Introduction
- (Novel Oral Anticoagulants) or DOACs (Direct Oral Anticoagulants)
- Alternatives to Warfarin for those with non-valvular AF
Uses
- Non-Valvular AF or Venous thromboembolism
- Not for those with valvular heart disease and/or artificial valves
Pharmacology of DOACs for Non-Valvular AF
| Name and BNF link | Dabigatran (Pradaxa) | Rivaroxaban (Xarelto) | Apixaban (Eliquis) | Edoxaban |
|---|
| Class | Direct thrombin inhibitors | Factor Xa inhibitors | Factor Xa inhibitors | Factor Xa inhibitors |
|---|
| Dose | For Adult 18-74 years 150 mg BD. Adult 75-79 years 110-150 mg BD Adult 80 years and over 110 mg BD. | 20 mg/d (Once daily) to be taken with food. | 5 mg BD, reduce dose to 2.5mg BD in patients with at least two of the following characteristics: age 80 years and over, body-weight less than 61 kg, or serum creatinine > 133 micromol/litre. | For Adult (body-weight up to 61 kg)
30 mg OD. For Adult (body-weight 61 kg and above) 60mg OD. |
|---|
| Half life | 14-18 (longer in impaired renal function) | 5-9 h (young), 11-13 h elderly | 12h | 10-14h |
|---|
| Bioavailability | 6.5% | 80-100% | 50% | 62% |
|---|
| Prodrug | Yes | No | No | No |
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| Food effects | No | 20mg and 15 mg dose need to be taken with food | No | No |
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| Reversal | Idarucizumab 5 g IV | Give PCC and supportive | Give PCC and supportive | Give PCC and supportive |
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| Elimination | 80% renal | 66% renal | 28% renal | 33% renal |
|---|
| Side effects | Bleeding, Tartaric acid moiety in dabigatran may create relatively more GI upset | Bleeding | Bleeding | Bleeding |
|---|
| Notes | Dabigatran is a pro drug that requires metabolism. Elimination is primarily renal.
| Elimination mainly biliary | Elimination mainly biliary. Preferred in CKD | Renal/Biliary |
|---|
Choice of DOAC
The BMJ have recently published a review from primary care. The paper titled "Risks and benefits of direct oral anticoagulants versus warfarin in a real-world setting: cohort study in primary care found that Apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose Apixaban were, however, associated with increased risks of all-cause mortality compared with warfarin. Other factors in choice are the issues around reversibility and for Dabigatran there is a specific antidote.
A newer study is shown below. The ARISTOPHANES Study group was the largest observational study to date on NOACs and warfarin. The study showed that the NOACs had lower rates of stroke/ Systemic emboli and variable comparative rates of Major Bleed versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients link.
Dabigatran
Dabigatran etexilate is an oral prodrug that is rapidly converted by a serum esterase to dabigatran, a potent, direct, competitive inhibitor of thrombin. It has an absolute bioavailability of 6.5%, 80% of the given dose is excreted by the kidneys, its serum half-life is 12 to 17 hours, and it does not require regular monitoring.
Evidence base
| Anticoagulation for AF | Authors | Outcome |
|---|
|
Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients 8 Nov 2018 Stroke. 2018;49:2933-2944"
| The ARISTOPHANES Study group |
In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/ Systemic emboli and variable comparative rates of Major Bleed versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients |
|
Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation September 8, 2011 N Engl J Med 2011; 365:883-891
| The ROCKET AF Steering Committee et al. for the ROCKET AF Investigators* |
In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group |
|
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
N Engl J Med 2009; 361:1139-1151
| The RE-LY Steering Committee and Investigators
| In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major haemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major haemorrhage.
|
|
Apixaban versus Warfarin in Patients with Atrial Fibrillation
N Engl J Med 2011; 365:981-992 | ARISTOTLE Committees and Investigators*
| In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality
|
|
Edoxaban versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2013; 369:2093-2104
| ENGAGE AF-TIMI 48 Investigators* |
Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes.
|
Indications
Generally these are used in an elderly population with no valvular heart disease or artificial valves in preference to warfarin. Ensure to check good renal function without co-morbidities likely to lead to unrecognised decreases in renal function. Check no interacting medications. If on medications with potential interaction, watch out for effects of reduced renal function, poorer clearance with age. Remembers their medication. Once-daily dosing may be better than twice daily in terms of compliance. Limited concern for bleeding.
Pregnancy
Not advised in pregnancy as there is no safety data. The intact drug is found in breast milk in animal studies so currently not advised for women who are breastfeeding
Reversibility
- Primary focus is to address the bleeding. Efforts to address the drug. No benefit to FFP, vitamin K
- Decrease quantity of drug with activated charcoal if thought to still be in the stomach
- Dabigatran may be reversed with Idarucizumab 5 g
- Bypass the drug effect: Prothrombin complex (PCC), factor VIIa concentrates anecdotally used - no controlled trials
- Recent study suggested PCC may work best for anti-Xa (rivaroxaban, apixaban) but not anti-thrombin (dabigatran)
Idarucizumab (Praxbind)
Idarucizumab 5 g IV binds specifically to dabigatran and its metabolites. It will not reverse the effects of any other anticoagulant. In the REVERSE AD trial in adults taking dabigatran etexilate who have either serious bleeding or require urgent surgery, interim results from 90 people found treatment with a Idarucizumab reversed the anticoagulant effect of dabigatran etexilate (median maximum reversal 100%) normalised dilute thrombin time and ecarin clotting time in 88-98% of people (efficacy analysis; n=68 to 81). According to the summary of product characteristics for Idarucizumab, no adverse reactions to Idarucizumab were identified when safety was evaluated in 224 healthy people as well as 123 people in the ongoing REVERSE AD study. Reversing the anticoagulant effect of dabigatran etexilate with Idarucizumab exposes people to the thrombotic risk of their underlying disease; restarting anticoagulant therapy should be considered as soon as is medically appropriate. Idarucizumab costs £2,400 per 5 g (2×2.5 g/50ml) dose excluding VAT (MIMS, April 2016). Idarucizumab 5 g is given intravenously as 2 consecutive infusions of 2.5 g/50 ml over 5 to 10 minutes each or as 2 consecutive 2.5 g bolus injections. Administration of a second 5 g dose of idarucizumab may be considered in the following clinical situations:
- recurrence of clinically relevant bleeding together with prolonged clotting times or
- if potential rebleeding would be life-threatening and prolonged clotting times are observed or
- patients require a second emergency surgery or urgent procedure and have prolonged clotting times.
FAQ Information for Patients
| You must let other healthcare professionals treating you know that you are taking a DOAC. This includes anyone who prescribes you medication or carries out a procedure, for example, a dentist. |
Why have been prescribed a DOACs: Warfarin has been used to prevent stroke in people with AF for many years. DOACs, such as apixaban, rivaroxaban, edoxaban and dabigatran, are suitable alternatives to warfarin for this condition. Unlike warfarin, they are used at a fixed dose, and they do not require close monitoring of blood levels. Before you start taking a new anticoagulant, you will be able to discuss it with your consultant. It is important that you choose a medicine that suits you best.
How do I take the medicine? : The dose and frequency (how often you need to take the medicine) will depend on which anticoagulant has been prescribed for you. This will be explained to you and will also be written on the medicine label and on your discharge letter. Please make sure you understand how to take the medicine and ask if you have any questions. If we have asked you to take your medication twice a day, please make sure you take it 12 hours apart, for example at 8 am and 8 pm.
What if I miss a dose? : If you miss a dose, take it as soon as you remember, but don't double up on the total daily dose. Please refer to the patient information leaflet supplied with your medicine for specific information or call our Pharmacy Medicines Helpline for advice (please see the back page for contact details).
Are there any side effects? : Bleeding is the most common side effect of DOACs, as they increase the time it takes for your blood to clot. Please seek medical advice immediately if you suffer a significant blow to the head or have been involved in an accident, or if you have any of the following:
- Prolonged nosebleeds (over 10 minutes)
- Unusual headaches
- Blood in your urine, stools or vomit
- Black stools
- Unexplained or severe bruising
Cautions
- Avoid Aspirin or medicines containing aspirin unless prescribed by your doctor
- Never miss a dose of DOAC unless advised by us to do so
- Never take extra doses or change your dose of DOAC without first discussing with the anticoagulant practitioners
- Ensure that you never run out of DOAC tablets.
- Ask your GP for a repeat prescription in good time.
- Avoid contact sports such as rugby or extreme sports. An injury could cause serious bleeding or bruising.
If you cut yourself, apply pressure as you normally would. It may take longer for the wound to stop bleeding. If the bleeding does not stop within 10 minutes, go to your nearest Emergency Department (A&E). Please make sure you tell the person treating you that you are taking an anticoagulant and bring them with you if possible.
What about my other medicines?: Your medicines will be reviewed when you are first prescribed a DOAC, and any necessary changes will be made. As other medicines (including herbal remedies) may interact with DOACs, it is important that you check with a pharmacist before starting any new medicines or stopping any existing ones. You should avoid taking any other medicines that may increase your risk of bleeding (such as aspirin or ibuprofen) unless your doctor has specifically prescribed them for you. If you need a painkiller, paracetamol and codeine are acceptable. Be aware that medicines bought in pharmacies can contain other ingredients - please speak to your pharmacist if you are unsure.
Do I need to change my diet or alcohol intake? You do not need to change what you eat when taking a DOAC. You should maintain a healthy and balanced diet. DOACs are not directly affected by alcohol. However, we recommend that you do not exceed the safe limits of alcohol (14 units per week for men or women), as this can increase your risk of bleeding.
Can I use a dosette tray?: Yes, you can use a dosette tray for your DOACs except for dabigatran. Please contact us if you require a monitored dosage system for dabigatran.
If you are taking dabigatran, it is important not to open the capsule and the foil packet until you are about to take it.
Can I crush the tablets? : Rivaroxaban - You can crush the tablet and mix the medicine in 50 ml of water before giving it via a feeding tube. Do not crush - Dabigatran, Apixaban and Edoxaban.
What about monitoring me? The DOACs do not require routine anticoagulation monitoring for short or long-term treatment. However, we do recommend that your kidney function is checked prior to starting a DOAC and then at least once a year. If you have kidney problems you require more frequent monitoring. Your GP will review this medication with you annually.
What if I forget a dose?: If you are taking a once a day drug: please take it as soon as you remember but make sure you do not take more than one tablet in a single day.
If you are taking a twice a day drug: please take your missed dose if it is more than 6 hours to your next dose. if it is less than 6 hours to your next dose, please miss out the dose you forgot and then take your next dose at the usual time.
What should I do if I think I may be pregnant? : A DOAC taken during the early weeks of pregnancy may damage the unborn baby. Do not plan to become pregnant without consulting your doctor. If you think you may be pregnant while taking a DOAC, please contact your doctor at once.
What should I do if I need surgery or a tooth extraction?: If you are due for an operation, please let the surgeon know you are on a DOAC. The pre-assessment clinic will advise you when to stop your medication