Before initiating oral antithrombotic therapy, the benefits of treatment must be weighed against the risks of bleeding. Relevant risk assessment tools, such as CHA2DS2-VASc and HAS-BLED (see modules 3 and 4), can be used to determine a patient’s thrombotic and individual bleeding risks, and to guide management decisions (e.g. whether to start antithrombotic therapy, if so with what drugs, the duration of therapy, and whether gastroprotection is required, and managing any factors that may increase the risk of bleeding (e.g. optimisation of blood pressure).
It is good practice before initiating antithrombotics to ensure a full coagulation screen has been undertaken (including INR and activated partial thromboplastin time [APTT]), as well as a full blood count, and renal and liver function tests to identify any inherent bleeding issues.
Pharmacists play an integral role as members of a multidisciplinary team, ensuring that patients receive the correct drug and dose in a timely manner. They must also consider patient factors such as renal and hepatic dysfunction, as well as drug factors, such as interactions or drugs predisposing the patient to a greater risk of adverse effects (e.g. bleeding with non-steroidal anti-inflammatory drugs [NSAIDs]).
With the increasing use of direct oral anticoagulants (DOACs) as an option for anticoagulation, it is becoming more imperative that we are aware of the responsibilities for all anticoagulant therapy – that is:
- to ensure the anticoagulant is appropriate for the individual patient (involving the patient in decision making)
- to initiate anticoagulant treatment with appropriate liaison between prescribers and anticoagulation clinics for ongoing monitoring and supply. This should take into consideration the needs of the patient (which may include home monitoring and initial supply of reagent strips)
- to ensure the patients receive the relevant anticoagulant card, and particularly for warfarin, the monitoring book, which allows any healthcare professional to review INR control.
Commissioning effective anticoagulation services
The proportion of eligible patients in England prescribed anticoagulants for atrial fibrillation (AF), without exceptions for clinical complexity or patient dissent, increased from 65.1% in 2012–2013 to 81.4% in 2016–2017.1 The need for anticoagulation is expected to increase in coming years as the UK population ages and the rates of AF rise. Evidence suggests that without adequate anticoagulation, one in 20 AF patients will suffer a stroke every year.2 This led to the improvement of anticoagulation becoming a national quality, innovation, productivity and prevention (QIPP) initiative.
There is no standard definition of what constitutes an anticoagulation service, and models of care have evolved to meet the needs of local populations. There have been concerns around the variation in the activities, and in the quality and safety of anticoagulation therapy across the country. The London Clinical Networks have produced a commissioning document titled ‘Excellence in anticoagulant care. Defining the elements of an excellent anticoagulation service’ which lists out the components of an excellent anticoagulation service for patients with AF as a helpful guide for providers and commissioners when redesigning services according to advances in medical technology and changing patient needs.3
Counselling patients initiated on warfarin and DOACs
Due to their unpredictable pharmacokinetics and narrow therapeutic windows, routine coagulation monitoring using international normalised ratio (INR) is essential for vitamin K antagonist (VKA) anticoagulants. DOACs demonstrate predictable and stable pharmacokinetics and do not require routine coagulation monitoring.
The need for regular monitoring must be explained to the patient. The INR can define how quickly the blood clots in relation to someone who is not on warfarin, i.e. a value of three indicates that it will take three times longer for someone’s blood to clot in comparison to someone not on warfarin. The patient will appreciate that too low an INR (INR <2) will not give the full benefit of preventing strokes, whereas too high an INR (INR >4) can put the patient at risk of bleeding heavily should they cut themselves, or bruising badly if they fall.
When patients first start taking warfarin, they will attend the anticoagulant clinic frequently, as they adjust their dosage to an appropriate level. Most people find that once they are established on warfarin their INR is fairly stable, and they need only attend the clinic every six to 12 weeks.
There are multiple factors that can influence the efficacy of warfarin, including: liver function; age; concomitant medicines; dietary intake of leafy vegetables; and alcohol. As such, the required dose of warfarin needs to be tailored to each individual and may change from time to time, for example when drinking more alcohol, going on holiday, or taking a course of antibiotics.
WARFARINISED (see table 1) is a good acronym to remember the important counselling points for patients starting therapy with warfarin.
Considerations for use of DOACs
The DOACs are covered in previous modules (modules 3 and 4). All DOACs are partially eliminated via the kidney. Assessment of kidney function is thus important to estimate their clearance from the body. Based on these properties, apixaban, edoxaban and rivaroxaban4 are not recommended in patients with AF who have creatinine clearance (CrCl) <15 mL/min and dabigatran5 is contraindicated in patients with CrCl <30 mL/min. However, there are no effectiveness and safety outcome data for DOACs in patients with advanced chronic kidney disease (CKD) (CrCL <30 mL/min), and the current European Society of Cardiology (ESC) Guidelines recommend against their use in such patients.6
DOACs are all substrates of P-glycoprotein (Pgp), a transport protein present in enterocytes and the liver, which reduces the bioavailability of its substrates.7 Hence, even if the potential for drug–drug interactions is less with DOACs compared to VKAs, there is still a significant potential for interactions. Thus caution is required when DOACs are co-administered with drugs such as verapamil, amiodarone and dronedarone. By contrast, drug–food interactions are not expected with the new anti-Xa anticoagulants as vitamin K intake does not influence their mechanism of action.7
In addition to the the risk of drug-related problems due to pharmacological properties of oral anticoagulants (bleeding and interactions), both health care professionals and patients should be actively supported to ensure safe and effective medication care. Studies have indicated the potential for errors associated with oral anticoagulants. They are often under dosed, inadequately monitored, inadequately stored, and not taken as prescribed, increasing the risk for adverse drug events in patients receiving oral anticoagulation.8
Pharmacists have a role in ensuring appropriate dosing of DOACs is undertaken based on renal function. It is worth noting that clinical trials with DOACs for stroke prevention in AF used the Cockcroft-Gault equation to estimate CrCl as a measure of renal function, and subsequent assessment of drug eligibility and dosing were determined. A cross-sectional study demonstrated when the Modified Diet in Renal Disease (MDRD) formula is used, which is a more widely available and more commonly used equation for assessing CrCl, rather than the Cockcroft-Gault formula (used in clinical trials), patients would receive higher doses or be deemed incorrectly suitable for eligibility for DOAC treatment. The safety and efficacy of using the MDRD equation has not been established.9
To safeguard appropriate prescribing for DOACs in non-valvular AF (NVAF), a simple ABCD can be used whereby;
- A = age – certain DOACs require a consideration for dose reduction depending on age
- B = body weight – certain DOACs require a dose reduction if body weight <60 kg
- C = creatinine clearance (Cockroft-Gault) – all DOACs are dependent on renal function and require a dose reduction as renal function decreases
- D = check for drug interactions – all DOACs may interact with p-glycoprotein inhibitors or drugs that may induce or inhibit cytochrome P450 system – check against product characteristics
Note that for dabigatran and rivaroxaban, indigestion is a known adverse effect and, as such, patients should be counselled and gastric protection considered as appropriate. All of the DOACs have a shorter half-life than warfarin, such that the drug concentration (and, thus, anticoagulant effect) would decline soon after one or more doses are missed. If the patient misses a dose of rivaroxaban or edoxaban, it is recommended that they take it as soon as possible. However, not more than one tablet in a single day should be taken to make up for a missed dose. For dabigatran, patients should immediately take the missed dose unless the next is due within six hours, in which case it should be discounted. For apixaban, if a dose is missed, the patient should take it immediately and then continue with twice daily intake as before.
Lastly, ensure patients receive their respective anticoagulant alert card and carry it with them at all times, to present to any relevant healthcare professional who is managing their care.
Switching between anticoagulants
The National Institute for Health and Care Excellence (NICE) guideline10 on anticoagulation in AF recommends the use of either DOACs or VKAs. It is, however, patient preference, cognitive function, co-morbidities and liable INR that can determine choice of anticoagulant. These parameters can change throughout a patient’s clinical condition, which may require an anticoagulation switch.
Instances where VKAs may need to be switched to a DOAC can be determined by time in therapeutic range (TTR). NICE highlights the following factors to reassess therapy and possibly to switch to a DOAC:
- Two INR values higher than 5 or one INR value higher than 8 within the past six months
- Two INR values less than 1.5 within the past six months
- TTR less than 65%.
On the flip side, patients well-established on a DOAC, may need to switch to a VKA, for example, if they are having a mechanical valve replacement since DOACs are only being licensed for non-valvular AF.
The dosing recommendations on switching can be found in the summary of product characteristics (SPCs).
Role of the community pharmacist in optimising this patient’s care
Patients have regular access to community pharmacists, who can add to the care of a patient medicated with anticoagulation and antiplatelet therapy. Anticoagulants are one of the classes of medicines most frequently identified as causing preventable harm and admission to hospital.
Following the National Patient Safety Agency guidance11 issued in March 2007 on the safe use of anticoagulant therapy, pharmacists are in a prime position to provide both medication and disease-state counselling. The guidance recommends that patients receive appropriate information throughout the course of their treatment, and that their INRs (for warfarin) are monitored regularly, to ensure they are at a safe level (see figure 1), before repeat prescriptions for oral anticoagulation are dispensed.
The guidance also suggests that pharmacists dispensing clinically significant interacting medicines, such as antibiotics, or another medication that may increase the risk of bleeding (e.g. selective serotonin re-uptake inhibitors, or non-steroidal anti-inflammatory drugs [NSAIDs]), should take additional safety precautions. These include:
- informing the anticoagulant service that an interacting medicine has been prescribed
- ensuring additional INR blood tests have been arranged to monitor any changes.
More recently, the New Medicines Service (NMS)12 has been introduced as an advanced service to the community pharmacy contract. The service provides support for people with long-term conditions newly prescribed a medicine, helping to improve medicine adherence. The optimal use of appropriately prescribed medicines is vital to the self-management of most long-term conditions, but reviews conducted across disease states are consistent in estimating that between 30–50% of prescribed medicines are not taken as recommended. This represents a failure to translate the technological benefits of new medicines into health gain for individuals. Sub-optimal medicine use can lead to inadequate management of long-term conditions, and a cost to the patient, the NHS, and to society.
The NMS currently focuses on specific patient groups and conditions, including antiplatelet and anticoagulant therapy.
The service is such that all patients newly prescribed an anticoagulant, for example, will be eligible to receive it. The NMS provides an interview schedule to facilitate discussions between pharmacist and patient. These include:
- Have you had a chance to start taking your new medicine yet?
- How are you getting on with it?
- Are you having any problems with your new medicine, or concerns about taking it?
If you are a hospital-based pharmacist or prescriber, consider referral to the new medicine service. This will provide the reassurance that any information provided to the patient is reinforced by community pharmacy colleagues, and that any problems patients experience will be addressed and discussed.
1. Health and Social Care Information Centre. NHS payments to general practice, England, 2016-17. HSCIC, 2017. https://digital.nhs.uk/data-and-information/publications/statistical/quality-and-outcomes-framework-achievement-prevalence-and-exceptions-data/quality-and-outcomes-framework-qof-2016-17 (accessed 12th December 2018).
2. Dorian P, Jung W, Newman D et al. The Impairment of health related quality of life in patients with intermittent AF; implications of the assessment of investigational therapy. J Am Coll Cardiol 2000;36:1303–9. http://dx.doi.org/10.1016/S0735-1097(00)00886-X
3. London Clinical Networks. Excellence in anticoagulant care. Defining the elements of an excellent anticoagulation service. http://www.londonscn.nhs.uk/wp-content/uploads/2016/08/stroke-af-anticoag-082016.pdf (accessed 18th October 2018)
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5. Summary of product characteristics for dabigatran. Electronic Medicines Compendium . Available from http://emc.medicines.org.uk/ (accessed 12th December 2018)
6. Kirchhof P, Benussi S, Kotecha D, et al. 2016 European Society of Cardiology Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37;2893–962. https://doi.org/10.1093/eurheartj/ehw210
7. Salem J-EJ, Sabouret P, Funck-Brentano C, Hulot J-S. Pharmacology and mechanisms of action of new oral anticoagulants. Fundam Clin Pharmacol [Internet] 2015;29:10–20. https://doi.org/10.1111/fcp.12091
8. Cutler TW, Chuang A, Huynh TD, et al. A retrospective descriptive analysis of patient adherence to dabigatran at a large academic medical center. J Managed Care Specialty Pharm 2014;20:1028–34. https://doi.org/10.18553/jmcp.2014.20.10.1028
9. Maccallum PK, Mathur R, Hull SA, et al. Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study. BMJ Open 2013;3(9):e003343. https://doi.org/10.1136/bmjopen-2013-003343
10. National Institute for Health and Care Excellence (NICE). Atrial fibrillation: the management of atrial fibrillation. Clinical guideline [CG180]. London: NICE, June 2014, last modified August 2014. https://www.nice.org.uk/guidance/cg180/resources/guidance-atrial-fibrillation-the-management-of-atrial-fibrillation-pdf
11. National Patient Safety Agency. Patient safety alert: actions that can make anticoagulant therapy safer(Alert 18), 2007. Available from http://www.nrls.npsa.nhs.uk/resources/?entryid45=59814 (archived 30th October 2017)
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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