Anticoagulants Flashcards
What are the different classes of anticoagulants?
- Vitamin K antagonists
- DOACs / NOACs
What are examples of NVKA?
Warfarin
What are examples of DOACs?
- Edoxaban
- Rivaroxaban
- Dabigatran
- Apixaban
What 2 processes are involved in the clotting cascade?
- Platlet activation
- Coagulation Cascade
How does platlet activation contribute to clot formation?
Upon endothelial damage platelets become activated and begin to stick together, forming a mechanical plug.
How does the coagulation cascade contribute to clot formation?
The coagulation cascade is also activated in response to injury. The coagulation cascade refers to a range of coagulation proteins in the plasma that become activated and form an signalling pathway which causes soluble fibrinogen to transform into insoluble fibrin. This forms a mesh of insoluble proteins – this acts as scaffolding which holds the newly formed clot structure together.
What is virchow Triad?
A combination of major risk factors for clotting.
- Stasis
- Vessel wall injury
- Hypercoagulability
In terms of the virchow Triad, describe how **STASIS **relates to increased risk of clot formation
Blood is in near constant motion. If blood pools or enters ‘stasis’ then clotting will occur e.g. in AF or periods of immobilisation (hospital stay).
In terms of the virchow Triad, describe how **Vessel wall injury **relates to increased risk of clot formation
Trauma to the blood vessels release signalling molecules activating the platelet and clotting cascade.
In terms of the virchow Triad, describe how **Hypercoagulability **relates to increased risk of clot formation
Also known as thrombophilia or prothrombotic state. This involves abnormal changes in blood itself making it more prone to clotting. These mechanisms include genetic and environmental factors.
What are signs and symptoms of DVTs
What Scoring chart can be used to help diagnosis DVT and what do values mean?
Signs and symptoms of DVT are as follows:
- Leg pain & tenderness
- Leg swelling
- Warmth around area
- Redness
- Tachycardia
These symptoms are non-specific so the Wells score can be used to diagnosis DVT. A score >2 are likely and will have an ultra sound. Those <2 are unlikely and will have a blood test (d-dimer).
Signs and symptoms of PE
Signs and symptoms of PE are as follows:
- New or worsening SOB
- Fast RR
- Chest pain
- Tachycardia
- Coughing up blood
The PE well score can be used to help aid diagnosis.
Signs and Symptoms of AF
Signs and symptoms of AF:
* Palpations
* Fatigue
* Lightheaded or fainting
* Chest pain
* SOB
What is ACS?
Signs and Symptoms?
ACS is when a clot has formed within the coronary vasculature, restricting the flow of oxygenated blood to the heart. It encompasses unstable angina, STEMI and NSTEMI.
Signs and symptoms include:
- Central chest pain
- Chest tightness – like a band across chest
- Radiates to jaw and shoulder
- Sweating
- Tachycardia
- Weak / light-headed
- Coughing up blood
- Overwhelmed / panicked
The following drugs belong to which class:
* AC
* AP
* Fibrinolytics
What type of thrombosis are anticoagulants used for?
Where do they generically act?
Treatment and prevention of venous thrombosis embolisms
Inhibit coagulation cascade
What type of thrombosis are antiplatlets used for?
Where do they generically act?
Used for treatment and prevention of arterial thrombosis embolisms e.g. MI or stroke
Inhibit platelet activation
What are fibrinolytic agent used for?
How do they work?
What is the mechanism of action of DOACs?
What is the advantage of this mechanism?
DOACs inhibit parameters in the coagulation cascade.
Apixaban, edoxaban and rivaroxaban all inhibit factor Xa involved in the conversion of prothrombin to thrombin. Dabigatran is a thrombin inhibitor.
These are more selective and therefore have more predictable effects.
Additionally, there is reduced bleeding risk compared to warfarin.
What is the mechanism of action of VKAs
VKAs target multiple points in the coagulation cascade – particularly II, VII, IX and X. This inhibits the critical output of the cascade, which is the transformation of fibrinogen to fibrin.
What monitoring is required with warfarin?
VKAs have inter-individual and intra-individual variability. Titration of the dose of warfarin is required to achieve the desired therapeutic effect and different patients require a range of doses to achieve the shared target.
Regular monitoring is required – INR is used. This is a measurement of how long it takes for blood to clot.
What does an INR of 2 mean
For example, if your INR is 2, this means it takes twice as long for blood to clot as someone who doesn’t take warfarin.
What does a high and low INR mean?
High - high risk of bleeding
Low - High risk of clot
What agents are typically used for VTE prophylaxis?
When else may this drug be used?
LMWHs e.g. enoxaparin
Treatment with parenteral agents also included initial acute management of ACS and VTE.
What are risk factors for bleeding and risk factors for clots to be considered when deciding on whether to give VTE prophylaxis?
For VTE prophylaxis, patients are normally initated on parenteral LMWHs and then switched to oral AC. In which patients would you continue LMWH?
Patients with active cancer or for pregnancy prophylaxis may continue on these agent
When are parenteral AC used?
What are examples of parenteral AC?
- Treatment with parenteral agents also included initial acute management of ACS and VTE.
- VTE Prophylaxis
- Fondaprinux
- LMWH
- Heparin
How does Fondaparinux work?
What is it used for?
- Fondaparinux is a direct factor Xa inhibitor.
- Used in prevention of VTE, treatment of VTE, treatment of superficial thrombophlebitis and treatment of ACS.
What is the mechanism of action of LMWHs?
Examples of LMWHs?
- More predictable pharmacokinetics compared to heparin
- Includes: enoxaparin, tinzaparin and dalteparin
- Antithrombin inhibitor
What is the mechanism of action of heparin?
- Enhances action of antithrombin II – this goes on to inhibit multiple parts of the coagulation cascade
- Often referred to as unfractionated heparin
Which class of parenteral AC is not animal dervived?
Fdaparinux is synthetically produced compared to LMWH and UF Heparin which are animal derived.
Where might AC be used?
Anticoagulants may be used in the following circumstances:
* AF
* VTE
* ACS
* Mechanical heart valve
When should AC be offered in AF?
CHADVAS:
Anticoagulants should be offered to all patients with a score >1. Those with a score = 1 coagulation should be considered. Note: a score of 1 for females should not be offered.
What are the CHA2DS2VASc factors?
- C - Congestive Heart Failure
- H - Hypertension
- A - Age
- D - Diabetes
- S2 - Stroke
- V - Vascular disease
Congestive HF:
* Heart failure with reduced ejection fraction
* Recent decompensated HF requiring hospitalisation irrespective of ejection fraction
Hypetension
* Resting BP >140 systolic or >90 diastolic
* On 2 current antihypertensive treatment
Age
* 65 – 74 years = 1
* 75 and older = 2
Diabetes
* Fasting plasma glucose >7mmol/L
* Oral hypoglycaemic drug or insulin
Vascular disease
* Prior MI, peripheral arterial disease or aortic plaque
What does warfarin/DOACs and aspirin reduce the risk of stroke by in AF?
When should aspirin be used in AF?
Warfarin reduces stroke risk by 65% and DOACs similar.
Antiplatelets only reduce risk by around 20% and should not be used unless anticoagulants have been declined.
What are HASBLED factors?
Anticoagulation carry risk of bleeding.
H Hypertension
A Abnormal renal/hepatic function
S Stroke history
B Bleeding
L Liable INRs
E Elderly
D Drugs/alcohol
Hypertension
* Uncontrolled hypertension with systolic >160mmHg
Abnormal renal/hepatic function
Renal:
* Routine dialysis
* Renal transplantation
* Creatine >200
Liver:
* Chronic hepatic disease e.g. cirrhosis
* Bilirubin >2x ULN and Transaminases >3x ULN
Stoke History
* Ischaemic stroke or TIA
Bleeding
* Prior major bleeding or pre-disposition to bleeding
Age
* Age >65
Drugs and Alcohol
* Antiplatelets & NSAIDS
* Alcohol out with recommended limits
What is the treatment of VTE?
Patient with suspected with VTE are often stated on a LMWH then switched to oral anticoagulant once diagnosis confirmed e.g. DOAC or warfarin.
How long does VTE treatment typically last?
3-6 months
Describe switching between LMWH and anticoagulation for VTE treatment
What are commonly used agents in ACS
An ACS is thought to be a thrombotic progression of atherosclerosis, antiplatelet and anticoagulation therapies target the process underlying the condition.
Fondaparinux and enoxaparin are commonly used agents.
What AC should be used in patients with mechanical heart valves.
What should NOT be used and why?
Patients with mechanical heart valves should be given VKAs. They should NOT be given DOACs – increased bleeding and thromboembolic event.
What is target INR for patients with mechanical heart valves?
What should be used if patients INR is low with mechanical heart valve?
Interruptions to anticoagulation should be avoided. If patients are found to have a lower INR then ‘bridging’ anticoagulation with heparin should be considered until the INR is within range.
How would valvular AF affect choice of AC?
DOACs are licenced for ‘non-valvular AF’. This refers to AF in the absence of mechanical prosthetic heart valve or moderate to severe mitral stenosis.
Warfarin would be more appropriate.
What is anti-phsopholipid syndrome and how would it affect choice of AC?
APS is an autoimmune condition. This means the immune system, which usually protects the body from infection and illness, attacks healthy tissue by mistake. In APS, the immune system produces abnormal antibodies called antiphospholipid antibodies. These target proteins attached to fat molecules (phospholipids), which makes the blood more likely to clot.
DOACs are not recommended due to increased risk of recurrent thrombotic events. Instead VKA should be used.
How would weight affect AC choice?
DOACs should not be used in patients with a BMI >40 or a weight >120kg. There is limited data and concerns of underdosing at extremes of weight.
How would renal impairment affect choice of AC?
DOACs are renally cleared to various extents.
Check licencing of DOACs in renal impairment and necessity for dose reductions. No DOAC is licenced if CrCl <15mL/min and therefore warfarin should be considered.
If CrCl is >95mL/min then edoxaban is cautioned – it may be cleared too quickly reducing the efficacy
Warfarin Vs DOAC
What are the monitoring requirements with warfarin
INR Monitoring:
- **Daily or alternate days **until it is within therapeutic range on 2 consecutive occasions (ideally 2.5 target). A meaningful INR can only be obtained 3-4 days after starting treatment.
- Then,** twice weekly for 1-2 weeks**, followed by weekly measurements until at least two INRs within therapeutic range
- Then longer intervals (e.g. monthly) up to 12 weeks
What are monitoring requirements with heparins?
Unfractionated Heparin
Requires very frequent monitoring (1-6 hourly) of activated partial thromboplastin time ratio (aPTTR) to ensure therapeutic anticoagulation is achieved. The dose of heparin can be adjusted to ensure a the aPTTR sits within the therapeutic window (generally 1.5 – 3.5). Patients require a continuous infusion of UF heparin to achieve this.
LMWH
Do not require aPTTR monitoring as therapeutic effect more predictable
Both
* Heparins can cause heparin induced thrombocytopenia and heparin induced hypoaldosteronism (dangerous raised K+). Therefore, platelet and potassium should be monitored.
* Monitor platelets before treatment and if given longer than 4 days.
* Monitor K+ before treatment and regularly thereafter, especially if treatment longer than 7 days.
Monitoring requirements with fondaparinux
Fondaparinux does not require regular monitoring
Which AP should be avoided in combination with all AC?
Ticagrelor
What are the monitoring requirements for DOACs
Start of treatment:
- Renal function Tests
- LFT
- FBC
- Baseline clotting screen
**
Once treatment has started:** - Renal function tests, LFTs and FBC yearly (6 monthly if >75 years or if CrCl <30mL/min then divide by 10 to determine month interval)
- Review patient after 1 month and then at least 3 monthly there after (may be 6 monthly or less depending on patient)
Throughout Check:
- Weight
- Health status
- Concomitant medicines
What are target INR for warfarin:
1. Normally
2. Mechanical heart valve
- 2-3
- 3-4
What are contraindications with DOACs?
General Contraindications:
- CrCl <15 mL/min
- Active or recent GI bleed
- Antiphospholipid syndrome – increased risk of thrombotic events
- Prosthetic heart valve and moderate-severe mitral stenosis
- Uncontrolled severe hypertension
- Liver disease associated with coagulopathy and clinically relevant bleeding risk
- Use with any other anticoagulant (except when switching/UFH)
Significant risk of major bleeding:
Avoid in conditions with significant risk factors for major bleeding, including current or recent gastrointestinal ulceration, malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
What are cautions to DOACs
- Risk of bleeding
- Surgery
What are side-effects of DOACs
Abdominal pain; anaemia; GI disorders; dizziness; haemorrhage; headache; nausea; skin reactions; abnormal liver function tests
What are interactions with DOACs
- NSAIDs – Increased bleeding risk
- Anticoagulants / Antiplatelets – Increased bleeding risk
- SSRIs / SNRIs – Bleeding risk
- Strong P-Glycoprotein inducers e.g. Carbamazepine, Phenytoin, Rifampicin, St John’s Wort – plasma concentration of DOAC may be reduced
- Strong inhibitors of P-gp e.g. itraconazole, ketoconazole, erythromycin, ciclosporin, dronedarone - Plasma concentration of DOAC increased
- Mild to moderate P-gp inhibitors such as amiodarone, verapamil and quinidine - Dabigatran ONLY – plasma concentrations increased of dabigatran. If concurrent use of verapamil reduce dose of AC to 110mg BD
What is the maximum dose of edoxaban with strong P-gp inhibitors like ketoconazole, itraconazole, erythromycin, ciclosporin and dronedarone?
30mg OD
What is the maximum dose of dabigatran with verapamil?
110mg BD
What should you do if you miss a dose of a DOAC?
In ensesnse, take it up to half time of dosing intervals
Edoxaban:
* * Can take up until 12 hours after when dose due. After this wait until next dose due
Apixaban
* * Can be taken up until 6 hours after scheduled intake (this interval may be extended in those with a high stroke risk and low bleeding risk)
Rivaroxaban
* * For BD regimens forgotten dose can be taken up to 6 hours after schedules
* Exception:- if dose is missed during 15mg BD treatment for VTE then 2 tablets can be taken at once to ensure 30mg/day
- For OD regimens forgotten dose can be taken up until 12 hours after scheduled intake
**
Dabigatran **
* * For BD regimens forgotten dose can be taken up to 6 hours after schedules intake
* * For OD regimens forgotten doses can be taken up to 12 hours after scheduled intake
*
What do you do for DOACs if double dose taken?
Edoxaban:
* Take the next dose as normal the following day
Apixaban
* Omit next planned dose (one in 12 hours) then resume treatment as normal
Rivaroxaban
* For BD regimen, omit next planned dose (one in 12 hours) then resume treatment as normal
* For OD regimen, take as normal the following day
Dabigatran
* For BD regimen, omit next planned dose (one in 12 hours) then resume treatment as normal
* For OD regimen, take as normal the following day
What do you do for DOACs if you are unsure whether a dose has been taken?
Edoxaban
* if CHADSVASc >3 take another dose.
For Rivaroxaban, dabigatran and apixaban:
* For BD regimen it is not advisable to take another dose. Take normal dose 12 hours later.
* For OD regimen if CHADSVASc >3 take another dose
Fill in the dosing table for these DOACs:
- VTE prophylaxis (hip/knee replacement)
- VTE treatment
- Stroke prophylaxis in AF
Dosing of Warfarin
Initially 5–10 mg, to be taken on day 1; subsequent doses dependent on the prothrombin time, reported as INR (international normalised ratio), a lower induction dose can be given over 3–4 weeks in patients who do not require rapid anticoagulation, elderly patients to be given a lower induction dose; maintenance 3–9 mg daily, to be taken at the same time each day.
Warfarin contraindications
- Haemorrhagic stroke
- Clinically significant bleeding
- Severe hepatic impairment
- Within 72 hours of major surgery
- Within 48 hours postpartum
- In pregnant women – due to the risk teratogenicity
- In people taking drugs where interactions lead to significantly increased risk of bleeding
Warfarin cautions
- Elderly
- Increased bleeding risk
- History of GI bleeding
- Recent ischaemic stoke
- Uncontrolled hypertension
- Concurrent use of meds which increase bleed risk
- Recent surgery
- Postpartum
- Thyroid disorders (warfarin metabolism depends on thyroid status)
- Mild-moderate renal or hepatic impairment
- Thrombophilia
What can affect the dose of warfarin?
Polymorphisms in CYP2CP or VKORC1 can impact warfarin metabolism.
Dose reduction may be needed:
* Weight-loss
* Acute illness
* Smoking cessation
Dose increase may be needed:
* Weight gain
* Diarrhoea
* Vomitting
Side-effects of warfarin
- Common – haemorrhage
- Rare – alopecia, nausea, vomiting
- Severe (rare) – calciphylaxis, Skin necrosis
Interactions with warfarin
Advice for those on warfarin
- Importance of compliance
- Carry alert card
- Advise taking AC when buying OTC/dentist/doctor
- Regular monitoring
- Yellow book
Red-flag symptoms:
* Spontaneous bleeding, not stopping or recurring e.g. bruising, bleeding gums, nose bleeds, prolonged bleeding, blood in urine, stools or sputum
* Sudden back pain
* Difficulty breathing, chest pain or increased RR
antidote
Vitamin K1 (phytomadione)
What do you do if you miss a warfarin dose?
- Missed doses can be taken up until midnight. Never take a double dose.
What do you do if you take a double dose of warfarin?
- Contact Warfarin clinic/GP to have blood tested
How do you switch from Warfarin to a DOAC
Stop warfarin, and measure the international normalized ratio (INR):
* If the INR is less than 2, start edoxaban.
* If the INR is between 2 and 2.5, start edoxaban the next day.
* If the INR is greater than 2.5, wait until the person’s INR has dropped to less than 2 before starting edoxaban.
How do you switch from DOAC to warfarin?
- Start Warfarin and reduce dose of edoxaban by half
- Continue warfarin and edoxaban until INR in target range then stop edoxaban (stop edoxaban after 14 days if not reached)
- Monitor INR regularly and after stopping edoxaban
How do you switch from one DOAC to another
- Stop DOAC then start other DOAC when next dose due
What DOACs have reversal agents?
Reversal agents available for Dabigatran, apixaban and rivaroxaban. Not for edoxaban.
What DOACs are subject to additional monitoring?
Rivaroxaban (Xarelto) and Edoxaban (lixiana) are subject to additional monitoring so any adverse effect should be reported
Renal impairment and warfarin
- Use with caution in mild to moderate impairment
- In severe renal impairment monitor INR more frequently
hepatic impairment and warfarin
In general, manufacturers advise caution in mild to moderate impairment; avoid in severe impairment.
DOACs and hepatic impairment
Manufacturer advises caution in mild to moderate impairment, or if liver transaminases greater than 2 times the upper limit of normal, or total bilirubin 1.5 times the upper limit of normal or greater; avoid in severe impairment or hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
What is the dose of enoxaparin for VTE treatment?
In cancer?
1.5mg/kg 12 hourly
1mg/kg 12 hourly (cancer patients)
What is the dose of enoxaparin for prophylaxis of VTE?
40mg OD
40mg BD (>100kg)
20mg OD (<50kg or CrCl <30mL/min)
