establishing peer-consensus for the optimal
TRANSCRIPT
Establishing peer-consensus for the optimal anticoagulation
treatment in the ageing population with NVAF A Prescriber
supplement commissioned and sponsored by Daiichi Sankyo UK
Ltd
CURRENT THINKING
2 A Prescriber publication 2021
Background Atrial fibrillation (AF) is the most com- monly sustained cardiac arrhythmia, with an increasing prevalence due to improved survival rates from conditions such as ischaemic heart disease (IHD) as well as an expanding ageing population.1
AF that does not result from a mechanical heart valve or mitral stenosis is often referred to as nonvalvular AF or NVAF. One in four middle-aged adults in Europe will develop AF and this is expect- ed to rise sharply in the future. Estimates suggest an AF prevalence of approx- imately 3% in adults aged 20 years or older, with greater prevalence in older persons and in patients with conditions such as hypertension, heart failure, coro- nary artery disease (CAD), valvular heart disease, obesity, diabetes mellitus, or chronic kidney disease (CKD).2
AF presents a significant risk if untreated If left untreated, AF is a significant risk factor for stroke and other morbidities such as thromboembolism. In particular, AF is associ- ated with a 3- to 5fold increased risk of ischaemic stroke, and the attributable risk of stroke associated with AF increases from 1.5% in subjects aged 50 to 59 years of age to 23.5% among those aged 80 to 89 years. Up to 30% of ischaemic stroke patients have AF diagnosed before, during or after the initial event.1-4
In the occurrence of stroke, the presence of AF is associated with greater severity of stroke and increased risk of early death com- pared with non-AF.5,6
Costs of AF and stroke are significant In 2016, the overall burden of management of patients with AF with/without an ischae-
mic stroke/major bleeding event would relate to an annual cost between £9,000- 18,000, this equates to total annual direct cost to the NHS of between £8.1 and £16.2 billion.1 In 2015, the average cost of a stroke per person was £45,409 in the first 12 months after stroke (cost of incident stroke), plus £24,778 in subsequent years (cost of preva- lent stroke). Stroke is a principle cause of disa- bility in the UK, with almost two thirds of sur- vivors in England, Wales and Northern Ireland leaving hospital with a disability.7,8 The aver- age cost of NHS and Personal Social Services (PSS) care in the first year after a severe stroke is almost double that for a minor stroke (£24,003 compared to £12,869). Of the NHS and PSS costs, the cost attributed to NHS-funded care is £3.4 billion.7
Effective stroke prevention in NVAF Anticoagulation remains the single inter-
Establishing peer-consensus for the optimal anticoagulation treatment in the ageing population with NVAF
Authors
Bakhai A, Royal Free Hospital, London Batt T, Aneurin Bevan University Health Board (Retired), Wales Beale K, University Hospitals Birmingham NHS Foundation Trust, Birmingham Chelliah R, University Hospitals of Leicester, Leicester Guyler P, Southend University Hospital Trust, Southend Kankum P, Kent & Medway CCG, Kent Kavia K, Manor Medical Centre, Thurmaston Mashru V, East Leicestershire and Rutland Clinical Commissioning Group, Leicester Prescott C, University Hospitals Dorset, Dorset
Declarations of interest AB: clinical trials for var. pharma and device partners, incl. Roche; scientific advice and educational services to Roche and other companies. TB, KB, VM: no declarations. RC: no conflicts. PG: travel grants, conference and/or speaker fees from pharma compa- nies involved in DOAC therapies, incl. Daiichi Sankyo, Boehringer Ingelheim, Bayer, BMS Pfizer; principal investigator for NIHR-ap- proved clinical trials funded by some of these companies, but no direct financial interest from these. PK: travel grants from Daiichi Sankyo. KK: speaker fees: Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmith- Kline, Novartis, Novo Nordisk, Pfizer, Sanofi; Diabetes Professional Care publication(s): Novo Nordisk; advisory boards: Amgen, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Eli Lilly; research grants/funding: Bristol-Myers Squib, Pfizer, Daiichi Sankyo, Novo Nordisk. CP: consultancy work with Bayer and BMS-Pfizer.
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3A Prescriber publication 2021
vention which can mitigate the risk of stroke; a leading cause of disability and mortality.9,10 If patients are given the correct treatment, anticoagulation can prevent most ischaemic strokes in patients with AF and prolong life.2 Oral anticoagulants (OACs) such as vitamin K antagonists (VKA) have been commonly used but over the last decade direct oral anticoagulants (DOACs, sometimes called novel oral anti- coagulants or NOACs) have been intro- duced as a more convenient, fixed-dose alternative. Compared with VKA, DOAC therapy avoids the need for regular labora- tory monitoring of patients by international normalised ratio (INR) testing due to a wider therapeutic window, allows once (edox- aban, rivaroxaban) or twice (apixaban, dab- igatran) daily intake and is associated with fewer drug–drug interactions.9 The practi- cal aspects of a DOAC are important and include convenience, frequency of dosage and the need to take with or without food. European Society of Cardiology (ESC) guidelines (2016) state: When oral antico- agulation is initiated in a patient with AF who is eligible for a DOAC (apixaban, dab- igatran, edoxaban or rivaroxaban), a DOAC is recommended in preference to a vitamin K antagonist.2
The risk of all-cause mortality is lower with DOACs compared with warfarin and the risk of major or intracranial bleeding is reduced with most of the DOACs relative to warfarin, although the DOACs are asso- ciated with substantial non-neurological bleeding risk.10
Despite the publication of numerous guidelines on AF management, a substan- tial proportion of eligible patients are undertreated (Figure 1).11,12 Antico ag- ulation can significantly reduce the risk of stroke and though some doctors have been reluctant to prescribe these drugs because of concerns about bleeding, for most people this benefit (stroke risk reduction) outweighs the risks.12
Ageing patients with AF Patients with NVAF are at increased risk of both stroke and bleeding events as they
age2–4, making treatment particularly com- plex. Many clinicians continue to underuse anticoagulation in those elderly patients (i.e. filtered by chronological age alone) who could benefit from it. Although clinical experience with the DOACs is limited compared to that of warfarin, sub- group analyses demonstrate the relative merits of DOACs in the treatment of the latter cohort.12
A significant number of stroke patients are below 70 years of age (Figure 2), suggesting that the term ‘elderly’ is of limited use in defining this patient cohort; there is a need to consider other factors such as the presence of comorbidities and complexities when assessing stroke risk and appropriate preventative interven- tions. Approximately 73% of all stroke patients in the UK have at least one comor-
bidity, and 13% have three or more (Figure 3). Regardless of ‘elderly’ status, these patients could be considered to be part of an ‘ageing’ NVAF population.15
Age is not the only proxy in determining risks associated with NVAF. The authors agreed the following definition of ageing patients with NVAF:
Patients with NVAF living with, and developing, comorbidities and medical complexity as they age16
Objectives The objectives of this project are to under- stand the attitudes of clinicians from across the UK and define a clear consensus from a large sample of respondents. This will provide clarity on the specific consid- erations required in the approach to NVAF management in ageing patients and the optimal use of OACs in stroke prevention. In pursuing these objectives, this group intends to understand attitudes and identify challenges within it so that clear calls-to-action may be defined. This may help to support alignment between the views of various roles and regions of the
The prevalence of AF increases with age and occurs in 6% of the over 65 population.14
Figure 1. Percentage of patients in AF receiving anticoagulation treatment13
The percentage of patients with AF receiving anticoagulation treatment by age group for the period April 2017 to March 2018. Adapted from: Healthcare Quality Improvement Partnership. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit April 2013 – March 2018 Annual Public Report. National Results. June 2019. SSNAP applies to England, Wales and Northern Ireland.
40
30
20
10
0
UK and inform practice in managing NVAF in ageing patients.
Methodology A UK expert-steering group met in October 2019 to review the current land- scape and identify key topics in the NVAF care pathway through discussion. The key topics agreed were: 1. Differing complexities of patients with
NVAF (Table 2) 2. Prescribing considerations (Table 4) 3. NVAF monitoring (Table 6)
4. Anticoagulation service delivery (Table 7)
5. Education and counselling (Table 8) 6. Research (Table 9)
These topics were each further discussed in order to generate consensus statements that reflected the group’s thinking, for testing across a wider audience of healthcare profes- sionals (HCPs) involved in NVAF care. Consen- sus statements (n=40) were identified (see Appendix), these statements were construct- ed to provide insight into the use of anticoag-
ulants in UK practice. The statements were collated into a questionnaire, which was sent to HCPs (Geriatricians, Cardiologists, Emer- gency Physicians, GPs, Nurses, Pharmacists, Heads of Medicine Management (HoMM) and Clinical Commissioning Group (CCG) Commissioners) who identified themselves as being involved in the care of patients with NVAF. Respondents were engaged by an independent agency using a third party data- base. No honorarium was provided for com- pletion of the questionnaire. The group wished to compare any pat- terns of response from different roles and regions of the UK, so the questionnaire cap- tured role and geographic region. Respondents were offered a 4-point Lik- ert scale to rate their agreement with each statement, ranging across ‘strongly disagree’, ‘tend to disagree’, ‘tend to agree’ and ‘strongly agree’. Completed questionnaires were collat- ed and the individual scores for each state- ment analysed in order to produce an arith- metic agreement score for each. The responses were broken down further by role and UK region in order to identify variances in the respondent’s agreement scores. The majority of responses were from England (313/371; Table 1). The steering group (A Bakhai, T Batt T, K Beale, R Chelliah, P Guyler, P Kankum, K Kavia, V Mashru, C Prescott – see author details for affiliations) predefined the threshold of agreement for consensus at 70% and over. Consensus was defined as ‘high’ at ≥70% and ‘very high’ at ≥90%. Further rounds of ques- tionnaire distribution were considered; how- ever, due to the high levels of agreement with all but two of the 40 statements, the group elected to work with the original responses to the statements.
Results Completed questionnaires were returned by 371 UK respondents and analysed to define the total level of agreement with each of the 40 statements. Figure 4 and Table 1 summa- rise the demographics of the respondents. Tables 2, 4 and 6–9 show the 40 statements and the consensus score for each one. The scores are also summarised in Figure 5.
35
30
25
20
15
10
5
Age breakdown (years)
(% )
Figure 2. Age profiles of stroke admissions and discharges in the UK (Jan-Mar 2020)
16.0
10.1
15.1
Figure 3. Comorbidity profiles of stroke admissions and discharges in the UK (Jan-Mar 2020)
Adapted from: Healthcare Quality Improvement Partnership. SSNAP Portfolio for January–March 2020 admissions and discharges. July 2020.15 SSNAP applies to England, Wales and Northern Ireland.
35
30
25
20
15
10
5
Number of comorbidities
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Discussion Respondents agreed that ageing patients represent those who are not actively anticoagulated due to the presence of risk factors such as advanced age, the presence of one or more comorbidities or those at a high risk of falls (Statement 1, 71%). • The HAS-BLED17 score is used to assess
major bleeding risk in patients with AF and includes age >65 years as a contributor to overall risk of bleeding.
• The exclusion of ageing (elderly and/or complex) patients from many clinical trials can limit best clinical practice (State- ment 3, 81% agreement), it is therefore mportant to extrapolate relevant data from clinical studies including real world evi- dence (RWE).
• There was no overall consensus regarding a lack of clinical guidelines for ageing patients with NVAF being a limiting factor for best clinical practice; this may be due to differ- ences in perception of the term ‘ageing’ or potential variations in practice.
Analysis of this question based on role shows that no specific role group achieved consen- sus agreement for this statement and the lowest agreement was among geriatricians with an agreement score of 33%, this sug- gests that specialists in treating NVAF may be more cognisant of guidelines or more com- fortable in applying best practice in their absence. HCPs strongly agree that evidence should be applied in making treatment deci- sions (Statement 4, 92% agreement) and that
those classed as complex are best managed by specialist multidisciplinary team (MDT) (Statement 5, 80% agreement). All groups agreed that a lack of confidence in the HCP may deem some patients to be seen as com- plex (Statement 6, 81% agreement) indicat- ing perhaps that HCP education regarding AF may be needed for some specific roles (HoMM and Nurses provided the strongest agreement to this statement of 86% and 83%, respectively). There was also clear agreement that complex patients with NVAF may not always receive appropriate anticoag- ulation. Primary Care practitioners may focus on onward referral for complex patients (as t h e a v e r a g e p r i m a r y c a r e practitioner may not see many patients with AF annually) whereas ambulatory care patients may be afforded greater consideration and would be actively monitored by hospital specialists. ESC and NICE guidance are seen as key in the UK, but community HCPs may not be as familiar with differentiating or supporting data as specialists. The NHS Long Term Plan18 prioritises the prevention of strokes through anticoagula- tion of patients with AF; this will become even more important as the UK population ages. If a decision is made not to anticoagu- late a patient then that patient will be at greater risk of stroke with potentially greater healthcare resource need and costs to the wider health system (e.g. care costs, drug costs, social care costs, loss of employment). The decision not to anticoagulate a patient should therefore be made in conjunction with a specialist MDT. Even when best practice is adopted and anticoagulation is recommended, poor ad herence to treatment will result in lack of adequate stroke prevention. Adherence in ageing patients is challenging due to the greater incidence of comorbidities such as dementia and poor mobility. It is recommended to use CHA2DS2- VASc19 and HAS-BLED to assess risk along- side other factors (including adherence) when considering treatment for the age- ing population with NVAF. It should be noted that the HAS-BLED score was not
Table 1. Respondents by UK region
Group Number of respondents (n)
England (North) 77
England (South or South West exc. London) 70
England (London) 79
n= 9
n= 14
n= 71
n= 66
n= 40
n= 81
n= 37
n= 53
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6 A Prescriber publication 2021
designed to avoid or stop anticoagulation but to assess/modify risk of bleeding. It is important that these patients are reviewed at least annually (and more frequently as need-
ed) with each identified risk factor addressed. When selecting a DOAC for use in ageing patients, it is recommended that: • Randomised Controlled Trial (RCT) data be
extrapolated for this population; • Chronological age, co-morbidities (includ-
ing polypharmacy) and frailty are consid- ered;
• Differences in mechanism of action and the potential implications for drug metabolism and drug-drug interactions should always be considered.
The high level of agreement of all state- ments in this section provides a strong base to make recommendations regarding pre- scribing considerations, although response to Statement 12 was at the threshold of con- sensus. Analysis of responses to Statement 12 reveals some variation, the highest level of agreement was from Pharmacists (83.1; n=71) and the lowest was from Geriatricians (42.5%; n=40). Optimal persistence and adherence are a key factor in preventing strokes using oral anticoagulants. In this context, some HCPs m ay c o n s i d e r d o s i n g re g i m e n s relevant. A meta-regression of persistence to cardiac medications confirmed that people on twice-daily dosages are 23% less likely to have good persistence than those with once-daily regimes, and a US study (n=36,868) comparing DOACs noted higher likelihood of suboptimal adherence for twice-daily dosing with apixaban or dabiga- tran (combined), than for once - daily dosing with edoxaban or rivaroxaban (combined).25 Counselling for DOACs should be based on stroke prevention rather than treatment to assist in achieving adherence as patients are often asymp tomatic and less inclined to adhere to regular DOAC use.26
When considering an appropriate DOAC treatment, ageing patients with NVAF may require: • As simple a routine as possible (such as
once-daily dosing) • The ability to take a DOAC with or without
food; this is important in patients who have erratic eating habits (i.e. patients with dementia)
• Considerations around potential poor vision
• Considerations around poor dexterity • Considerations around cognitive
function and memory (including carer
100
90
80
70
60
50
40
30
20
10
0
Figure 5: Consensus Scores by Statement
NOTE: Green horizontal line represents the 70% threshold for consensus agreement, red line shows the 33% agreement level, the blue line indicates the threshold for very high consensus (90%).
Table 2. Differing complexities of patients with NVAF
No: Topic: Statement: Score %
1 Differing complexities of patients with NVAF
Ageing patients with NVAF are those who are within licence, but not actively anticoagulated due to concerns about potential risk (e.g. due to age, comorbidity or those at a high risk of fall)
71%
2 Ageing patients with NVAF do not fit into current clinical guidelines and this can limit best clinical practice
50%
3 Best clinical practice can be limited due to the fact that many trials exclude complex and ageing patients in their study population
86%
4 All patients with AF should be managed according to available evidence
92%
5 Complex patients with AF are best managed via a specialist MDT
80%
6 A lack of confidence of behalf of the HCP can deem some patients to be seen as complex
81%
7 A significant number of complex patients do not receive appropriate anticoagulation
77%
support levels) • Patient education and close monitoring to
ensure good adherence Data from ETNA-AF-Europe32 n= 13,092) and the European cohort of ENGAGE AF-TIMI 4833 (n= 3322) respectively, demonstrates
that compared with warfarin, edoxaban is associated with a lower incidence of major bleeding (1.05% vs 2.15%); a similar rate of all-cause mortality (3.50% vs 3.46%); a lower incidence of CV-mortality (1.63% vs 2.47%) (see Figure 6).
ETNA-AF-Europe provides further evidence for the use of edoxaban in ageing patients; the mean age of patients complet- ing 1-year follow up was 73.6 years, rising to 79.5 years among patients who received a dose reduction.31
Increased risk of falling is indepen- dently associated with an elevated risk for major bleeding, fractures caused by a fall, and mor- tality in ageing anticoagulated patients. A pre-specified analysis of ENGAGE AF-TIMI 48 found that compared with warfarin, edox- aban has demon- strated a greater absolute risk reduction in severe bleeding events (ARR, –141 events/10,000 patient-years [95% CI: –272 to –10]) and all-cause mortality (ARR, –66 [95% CI: –331 to +199]) in these patients.34 Frailty levels, comorbidity profiles, poten- tial drug–drug interactions and age should all be considered when selecting a DOAC. One- year safety results appear to support the safety profile of edoxaban in routine clinical practice and reinforce the results previously reported in randomised-controlled trials. Edoxaban should therefore be considered an appropriate treatment for ageing patients with NVAF. There was strong agreement for each statement in this topic (92–97% agreement) demonstrating the importance of monitor- ing DOAC patients within 3 months of initia- tion and then at least annually for non-com- plex patients. More complex patients
Table 3. Impact of CYP metabolism in patients with comorbidities who are on polypharmacy – features of current DOACs.
Dabigatran20 Rivaroxaban20,21 Apixaban20,22 Edoxaban23,24
Target IIa (thrombin) Xa Xa Xa
Hours to Cmax 1.25-3 2-4 3-4 1-2
CYP metabolism None 66% Yes <1%
Bioavailability ~6.5% ~90% ~50% for doses up to 10mg ~62%
Transporters P-gp P-gp/BCRP P-gp/BCRP P-gp
Protein binding 35% in humans 92-95% in humans 87% in humans 55% in vitro
Half-life 12-14 h 5-13 h ~12h 10-14 h
Renal elimination 80% 33% 27% 50%
Table 4. Prescribing considerations
No: Topic: Statement: Score %
8 Prescribing considerations
When considering potential DOAC options, consideration should be given to dosing regimen
96%
9 When considering potential DOAC options, consideration should be given to adherence
99%
10 When considering potential DOAC options, consideration should be given to frailty levels
89%
11 When considering DOAC options, consideration should be given to the safety profile
98%
12 When considering potential DOAC options, consideration should be given to age
70%
13 When considering potential DOAC options, consideration should be given to a patient’s comorbidities
96%
14 When considering potential DOAC options, consideration should be given to a patient’s counselling needs
85%
15 When considering potential DOAC options, consideration should be given to a patient’s monitoring needs
89%
8 A Prescriber publication 2021
(including ageing patients) may require more frequent monitoring, particularly during any intercurrent condition likely to impact on renal and/or liver function. Where specialist resource to monitor patients is in limited supply, there may be utility in the use of the wider healthcare team including HCAs and pharmacy technicians. Any personnel undertaking monitoring of patients taking a DOAC should have a clear understanding of any ‘red flags’ that would require rapid referral to specialist support. Patients should be reviewed within 1 month of DOAC initiation in ageing patients or soon- er if the patient makes contact with the healthcare provider. In some instances, patients can be reviewed online or via tele- phone or videoconference using different toolkits including questionnaires. The COVID-19 pandemic is having a sig- nificant impact on the UK and it is important that consideration is given to protecting vul- nerable patients, including the need for shielding and the impact on the HCP deliver- ing care. There is a need for the NHS to risk-stratify patients with NVAF and prioritise monitoring; the NHS must ensure prescribing decisions are informed by available evidence for the ageing population with NVAF. NHS England guidance35 (March 2020) in light of COVID-19 recommends that DOACs should be initiated, if possible, instead of warfarin to minimise the monitoring burden and that remote consultations to initiate anticoagu-
lant therapy and provision of follow-up by telephone be used, where possible. All statements in this section achieved consensus (70–98% agreement). There was agreement that cost is a consideration when choosing a DOAC in the UK (Statement 22, 70%), but responses to this statement may differ in other health economies. Respondents agree that DOACs should be regarded as the standard of care for anti- coagulation in NVAF. It was agreed by respondents that pharmacy and nursing staff are currently under utilised in monitoring patients; services should consider how these
roles are best deployed to achieve good out- comes for the patient and the NHS. To support the wider use of different roles in managing patients with NVAF (including the primary/secondary care inter- face) providers should consider the use of an integrated care pathway (ICP) for ageing patients with NVAF seen in Primary Care as this would be helpful to commission NVAF services against. An ICP may also help to reduce variations in care and support audit activity. In general, respondents feel confident in initiating and managing DOAC treatment
Table 5. Clinical outcomes of DOACS vs. warfarin in patients ≥75 years27
DOAC (Study) N. patients
Dabigatran 110 mg/ 150 mg (RE-LY)28
7,258 Median 2.0 Stroke/ SEE D110 vs. W: HR 0.88 (0.66-1.17) D150 vs. W: HR 0.67 (0.49-0.90)
D110 4.4% yr / D150 5.1% yr vs. W 4.4% yr D110 vs. W: P=0.89 D150 vs. W: P=0.07
Rivaroxaban 20 mg vs. warfarin (ROCKET AF)29
6,229 2 Stroke/ SEE HR 0.80 (0.63-1.02) 4.9% yr vs. 4.4 % yr HR 1.11 (0.92-1.34)
Apixaban 5 mg (ARISTOTLE)30
5,678 1.8 Stroke/ SEE HR 0.71 (0.53-0.95) 3.3%yr vs. 5.2 %yr P<0.05
Edoxaban 60 mg (ENGAGE AF)31
8,474 2.8 Stroke/ SEE HR 0.83 (0.66-1.04) 4.0% yr vs. 4.8% yr P<0.05
HR, hazard ratio; OR, odds ratio; RR, risk reduction; SEE, systemic embolic event; W, warfarin.
5.0
4.0
3.0
2.0
1.0
0.0 Incidence of Rate of all-cause Incidence of major bleeding mortality cardiovascular mortality
P ec
en ta
g e
o f
p at
ie nt
)
Figure 6. Bleeding and mortality outcomes for patients treated with edoxaban and warfarin32,33
ETNA-AF-Europe (n=13,092)
1.05
2.15
9A Prescriber publication 2021
in patients with NVAF, however , there was a clear difference of opinion regarding com- plex patients (Statement 35, 67%). Special- ist respondents (Geriatrician, Cardiologist)
are confident in managing complex patients (98% and 86% agreement, respec- tively) but other roles (Nurse, Pharmacist, HoMM, Emergency Physician) did not
achieve consensus in their individual responses (45%, 52%, 54%, 57% agree- ment, respectively). This difference is per- haps to be expected; it is logical that those in roles who have the greatest experience of prescribing DOACs in NVAF would be more confident in doing so. It is encourag- ing that GPs achieved consensus agree- ment with Statement 35 (72% agreement) although there is some variation given the response to Statement 23 (There is a cohort of ageing patients with NVAF who are not anticoagulated in Primary Care but should be; 85% agreement), which is supported by the evidence base1 that suggests approxi- mately 15% of patients with AF are not pre- scribed anticoagulants in Primary Care. Data from SSNAP15 (January–March 2020, n=21,379) reports that 19% of UK stroke patients had an existing AF diagnosis on admission to hospital and a further 6% received a diagnosis during their hospital admission; this suggests that approximate- ly a quarter of patients with AF are undiag- nosed prior to a stroke. The majority of diag- nosed pat ients were prescr ibed anticoagulant medication with 76% receiv- ing a DOAC and 24% a VKA. The INR of those patients prescribed a VKA varied sig- nificantly with 38% within the broadly opti- mal 2–3 range.36 Primary care prescribers should have confidence in both initiation and repeat prescription of DOACs in ageing patients but with appropriate referral for the most complex cases. The Primary Care Network (PCN) should refer to the Secondary Care link (i.e. anti-coagulation MDT representa- tive) as needed. Evidence is emerging regarding the safety of using DOACs in age- ing patients and clinicians should consider the safety profiles of individual DOAC treat- ments when making prescribing decisions. Respondents agreed that education and counselling should be accessible and ongoing. In response to COVID-19, it is anticipated that this will move to virtual delivery over time. Those patients who can- not access virtual methods (particularly relevant in ageing patients) may require individualised plans.
Table 6. NVAF Monitoring
No: Topic: Statement: Score %
16 NVAF Monitoring
Within 3-months after DOAC initiation, all patients should be reviewed to ensure correct dosing
92%
17 All DOAC patients should be monitored at least annually in line with NICE guidance
97%
18 Some patients, including those deemed complex, require more frequent monitoring
94%
19 Access to timely specialist advice should be available for all DOAC patients when required
96%
No: Topic: Statement: Score %
20 Anticoagulation service delivery
All DOAC patients should know which HCP to contact when required
98%
21 An interruption to DOAC therapy may require MDT support
73%
22 Cost is a consideration when choosing an appropriate DOAC
70%
23 There is a cohort of ageing patients with NVAF who are not anticoagulated in Primary Care but should be.
86%
82%
25 Choice of anticoagulation treatment should not be determined by commissioning arrangements
81%
26 DOACs should be the standard of care for anticoagulation in NVAF
91%
27 Pharmacy has an under-utilised role in the monitoring of anticoagulation patients at present
83%
28 Nursing has an under-utilised role in the monitoring of anticoagulation patients at present
74%
29 An integrated care pathway for ageing patients with NVAF seen in Primary Care would be helpful to commission NVAF services against
96%
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There was strong agreement with all three statements in this topic, confirming the importance and relevance of RWE in informing practice in NVAF. Regarding DOACs, RWE studies may vary greatly in design and outcomes; large multi-centre studies may provide the most robust data to add to the evidence base. Age is not the only factor in determin- ing risks associated with NVAF, for exam- ple, a fit and healthy 85 year old may be associated with lower bleeding and stroke risks than a younger but frailer individual. The Rockwood score37 gives a score ofclinical frailty but is not helpful in isolation. The HAS-BLED score is used to determine major bleeding risk, the
CHA2DS2-VASc calculates stroke risk for patients with AF. Due to the significance of a stroke to the patient, if there is a risk of stroke, neither the Rockwood nor HAS- BLED scores should be reasons NOT to anticoagulate a patient with NVAF. Anti- coagulation can significantly reduce the risk of stroke and though some doctors have been reluctant to prescribe these drugs because of concerns about bleed- ing, for most people this benefit (stroke risk reduction) greatly outweighs the risks.12
Conclusion NVAF is a significant risk factor for stroke and thromboembolism, both of which are
associated with significant patient impact (including mortality) and costs to the wider health system. The use of anticoag- ulants in patients with NVAF has been established in common medical practice for many years; more recently, the devel- opment of DOACs has provided a more convenient, fixed-dose alternative to VKA with reduction in major bleeding, in par- ticular intracranial hemorrhage. Despite these recent advances there are a number of patients who are currently undertreat- ed. This consensus project was established to understand the attitudes of HCPs towards NVAF treatment (and specifically DOACs in ageing/complex patients) in the UK and to provide a set of recommenda- tions to inform practice regarding the opti- mum anticoagulation treatment in the ageing population with NVAF. Responses from 371 HCPs involved in the management of NVAF demonstrated agreement with 95% (38/40) of the state- ments developed by the steering group. Two statements did not achieve consensus threshold (Statements 2 and 35). The response to Statement 2 (Ageing patients with NVAF do not fit into current clinical guidelines and this can limit best clinical practice; 50%) could be due to specialists being most comfortable with relevant guidelines and best practice compared to other roles (i.e. pharmacist, nurse, CCG commissioner), or it may be that there is an element of ambiguity in the use of the term ‘ageing patients’; a universal defini- tion of this cohort of patients would be useful when discussing best practice. Statement 35 (I feel confident in my ability to initiate DOAC use in complex patients; 67%) also did not achieve consensus, and the response levels between roles indicate that specialist roles (geriatrician, cardiolo- gist) achieved consensus agreement and whereas non-specialist roles achieved lower levels of agreement. The high levels of consensus provide a strong platform for the recommendations made by the steering group and support the role of DOACs in the anticoagulation of ageing patients with NVAF. These recom-
Table 8. Education & Counselling
No: Topic: Statement: Score %
30 Education & Counselling
Access to counselling should be available for all DOAC patients when required
96%
31 Both NVAF patient education and DOAC counselling should be ongoing
89%
32 I feel confident in my ability to initiate DOAC use in general
86%
33 I feel confident in my ability to continue prescribing of DOACs in general
86%
34 I feel confident in my ability to monitor DOACs in general
86%
35 I feel confident in my ability to initiate DOAC use in complex patients
67%
36 I feel confident in my ability to continue prescribing of DOACs in complex patients
70%
37 I feel confident in my ability to monitor DOACs in complex patients
75%
No: Topic: Statement: Score %
38 Research Real world evidence (RWE) should be proactively collected about the use and monitoring of DOACs
96%
39 Collecting RWE can support continuity of care of NVAF in an ageing population
97%
40 Collecting RWE will support the knowledge base to improve NVAF care in an ageing population
97%
11A Prescriber publication 2021
mendations are offered in order to provide guidance on the appropriate use of DOACs in a cohort of ageing patients who may currently be under treated and therefore at risk of stroke.
Recommendations The following recommendations are offered based on the learnings identified through the consensus exercise : 1. An ageing patient is defined as: A patient with NVAF living with, and devel- oping, comorbidities and medical complexity as they age 2. The following criteria should be assessed by the non-specialist to identify and con- sider the ageing patient with NVAF: • Renal function (creatine clearance) • Age and weight (dosing) • Drug-drug interactions (polypharmacy) • Frailty and fall risk • Previous GI bleed and history of peptic
ulcers. • History of IHD and potential need for
concurrent antiplatelet treatment • CHA2DS2-VASc/HAS-BLED Score • Other lifestyle factors (diabetes, social
history, use of NSAIDs) • Alcohol use 3. Non-specialists should be able to initiate DOACs (or know where to refer) in Primary Care and should consider the following: • Is there a clinical reason not to anticoag-
ulate an ageing patient with NVAF? • DOACs are preferable over warfarin in
ageing patients with NVAF where no exclusion criteria exist
4. Choice of a DOAC should be proactively considered with ageing patients and prac- tical factors are important such as: • Age • Frailty • Co-morbidities • Eating patterns • Adherence/persistence • Dosing • Polypharmacy and potential drug–drug
interactions
• Side-effect profile 5. A DOAC should be selected with evi- dence that substantiates its choice in the ageing patient cohort and edoxaban should be considered as an option for treating ageing patients with NVAF. 6. A specialist MDT should be organised (according to locality) and these ageing patients should be referred to the MDT and regional networks.
Limitations As with all surveys, potential limitations of this study include the way in which the questions were worded and the order in which they were asked, and how respond- ents were approached. However, the questions were constructed by the steer- ing group who also ratified the final form of the questionnaire before distribution. There was no specific representation from GPs on the steering group, this would have been useful in order to draw out any specific issues relating to the role of the
50
40
30
20
10
INR at arrival to hospital
P er
ce nt
(% )
Figure 7. AF diagnosis and medication status of stroke patients in the UK (Jan-Mar 2020)15
Of those with existing AF diagnosis, 66% were prescribed an anticoagulant
Of those receiving anticoagulant treatment, 76%
were prescribed a DOAC
Of those receiving VKA treatment, 38% had an International Normalised Ratio (INR) of 2–3 on arrival at hospital
Adapted from: Healthcare Quality Improvement Partnership. SSNAP Portfolio for January - March 2020 admissions and discharges. July 2020.15
New diagnosis on admission to hospital 6%, n=1190
Existing AF diagnosis 19%, n=4072
No existing AF diagnosis 75%, n=16,117
Antiplatelet only 8%, n=342
Neither medication 26%, n=1069
Anticoagulant and antiplatelet medication 3%, n=137
Anticoagulant only 62%, n=2,524
DOAC 75%, n=2480
42 38
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12 A Prescriber publication 2021
GP in managing NVAF. There was a strong response from England (313/371) compared with other regions (other parts of the UK). The overall results were therefore heavily influenced by practice in England. That said, comparison of responses between England and other regions did not show any significant variation in attitude to the consensus statements. This consensus was focussed specifically on clinical opinion with a view to defining and recognising the issues attached to anti- coagulation in ageing patients with NVAF. Patient experience has not been captured, this may help to further the understanding of NVAF and anticoagulation from the patient perspective and the optimal approach to pre- vention of strokes in these patients. It is hoped that this consensus review may act as a springboard to raise the issue of anticoagulation in ageing patients and con- tribute to the evidence base to support the Primary Care prescribing of DOACs in patients with NVAF.
Summary The results of the consensus have pro vided a strong indication of the atti- tudes of clinicians to the use of DOACs in the prevention of strokes in a patient cohort that may be under prescribed in Primary Care. The steering group were able to form a strong set of recommendations with the aim of clarifying the role of Pri- mary Care in managing a greater number of ageing patients with NVAF optimally
with DOACs. This consensus review should be repeated in 5 years to assess changes in practice and define more appropriate recommendations at that time.
References 1. Bakhai A, et al. J Eval Clin Pract 2020;27:119–33. 2. Kirchhof P, et al. Eur Heart J 2016;37:2893–962. 3. NICE. Atrial fibrillation: management [CH180]. https://www.nice.org.uk/guidance/cg180/ chapter/Introduction [Accessed 02 July 2020]. 4. Wolf PA et al. Stroke1991;22:983–8. 5. Kimura K, et al. J Neurol Neurosurg Psychiatry 2005;76:679–83. 6. Henninger N, et al. Stroke 2016;47:1486–92. 7. Stroke Association. Current, future and avoidable costs of stroke in the UK. Executive summary Part 2. October 2017. 8. Adamson J, et al. J Stroke Cerebrovasc Dis 2004;13:171–7. 9. Maura G, et al. BMJ Open 2019;9(4):e026645. 10. López-López JA, et al. BMJ 2017;359:j5058. 11.Marzec LN, et al. J Am Coll Cardiol 2017; 69:2475–84. 12. Foody JM. Clin Interv Aging 2017;12:175–87. 13. Healthcare Quality Improvement Partner- ship. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit April 2013–March 2018 Annual Public Report. National Results. June 2019. 14. Feinberg WM, et al. Arch Intern Med 1995;155:469–73. 15. Healthcare Quality Improvement Partner- ship. SSNAP Portfolio for January – March 2020 admissions and discharges. July 2020. 16. Guyler, P. Presentation at UK Stroke Forum, 7th December 2020. Prevention better than
cure: Addressing health inequalities to improve stroke prevention during COVID-19. 17. Pisters R, et al. Chest 2010;138:1093–100. 18. NHS. The NHS Long Term Plan. January 2019. 19. Lip GY, et al. Chest 2010;137:263–72. 20. Eriksson B, et al. Clin Pharmacokinet 2009;48:1–22. 21. Xarelto Summary of Product Characteristics. 22. ELIQUIS Summary of Product Characteristics. 23. LIXIANA Summary of Product Characteristics. 24. Parasrampuria DA, Truitt KE. Clin Pharmacokinet 2016;55:641–55. 25. Alberts MJ, et al. Int J Cardiol 2016;215:11–3. 26. Horne R, et al. PLoS One 2013;8:e80633. 27. Cavallari I, Patti G. Anatol J Cardiol 2018;19:67–71. 28. Eikelboom JW, et al. Circulation 2011; 123:2363–72. 29. Halperin JL, et al. Circulation 2014;130:138–46. 3 0 . H a l vo r s e n S , e t a l . Eu r H e a r t J 2004;35:1864–72. 31. K ato E T, et al . J Am Hear t Assoc 2016;5:e003432. 32. de Groot JR, et al. Eur Heart J Cardiovasc Pharmacother 2020; pvaa079. 33. de Groot JR, et al. Poster P4756. Presented at European Society of Cardiology Congress 2019, Paris, France; 31st August – 4th September 2019. 34. Steffel J, et al . J Am Coll Cardiol 2016;68:1169–78. 35. NHS England. Clinical guide for the man- agement of anticoagulant services during the coronavirus pandemic. 31 March 2020. 36. Lip GY, et al. BMJ 2002;325:1022–5. 37. Rockwood K, et al. CMAJ 2005;173:489–95.
Daiichi Sankyo UK Ltd were involved in the outline development and medico-legal approval of this supplement and provided financial support for its publication. The authors and publisher retained final editorial control of the content. The opinions expressed in the supplement are not necessarily those of the publisher or Daiichi Sankyo UK Ltd. Printed and published by John Wiley & Sons, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ © John Wiley & Sons 2021 Pr.2055
Date of preparation: July 2021 EDX/21/0629
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2 A Prescriber publication 2021
Background Atrial fibrillation (AF) is the most com- monly sustained cardiac arrhythmia, with an increasing prevalence due to improved survival rates from conditions such as ischaemic heart disease (IHD) as well as an expanding ageing population.1
AF that does not result from a mechanical heart valve or mitral stenosis is often referred to as nonvalvular AF or NVAF. One in four middle-aged adults in Europe will develop AF and this is expect- ed to rise sharply in the future. Estimates suggest an AF prevalence of approx- imately 3% in adults aged 20 years or older, with greater prevalence in older persons and in patients with conditions such as hypertension, heart failure, coro- nary artery disease (CAD), valvular heart disease, obesity, diabetes mellitus, or chronic kidney disease (CKD).2
AF presents a significant risk if untreated If left untreated, AF is a significant risk factor for stroke and other morbidities such as thromboembolism. In particular, AF is associ- ated with a 3- to 5fold increased risk of ischaemic stroke, and the attributable risk of stroke associated with AF increases from 1.5% in subjects aged 50 to 59 years of age to 23.5% among those aged 80 to 89 years. Up to 30% of ischaemic stroke patients have AF diagnosed before, during or after the initial event.1-4
In the occurrence of stroke, the presence of AF is associated with greater severity of stroke and increased risk of early death com- pared with non-AF.5,6
Costs of AF and stroke are significant In 2016, the overall burden of management of patients with AF with/without an ischae-
mic stroke/major bleeding event would relate to an annual cost between £9,000- 18,000, this equates to total annual direct cost to the NHS of between £8.1 and £16.2 billion.1 In 2015, the average cost of a stroke per person was £45,409 in the first 12 months after stroke (cost of incident stroke), plus £24,778 in subsequent years (cost of preva- lent stroke). Stroke is a principle cause of disa- bility in the UK, with almost two thirds of sur- vivors in England, Wales and Northern Ireland leaving hospital with a disability.7,8 The aver- age cost of NHS and Personal Social Services (PSS) care in the first year after a severe stroke is almost double that for a minor stroke (£24,003 compared to £12,869). Of the NHS and PSS costs, the cost attributed to NHS-funded care is £3.4 billion.7
Effective stroke prevention in NVAF Anticoagulation remains the single inter-
Establishing peer-consensus for the optimal anticoagulation treatment in the ageing population with NVAF
Authors
Bakhai A, Royal Free Hospital, London Batt T, Aneurin Bevan University Health Board (Retired), Wales Beale K, University Hospitals Birmingham NHS Foundation Trust, Birmingham Chelliah R, University Hospitals of Leicester, Leicester Guyler P, Southend University Hospital Trust, Southend Kankum P, Kent & Medway CCG, Kent Kavia K, Manor Medical Centre, Thurmaston Mashru V, East Leicestershire and Rutland Clinical Commissioning Group, Leicester Prescott C, University Hospitals Dorset, Dorset
Declarations of interest AB: clinical trials for var. pharma and device partners, incl. Roche; scientific advice and educational services to Roche and other companies. TB, KB, VM: no declarations. RC: no conflicts. PG: travel grants, conference and/or speaker fees from pharma compa- nies involved in DOAC therapies, incl. Daiichi Sankyo, Boehringer Ingelheim, Bayer, BMS Pfizer; principal investigator for NIHR-ap- proved clinical trials funded by some of these companies, but no direct financial interest from these. PK: travel grants from Daiichi Sankyo. KK: speaker fees: Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmith- Kline, Novartis, Novo Nordisk, Pfizer, Sanofi; Diabetes Professional Care publication(s): Novo Nordisk; advisory boards: Amgen, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Eli Lilly; research grants/funding: Bristol-Myers Squib, Pfizer, Daiichi Sankyo, Novo Nordisk. CP: consultancy work with Bayer and BMS-Pfizer.
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3A Prescriber publication 2021
vention which can mitigate the risk of stroke; a leading cause of disability and mortality.9,10 If patients are given the correct treatment, anticoagulation can prevent most ischaemic strokes in patients with AF and prolong life.2 Oral anticoagulants (OACs) such as vitamin K antagonists (VKA) have been commonly used but over the last decade direct oral anticoagulants (DOACs, sometimes called novel oral anti- coagulants or NOACs) have been intro- duced as a more convenient, fixed-dose alternative. Compared with VKA, DOAC therapy avoids the need for regular labora- tory monitoring of patients by international normalised ratio (INR) testing due to a wider therapeutic window, allows once (edox- aban, rivaroxaban) or twice (apixaban, dab- igatran) daily intake and is associated with fewer drug–drug interactions.9 The practi- cal aspects of a DOAC are important and include convenience, frequency of dosage and the need to take with or without food. European Society of Cardiology (ESC) guidelines (2016) state: When oral antico- agulation is initiated in a patient with AF who is eligible for a DOAC (apixaban, dab- igatran, edoxaban or rivaroxaban), a DOAC is recommended in preference to a vitamin K antagonist.2
The risk of all-cause mortality is lower with DOACs compared with warfarin and the risk of major or intracranial bleeding is reduced with most of the DOACs relative to warfarin, although the DOACs are asso- ciated with substantial non-neurological bleeding risk.10
Despite the publication of numerous guidelines on AF management, a substan- tial proportion of eligible patients are undertreated (Figure 1).11,12 Antico ag- ulation can significantly reduce the risk of stroke and though some doctors have been reluctant to prescribe these drugs because of concerns about bleeding, for most people this benefit (stroke risk reduction) outweighs the risks.12
Ageing patients with AF Patients with NVAF are at increased risk of both stroke and bleeding events as they
age2–4, making treatment particularly com- plex. Many clinicians continue to underuse anticoagulation in those elderly patients (i.e. filtered by chronological age alone) who could benefit from it. Although clinical experience with the DOACs is limited compared to that of warfarin, sub- group analyses demonstrate the relative merits of DOACs in the treatment of the latter cohort.12
A significant number of stroke patients are below 70 years of age (Figure 2), suggesting that the term ‘elderly’ is of limited use in defining this patient cohort; there is a need to consider other factors such as the presence of comorbidities and complexities when assessing stroke risk and appropriate preventative interven- tions. Approximately 73% of all stroke patients in the UK have at least one comor-
bidity, and 13% have three or more (Figure 3). Regardless of ‘elderly’ status, these patients could be considered to be part of an ‘ageing’ NVAF population.15
Age is not the only proxy in determining risks associated with NVAF. The authors agreed the following definition of ageing patients with NVAF:
Patients with NVAF living with, and developing, comorbidities and medical complexity as they age16
Objectives The objectives of this project are to under- stand the attitudes of clinicians from across the UK and define a clear consensus from a large sample of respondents. This will provide clarity on the specific consid- erations required in the approach to NVAF management in ageing patients and the optimal use of OACs in stroke prevention. In pursuing these objectives, this group intends to understand attitudes and identify challenges within it so that clear calls-to-action may be defined. This may help to support alignment between the views of various roles and regions of the
The prevalence of AF increases with age and occurs in 6% of the over 65 population.14
Figure 1. Percentage of patients in AF receiving anticoagulation treatment13
The percentage of patients with AF receiving anticoagulation treatment by age group for the period April 2017 to March 2018. Adapted from: Healthcare Quality Improvement Partnership. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit April 2013 – March 2018 Annual Public Report. National Results. June 2019. SSNAP applies to England, Wales and Northern Ireland.
40
30
20
10
0
UK and inform practice in managing NVAF in ageing patients.
Methodology A UK expert-steering group met in October 2019 to review the current land- scape and identify key topics in the NVAF care pathway through discussion. The key topics agreed were: 1. Differing complexities of patients with
NVAF (Table 2) 2. Prescribing considerations (Table 4) 3. NVAF monitoring (Table 6)
4. Anticoagulation service delivery (Table 7)
5. Education and counselling (Table 8) 6. Research (Table 9)
These topics were each further discussed in order to generate consensus statements that reflected the group’s thinking, for testing across a wider audience of healthcare profes- sionals (HCPs) involved in NVAF care. Consen- sus statements (n=40) were identified (see Appendix), these statements were construct- ed to provide insight into the use of anticoag-
ulants in UK practice. The statements were collated into a questionnaire, which was sent to HCPs (Geriatricians, Cardiologists, Emer- gency Physicians, GPs, Nurses, Pharmacists, Heads of Medicine Management (HoMM) and Clinical Commissioning Group (CCG) Commissioners) who identified themselves as being involved in the care of patients with NVAF. Respondents were engaged by an independent agency using a third party data- base. No honorarium was provided for com- pletion of the questionnaire. The group wished to compare any pat- terns of response from different roles and regions of the UK, so the questionnaire cap- tured role and geographic region. Respondents were offered a 4-point Lik- ert scale to rate their agreement with each statement, ranging across ‘strongly disagree’, ‘tend to disagree’, ‘tend to agree’ and ‘strongly agree’. Completed questionnaires were collat- ed and the individual scores for each state- ment analysed in order to produce an arith- metic agreement score for each. The responses were broken down further by role and UK region in order to identify variances in the respondent’s agreement scores. The majority of responses were from England (313/371; Table 1). The steering group (A Bakhai, T Batt T, K Beale, R Chelliah, P Guyler, P Kankum, K Kavia, V Mashru, C Prescott – see author details for affiliations) predefined the threshold of agreement for consensus at 70% and over. Consensus was defined as ‘high’ at ≥70% and ‘very high’ at ≥90%. Further rounds of ques- tionnaire distribution were considered; how- ever, due to the high levels of agreement with all but two of the 40 statements, the group elected to work with the original responses to the statements.
Results Completed questionnaires were returned by 371 UK respondents and analysed to define the total level of agreement with each of the 40 statements. Figure 4 and Table 1 summa- rise the demographics of the respondents. Tables 2, 4 and 6–9 show the 40 statements and the consensus score for each one. The scores are also summarised in Figure 5.
35
30
25
20
15
10
5
Age breakdown (years)
(% )
Figure 2. Age profiles of stroke admissions and discharges in the UK (Jan-Mar 2020)
16.0
10.1
15.1
Figure 3. Comorbidity profiles of stroke admissions and discharges in the UK (Jan-Mar 2020)
Adapted from: Healthcare Quality Improvement Partnership. SSNAP Portfolio for January–March 2020 admissions and discharges. July 2020.15 SSNAP applies to England, Wales and Northern Ireland.
35
30
25
20
15
10
5
Number of comorbidities
5A Prescriber publication 2021
Discussion Respondents agreed that ageing patients represent those who are not actively anticoagulated due to the presence of risk factors such as advanced age, the presence of one or more comorbidities or those at a high risk of falls (Statement 1, 71%). • The HAS-BLED17 score is used to assess
major bleeding risk in patients with AF and includes age >65 years as a contributor to overall risk of bleeding.
• The exclusion of ageing (elderly and/or complex) patients from many clinical trials can limit best clinical practice (State- ment 3, 81% agreement), it is therefore mportant to extrapolate relevant data from clinical studies including real world evi- dence (RWE).
• There was no overall consensus regarding a lack of clinical guidelines for ageing patients with NVAF being a limiting factor for best clinical practice; this may be due to differ- ences in perception of the term ‘ageing’ or potential variations in practice.
Analysis of this question based on role shows that no specific role group achieved consen- sus agreement for this statement and the lowest agreement was among geriatricians with an agreement score of 33%, this sug- gests that specialists in treating NVAF may be more cognisant of guidelines or more com- fortable in applying best practice in their absence. HCPs strongly agree that evidence should be applied in making treatment deci- sions (Statement 4, 92% agreement) and that
those classed as complex are best managed by specialist multidisciplinary team (MDT) (Statement 5, 80% agreement). All groups agreed that a lack of confidence in the HCP may deem some patients to be seen as com- plex (Statement 6, 81% agreement) indicat- ing perhaps that HCP education regarding AF may be needed for some specific roles (HoMM and Nurses provided the strongest agreement to this statement of 86% and 83%, respectively). There was also clear agreement that complex patients with NVAF may not always receive appropriate anticoag- ulation. Primary Care practitioners may focus on onward referral for complex patients (as t h e a v e r a g e p r i m a r y c a r e practitioner may not see many patients with AF annually) whereas ambulatory care patients may be afforded greater consideration and would be actively monitored by hospital specialists. ESC and NICE guidance are seen as key in the UK, but community HCPs may not be as familiar with differentiating or supporting data as specialists. The NHS Long Term Plan18 prioritises the prevention of strokes through anticoagula- tion of patients with AF; this will become even more important as the UK population ages. If a decision is made not to anticoagu- late a patient then that patient will be at greater risk of stroke with potentially greater healthcare resource need and costs to the wider health system (e.g. care costs, drug costs, social care costs, loss of employment). The decision not to anticoagulate a patient should therefore be made in conjunction with a specialist MDT. Even when best practice is adopted and anticoagulation is recommended, poor ad herence to treatment will result in lack of adequate stroke prevention. Adherence in ageing patients is challenging due to the greater incidence of comorbidities such as dementia and poor mobility. It is recommended to use CHA2DS2- VASc19 and HAS-BLED to assess risk along- side other factors (including adherence) when considering treatment for the age- ing population with NVAF. It should be noted that the HAS-BLED score was not
Table 1. Respondents by UK region
Group Number of respondents (n)
England (North) 77
England (South or South West exc. London) 70
England (London) 79
n= 9
n= 14
n= 71
n= 66
n= 40
n= 81
n= 37
n= 53
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6 A Prescriber publication 2021
designed to avoid or stop anticoagulation but to assess/modify risk of bleeding. It is important that these patients are reviewed at least annually (and more frequently as need-
ed) with each identified risk factor addressed. When selecting a DOAC for use in ageing patients, it is recommended that: • Randomised Controlled Trial (RCT) data be
extrapolated for this population; • Chronological age, co-morbidities (includ-
ing polypharmacy) and frailty are consid- ered;
• Differences in mechanism of action and the potential implications for drug metabolism and drug-drug interactions should always be considered.
The high level of agreement of all state- ments in this section provides a strong base to make recommendations regarding pre- scribing considerations, although response to Statement 12 was at the threshold of con- sensus. Analysis of responses to Statement 12 reveals some variation, the highest level of agreement was from Pharmacists (83.1; n=71) and the lowest was from Geriatricians (42.5%; n=40). Optimal persistence and adherence are a key factor in preventing strokes using oral anticoagulants. In this context, some HCPs m ay c o n s i d e r d o s i n g re g i m e n s relevant. A meta-regression of persistence to cardiac medications confirmed that people on twice-daily dosages are 23% less likely to have good persistence than those with once-daily regimes, and a US study (n=36,868) comparing DOACs noted higher likelihood of suboptimal adherence for twice-daily dosing with apixaban or dabiga- tran (combined), than for once - daily dosing with edoxaban or rivaroxaban (combined).25 Counselling for DOACs should be based on stroke prevention rather than treatment to assist in achieving adherence as patients are often asymp tomatic and less inclined to adhere to regular DOAC use.26
When considering an appropriate DOAC treatment, ageing patients with NVAF may require: • As simple a routine as possible (such as
once-daily dosing) • The ability to take a DOAC with or without
food; this is important in patients who have erratic eating habits (i.e. patients with dementia)
• Considerations around potential poor vision
• Considerations around poor dexterity • Considerations around cognitive
function and memory (including carer
100
90
80
70
60
50
40
30
20
10
0
Figure 5: Consensus Scores by Statement
NOTE: Green horizontal line represents the 70% threshold for consensus agreement, red line shows the 33% agreement level, the blue line indicates the threshold for very high consensus (90%).
Table 2. Differing complexities of patients with NVAF
No: Topic: Statement: Score %
1 Differing complexities of patients with NVAF
Ageing patients with NVAF are those who are within licence, but not actively anticoagulated due to concerns about potential risk (e.g. due to age, comorbidity or those at a high risk of fall)
71%
2 Ageing patients with NVAF do not fit into current clinical guidelines and this can limit best clinical practice
50%
3 Best clinical practice can be limited due to the fact that many trials exclude complex and ageing patients in their study population
86%
4 All patients with AF should be managed according to available evidence
92%
5 Complex patients with AF are best managed via a specialist MDT
80%
6 A lack of confidence of behalf of the HCP can deem some patients to be seen as complex
81%
7 A significant number of complex patients do not receive appropriate anticoagulation
77%
support levels) • Patient education and close monitoring to
ensure good adherence Data from ETNA-AF-Europe32 n= 13,092) and the European cohort of ENGAGE AF-TIMI 4833 (n= 3322) respectively, demonstrates
that compared with warfarin, edoxaban is associated with a lower incidence of major bleeding (1.05% vs 2.15%); a similar rate of all-cause mortality (3.50% vs 3.46%); a lower incidence of CV-mortality (1.63% vs 2.47%) (see Figure 6).
ETNA-AF-Europe provides further evidence for the use of edoxaban in ageing patients; the mean age of patients complet- ing 1-year follow up was 73.6 years, rising to 79.5 years among patients who received a dose reduction.31
Increased risk of falling is indepen- dently associated with an elevated risk for major bleeding, fractures caused by a fall, and mor- tality in ageing anticoagulated patients. A pre-specified analysis of ENGAGE AF-TIMI 48 found that compared with warfarin, edox- aban has demon- strated a greater absolute risk reduction in severe bleeding events (ARR, –141 events/10,000 patient-years [95% CI: –272 to –10]) and all-cause mortality (ARR, –66 [95% CI: –331 to +199]) in these patients.34 Frailty levels, comorbidity profiles, poten- tial drug–drug interactions and age should all be considered when selecting a DOAC. One- year safety results appear to support the safety profile of edoxaban in routine clinical practice and reinforce the results previously reported in randomised-controlled trials. Edoxaban should therefore be considered an appropriate treatment for ageing patients with NVAF. There was strong agreement for each statement in this topic (92–97% agreement) demonstrating the importance of monitor- ing DOAC patients within 3 months of initia- tion and then at least annually for non-com- plex patients. More complex patients
Table 3. Impact of CYP metabolism in patients with comorbidities who are on polypharmacy – features of current DOACs.
Dabigatran20 Rivaroxaban20,21 Apixaban20,22 Edoxaban23,24
Target IIa (thrombin) Xa Xa Xa
Hours to Cmax 1.25-3 2-4 3-4 1-2
CYP metabolism None 66% Yes <1%
Bioavailability ~6.5% ~90% ~50% for doses up to 10mg ~62%
Transporters P-gp P-gp/BCRP P-gp/BCRP P-gp
Protein binding 35% in humans 92-95% in humans 87% in humans 55% in vitro
Half-life 12-14 h 5-13 h ~12h 10-14 h
Renal elimination 80% 33% 27% 50%
Table 4. Prescribing considerations
No: Topic: Statement: Score %
8 Prescribing considerations
When considering potential DOAC options, consideration should be given to dosing regimen
96%
9 When considering potential DOAC options, consideration should be given to adherence
99%
10 When considering potential DOAC options, consideration should be given to frailty levels
89%
11 When considering DOAC options, consideration should be given to the safety profile
98%
12 When considering potential DOAC options, consideration should be given to age
70%
13 When considering potential DOAC options, consideration should be given to a patient’s comorbidities
96%
14 When considering potential DOAC options, consideration should be given to a patient’s counselling needs
85%
15 When considering potential DOAC options, consideration should be given to a patient’s monitoring needs
89%
8 A Prescriber publication 2021
(including ageing patients) may require more frequent monitoring, particularly during any intercurrent condition likely to impact on renal and/or liver function. Where specialist resource to monitor patients is in limited supply, there may be utility in the use of the wider healthcare team including HCAs and pharmacy technicians. Any personnel undertaking monitoring of patients taking a DOAC should have a clear understanding of any ‘red flags’ that would require rapid referral to specialist support. Patients should be reviewed within 1 month of DOAC initiation in ageing patients or soon- er if the patient makes contact with the healthcare provider. In some instances, patients can be reviewed online or via tele- phone or videoconference using different toolkits including questionnaires. The COVID-19 pandemic is having a sig- nificant impact on the UK and it is important that consideration is given to protecting vul- nerable patients, including the need for shielding and the impact on the HCP deliver- ing care. There is a need for the NHS to risk-stratify patients with NVAF and prioritise monitoring; the NHS must ensure prescribing decisions are informed by available evidence for the ageing population with NVAF. NHS England guidance35 (March 2020) in light of COVID-19 recommends that DOACs should be initiated, if possible, instead of warfarin to minimise the monitoring burden and that remote consultations to initiate anticoagu-
lant therapy and provision of follow-up by telephone be used, where possible. All statements in this section achieved consensus (70–98% agreement). There was agreement that cost is a consideration when choosing a DOAC in the UK (Statement 22, 70%), but responses to this statement may differ in other health economies. Respondents agree that DOACs should be regarded as the standard of care for anti- coagulation in NVAF. It was agreed by respondents that pharmacy and nursing staff are currently under utilised in monitoring patients; services should consider how these
roles are best deployed to achieve good out- comes for the patient and the NHS. To support the wider use of different roles in managing patients with NVAF (including the primary/secondary care inter- face) providers should consider the use of an integrated care pathway (ICP) for ageing patients with NVAF seen in Primary Care as this would be helpful to commission NVAF services against. An ICP may also help to reduce variations in care and support audit activity. In general, respondents feel confident in initiating and managing DOAC treatment
Table 5. Clinical outcomes of DOACS vs. warfarin in patients ≥75 years27
DOAC (Study) N. patients
Dabigatran 110 mg/ 150 mg (RE-LY)28
7,258 Median 2.0 Stroke/ SEE D110 vs. W: HR 0.88 (0.66-1.17) D150 vs. W: HR 0.67 (0.49-0.90)
D110 4.4% yr / D150 5.1% yr vs. W 4.4% yr D110 vs. W: P=0.89 D150 vs. W: P=0.07
Rivaroxaban 20 mg vs. warfarin (ROCKET AF)29
6,229 2 Stroke/ SEE HR 0.80 (0.63-1.02) 4.9% yr vs. 4.4 % yr HR 1.11 (0.92-1.34)
Apixaban 5 mg (ARISTOTLE)30
5,678 1.8 Stroke/ SEE HR 0.71 (0.53-0.95) 3.3%yr vs. 5.2 %yr P<0.05
Edoxaban 60 mg (ENGAGE AF)31
8,474 2.8 Stroke/ SEE HR 0.83 (0.66-1.04) 4.0% yr vs. 4.8% yr P<0.05
HR, hazard ratio; OR, odds ratio; RR, risk reduction; SEE, systemic embolic event; W, warfarin.
5.0
4.0
3.0
2.0
1.0
0.0 Incidence of Rate of all-cause Incidence of major bleeding mortality cardiovascular mortality
P ec
en ta
g e
o f
p at
ie nt
)
Figure 6. Bleeding and mortality outcomes for patients treated with edoxaban and warfarin32,33
ETNA-AF-Europe (n=13,092)
1.05
2.15
9A Prescriber publication 2021
in patients with NVAF, however , there was a clear difference of opinion regarding com- plex patients (Statement 35, 67%). Special- ist respondents (Geriatrician, Cardiologist)
are confident in managing complex patients (98% and 86% agreement, respec- tively) but other roles (Nurse, Pharmacist, HoMM, Emergency Physician) did not
achieve consensus in their individual responses (45%, 52%, 54%, 57% agree- ment, respectively). This difference is per- haps to be expected; it is logical that those in roles who have the greatest experience of prescribing DOACs in NVAF would be more confident in doing so. It is encourag- ing that GPs achieved consensus agree- ment with Statement 35 (72% agreement) although there is some variation given the response to Statement 23 (There is a cohort of ageing patients with NVAF who are not anticoagulated in Primary Care but should be; 85% agreement), which is supported by the evidence base1 that suggests approxi- mately 15% of patients with AF are not pre- scribed anticoagulants in Primary Care. Data from SSNAP15 (January–March 2020, n=21,379) reports that 19% of UK stroke patients had an existing AF diagnosis on admission to hospital and a further 6% received a diagnosis during their hospital admission; this suggests that approximate- ly a quarter of patients with AF are undiag- nosed prior to a stroke. The majority of diag- nosed pat ients were prescr ibed anticoagulant medication with 76% receiv- ing a DOAC and 24% a VKA. The INR of those patients prescribed a VKA varied sig- nificantly with 38% within the broadly opti- mal 2–3 range.36 Primary care prescribers should have confidence in both initiation and repeat prescription of DOACs in ageing patients but with appropriate referral for the most complex cases. The Primary Care Network (PCN) should refer to the Secondary Care link (i.e. anti-coagulation MDT representa- tive) as needed. Evidence is emerging regarding the safety of using DOACs in age- ing patients and clinicians should consider the safety profiles of individual DOAC treat- ments when making prescribing decisions. Respondents agreed that education and counselling should be accessible and ongoing. In response to COVID-19, it is anticipated that this will move to virtual delivery over time. Those patients who can- not access virtual methods (particularly relevant in ageing patients) may require individualised plans.
Table 6. NVAF Monitoring
No: Topic: Statement: Score %
16 NVAF Monitoring
Within 3-months after DOAC initiation, all patients should be reviewed to ensure correct dosing
92%
17 All DOAC patients should be monitored at least annually in line with NICE guidance
97%
18 Some patients, including those deemed complex, require more frequent monitoring
94%
19 Access to timely specialist advice should be available for all DOAC patients when required
96%
No: Topic: Statement: Score %
20 Anticoagulation service delivery
All DOAC patients should know which HCP to contact when required
98%
21 An interruption to DOAC therapy may require MDT support
73%
22 Cost is a consideration when choosing an appropriate DOAC
70%
23 There is a cohort of ageing patients with NVAF who are not anticoagulated in Primary Care but should be.
86%
82%
25 Choice of anticoagulation treatment should not be determined by commissioning arrangements
81%
26 DOACs should be the standard of care for anticoagulation in NVAF
91%
27 Pharmacy has an under-utilised role in the monitoring of anticoagulation patients at present
83%
28 Nursing has an under-utilised role in the monitoring of anticoagulation patients at present
74%
29 An integrated care pathway for ageing patients with NVAF seen in Primary Care would be helpful to commission NVAF services against
96%
10 A Prescriber publication 2021
There was strong agreement with all three statements in this topic, confirming the importance and relevance of RWE in informing practice in NVAF. Regarding DOACs, RWE studies may vary greatly in design and outcomes; large multi-centre studies may provide the most robust data to add to the evidence base. Age is not the only factor in determin- ing risks associated with NVAF, for exam- ple, a fit and healthy 85 year old may be associated with lower bleeding and stroke risks than a younger but frailer individual. The Rockwood score37 gives a score ofclinical frailty but is not helpful in isolation. The HAS-BLED score is used to determine major bleeding risk, the
CHA2DS2-VASc calculates stroke risk for patients with AF. Due to the significance of a stroke to the patient, if there is a risk of stroke, neither the Rockwood nor HAS- BLED scores should be reasons NOT to anticoagulate a patient with NVAF. Anti- coagulation can significantly reduce the risk of stroke and though some doctors have been reluctant to prescribe these drugs because of concerns about bleed- ing, for most people this benefit (stroke risk reduction) greatly outweighs the risks.12
Conclusion NVAF is a significant risk factor for stroke and thromboembolism, both of which are
associated with significant patient impact (including mortality) and costs to the wider health system. The use of anticoag- ulants in patients with NVAF has been established in common medical practice for many years; more recently, the devel- opment of DOACs has provided a more convenient, fixed-dose alternative to VKA with reduction in major bleeding, in par- ticular intracranial hemorrhage. Despite these recent advances there are a number of patients who are currently undertreat- ed. This consensus project was established to understand the attitudes of HCPs towards NVAF treatment (and specifically DOACs in ageing/complex patients) in the UK and to provide a set of recommenda- tions to inform practice regarding the opti- mum anticoagulation treatment in the ageing population with NVAF. Responses from 371 HCPs involved in the management of NVAF demonstrated agreement with 95% (38/40) of the state- ments developed by the steering group. Two statements did not achieve consensus threshold (Statements 2 and 35). The response to Statement 2 (Ageing patients with NVAF do not fit into current clinical guidelines and this can limit best clinical practice; 50%) could be due to specialists being most comfortable with relevant guidelines and best practice compared to other roles (i.e. pharmacist, nurse, CCG commissioner), or it may be that there is an element of ambiguity in the use of the term ‘ageing patients’; a universal defini- tion of this cohort of patients would be useful when discussing best practice. Statement 35 (I feel confident in my ability to initiate DOAC use in complex patients; 67%) also did not achieve consensus, and the response levels between roles indicate that specialist roles (geriatrician, cardiolo- gist) achieved consensus agreement and whereas non-specialist roles achieved lower levels of agreement. The high levels of consensus provide a strong platform for the recommendations made by the steering group and support the role of DOACs in the anticoagulation of ageing patients with NVAF. These recom-
Table 8. Education & Counselling
No: Topic: Statement: Score %
30 Education & Counselling
Access to counselling should be available for all DOAC patients when required
96%
31 Both NVAF patient education and DOAC counselling should be ongoing
89%
32 I feel confident in my ability to initiate DOAC use in general
86%
33 I feel confident in my ability to continue prescribing of DOACs in general
86%
34 I feel confident in my ability to monitor DOACs in general
86%
35 I feel confident in my ability to initiate DOAC use in complex patients
67%
36 I feel confident in my ability to continue prescribing of DOACs in complex patients
70%
37 I feel confident in my ability to monitor DOACs in complex patients
75%
No: Topic: Statement: Score %
38 Research Real world evidence (RWE) should be proactively collected about the use and monitoring of DOACs
96%
39 Collecting RWE can support continuity of care of NVAF in an ageing population
97%
40 Collecting RWE will support the knowledge base to improve NVAF care in an ageing population
97%
11A Prescriber publication 2021
mendations are offered in order to provide guidance on the appropriate use of DOACs in a cohort of ageing patients who may currently be under treated and therefore at risk of stroke.
Recommendations The following recommendations are offered based on the learnings identified through the consensus exercise : 1. An ageing patient is defined as: A patient with NVAF living with, and devel- oping, comorbidities and medical complexity as they age 2. The following criteria should be assessed by the non-specialist to identify and con- sider the ageing patient with NVAF: • Renal function (creatine clearance) • Age and weight (dosing) • Drug-drug interactions (polypharmacy) • Frailty and fall risk • Previous GI bleed and history of peptic
ulcers. • History of IHD and potential need for
concurrent antiplatelet treatment • CHA2DS2-VASc/HAS-BLED Score • Other lifestyle factors (diabetes, social
history, use of NSAIDs) • Alcohol use 3. Non-specialists should be able to initiate DOACs (or know where to refer) in Primary Care and should consider the following: • Is there a clinical reason not to anticoag-
ulate an ageing patient with NVAF? • DOACs are preferable over warfarin in
ageing patients with NVAF where no exclusion criteria exist
4. Choice of a DOAC should be proactively considered with ageing patients and prac- tical factors are important such as: • Age • Frailty • Co-morbidities • Eating patterns • Adherence/persistence • Dosing • Polypharmacy and potential drug–drug
interactions
• Side-effect profile 5. A DOAC should be selected with evi- dence that substantiates its choice in the ageing patient cohort and edoxaban should be considered as an option for treating ageing patients with NVAF. 6. A specialist MDT should be organised (according to locality) and these ageing patients should be referred to the MDT and regional networks.
Limitations As with all surveys, potential limitations of this study include the way in which the questions were worded and the order in which they were asked, and how respond- ents were approached. However, the questions were constructed by the steer- ing group who also ratified the final form of the questionnaire before distribution. There was no specific representation from GPs on the steering group, this would have been useful in order to draw out any specific issues relating to the role of the
50
40
30
20
10
INR at arrival to hospital
P er
ce nt
(% )
Figure 7. AF diagnosis and medication status of stroke patients in the UK (Jan-Mar 2020)15
Of those with existing AF diagnosis, 66% were prescribed an anticoagulant
Of those receiving anticoagulant treatment, 76%
were prescribed a DOAC
Of those receiving VKA treatment, 38% had an International Normalised Ratio (INR) of 2–3 on arrival at hospital
Adapted from: Healthcare Quality Improvement Partnership. SSNAP Portfolio for January - March 2020 admissions and discharges. July 2020.15
New diagnosis on admission to hospital 6%, n=1190
Existing AF diagnosis 19%, n=4072
No existing AF diagnosis 75%, n=16,117
Antiplatelet only 8%, n=342
Neither medication 26%, n=1069
Anticoagulant and antiplatelet medication 3%, n=137
Anticoagulant only 62%, n=2,524
DOAC 75%, n=2480
42 38
CURRENT THINKING
12 A Prescriber publication 2021
GP in managing NVAF. There was a strong response from England (313/371) compared with other regions (other parts of the UK). The overall results were therefore heavily influenced by practice in England. That said, comparison of responses between England and other regions did not show any significant variation in attitude to the consensus statements. This consensus was focussed specifically on clinical opinion with a view to defining and recognising the issues attached to anti- coagulation in ageing patients with NVAF. Patient experience has not been captured, this may help to further the understanding of NVAF and anticoagulation from the patient perspective and the optimal approach to pre- vention of strokes in these patients. It is hoped that this consensus review may act as a springboard to raise the issue of anticoagulation in ageing patients and con- tribute to the evidence base to support the Primary Care prescribing of DOACs in patients with NVAF.
Summary The results of the consensus have pro vided a strong indication of the atti- tudes of clinicians to the use of DOACs in the prevention of strokes in a patient cohort that may be under prescribed in Primary Care. The steering group were able to form a strong set of recommendations with the aim of clarifying the role of Pri- mary Care in managing a greater number of ageing patients with NVAF optimally
with DOACs. This consensus review should be repeated in 5 years to assess changes in practice and define more appropriate recommendations at that time.
References 1. Bakhai A, et al. J Eval Clin Pract 2020;27:119–33. 2. Kirchhof P, et al. Eur Heart J 2016;37:2893–962. 3. NICE. Atrial fibrillation: management [CH180]. https://www.nice.org.uk/guidance/cg180/ chapter/Introduction [Accessed 02 July 2020]. 4. Wolf PA et al. Stroke1991;22:983–8. 5. Kimura K, et al. J Neurol Neurosurg Psychiatry 2005;76:679–83. 6. Henninger N, et al. Stroke 2016;47:1486–92. 7. Stroke Association. Current, future and avoidable costs of stroke in the UK. Executive summary Part 2. October 2017. 8. Adamson J, et al. J Stroke Cerebrovasc Dis 2004;13:171–7. 9. Maura G, et al. BMJ Open 2019;9(4):e026645. 10. López-López JA, et al. BMJ 2017;359:j5058. 11.Marzec LN, et al. J Am Coll Cardiol 2017; 69:2475–84. 12. Foody JM. Clin Interv Aging 2017;12:175–87. 13. Healthcare Quality Improvement Partner- ship. Sentinel Stroke National Audit Programme (SSNAP). Clinical audit April 2013–March 2018 Annual Public Report. National Results. June 2019. 14. Feinberg WM, et al. Arch Intern Med 1995;155:469–73. 15. Healthcare Quality Improvement Partner- ship. SSNAP Portfolio for January – March 2020 admissions and discharges. July 2020. 16. Guyler, P. Presentation at UK Stroke Forum, 7th December 2020. Prevention better than
cure: Addressing health inequalities to improve stroke prevention during COVID-19. 17. Pisters R, et al. Chest 2010;138:1093–100. 18. NHS. The NHS Long Term Plan. January 2019. 19. Lip GY, et al. Chest 2010;137:263–72. 20. Eriksson B, et al. Clin Pharmacokinet 2009;48:1–22. 21. Xarelto Summary of Product Characteristics. 22. ELIQUIS Summary of Product Characteristics. 23. LIXIANA Summary of Product Characteristics. 24. Parasrampuria DA, Truitt KE. Clin Pharmacokinet 2016;55:641–55. 25. Alberts MJ, et al. Int J Cardiol 2016;215:11–3. 26. Horne R, et al. PLoS One 2013;8:e80633. 27. Cavallari I, Patti G. Anatol J Cardiol 2018;19:67–71. 28. Eikelboom JW, et al. Circulation 2011; 123:2363–72. 29. Halperin JL, et al. Circulation 2014;130:138–46. 3 0 . H a l vo r s e n S , e t a l . Eu r H e a r t J 2004;35:1864–72. 31. K ato E T, et al . J Am Hear t Assoc 2016;5:e003432. 32. de Groot JR, et al. Eur Heart J Cardiovasc Pharmacother 2020; pvaa079. 33. de Groot JR, et al. Poster P4756. Presented at European Society of Cardiology Congress 2019, Paris, France; 31st August – 4th September 2019. 34. Steffel J, et al . J Am Coll Cardiol 2016;68:1169–78. 35. NHS England. Clinical guide for the man- agement of anticoagulant services during the coronavirus pandemic. 31 March 2020. 36. Lip GY, et al. BMJ 2002;325:1022–5. 37. Rockwood K, et al. CMAJ 2005;173:489–95.
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Date of preparation: July 2021 EDX/21/0629