Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 466–471

doi: 10.1111/jcpt.12291

Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics A. Stewart MRCP, A. Ganguli MRCP, R. FitzGerald MRCP and M. Pirmohamed PhD FRCP Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

Received 26 April 2015, Accepted 5 May 2015

Keywords: warfarin, anticoagulation, survey, prescribing, pharmacovigilance

The difficulty with warfarin dosing lies in the vast individual variation in response which is dependent on multiple factors including age, diet, weight, concurrent medications and genetic variability.3 Individual dosing requirements can range from 20 mg/week to well over 100 mg/week. Hence, trying to maintain patients within a narrow anticoagulation range poses a significant challenge for the prescribers. Advances in the field of pharmacogenetics have played a key role in our understanding of the individual variability in dosing requirements. Two major genes have been identified which are strongly associated with the warfarin response: CYP2C9 and VKORC1.3 The bulk of warfarin prescribing is usually performed by anticoagulation clinics which are linked to primary and secondary care facilities. Physician-led prescribing is now very rare with the majority being performed by specialist nurses and pharmacists with a large body of evidence indicating this is equally effective.4 In the UK, national guidelines have been developed by the British Committee for Standards in Haematology to aid prescribing and thereby safety of warfarin.5 However, it is not clear how well this guidance is followed, and currently, there is no published data on this. The objective of our study was to ascertain the degree of variation in clinical practice in the initiation, prescribing and monitoring of warfarin in the UK, and how this compares with national guidelines.

SUMMARY What is known and objective: Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The objective was to undertake a survey on current clinical practice in this area, and how it compares with national guidelines that have been developed by the British Committee for Standards in Haematology. Methods: A national online survey of anticoagulation clinics was performed using Survey Monkeyâ. The survey was designed to capture data for prescribing, dosing and monitoring of anticoagulation with warfarin. Results: Of 85 clinics who responded to the survey, most were run by secondary care (68%), facilitated by specialist nurses (58%) and followed standard guidelines for the management of warfarin (87%). The majority of clinics indicated their target international normalized ratio (INR) for patients with atrial fibrillation (AF) (69/73; 945%) was between 20 and 30, but the indicated target INR for mechanical heart valves was more variable. Initiation and loading dosing regimens were a major source of variability with uncertainty surrounding individual patient factors such as age, ethnicity and BMI. What is new and conclusions: Current practice amongst UK anticoagulation clinics largely follows current national guidelines but better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements would improve and standardize oral anticoagulation with warfarin.

METHODS Using Survey Monkeyâ, we designed a survey to capture data for prescribing and the monitoring of anticoagulation with warfarin. Two hundred anticoagulant clinics were contacted via email and directly by phone following a web-based search. Eighty-five clinics (43%) around the UK completed the survey. Variables that were assessed included the use of local over national guidelines, recommended therapeutic international normalized ratio (INR) ranges, loading regimen, monitoring of INR, and patient counselling and education. The results of the survey were then analysed against the national guidelines to determine the variability in warfarin prescribing and monitoring across the UK. Local Research Ethics Committee approval was not sought as this was a survey of current clinical practice. Verbal consent from healthcare professionals was obtained via telephone for AS to make contact via their NHS email with a survey link.

WHAT IS KNOWN AND OBJECTIVE Clinicians have been familiar with warfarin prescribing for the prevention and treatment of thromboemboli for more than 50 years. Warfarin (3 a-acetonylbenzyl-4-hydroxycoumarin) is a vitamin K antagonist with good evidence for the primary prevention of cardioembolic stroke in atrial fibrillation.1 Warfarin remains a cheap and cost-effective anticoagulant, but its narrow therapeutic index remains problematic with bleeding being the most common adverse event. Increasing age, hypertension, diabetes, hepatic or renal disease, and concurrent use of aspirin increase this risk.2

RESULTS Correspondence: Prof M. Pirmohamed, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Block A: Waterhouse Buildings, 1-5 Brownlow Street, Liverpool L69 3GL, UK. Tel.: 0151 794 5549; fax: 0151 794 5059; e-mail: [email protected]

© 2015 John Wiley & Sons Ltd

Service provision Over two-thirds of clinics contacted were run by secondary care [58/85, (682%)]. Only six clinics were led by primary care services

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Table 1. Responses in relation to the question: ‘What is your clinic’s target international normalized ratio (INR) for venous thromboembolism and atrial fibrillation?’

(71%), and sixteen were run by a joint service (188%). The majority of clinics surveyed were facilitated by specialist nurses (see Fig. 1) [49/85, (576%)], with only one clinic that responded led by a Physician [1/85, (12%)]. Of the 48 individuals who responded regarding their role in the anticoagulation service, the majority were specialist nurses (37/48; 771%), with biomedical scientists (6/48; 125%) and pharmacists (5/48; 104%) contributing to the remainder. All regions of the UK were included in this survey (see Fig. 1).

Indication

Target INR

Pulmonary embolus n = 74 (% Respondents)

Deep venous thrombosis n = 75 (% Respondents)

Atrial fibrillation n = 73 (% Respondents)

Guidelines Over three quarters of clinics surveyed indicated that they had standard guidelines for the initiation of warfarin [74/85, (871%)]. Only two participants indicated that their service did not adhere to standard guidelines (24%). Most of these guidelines, however, were local (565%) with a smaller proportion of respondents indicating national guidelines were followed (247%).

20–25 20–30 20–35 25–30 20–40 30–50

41 919 14 14 14

40 947 13

41 945

14

The bold values indicate the recommended target INR.

Target international normalized ratios that a rapid loading regimen was not used, choosing instead to give 3 or 2 mg on days one, two and three [day 1 (6/61; 98%), (1/ 61; 16%); day 2 (6/52; 115%), (1/52; 19%); day 3 (6/41; 146%) and (1/41; 24%), respectively]. Taking all dosing regimens together, the mean dose on day 1 was 8 mg (median 10 mg, range 2–10); on day 2, it was 73 mg (median 9 mg, range 2–10); on day 3, it was 52 mg (median 5 mg, range 2–10); and on day 4, it was 39 mg (median 3 mg, range 1–9 mg). Survey participants were asked whether the loading dose was the same for all indications of anticoagulation: 871% (54/62) answered ‘no’. Following on from this question, those who completed the survey were asked whether certain individual patient factors altered the loading dose. The elderly and patients with liver disease were most likely to receive an altered loading dose regimen (54/60; 900% and 51/56; 911%, respectively). Other factors leading to an altered loading dose regimen included malnourishment (33/47; 702%), renal failure (32/48; 667%), concomitant interacting medication (33/51; 647%), increased alcohol consumption (30/49; 612%), a low BMI (27/49; 551%) and aspirin use (10/49; 204%). Ethnic origin and a raised BMI

This survey asked respondents to state the recommended INR ranges for a list of indications. The majority of clinics surveyed indicated their target INR for patients with atrial fibrillation (AF) (69/73; 945%) and with a first presentation of venous thromboembolism [68/74; 919% pulmonary embolism (PE), 71/75; 947% deep vein thrombosis (DVT)] was between 20 and 30, with a target of 25 (see Table 1). The indicated target INR for mechanical heart valves was more variable. The majority of survey respondents indicated a target INR of 30–40 (29/69; 420%), followed closely by a target INR of 25–35 (21/69; 304%). The remaining participants responded with a target INR of 20–40 (3/69; 43%), 20–45 (1/69; 14%), 25–25 (2/69; 29%), 25–40 (2/69; 29%), 25–45 (1/69; 14%), 30–35 (1/ 69; 14%), 30–45 (6/69, 87%), 30–55 (1/69; 14%) and 35–45 (2/ 69; 29%). Loading dose. Survey participants were asked regarding the usual warfarin loading regimen (see Table 2). The majority of respondents give either 10 mg (34/61; 558%) or 5 mg (12/61; 210%) loading dose on day 1. A minority of survey participants indicated

(a)

Specialist Nurses, Pharmacists & Biomedical Sciensts 1%

(b) Physician 1%

Scotland 7%

Unknown 9%

Specialist nurses and scienst 6%

Wales 5%

N Ireland 2%

Specialist nurses and pharmacist 6%

Biomedical sciensts 5%

Pharmacists 13%

Specialist Nurses 58%

England 86%

Fig. 1. Responses from participants asked the following questions: (a) ‘who runs your anticoagulation service?’ and (b) ‘in which country is your clinic based?’

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respondents indicated would be checked the following day (27/54; 500%). The mean INR which survey respondents indicated warfarin would be suspended (even if the patient was not overtly bleeding) was 47 (n = 30; range 35–100). The majority of respondents gave vitamin K if the INR was over 80 (even in the absence of bleeding) (48/55; 873%). Participants were most likely to give 2 mg of vitamin K for a high INR (25/49; 510%). In the majority of cases, this was administered via the oral route (52/55; 945%), with only three of 55 survey participants stating intravenous vitamin K would be administered.

Table 2. Reponses from participants in relation to the question: ‘What is the usual warfarin loading regimen?’ Day 1

10 mg 9 mg 8 mg 7 mg 6 mg 5 mg 4 mg 3 mg 2 mg 1 mg Unknown Not applicable

Day 2

Day 3

Day 4

n

%

n

%

n

%

n

%

34 7 0 0 0 12 1 6 1 0 24 0

557 115 00 00 00 197 16 98 16 00

21 7 1 0 0 15 1 6 1 0 24 9

344 115 16 00 00 246 16 98 16 00

3 1 0 0 6 23 1 6 1 0 25 19

50 17 00 00 100 383 17 100 17 00

0 1 0 0 0 5 1 6 1 1 25 45

00 17 00 00 00 83 17 100 17 17

00

148

317

Patient counselling and other services offered. Of the 55 individuals who responded, the majority offer counselling prior to warfarin therapy (51/55; 927%), with all respondents stipulating a written information leaflet was supplied. The majority of clinics surveyed offered point-of-care testing via finger prick for outpatient management (43/55; 782%). Patient self-management using personal testing kits was, however, infrequently issued in UK anticoagulant clinics (2/56; 36%).

750

Genetic testing for warfarin dose determination. Genetic testing for CYP2C9 and VKORC1 is infrequently carried out by nationwide anticoagulation clinics. No clinics surveyed indicated this was routinely performed, with only eight of 56 (143%) respondents stating this was performed in a select patient cohort. The most common indication given for genetic testing was ‘consultant decision/individual clinical judgement’ cited by five survey respondents.

Answers were received from 61 of 85 clinics for days 1 and 2, and for 60 of 85 clinics for days 3 and 4. The percentage has been calculated using the number who answered as the denominator.

were considered less important factors by survey participants to alter the loading dose (3/46; 65% and 2/46; 43%, respectively). Anticoagulation monitoring. Most anticoagulant clinics surveyed used a computer software program for dose adjustment (44/58; 759%) with only 18 of 58 (310%) indicating they perform manual dose adjustment. When therapeutic range is established, the average frequency of INR check was 22 days (n = 50), although this was variable ranging from 2 days to 8 weeks (median = 14 days). The majority of survey respondents indicated that therapeutic LMWH would be given in the event of a subtherapeutic INR (49/60; 817%). Many answers were qualified, however, with the caveat that it would depend entirely on the indication and circumstances. In the event of a high INR, survey respondents were asked how soon an INR was repeated. This varied depending on the level over the therapeutic range, and the results are summarized in Table 3. If the INR was 10 over the therapeutic range, the majority of patients had their INR checked on day 7 (27/51; 523%), in comparison with an INR 50 over target which the majority of

DISCUSSION Conducting surveys in healthcare professionals can be complex, with issues that are distinct in comparison with conducting general population surveys. For instance, survey participation amongst healthcare professionals represents a high opportunity cost due to their demanding work schedules.6 Furthermore, physicians are often inundated with ‘medical junk mail’ and are therefore less likely to respond to an online survey via an email invitation.7 Despite these difficulties, our response rate was 43%. Survey response rates are often viewed as an indicator of survey quality, with the general assumption that the lower the response rate, the worse the data in the survey. However, this is not completely borne out in the literature. For example, surveys with lower response rates (as low as 20%) can produce more accurate results than those with higher response rates.8 Furthermore, Keeter et al.9 compared two surveys with differing response rates (25% vs. 50%)

Table 3. Reponses to the question ‘When is the international normalized ratio (INR) repeated after a high INR?’ Day (%) INR Value above therapeutic range

1

2

3

4

5

7

14

21

28

No. Respondents

Mean (days)

Median (days)

10 20 30 40 50

00 19 77 197 500

78 77 173 254 204

59 192 308 294 148

00 58 77 39 93

20 19 58 176 00

523 560 288 00 93

197 77 19 00 00

39 00 00 00 00

78 00 00 00 00

51 52 52 51 54

99 61 42 32 22

7 7 3 3 15

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important than factors such as age and BMI.23 Genotype-guided initiation of warfarin is not currently recommended in UK guidelines. A recent clinical trial conducted in the UK and Sweden showed that genotype-guided dosing led to higher time in therapeutic range than standard dosing; it was also superior in relation to time to therapeutic INR.24 The incidence of high INRs was also lower with genotype-guided dosing than standard dosing.24 However, this was not replicated by a US trial25, but there were design differences between the two trials, the most important being the differences in algorithmic strategy.26 The importance of genetic variation in predisposing to bleeding in the first 90 days after starting warfarin has also recently been demonstrated in an analysis of the warfarin arm from the ENGAGE AF-TIMI 48 trial.27 In terms of anticoagulation monitoring, over three quarters of clinics surveyed (76%) use a computer software program for dose adjustment. Studies have shown computerized dosing is superior in terms of time-in-range and reduced risk of adverse events.28 The majority of survey respondents were aware of the national guidance for the management of a high INR. A mean INR of 47 was reported for the level at which warfarin would be withheld which correlates closely with the national recommendations of an INR >50.5 The majority of participants (87%) would give vitamin K if the INR was >80 and were most likely to give 2 mg (51%) via the oral route (95%). The current UK guidelines5 in the nonbleeding patient recommend patients should receive 1–5 mg of oral vitamin K if the INR is >80 based on evidence that demonstrates its efficacy, and resistance to re-anticoagulation does not occur.29 Warfarin is consistently amongst the top 3 drugs leading to hospital admissions secondary to an adverse drug reaction.30 Patient information is an essential component of pharmacovigilance and is of key importance in warfarin therapy where food and drug interactions are plenty. Although the majority of survey respondents stated patient counselling was offered prior to warfarin therapy (93%), there was still a selection of people who did not indicate this was routine clinical practice, thus indicating significant scope for improvement. Patient self-management using personal testing kits is not commonplace amongst UK anticoagulant clinics with only two clinics stating they had issued these to patients. A Cochrane systematic review in 2010 involving 18 randomized controlled trials in nearly 5000 patients concluded that self-management led to a significant improvement in the quality of oral anticoagulation, with a reduction in thromboembolic events and overall mortality.31 Current 2014 UK National Guidelines recommend self-testing and self-management of oral anticoagulant therapy for an indication of more than 12 months in selected patients only. There is currently no clear consensus on which patients should be selected, but they should be willing to participate and successfully complete a training programme.32

and found the results to be statistically indistinguishable from each other. Other surveys amongst doctors and undergraduates have published a wide range of response rates (21%-78%).10,11 This represents the largest national survey of anticoagulant practices in the UK even with the 43% response rate. Previous surveys have covered service provision focusing on the increased demand for anticoagulation following the widespread use of warfarin in patients with AF.12–14 A regional survey from Newcastle showed that only a minority of regional clinics were based in primary care, consistent with our findings.13 Our survey has demonstrated that the majority of UK anticoagulation clinics are facilitated by specialist nurse clinicians and pharmacists. Comparison of a consultant-led service with a nurse specialist service has shown that therapeutic control was equivalent and equally cost-effective.15 Up to 60% of clinics surveyed indicated that guidelines were followed, but the majority followed local guidelines, which may lead to variability in clinical practice nationally. In line with national guidance5, the majority of respondents used the recommended INR range 20–30 for atrial fibrillation and venous thromboembolism, which is known to reduce the risk of ischaemic stroke in nonvalvular AF by approximately two-thirds and is the optimum range for both the initial management and the long-term prevention of recurrent VTE in high-risk groups.1 The variability in recommended INR for mechanical heart valves is likely to reflect the variability in national recommendations based on individual patient factors, including valve position, previous arterial thromboembolism and prosthesis thrombogenicity. These complexities are particularly evident with new prosthetic designs where there is insufficient data on valve thrombosis rates at different levels of INR.16 Current British Committee for Standards in Haematology guidelines do not comment on the superiority of using a 10 or 5 mg loading dose.5 Kovacs et al.17 reported the mean time to reach therapeutic range was significantly shorter with 10 mg than 5 mg (56 vs. 42 days, P < 0001); however, a subsequent Cochrane meta-analysis showed no overall difference between 10 and 5 mg loading doses across four studies (95% CIs, P = 046), but there was heterogeneity between the studies.18 An important finding of our survey is the variability in clinical practice in the doses used for the initiation of warfarin therapy. A higher dose loading strategy may lead to therapeutic INR more quickly but does have the disadvantage of a higher frequency of above therapeutic range INRs at initiation, particularly in the elderly.19 Thus, the majority of survey respondents indicated that an altered loading dose regimen was prescribed in the elderly (90%), in keeping with recommendations5, and the evidence which shows that adjustment of warfarin loading doses for age reduces the proportion of patients experiencing a supratherapeutic INR (greater than or equal to 40).20 However, very little adjustment for dosing was undertaken for other factors such as the following: • Obesity – only 4% made dose adjustments. A retrospective review demonstrated that obese and morbidly obese patients required higher warfarin doses and a significantly longer median time to achieve therapeutic INR.21 • Ethnicity – only 6% took this into account. In general, it has been shown that patients of African origin require higher daily doses, whereas Asian patients require lower doses.22 The huge variability in dosing schedules used in different anticoagulant clinics may at least partially be responsible for variability in quality of anticoagulant care. Genetic factors are also known to affect individual daily dose requirements for warfarin and are in fact quantitatively more

WHAT IS NEW AND CONCLUSION In summary, this national survey provides an understanding of the current practices amongst anticoagulation clinics in the UK. We conclude that the majority of clinics who participated are aware of and largely follow some guidelines (largely local) on anticoagulation. A major source of variability in these guidelines seems to be dosing on initiation of warfarin, which is a key determinant of time in therapeutic range. Better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements, would improve and standardize oral anticoagulation with warfarin. Of course, the

© 2015 John Wiley & Sons Ltd

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new oral anticoagulants which do not need monitoring and have fixed dose regimens are likely to be increasingly used in the future, but these have their own complexities,26 but the principles of pharmacovigilance, patient counselling, assessing compliance and dealing with adverse events will remain.

contacted survey participants and contributed to the writing of the manuscript. RF designed the survey, contacted survey participants, analysed the data and contributed to the writing of the manuscript. MP led the design of the survey and contributed to the analysis and writing of the manuscript. MP is an NIHR Senior Investigator.

ACKNOWLEDGEMENTS SOURCE OF FUNDING

We gratefully acknowledge all our participants for taking the time to complete this survey.

This survey was funded by the Wolfson Centre for Personalised Medicine and NHS Chair for Pharmacogenetics.

CONTRIBUTORS CONFLICT OF INTEREST

AS contacted survey participants, performed the research, analysed the data and wrote the manuscript. AG designed the survey,

None.

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Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 466–471 471

Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics.

Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The...
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