Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38698.709572.55 (Published 19 January 2006) Cite this as: BMJ 2006;332:141
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This paper on adverse events and warfarin prescribing raises the
question of whether it is possible to identify patients at a high risk of
bleeding before treatment is started[1]. Whilst some of this information
may be gleaned from the clinical history, physical examination and other
phenotypic tests, the use of warfarin in atrial fibrillation may be one
example of where pharmacogenetic testing may have a role. Whilst there
seems to be little point in performing genetic tests on patients already
stabilised on warfarin, the evidence suggests that the early phases of
treatment are the most critical and when patients are most vulnerable[2].
A systematic review and meta-analysis of studies investigating the
impact of genetic variants of the cytochrome P450 enzyme CYP2C9 and
warfarin has shown that patients with these variants require lower daily
maintenance doses and are at an increased risk of bleeding[3]. Recent
research has also shown that haplotypes of the Vitamin K epoxide reductase
gene VKORC1 can stratify patients into low- medium- and high-dose groups
and that these haplotypes vary between ethnic groups[4]. Whilst neither of
these studies is conclusive, it does perhaps provide one example where pre
-prescription pharmacogenetic testing may have a role and should be
investigated further – it may help allay the fears of patients and doctors
alike.
Reference List
1.Choudhry,N.K. et al. Impact of adverse events on prescribing
warfarin in patients with atrial fibrillation: matched pair analysis. BMJ
332, 141-145 (2006).
2.Higashi,M.K. et al. Association between CYP2C9 genetic variants and
anticoagulation-related outcomes during warfarin therapy. JAMA 287, 1690-
1698 (2002).
3.Sanderson,S., Emery,J. & Higgins,J. CYP2C9 gene variants, drug
dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic
review and meta-analysis. Genet. Med. 7, 97-104 (2005).
4.Rieder,M.J. et al. Effect of VKORC1 haplotypes on transcriptional
regulation and warfarin dose. N. Engl. J. Med. 352, 2285-2293 (2005).
Competing interests:
None declared
Competing interests: No competing interests
Choudhry et al's paper shows that physicians are less likely to
prescribe warfarin for AF after they have treated haemorrhagic
complications of warfarin, but not more likely to prescribe warfarin for
AF after they have treated thrombo-embolic complications of AF. At first
site this is surprising. On second thoughts it is not so surprising. All
it shows is that physicians are more easily swayed from a "sin of
commission" (prescribing warfarin when things go wrong) than from a "sin
of ommission" (not prescribing warfarin when things go wrong). First do
no harm, indeed !
Competing interests:
None declared
Competing interests: No competing interests
Choudhry et al report that physicians do not change their prescribing
habits of warfarin if a patient with known atrial fibrillation (AF) is
admitted with ischaemic stroke. It is probably fair to state that many
doctors learn from their own mistakes to a greater extent compared to the
mistakes of their peers. Imagine a scenario of a particular doctor
learning that he or she omitted to anticoagulate a suitable patient with
AF. If the doctor later learns that the patient suffered an avoidable and
disabling ischaemic stroke then it is likely his or her clinical practice
would change, particularly if a clinical complaint were made. If doctors
were informed of their over-sights, then underprescription of warfarin may
be reduced.
Competing interests:
None declared
Competing interests: No competing interests
Barriers to the use of warfarin in non-valvular atrial fibrillation
Anticoagulation is under-utilised in the treatment of non-valvular
atrial fibrillation (NVAF). The study by Choudhry et al (1) suggests that
adverse outcomes from anticoagulation have greater influence on the
management of NVAF than occurrences of avoidable ischaemic stroke. The
authors speculate that this result arises from undue fear or concern about
adverse consequences of anticoagulation.
We are conducting a representative national survey of 1000 Australian
general practitioners (GPs) addressing how fear of anticoagulation affects
management of NVAF. Our preliminary findings indicate that aversion to
the risk of intracranial haemorrhage was substantial. Doctors are overly
cautious in prescribing anticoagulation where there is a perceived risk of
major and even minor bleeding even when the benefits of anticoagulation
outweigh the risks.
In 207 early responses, 45.9% of GPs reported the experience of an
ischaemic stroke in their NVAF patients without anticoagulation. Only 13%
reported experiencing an intracranial haemorrhage in NVAF patients on
anticoagulants. Over half of GPs (54.1%) expected to feel equal
responsibility for either an intracranial haemorrhage in a patient on
anticoagulants or a fatal or disabling ischaemic stroke without
anticoagulation. Nineteen percent would feel more responsible for an
intracranial haemorrhage.
When asked to select treatment for a hypothetical NVAF patient at
‘high’ risk of stroke (2), 72.5% of GPs would appropriately select
warfarin. A perceived risk of bleeding markedly reduced selection of
warfarin even when the risk of bleeding was acceptable according to best
available evidence (3,4). In the presence of a minor falls risk that
would not contraindicate anticoagulation (3) fewer than half of GPs
(46.6%) selected warfarin. Only 28% would anti-coagulate the patient at
high risk of stroke with a history of recurrent nose-bleeds. Only 20.3%
of GPs would anti-coagulate such a patient with a previously treated
peptic ulcer bleed.
Implementing evidence-based management of NVAF is proving difficult
and the potential to reduce stroke risk is yet to be fully realised (5).
Our preliminary findings support Choudhry et al’s (1) assertion that there
is a profound psychological dimension in the under-prescribing of
anticoagulants for NVAF. Any strategy to improve the evidence-based
management of NVAF will need to address the excessive concerns clinicians
have about anticoagulation. We need to reduce anxiety about ‘acts of
commission’ in the management of NVAF.
1. Choudhry NK, Anderson GM, Laupacis A et al. Impact of adverse
events on prescribing warfarin in patients with atrial fibrillation:
matched pair analysis. BMJ 2006; 332; 141-145.
2. Gage BF, Waterman AD, Shannon W, et al Validation of clinical
classification schemes for predicting stroke: results from the National
Registry of Atrial Fibrillation. JAMA 2001; 285:2864-70.
3. Gage BF. Birman-Deych E. Kerzner R. Radford MJ. Nilasena DS. Rich
MW. Incidence of intracranial hemorrhage in patients with atrial
fibrillation who are prone to fall. American Journal of Medicine. 2005;
118:612-7
4. Man-Son-Hing M et al Choosing anti-thrombotic therapy for elderly
patients with atrial fibrillation who are at risk of falls. Archives of
Internal Medicine 1999; 159: 677-85.
5. Evans A, Davis S, Kilpatrick C et al. The morbidity related to
atrial fibrillation at a tertiary centre in one year: 9.0% of all strokes
are potentially preventable. Journal of Clinical Neuroscience 2002; 9:
268-272
Competing interests:
None declared
Competing interests: No competing interests