Warfarin is the most used anticoagulant in the UK, with a history going back to the 1950s when it was approved for human use in 1954. Over 60 years later and the popularity of warfarin is indisputable. Two factors contributing to the wide use of warfarin are the effectiveness and low cost of the drug. However, as you are about to learn from this post, the prescribing of warfarin is in decline in place of warfarin alternative drugs, a new group of novel anticoagulant drugs known as Non-Vitamin K antagonist oral anticoagulants (NOAC). I this post will review:
- warfarin mechanism of action and indicated use,
- discuss the advantages and disadvantages of treatment
- warfarin alternative drugs:
- the prescribing trend in the UK for anticoagulants
- indicated use for each NOAC
- common side effect associated with warfarin alternative drugs
- effectiveness of NOACs as compared to warfarin
What are anticoagulants used for?
Anticoagulants are the drugs which prevent the formation of blood clots in the body. Formation of a blood clot can lead to serious health emergencies such as stroke and heart attack. Anticoagulants can be used in treatment and/or prevention of clot formation in the following conditions:
- Venous thromboembolism (VTE):
- deep vein thrombosis (DVT): formation of a blood clot in the vein located in the leg
- pulmonary embolism: blood clot travels in the blood and blocks to blood vessels located in the lungs
- Atrial fibrillation (irregular heartbeat): Patients with atrial fibrillation are at risk of having a stroke as the consequence of clot formation.
- Patients who had transient ischaemic attacks “mini-stroke.”
What is Warfarin?
Warfarin: treatment indications
Warfarin is an anticoagulant drug which prevents the formation of clots from the blood. Commonly known as a blood thinner, warfarin is used in:
- Treatment and prevention of deep vein thrombosis (DVT)
- Treatment and prevention of pulmonary embolism
- Prevention of clot formation in patients with atrial fibrillation.
- Prevention of clot formation in patients with prosthetic heart valve
- Patients who had transient ischaemic attacks (“mini-stroke”)
Warfarin: mechanism of action
Warfarin stops the production of Vitamin K, which is needed for the production of a blood clot.
Warfarin is taken daily, at the same time of the day, according to the dose set by blood tests (coagulation tests), which tells how much time it takes for blood to clot. This parameter is known as the International Normalised Ratio (INR). Each patient has an INR target, usually set at 2.5 with an acceptable range between 2-3; however, the INR target can differ, depending on the indicated use. It is very common for INR to change. If this happens, patients need to adjust their dose by increasing or decreasing the number of tablets they take. Warfarin comes in three different tablet strengths:
- Warfarin 0.5mg
- Warfarin 1mg
- Warfarin 3mg
Advantages of warfarin treatment
- a long history of use
- in an emergency, actions of warfarin can be reversed for example with Vitamin K
Disadvantages of warfarin treatment
- Takes a few days to work (slow onset of action)
- Frequent monitoring (blood test to check INR) and dose adjustments needed
- Narrow therapeutic window: small changes in the drug concentration (how much drug is in the body) for example due to interaction with another drug or major dietary changes can cause significant side effects (thrombosis: clotting of the blood if INR below 2 or risk of bleeding if INR above 3)
- Interacts with many drugs
- Dietary restrictions and interaction with food containing Vitamin K
Warfarin alternatives: Non-Vitamin K antagonist oral anticoagulants (NOAC)
Novel anticoagulants, Non-Vitamin K Antagonist Oral Anticoagulants (NOAC), work in a different way to warfarin. In simple terms, this group of warfarin alternative drugs stops the production of chemicals (enzymes) which are needed in production of fibrin, a compound (protein) which play role in the clotting of the blood. Currently four NOACs are licensed in the UK:
- Rivaroxaban (brand name: Xarelto)
- Dabigatran (brand name: Pradaxa)
- Apixaban (brand name: Eliquis)
- Edoxaban (brand name: Savaysa)
Warfarin alternative drugs: main advantages over warfarin
- fast onset of action (the time it takes to work), for example, rivaroxaban and dabigatran, start to work within 30 mins after oral administration (Brighton, 2010).
- fewer drug interactions than warfarin
- fewer interactions with food
- more predictable actions of the drug
- monitoring (blood tests) not required
- simple dosing as compared with warfarin
- lower incidence of major bleeding
Warfarin alternative drugs: main disadvantages
- currently, a significantly higher cost of each drug as compared with warfarin
- in an emergency, for example, trauma or surgery, NOACs have no antidote (to decrease the risk of bleeding), apart from dabigatran. Some NOAC ‘antidote’ drugs are in different stages of development (Levy et al, 2018).
Warfarin vs warfarin alternative drugs: prescribing trends
The graph below represents a number of items prescribed for each anticoagulant in the UK between 2015 and 2018. Data from 2019 was excluded as prescribing information is not provided yet for the whole of 2019. Although warfarin is still the most prescribed oral anticoagulant in the UK, you can easily see that the number of prescriptions issued for this drug has been decreasing each year. Newer anticoagulants such as apixaban and rivaroxaban have been gaining popularity quickly at the expense of warfarin. Looking at the current growth trend, one would expect to see apixaban and rivaroxaban becoming more prescribed drugs than warfarin in the next couple of years.
1. Dabigatran (brand name: Pradaxa) as an alternative to warfarin
Dabigatran was the first approved ‘novel’ anticoagulant. Dabigatran is licensed in the prevention of blood clot formation in patients who had total hip or knee replacement surgery. Patients who had one of these surgeries are at higher risk of blood clot formation in the vein located in a leg (DVT). Dabigatran is also licensed for stroke prevention in patients with nonvalvular atrial fibrillation, who also have an additional risk factor, for example, hypertension, diabetes, heart failure, previous stroke, or ‘mini’ stroke or patients who are 75 years of age or older.
Additional indications for dabigatran include:
- Treatment of deep vein thrombosis (DVT)
- Treatment of pulmonary embolism (PE), and
- Prevention of recurrent DVT and PE
Pradaxa capsules come in three different strengths:
- 75mg capsule
- 110mg capsule
- 150mg capsule
How to take dabigatran?
The dose depends on the condition being treated and timing of the treatment; for example, initiation dose may differ from the usual maintenance dose. Follow your prescriber’s directions on Pradaxa dosing. Dabigatran can be taken with or without food. Capsules should not be open, as this may increase the risk of bleeding (eMC, 2019).
Dabigatran side effects
Dabigatran use is associated with a number of possible side effects. The likelihood of some side effects depends on the condition being treated. Possible, common side effects experienced by up to 1 in 10 patients taking dabigatran relate to the risk of bleeding, for example, nose bleeds, bleeding from penis/vagina, rectum, or gums. Other common side effects include:
- Feeling sick
- Stomach ache
- Loose bowel movements
Rarely dabigatran may serious bleeding, which may lead to disability or become life-threatening or may lead to death.
Please refer to the patient information leaflet (PIL) for more details on possible side effects and how to recognise serious side effects. A link for PIL is included at the end of this post.
2. Rivaroxaban (brand name: Xarelto) as warfarin alternative
Rivaroxaban is licensed in the prevention of venous thromboembolism, such as DVT in patients who had hip or knee replacement surgery.
Additionally, rivaroxaban is licensed in the treatment of DVT and PE and prevention of both conditions from happening again. The treatment duration and dose depend on the condition that is being treated or prevented. The usual dose of rivaroxaban can range from 10mg to 20mg taken daily or twice daily. Follow the directions of your prescriber for dosing instructions.
How to take rivaroxaban?
Rivaroxaban is taken with or after food. Xarelto tablets can be crushed and mixed with water in patients with swallowing difficulties.
The patient information leaflet states that rivaroxaban can be taken with or without food. In July 2019, The Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update recommending that rivaroxaban 15mg and 20mg (only) should be taken with food as decreased effectiveness was observed, when 15mg or 20mg tablets were taken on an empty stomach (Gov.uk, 2019).
Rivaroxaban: what are the most common side effects?
The most common side effects (1 in 10 patients) associated with the use of rivaroxaban were bleedings:
- nose bleeds
- gastrointestinal bleeding (in the stomach)
- bleeding from gums
- heavy menstrual periods
- bleeding into eye
- bleeding under or from the skin
Other common side effects:
- rash, itchy skin
- indigestion, stomachache, constipation, diarrhoea
- felling or being sick
- weakness, tiredness
- a decrease in blood pressure
- change in liver or kidney
- change in liver enzymes and kidney functions
Rarely rivaroxaban can cause severe skin reactions. Refer to product information leaflet for details about more serious, rare side effects and how to recognise them. Link is given at the end of the post.
3. Apixaban (brand name: Eliquis) as an alternative to warfarin
Apixaban is licensed for:
- Prevention of blood clot formation in patients who had hip or knee replacement
- Prevention of blood clot formation in the heart due to the irregular heartbeat (atrial fibrillation)
- To treat blood clots associated with DVT and PE and to prevent re-occurrence of blood clots in both conditions
How to take apixaban?
Apixaban is usually taken twice a day. Recommended dosage may vary and depends on the condition being treated and timing; for example, starting dose may be different to maintenance (usual) dose. Apixaban (Eliquis) comes as 2.5 and 5mg tablets.
Apixaban can be taken with or without food at the same time every day.
Apixaban common side effects
As with other anticoagulants, common side effects for apixaban relate to the risk of bleeding, which very rarely can be life-threatening (bleeding in the brain). The possibility of common side effects vary and depend on the condition treated. See product information leaflet for more details on side effects and their frequency (eMC, 2019).
Common side-effects associated with apixaban use include:
- haemorrhage (bleeding from the nose, gums, urine, in the stomach, mouth or the vagina)
- bruising ad swelling
- epistaxis (nose bleeds), and
- haematoma (bruising)
- anaemia (can cause tiredness)
- feeling sick
- skin rash
4. Edoxaban (brand name: Lixiana) as warfarin alternative
Edoxaban is used for prevention of strokes in patients with atrial fibrillation, and prevention of blood clot formation in other parts of the body, in patients who have an additional risk such as hypertension, diabetes, heart failure, previous stroke or ‘mini’ stroke or patients who are 75 years of age or older. Additionally, edoxaban is licensed for treatment and prevention of blood clots in the veins of the leg (DVT) and in the blood vessels in the lungs (PE).
Edoxaban comes in the form of:
- 15mg tablets
- 30mg tablets and
- 60mg tablets
How to take edoxaban?
Dose, duration of treatment depends on the condition treated. Edoxaban can be taken with or without food. Follow the directions of your doctor on how to take edoxaban.
Edoxaban: common side effects
Similarly to all other anticoagulants, edoxaban can cause bleeding, which can be life-threatening in rare cases. Common side-effects associated with edoxaban include:
- anaemia (can cause tiredness)
- nose bleeds
- GI side effects (lower and upper gastrointestinal haemorrhage/bleeding, abdominal pain, oral bleeding or bleeding of pharynx, nausea)
- Hepatic disorders foe example increase of bilirubin
- Skin related side effects (rashes, itching, bleeding in the soft tissue)
- Vaginal bleeding (for women under 50 years of age)
Refer to product information leaflet for more information on side effects. The link is located at the end of this post.
Are warfarin alternatives better than warfarin?
There are definite advantages of warfarin alternatives when anticoagulants are needed in treatment. Two important factors which need addressing are safety and effectiveness of NOAC as compared to warfarin. Below is the summary of conclusions taken from the main clinical trials comparing each individual NOAC with warfarin.
Dabigatran vs warfarin: effectiveness and safety
A large trial (RE-LY) involving 18,113 patients compared the effectiveness of dabigatran and warfarin in stroke and clot prevention in patients with Nonvalvular Atrial Fibrillation (NVAF). This study concluded that dabigatran is noninferior (equivalent) to warfarin in the prevention of strokes or systemic clot formation (dose of dabigatran: 110mg). With this dose, dabigatran was associated with lower rates of major haemorrhage. Lower rates of strokes and clot formation were observed when dabigatran was used at a dose of 150mg; however, similar rates for major bleeding were observed (Connolly et al, 2009).
Rivaroxaban versus warfarin: effectiveness and safety
A ROCKET AF study compared the effectiveness of rivaroxaban and warfarin in stroke and systemic (in the body) clot prevention in patients with atrial fibrillation. It was concluded that rivaroxaban was noninferior (equivalent) to warfarin in the prevention of strokes and systemic clots. There was also no significant difference in the risk of major bleeding; however, treatment with rivaroxaban was associated with a lower incidence of bleeding in the skull (intracranial bleeding) and lower incidence of fatal bleeding (Patel et al, 2011).
The effectiveness of rivaroxaban was also compared in the treatment of an acute episode of deep vein thrombosis (DVT). Trail (EINSTEIN-DVT) involving 3449 patients with acute DVT. Patients were given either rivaroxaban or subcutaneous enoxaparin followed by a vitamin K antagonist (including warfarin). Rivaroxaban was found to be noninferior (equivalent) as ‘short-term’ and continued treatment of venous thrombosis, offering a straightforward, single-drug solution (EINSTEIN Investigators, 2010).
Apixaban vs warfarin: effectiveness and safety
Study (ARISTOTLE) of 18,201 patients with atrial fibrillation who had an additional risk factor for a stroke compared effectiveness of apixaban and warfarin in prevention of ischemic (blood vessel in the brain blocked by a clot) and haemorrhagic strokes (rupture of blood vessel in the brain and consequent leak of blood in the brain). This trial also looked at rates of major bleeds and deaths from any reasons during the trial. Main results from the trial (Granger et al, 2011):
- Apixaban was found to be superior (better) to warfarin in stroke prevention/clots formation in patients with atrial fibrillation.
- Apixaban was associated with less bleeding
- Lower deaths were recorded in the group treated with apixaban.
Edoxaban vs warfarin: effectiveness and safety
The main clinical trial involving edoxaban and warfarin compared the effectiveness of both drugs in the treatment of venous thromboembolism (for example, DVT – clot formation in a deep vein of the leg). 4921 patients who took part in this study received initial treatment with heparin (an injectable blood thinner) followed by treatment with either edoxaban or warfarin. Conclusions from the study (Hokusai-VTE Investigators, 2013):
- Edoxaban was found noninferior (equivalent) to standard treatment.
- Edoxaban was associated with (significantly) less bleeding in patients with venous thromboembolism.
Switching from warfarin to warfarin alternative drug (NHS)
Switching treatment from warfarin to NOAC (apixaban, dabigatran, rivaroxaban, or edoxaban) is possible; however, it will depend on personal circumstances. Generally switching from warfarin involves (NICE, 2019):
- Stopping the treatment with warfarin
- Measurement of INR with ideal target INR to be less than 2
- Treatment initiation with NOAC when INR is below 2
- If INR is between 2 and 2.5 treatment commerce the next day
- If INR is above 2.5, the start of a new treatment is delayed until INR drop below
Warfarin alternative drugs: conclusion
Newer anticoagulants offer more advantages than disadvantages as compared to warfarin treatment. Well designed and studied clinical trials confined all ‘newer’ anticoagulants are equivalently effective as warfarin, and in some cases, superior (better) to warfarin. Patients who wish to switch their treatment from warfarin to an alternative anticoagulant should, in the first instance, speak to their doctor.
Warfarin and warfarin alternative drugs leaflets
- Warfarin leaflet
- Dabigatran: Pradaxa leaflet
- Rivaroxaban: Xarelto leaflet
- Apixaban: Eliquis leaflet
- Edoxaban: Lixiana leaflet
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. Available at: https://doi.org/10.1056/NEJMoa0905561 Accessed on 22/01/2020
Brighton Timothy (2010). New oral anticoagulant drugs – mechanisms of action. Available at: http://dx.doi.org/10.18773/austprescr.2010.017 Accessed on 19/12/2019
eMC (2019). SmPC: Pradaxa 110 mg hard capsules. Available at: https://www.medicines.org.uk/emc/product/6229/smpc Accessed on 24/01/2020
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Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992. doi:10.1056/NEJMoa1107039 Available at: https://doi.org/10.1056/nejmoa1107039 Accessed on 22/02/2020
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Levy, J., Douketis, J. & Weitz, J. (2018). Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 15, 273–281 (2018) doi:10.1038/nrcardio.2017.223 Available at: https://doi.org/10.1038/nrcardio.2017.223 Accessed on 19/12/2019
NICE (2019). Anticoagulation – oral. Available at: https://cks.nice.org.uk/anticoagulation-oral#!topicSummary Accessed on 24/01/2020
OpenPrescribing.net (2019), EBM DataLab, University of Oxford, 2017 Available at: https://openprescribing.net/ Accessed on 22/01/2020
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891. doi:10.1056/NEJMoa1009638 Available at: https://doi.org/10.1056/nejmoa1009638 Accessed on 22/01/2020