Oral anticoagulants for stroke prevention in nonvalvular AF

Warfarin and direct oral anticoagulants (DOACs) have been shown to reduce the risk of stroke in patients with atrial fibrillation, yet many patients are still not being anticoagulated. This article discusses the barriers to the initiation of oral anticoagulants, in particular DOACs, and how these can be overcome.

Atrial fibrillation (AF) is the most common arrhythmia with over one million people diagnosed in the UK.1-3 It can lead to ischaemic stroke, which is one of the biggest causes of death in England and has annual health and social care costs of £4.38 billion in the UK.4 Ischaemic strokes associated with AF have poorer outcomes with a higher mortality and greater disability,5 yet strokes associated with AF are mainly preventable. It is estimated that 7000 strokes and 2000 premature deaths each year in England could be prevented using oral anticoagulants.6 Warfarin can reduce the risk of stroke by 64%7 and direct oral anticoagulants (DOACs) have been shown to be as effective as warfarin in the prevention of ischaemic stroke.8

Stroke prevention in atrial fibrillation

Warfarin and DOACs (apixaban, dabigatran, edoxaban and rivaroxaban) are recommended by NICE for stroke prevention in nonvalvular AF (SPAF). Aspirin monotherapy should not be used for SPAF as it is considerably less effective than warfarin or DOACs7,9 and possesses similar bleeding risks to warfarin.10 All patients with AF and a CHA2DS2-VASc score of 2 or more should be offered oral anticoagulants unless there is an absolute contraindication. Anticoagulation is not indicated for patients with AF at very low risk of stroke, ie under 65 years of age and no risk factors other than their sex.9

(click figure for full-size image)
Figure 1
. Anticoagulation of patients with known atrial fibrillation on admission for stroke in England, Wales and Northern Ireland, 2013–201611–14

Nationally, 22% of people with AF and a CHA2DS2-VASc score of 2 or more are still not anticoagulated according to the latest Quality and Outcomes Framework (QOF) data2 and a third of patients are inadequately treated with aspirin monotherapy.6 There has been a gradual increase in the levels of anticoagulation of patients with AF in England, Wales and Northern Ireland over the past few years, which seems to have been unaffected by the removal of aspirin from the guidelines or the increase in therapeutic options available (see Figure 1).11-14 The latest national stroke audit data showed that only 54% patients with AF admitted with stroke between August 2016 and November 2016 were taking oral anticoagulants. Almost one-fifth of patients were taking antiplatelet therapy only, such as aspirin, despite it being removed from the NICE guideline and QOF more than a year ago.14 There is also a wide variability in the use of DOACs across CCGs in England (see Figure 2).

Figure 2. Use of direct oral anticoagulants (DOACs) across CCGs in England, 2016. From: ABPI SAFI. One year on – Why are patients still having unnecessary AF-related strokes. May 201647

Barriers to initiating oral anticoagulants for SPAF

The perceptions of clinicians about risks associated with oral anticoagulants can be a barrier to the initiation of oral anticoagulation therapy. Clinicians, including GPs, have been shown to be reluctant to initiate oral anticoagulants in patients with advanced age, especially those older than 80 years, despite them being healthy and without contraindications to oral anticoagulation.15,16 Age on its own should not be a contraindication to anticoagulation as older patients (>75 years) are at higher risk of stroke and show greater benefit from the intervention.9,15,16 The reluctance to prescribe oral anticoagulants to patients with advanced age is a result of overestimation of the bleeding risk.15 Treatment is often withheld in elderly patients due to concerns over excessive bleeding risk,16 despite the net clinical benefit of oral anticoagulants increasing with age and being the highest among patients aged 85 years and older.17

There is no consensus among clinicians on what risk of bleeding is acceptable with oral anticoagulants.15,18 In a matched-pair analysis, clinicians were significantly less likely to prescribe oral anticoagulants to new patients after a previous patient had had a major bleeding adverse event associated with anticoagulation.19 Surprisingly, occurrence of ischaemic stroke in a non-anticoagulated patient with AF did not increase the use of oral anticoagulants in clinicians’ future patients.19 The perception of bleeding and stroke risks differs between physicians and patients. In an observational study, patients at high risk of developing AF were happy to accept a much higher risk of bleeding in order to avoid stroke compared with primary and secondary care clinicians.18 This means that patients should always be involved in shared decision-making about whether to prescribe or not (see below).

Falls with risk of intracranial bleeding were cited as a reason to withhold oral anticoagulants.16 Clinicians perceive that elderly patients will be at increased risk of falls and thus increased risk of bleeding and therefore oral anticoagulants are often not initiated. However, patients would need to fall around 300 times per year for the risk of intracranial bleeding to outweigh the benefits of oral anticoagulants.20 The reported annual sustained falls rate for elderly patients is only 1.81.21

The bleeding risk should be calculated using validated tools such as HAS-BLED.9 A high HAS-BLED score is not a reason to withhold treatment with oral anticoagulants; it should be used as a tool to correct modifiable bleed risks such as high blood pressure and co-prescribing of gastric irritant drugs such as corticosteroids and NSAIDs, and drugs with antiplatelet effects such as SSRIs, aspirin, ticagrelor, prasugrel and clopidogrel.

Meta-analysis of DOAC trials showed significantly lower rates of intracranial bleeding, similar major bleeding but higher gastrointestinal bleeding rates when compared with warfarin.22 DOACs overcome some of the barriers reported with warfarin use (extensive food and drug interactions, frequent monitoring requirements)9,23 but some physicians have been shown to be reluctant to initiate them, citing the lack of a reversal agent in a major bleeding event.23 The rapid onset of DOACs diminishes the need for an antidote in most situations. However, in certain situations such as a life-threatening bleed or urgent surgery, a reversal agent could be beneficial. There is now a licensed specific reversal agent for dabigatran called idarucizumab24 and several others are in the pipeline.25

Lack of experience is another key factor in preventing prescribing of oral anticoagulants for SPAF. A study interviewing GPs, practice managers and nurses observed that the majority of oral anticoagulation for SPAF was initiated in secondary care and hence primary care staff, including GPs, felt lacking in experience in starting anticoagulation.26 Inadequate communication between primary and secondary care was highlighted as another barrier.26

The prescribing behaviour of GPs is also influenced by secondary care specialists, consultants, clinical investigators and peers.27-31 Organisational barriers to the use of oral anticoagulants, especially DOACs, are less well described in the literature. The cost of DOACs is also perceived to be a barrier to their use. However, NICE concluded that they are cost-effective and should be made available in line with local guidance without additional funding or formulary restrictions.9

Locally, CCGs are responsible for medicines management in their area and can adapt medicines management processes to local area needs.32 CCGs should follow NICE recommendations, which state that warfarin or DOACs can be considered for newly diagnosed patients, patients inadequately managed with warfarin, and patients taking aspirin and thus should be made available locally.9

Shared decision-making

Patient-centred care is at the heart of the NHS and patients should be fully informed about their treatment options.33 Patients with AF requiring anticoagulation wish to be involved in shared decision-making about oral anticoagulation,34-37 even in situations when they defer decisions to physicians.34-36 Patients also want to receive new information after making the decision and again, it is important for them to be able to discuss their options with the physician.34 This observation is important since four DOACs have been introduced for SPAF and patients already taking warfarin should be offered the choice to change oral anticoagulant, if appropiate.9 However, the literature shows that patients usually have little or no say in such decisions.34,38,39 NICE has produced a patient decision aid to help them to make informed decisions about taking oral anticoagulants.40

Initiation and monitoring of DOACs

Historically some GPs have been reluctant to initiate DOACs as they did not consider themselves to have sufficient expertise. Currently, DOAC initiation is most often undertaken, or recommended, by specialists or GPs with a special interest. However, GPs are increasingly initiating DOACs, and as they are expected to continue the prescribing of DOACs started by others, they need to have the knowledge and skills to prescribe and monitor.

Initiation

NICE9,41 recommends that anticoagulation should be:
• Considered for men with a CHA2DS2-VASc score of 1, taking bleed risk into account
• Offered to people with a CHA2DS2-VASc score of 2 or above, taking bleed risk into account.

Firstly, patients with any absolute contraindications to anticoagulation should be identified, as these patients cannot be offered treatment. However, individual circumstances may change over time, so periodic reassessment is recommended. The number of absolute contraindications to DOACs is relatively small (see Table 1). There are also several relative contraindications to DOACs (see Table 2) and these should be taken into consideration when deciding whether to offer treatment.

Table 1. Absolute contraindications to direct oral anticoagulants (DOACs)41-46

Where treatment can be offered, patients must be involved in the decision. Patients need to know that DOACs, like warfarin, are potent anticoagulants so the same risks of minor and major bleeding still apply. The anticoagulant effects of DOACs wear off quickly (by the next day). This means that if patients miss a dose then they will not have anticoagulant cover and will be at increased risk of a stroke.

Table 2. Relative contraindications to direct oral anticoagulants (DOACs)41-46

Before starting treatment, modifiable risk factors should be managed such as controlling systolic blood pressure to <160mmHg and stopping gastric irritant medicines such as NSAIDS, and if possible antiplatelet therapy and other interacting drugs. Necessary tests should be up to date (kidney function tests, liver function tests, full blood count and clotting screen). Lifestyle modifications should also be discussed with the patient such as reducing alcohol intake, if applicable. Patients should be referred to the community pharmacist for a new medicines review and be given an anticoagulant warning card to carry at all times.

Monitoring until stable

Monitoring every three months is recommended to assess adherence, to reinforce advice regarding a regular dosing schedule and also to enquire about adverse effects such as bleeding.41 Patients should be assessed for the presence of thromboembolic events and enquiries should be made about other medicines the patient is taking, including OTC medicines.

Ongoing monitoring

Recall systems should be set up for monitoring of DOACs. Recalls can be set up on GP systems such as TPP SystmOne or EMIS, or anticoagulation software such as INRstar N3 can be used.

Monitoring parameters are shown in Table 3. The frequency of monitoring is consensus based. This guidance is based on advice from drug companies and NICE clinical knowledge summary guidance.

Table 3. Guidance on ongoing monitoring of direct oral anticoagulants (DOACs)41-44

Bleed risk needs to be managed both at initiation of DOAC treatment and on an ongoing basis, eg BP needs to be managed, alcohol intake should be limited and all gastric irritant drugs such as SSRIs and antidepressants need to be reviewed. A proton pump inhibitor can be offered on initiation of a DOAC if appropriate, especially if the patient is also prescribed gastric irritant drugs that can’t be stopped.

Summary

Strokes due to AF are effectively prevented with warfarin or DOACs. Anticoagulation in AF is still underused and one-third of patients are inadequately treated with aspirin, despite the strong evidence for oral anticoagulants and introduction of DOACs. The slow uptake of DOACs has been a result of a number of behaviours and organisation barriers. The net clinical benefit of oral anticoagulants increases with age and is the highest among older patients perceived to be at high risk of bleeding and falls. Tools such as HAS-BLED can be used to calculate the risk of bleeding and modifiable factors identified for correction rather than used as a stop tool for oral anticoagulation. Patients may have different perspectives on bleeding risks and accept a higher risk than clinicians in order to prevent disabling and debilitating strokes but their involvement is not always facilitated with shared decision making. The choice of oral anticoagulant offered should follow national guidelines. Patients identified to be at risk of AF-related stroke and patients inadequately anticoagulated with aspirin should be prescribed warfarin or a DOAC after discussion with them and consideration of risk and benefits. Education of both patients and prescribers continues to be a vital factor in overcoming barriers to use of oral anticoagulants for SPAF. GPs need to be provided with tools and support to confidentially and safely prescribe and monitor DOACs.

Declaration of interests

Duncan Petty has received a fee from Bayer for presenting at a conference.

Kristina Medlinskiene is a pharmacist at United Leeds Teaching Hospitals and a PhD student at University of Bradford School of Pharmacy and Duncan Petty is a research pharmacist at the University of Bradford School of Pharmacy and chairman of Prescribing Support Services Ltd.

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Oral anticoagulants for stroke prevention in nonvalvular AF

 

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