This module considers the clinical use of anticoagulants: the initiation of anticoagulation with vitamin K antagonists and practical issues around prescribing and monitoring; the use of direct oral anticoagulants (DOACs) and their effect on laboratory tests; interruption of anticoagulation for invasive procedures and in patients undergoing cardioversion; along with management of bleeding issues. The therapeutic indications for anticoagulants in acute coronary syndromes and non-valvular atrial fibrillation (AF), as well as their use in cardioversion for AF, are covered in module 3, which also considers the choice of anticoagulant for stroke prevention. The use of anticoagulants in heart valve disease is covered in module 7 of our heart valve disease learning programme.
Indications for anticoagulation treatment
Vitamin K antagonists (VKAs) are effective anticoagulants but have a poor safety profile and were the subject of a National Patient Safety Agency (NPSA) alert1 in 2007. They also feature as one of the High Risk Medications in the Patient Safety First campaign in England. The risk of major haemorrhage is 2–5% per year and is higher in the elderly or where other risk factors for bleeding co-exist. Bleeding risk can be estimated using the HAS-BLED score (see module 3). Good anticoagulant management is important in reducing risk. Warfarin is the VKA of choice in the UK and comes in four colour-coded doses (see figure 1).2
The level of anticoagulation is assessed using the International Normalised Ratio, or INR. The INR is derived from the prothrombin time, with a correction to adjust for the sensitivity of each laboratory’s reagents (see below). The INR therefore gives a standardised measure of the degree of anticoagulation with warfarin: it provides consistency between laboratories. The target INR depends on the indication for anticoagulation but for atrial fibrillation (AF) and most non-valvular cardiac conditions it is 2.5 (range 2.0–3.0).
Table 1 shows the various indications for anticoagulant treatment, as well as INR target and range and the duration of treatment.
There is great biological variability in response to VKAs. Most of this is genetically determined but there are also many interactions with drugs and foodstuffs. Two common polymorphisms in the cytochrome P450 2C9 system are associated with increased warfarin sensitivity, and mutations in the VKORC1 gene complex can cause either sensitivity or resistance to VKAs.
Drugs can interact with warfarin in a number of ways:
- antibiotics can reduce the synthesis of vitamin K, which is usually performed by gut bacteria
- some drugs can affect warfarin absorption (e.g. cholestyramine)
- Inducers or inhibitors of the cytochrome P450 system can have substantial effects on warfarin levels. Commonly-used drugs which can increase warfarin levels include several antibiotics, omeprazole, statins and amiodarone. Over-the-counter remedies can also affect levels (e.g. glucosamine can increase levels, St John’s Wort can reduce levels), as can some foods (e.g. grapefruit and cranberry can increase warfarin levels).
Always consult the full list of potential interactions in the British National Formulary. Great care should be taken when making changes to medication in patients taking warfarin, including more frequent INR checks.
Starting anticoagulation with warfarin
Anticoagulation should be initiated only when appropriate follow up has been arranged. Frequent checks of the INR are required until the dosage is stabilised, at least twice in the first week, and if the patient is to attend an anticoagulant clinic it is often safer to defer initiation until first attendance at the clinic.
Discuss the risks and benefits of anticoagulation with the patient and ensure they have consented to the treatment. If the patient is a younger woman, check that she is not pregnant or planning pregnancy as warfarin can cause embryopathy between six and 12 weeks gestation.
Check for bleeding history and other medication that may interact with warfarin (see table 2).
Also check baseline INR, full blood count, liver and renal function.
Complete the BSH/NPSA yellow Oral Anticoagulant Therapy card (figure 2) and dosage record (or other appropriate written information) and give this to the patient. Keep separate clinical notes including INR results and dosage.
Ensure the patient understands:
- the rationale for treatment
- the importance of regular blood tests
- variable warfarin doses and tablet strengths
- what to do and who to contact if bleeding or bruising or any other complications occur
- the importance of extra checks during periods of intercurrent illness, or when starting or stopping other medication, including self-medication
- the teratogenicity of warfarin in pregnancy where appropriate
- the possible effects of dietary changes and alcohol intake
- any limitations to sports and leisure activities
- the importance of informing health care professionals about anticoagulant use.
The effectiveness of warfarin hinges on its effects on vitamin K levels. Increasing the amount of vitamin K by eating more broccoli can make warfarin less effective.
Warfarin induction regimes
Rapid induction regimes are not suitable for out-patient or community use as they require daily INR checks. They are more likely to result in very high INR values or warfarin-induced skin necrosis caused by steep falls in protein C and S levels.
A suitable regime for patients with AF is the Tait and Sefcick algorithm.4* This uses a 5 mg dose of warfarin for the first four days provided the baseline INR is no greater than 1.4 and the patient is not on amiodarone, in which case 3 or 4 mg should be the initial dose and the dose adjustments modified. Other risk factors such as age >80 years, heart failure, liver disease or other bleeding risk should also prompt a reduced starting dose. INR checks are carried out twice weekly for the first two weeks at least.
Patients requiring cardioversion
These patients should have a therapeutic INR (>2.0) for at least three weeks before and four weeks after cardioversion to reduce the risk of embolisation. INR checks should be performed at least weekly during this period. As INR values do tend to fluctuate it is useful to aim for target INR between 2.5 and 3.0 to avoid dips below 2.0 that result in cancellation of the procedure.
If the patient has been in AF for a short period only, and cardioversion is performed after transoesphageal echocardiography has shown no evidence of intra-atrial thrombus, anticoagulation is not mandatory.
High INR values and bleeding in warfarinised patients
The British Committee for Standards in Haematology Guidelines on oral anticoagulation with warfarin (4th edition)3 has guidance on high INR and bleeding to which the reader is directed for more complete information (see also table 3). This is provided for educational purposes only – specialist advice should always be sought when required.
Interruption of anticoagulation for invasive procedures
For dental procedures, including extraction, warfarin should not be stopped, but the INR should be <4.0. Other low risk procedures, such as skin biopsy and endoscopy, without biopsy can also be performed without stopping warfarin.
If a reduction in INR to <1.5 is required, warfarin should be stopped three to five days (depending on INR and target range) before the procedure. Depending on thrombotic risk, (including CHADS2 or CHA2DS2-VASc score), bridging anticoagulation with heparin or low molecular weight heparin may be advisable. This is a specialist area and it is best to seek advice from a haematologist for an appropriate regime, especially if the patient has any history of thrombotic events.
There are a number of reliable INR monitors available that use capillary blood samples and are suitable for home INR testing. The CoaguChek® XS (see figure 3) has built in quality control material and gives good correlation with venous blood samples in patients who are stably anticoagulated. Patients on long-term anticoagulation may wish to purchase such a machine. The disposables required can be provided on NHS prescription. Patients who wish to self-test or self-manage should discuss this with their anticoagulant clinic before purchase of a machine, and should remain under the overall care of an anticoagulant service or their GP. The performance of the machine should be checked in the clinic every six months.
Practical issues associated with direct oral anticoagulants (DOACs)
In those who are suitable for a DOACs, the choice of drug must be selected carefully (See table 45 below taken from North Central London DOAC prescribing support)
Prior to starting patients on a DOAC, patients must be adequately informed of the importance of taking their medication at the same time every day and with instructions in the event of bleeding complications.
Laboratory measurement of anticoagulant effect
This is not required in routine use but it may be useful to know DOAC levels in certain situations such as:6
- In the presence of spontaneous or traumatic haemorrhage
- Following suspected overdose
- When patients are taking another interacting drug
- To monitor efficacy in patients presenting with new thrombosis whilst on the anticoagulant
- When emergency surgery is required
- In patients due to have neuraxial anaesthesia for elective or emergency procedures or surgery
- In patients requiring elective surgery and in whom the drug may still be present
- In patients with renal impairment
- When bridging from one anticoagulant to another
- To assess compliance
- At the extremes of body weight
- In subjects with prior intestinal surgery where it is unclear if absorption will be affected
- Trough levels may be useful to assess potential accumulation in very elderly patients
Although there is currently no routine measurement of anticoagulant effect with DOACs, it is important to monitor renal function and weight regularly (e.g every three to six months depending on baseline creatinine clearance) to ensure suitability and correct dosing.
Routine clotting tests and DOACs
When interpreting the results of screening clotting tests, it is useful to have the coagulation cascade in mind. Figure 4 shows the coagulation cascade, marked to show which bits are tested by the three screening clotting tests: PT (prothrombin time), APTT (activated partial thromboplastin time), and TT (thrombin time).
As might be predicted from figure 4, and a knowledge of the mechanism of action of DOACs, these anticoagulants may affect the results of screening clotting tests. However, results of these tests with DOACs are not consistent or standardised, and they therefore cannot be used for monitoring of these agents. Perhaps most importantly, results of standard clotting tests can be normal, even at therapeutic levels of anticoagulation with DOACs. Each lab will get different results depending on reagents, and results should be discussed with lab staff or a clinical haematologist. Table 5 is a guide showing the influence of DOACs on screening coagulation tests.3,7
For accurate measurement of drug levels, specialist assays have been developed (table 6). These may not be available in all laboratories.
Cessation of DOACs before invasive procedures
This is a confusing area. The manufacturers of each of the DOACs give recommendations, but pharmacokinetic modelling suggests that longer may be needed, especially in patients with impaired renal function, and where ensuring adequate haemostasis is crucial. Bridging anticoagulation with low molecular weight heparin is not usually necessary, but might be considered in certain high-risk situations.8 As ever, decisions should be individualised based on thrombotic and bleeding risk, and specialist advice sought. Table 7 is a guide.
Recommendations on drug intake before surgery have also been issued by the European Heart Rhythm Association.10
Management of bleeding with DOACs
For those on dabigatran, there is a reversal agent (Idarucizumab – discussed in more depth in module 3). The indications for when to use this include:11
- Life threatening bleeding including intracranial haemorrhage
- Bleeding in a closed space or critical organ such as intraspinal or intraocular area
- Persistent major bleeding despite local haemostatic measures or risk of recurrent bleeding because of delayed DOAC clearance or DOAC overdose
- Need for urgent intervention that is associated with a high risk of bleeding that can not be delayed to await drug clearance
- Emergency surgery or intervention in patients at high risk for procedural bleeding, for example – neurosurgery.
Idarucizumab should not be used in those having elective surgery, gastrointestinal bleeding that is responding to supportive measures, those with high drug levels without bleeding, and those who need surgery that can be delayed until dabigatran has cleared.
Although dabigatran has a reversal agent, the other DOACs do not yet have a licensed option so bleeding on these agents is considered as either mild, moderate or severe and treated as such (see figure 512 below). Please refer to guidelines at your local hospital and discuss with a haematologist when appropriate.
1. Patient safety alert 18. National Patient Safety Agency 2007. Available from http://www.npsa.nhs.uk/nrls/alerts-and-directives/alerts/anticoagulant/ (accessed 20/02/13)
2. Oral anticoagulant therapy patient information booklet. National Patient Safety Agency 2008. Available from http://www.nrls.npsa.nhs.uk/resources/?EntryId45=61777 (accessed 20/02/13)
3. Keeling D, Baglin T, Tait C et al. British Committee for Standards in Haematology Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011;154:1365–2141. http://dx.doi.org/10.1111/j.1365-2141.2011.08753.x
4. Tait RC, Sefcick A. A warfarin induction regimen for out-patient anticoagulation in patients with atrial fibrillation. Br J Haematol 1998;101:4504. http://dx.doi.org/10.1046/j.1365-2141.1998.00716.x
5. Drebes A, Gates C for the North Central London Joint Formulary Committee. DOAC prescribing support for NCL, AF and VTE. https://www.ncl-mon.nhs.uk/wp-content/uploads/Guidelines/9_DOAC_prescribing_support.pdf
6. Kitchen S, Gray E, Mackie I, Baglin T, Makris M and the BCSH committee. Measurement of non‐Coumarin anticoagulants and their effects on tests of haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2014;166:830–41. https://doi.org/10.1111/bjh.12975
7. Dale BJ, Chan NC, Eikelboom JW. Laboratory measurement of the direct oral anticoagulants. Br J Haematol 2015 (published online 22nd October 2015). http://dx.doi.org/1111/bjh.13810
8. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954–62. http://dx.doi.org/10.1182/blood-2012-06-415943
9. National Institute for Health and Care Excellence. NICE Clinical Knowledge Summaries. Anticoagulation – oral. Available at http://cks.nice.org.uk/anticoagulation-oral (Accessed 12th November 2018)
10. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467–507. http://dx.doi.org/10.1093/europace/euv309
11. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz J and Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: Guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:623–7. https://doi.org/10.1111/jth.13227
12. Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program 2015;2015117–24. http://www.doi.org/10.1182/asheducation-2015.1.117
Hicks T, Stewart F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 2016;3:e000279. http://dx.doi.org/10.1136/openhrt-2015-000279