin require dose adjustments in renal or hepatic dysfx?
No adjustments in renal/liver
How can warfarin be initiated? For which pt’s?
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
Describe a high and low INR
HIGH INR –> TOO GOOD –> BLEED EASIER (coughing up blood, bleeding form eyes)
LOW INR –> Clot again, VTE and PE sx or asymptomatic
How can a pharmacist deal with a sub-therapeutic or supra-therapeutic INR?
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
INR Values
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.
What are some considerations for the interpretation of a patient’s INR?
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
When should bridging onto to warfarin therapy occur?
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
Why is bridging onto warfarin required? How should it be done?
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
What is the main consideration when bridging someone off of Warfarin? How is this done?
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
What are some common side-effects of Warfarin?
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
What are some serious side-effects of Warfarin?
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%)
Warfarin Drug Interactions
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
What antibiotics interact with warfarin?
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
How can the drug interactions of warfarin be managed?
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
How should the safety and efficacy of Warfarin be monitored?
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
What is a clinical tip for Warfarin tx?
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”
What is the anti-dote for warfarin?
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
What are the available DOAC’s?
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
What is the MOA of the DOAC’s?
Rivaroxaban / Apixaban / Edoxaban:
Inhibits factor Xa
Dabigatran:
Directly inhibits thrombin
Onset of Effect DOAC’s
All achieve peak anti-coagulation in about 2 hours
Duration of effect DOAC’s
Rivaroxaban: t ½ 9h
Apixaban: t ½ of 8-14h
Dabigatran: t ½ 13h, up to 18h renal impairment
Edoxaban: t ½ 14h
Renal Impairment –> DOAC’s
CANNOT RENAL ADJUST –> IF CRCL BELOW< CANNOT USE
What is the risk of bleeding with DOAC’s?
High risk for all as no antidote
Can DOAC’s be used in preganncy?
No –> Not well studied and crosses placenta
In hepatic disease, which DOAC’s are acceptable?
Apixaban, Edoxaban, and Rivaroxaban –>NO
Dabigatran –> Caution
DOAC’s and dialysis
Dialysis does remove apixaban and dabigatran
Rivaroxaban C.I. Drug Interactions
Rivaroxaban: only CI with drugs if BOTH p-gp and 3A4. Just p-gp ok. 3A4 is cautioned. Not removed by dialysis
Describe the general drug interactions of DOAC’s
Drug Interactions of DOAC’s –> Specific Drugs
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
What is unique about dabigatran and edoxaban ?
Dabigatran / edoxaban unaffected by the CYP drug interactions
Dabigatran affected anything that raises pH
Dosing of DOAC’s –> Prevention after TKR/THR, Treatment and Prevention of Recurrent VTE
What is unique about the dosing of Dabi and Edox?
Dabi and Edox need a bridge
Edoxaban has simplest dosing
Convenience of Dosing DOAC’s
Convenience: Apix/dabi = BID; Riva/edox = OD
Rivaroxaban IMPORTANT Counselling
Any dose >10 mg –> TAKE WITH FOOD
AUC increased 40% with 20mg.
DOAC Dosing Adjustments
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)
DOAC Common Side-effects
Minor bleeding….
GI upset and dyspepsia ~ same as warfarin (Dabigatran more)
Diarrhea or constipation
Itch (not immune mediated)
What is unique about dabigatran in common side effects?
Dabigatran causes more G.I. upset and dyspepsia
What are the serious risks associated with DOAC’s?
Bleeding; but mostly better or same as warfarin
What is the benefit and risks associated with thrombolytics?
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
What are the thrombolytics available?
Alteplase and Tenecteplase
What is the indication for thrombolytics in VTE?
Only VTE indication:
High risk (Massive) pulmonary embolism
Duration of Treatment for VTE
Switching Warfarin to a DOAC
Warfarin to DOAC
To rivaroxaban: Stop warfarin, wait until INR is <2.5
To dabigatran / apixaban / edoxaban: Stop warfarin, wait until INR <2.0
Switching from DOAC to Warfarin
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
What are the recommendations for VTE prophylaxis in hospital?
Every person in hospital gets VTE prophylaxis unless:
What are some available mechanical VTE prophylaxis?
Graduated compression stockings
Intermittent pneumatic compression device
What is the VTE risk associated with air-travel?
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
Pharmacological tx for air travel
Pharmacologic prophylaxis NOT needed
Highest risk individuals may receive LMWH
Other antiplatelets or anticoagulants have no proven value in this scenario
Which pharmacotx agents are not to be used in pregnancy and post-partum?
A subset of patients will need anti-coagulation to reduce risk
Warfarin is teratogenic and cannot be used
NOACs have not been studied
What conditions require anti-coag tx in preganncy and post-partum?
What are the therapeutic agents used in pregnancy and post-partum?
UFH
LMWH –> DRUG OF CHOICE
Danaparoid / Fondaparinux
Multi-dose heparin preparations have benzyl alcohol as a preservative; must select preservative free options
What is the recommendation of intitiating tx, monitoring and dosing in pregnancy and post partum?
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
What are the dosing protocols of anti-coag in pregnancy and post-partum?
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
Dosing of Tinzaprin in Prehanncy/Post-partum according to dosing protocols?
Describe the process of pharmacotx in preganncy and post-partum?
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
What are the complications of anti-coag pharmacotx in pregnancy and post-partum?
Bleeds
HIT
–> Lower incidence in pregnancy
–> Platelets decrease in pregnancy
Bone loss
Counsel to use calcium / vitamin D for sure, weight bearing exercise
What is the relationship between cancer-related thrombosis and bleeding?
Malignancy and cancer –> More likely to bleed and more likely to clot
Varies from types of cancer and treatment given
What are bleeding risks associated with cancer related thrombosis?
Increased bleeding risk due to:
Cancer/chemotherapy-associated thrombocytopenia
Disseminated intravascular coagulation
Direct invasion of cancer
Increased fibrinolytic factors
Radiation-induced tissue damage
What is the pharmacotx for cancer associated thrombosis?
LMWH is the drug of choice historically
Evidence for DOAC usage
DOAC not recommended in GI/GU malignancy
What are some considerations for treatment of cancer associated thrombosis?
Drug interactions with chemotherapy
Renal impairment
Thrombocytopenia
Dosing in underweight cancer patients
ICH risk in brain cancers
