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The Anticoagulation Choices of Internal Medicine Residents for Stroke

Prevention in Non-Valvular Atrial Fibrillation
Nathaniel Moulson; William F McIntyre; Zardasht Oqab; Payam Yazdan-Ashoori; Kieran L Quinn; Erik van Oosten; Wilma M
Hopman; Adrian Baranchuk

Postgrad Med J. 2017;93(1100):308-312.

Abstract and Introduction

Abstract

Purpose of the study To explore the oral anticoagulation (OAC) prescribing choices of Canadian internal medicine residents, at
different training levels, in comparison with the Canadian Cardiovascular Society (CCS) guidelines for non-valvular atrial fibrillation
(NVAF).

Study design Cross-sectional, web-based survey, involving clinical scenarios designed to favour the use of non-vitamin K
antagonists (NOACs) as per the 2014 CCS NVAF guidelines. Additional questions were also designed to determine resident
attitudes towards OAC prescribing.

Results A total of 518 internal medicine responses were analysed, with 196 postgraduate year (PGY)-1s, 169 PGY-2s and 153
PGY-3s. The majority of residents (81%) reported feeling comfortable choosing OAC, with 95% having started OAC in the past 3
months. In the initial clinical scenario involving an uncomplicated patient with a CHADS2 score of 3, warfarin was favoured over
any of the NOACs by PGY-1s (81.6% vs 73.9%), but NOACs were favoured by PGY-3s (88.3% vs 83.7%). This was the only
scenario where OAC choices varied by PGY year, as each of the subsequent clinical scenarios residents generally favoured
warfarin over NOACs irrespective of level of training. The majority of residents stated that they would no longer prescribe warfarin
once NOAC reversal agents are available, and residents felt risk of adverse events was the most important factor when choosing
OAC.

Conclusions Canadian internal medicine residents favoured warfarin over NOACs for patients with NVAF, which is in discordance
with the evidence-based CCS guidelines. This finding persisted throughout the 3 years of core internal medicine training.

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a fourfold to fivefold increase in the risk of
stroke.[1] Strokes caused by AF are almost twice as likely to be fatal as strokes from other aetiologies.[2] Canada spends 815
million dollars annually on AF-related hospitalisations, including stroke and transient ischaemic attacks.[3]

Non-vitamin K antagonists (NOACs) have rapidly revolutionised stroke prevention therapy in non-valvular atrial fibrillation (NVAF).
[47] Warfarin had been the mainstay of oral anticoagulant (OAC) therapy for decades and while effective (relative risk reduction of
64% for ischaemic stroke), its use is complicated by several factors.[8] These include a narrow therapeutic window, need for
regular laboratory monitoring and individualised dosing, slow-onset of action, numerous food and drug interactions and high
incidence of intracranial haemorrhage (ICH).[4,9]

The NOAC agents, dabigatran, rivaroxaban, apixaban and edoxaban, have all demonstrated a favourable riskbenefit profile to
warfarin, including a combined 48% relative risk of ICH and reduction in all-cause mortality.[10,11] This has recently been
demonstrated in real-world follow-up of rivaroxaban, where similar low rates of adverse outcomes, including ICH, and
gastrointestinal bleeding (GIB) were observed.[12] The Canadian Cardiovascular Society (CCS) AF guidelines reflect this risk
benefit profile and recommend NOACs be used in preference to warfarin for NVAF, unless otherwise contraindicated.[13]

NOACs have been approved for use in Canada since 2008, starting with dabigatran for venous thromboembolism (VTE)
prophylaxis and for stoke prevention in NVAF starting in 2010.[14] A recent study on the uptake of NOACs in Canada from 2008 to
2014 revealed warfarin held a 76% share of all OAC physician prescriptions in 2013 (not stratified by indication). Internists
prescribed warfarin for 68% of all their OAC prescriptions.[14] Warfarin therefore still commands the vast majority of the market
share of OAC prescriptions in Canada, even for attending internists. The implication of this on resident prescribing patterns has, to
our knowledge, not been studied.

AF is a common co-morbidity on the internal medicine wards, and internal medicine residents at all stages of training are faced
with assessing the risk and benefit of OAC medications on a regular basis. Adherence to evidence-based AF OAC guidelines on
internal medicine wards has previously shown to be poor, and we have recently shown Canadian residents' choices of OAC
across various specialties are inconsistent with CCS guidelines.[15,16] The purpose of this subgroup study is to further examine
the OAC choices of Canadian internal medicine residents with regard to stroke prevention in patients with NVAF.
Study Design

A survey consisting of 16 multiple choice questions was distributed to internal medicine training programmes across Canada. The
complete methods and statistical analysis of our study have been previously described.[16]

Survey consisted of clinical scenarios involving a 76-year-old male patient with a CHADS2 score equal to 3 (age, congestive heart
failure (CHF) and hypertension). An additional clinical characteristic was added to the subsequent scenarios (GIB 1-year ago
while on acetylsalicylic acid (ASA), an ICH 1-year prior, stage 3 chronic kidney disease (CKD) (eGFR=3059 mL/min/1.73 m2),
labile international normalised ratio (INR) on warfarin therapy and GIB on a NOAC). The response choices were no
antithrombotic, ASA, warfarin, dabigatran, rivaroxaban, apixaban and unsure. Respondents were permitted to select more than
one option, to avoid giving preference to a specific therapy. The remaining questions pertained to resident demographic
information and assessed resident attitudes towards OAC.

Results
Participants

Eleven academic internal medicine programmes across Canada were invited and agreed to participate in the study. There were a
total of 518 analysed responses, with a response rate of 60%. The results of this survey are accurate at the 95% confidence level
plus or minus 4 percentage points. Postgraduate year (PGY)-1s accounted for 37.8%, PGY-2s for 32.6% and PGY-3s for 29.5%.
For further demographic details of the participants and a full description of the survey and clinical scenarios referenced below, see
our previous publication and supplementary materials.[16]

Experience With OAC

Residents were asked their experience with starting OAC in the past 3 months. The majority of internal medicine residents (55%)
had started 15 patients on OAC, 27% had started 610 patients and 14% had started more than 11. Only 5% of residents had
not started any. Subjective comfort level with prescribing OAC was also assessed, with 81% of residents reporting either very or
somewhat comfortable and only 1% reporting being very uncomfortable with OAC. When analysed by PGY year, experience over
the past 3 months was almost identical from PGY-1 to PGY-3. Subjective comfort level increased throughout core internal
medicine training, with 75% of PGY-1s, 79.2% of PGY-2s and 87.3% of PGY-3s, respectively, reporting being either somewhat or
very comfortable prescribing OAC.

Stroke and Bleeding Risk Assessment

Internal medicine residents used either the CHADS2 (89%) and/or the CHA2DS2-VASc (72%) for stroke risk assessment in NVAF.
With regard to bleeding risk assessment, the majority of residents reported using the HAS-BLED score alone (49.6%), with 11.8%
reporting the use of clinical impression alone and 34.9% reporting a combination of HAS-BLED and clinical impression.

Clinical Scenarios

Residents prescribed OAC in the majority of the scenarios, with the exception of ICH which had the lowest OAC rates ().

Table 1. Frequency of internal medicine resident choices of agents for stroke prevention in different clinical scenarios

Preferred choices when multiple Preferred choice when a single option

options selected selected
OAC Warfarin Warfarin NOAC ASA None Unsure
Clinical scenario (%) (N) NOAC (N) ASA (N) (N) (N) (N) (N) (N)
76 males with CHF, HTN 98.7 81.1% 80.2% 4.1% (22) 17.8% 17.5% 0% (0) 0.7% 0.6%
(434) (427) (95) (93) (1) (3)
76 males with CHF, HTN, 95.9 80.7% 52.2% 9.2% (39) 39.6% 14.4% 2.6% 0.4% 1.1%
Hx GIB (432) (277) (211) (77) (14) (2) (6)
76 males with CHF, HTN, 66.2 42.4% 38.9%* 26.5% 25.5% 21.4%* 18.4% 5.6% 9.8%
Hx ICH (227) (202) (142) (136) (112) (98) (30) (52)
76 males with CHF, HTN, 95.5 84.7% 35.3% 6.9% (37) 56.3% 10.6% 1.3% 1.1% 2.1%
S3 CKD (453) (187) (300) (56) (7) (6) (11)
76 males with CHF, HTN 99.4 30.3% 91.7% N/A 7.7% 68.6% N/A 0% (0) 0.6%
labile INR (162) (487) (41) (365) (3)

*Both low-dose and regular-dose options among the non-vitamin K antagonists (NOACs) (dabigatran 110 mg or 150 mg per oral
twice daily, rivaroxaban 15 or 20 mg per oral daily, apixaban 2.5 or 5 mg per oral twice daily).
Respondents only had low-dose options to choose from among the NOACs (dabigatran 110 mg per oral twice daily, rivaroxaban
15 mg per oral daily, apixaban 2.5 mg per oral twice daily).
ASA, acetylsalicylic acid; CHF, congestive heart failure; HTN, hypertension; Hx GIB, low-risk gastrointestinal bleed on ASA 1 year
prior; Hx ICH, low-risk intracranial haemorrhage 1 year ago; INR, international normalised ratio; N/A, not applicable; NOAC, novel
oral anticoagulant (includes dabigatran, rivaroxaban or apixaban); OAC, oral anticoagulant; S3 CKD, stable stage 3 chronic
kidney disease (eGFR 3059 mL/min/1.73 m2).

In an uncomplicated patient with CHADS2 of 3, warfarin was the preferred choice over NOACs, with the exception of PGY-3
residents who preferred NOACs to warfarin (88.3% vs 83.7%) (figure 1). In the clinical scenarios involving a history of GIB with
low rebleed risk on ASA, ICH with low rebleed risk or a history of stage 3 CKD, warfarin was the preferred choice across all years.
When faced with a patient already on warfarin with a labile INR, the majority of residents chose to switch to a NOAC (68.6%). In
the scenario of an upper GIB on a NOAC, with a low rebleed risk, 41.8% of residents elected to switch to warfarin, 43% elected to
restart the NOAC at the same or lower dose (30% and 13%, respectively) and 7.4% switched to a different NOAC. Only 1%
elected to stop indefinitely.

Figure 1.

Oral anticoagulation choices by postgraduate year (PGY) level. Each bar represents the percentage of residents, by PGY level,
choosing each anticoagulant option for the various clinical scenarios (options with less than 2% responses were not included). All
scenarios were designed to favour non-vitamin K antagonists (NOAC) over warfarin, in keeping with the Canadian Cardiovascular
Society guidelines. CHF, congestive heart failure; HTN, hypertension; Hx GIB, history of gastrointestinal bleeding; Hx ICH, history
of intracranial haemorrhage; S3 CKD, stage 3 chronic kidney disease; ASA, acetylsalicylic acid; INR, international normalised
ratio; PGY, postgraduate year.

In the ICH scenario, only 66.2% of residents selected OAC. The percentage of residents choosing a form of OAC in this scenario
increased throughout the PGY years (59.2% to 65.5% to 73.7%), with warfarin being the preferred choice. This scenario had the
highest number of unsure responses (9.8%), with rates declining as training progressed, with 13.3% of PGY-1s unsure and 5.9%
of PGY-3s.

Residents were asked about the potential change in attitude if reversal agents for NOACs were to become universally available.
The majority (59%) of residents either somewhat or strongly agreed they would no longer prescribe warfarin for NVAF.

Residents were asked to rank characteristics they considered most important when choosing OAC for their patients on a scale of
15, with 1 being the least and 5 being the most important.

Risk of adverse events (4.2 points) and convenience to patient (3.7 points) were the two most important factors. The availability of
a reversal agent (3.4 points), cost to the patient (3.5 points) and personal familiarity with the medication (3.4 points) were all
ranked as less important.

Discussion

Residents are involved in every aspect of the decision-making process in prescribing OAC in new patients with NVAF. With this in
mind, the aim of our study was to explore the attitudes and choices of OAC prescribing among Canadian internal medicine
residents. Overall, internal medicine residents' responses were incongruent with the CCS guidelines with regard to choice of OAC
therapy.[13] This incongruence was consistent throughout the 3 years of core internal medicine training, with few exceptions,
discussed below. These findings are consistent with Canadian residents in family medicine, emergency medicine and adult
cardiology.[16]

The clinical scenarios in our study were specifically designed to favour NOACs over warfarin as the OAC of choice, in keeping
with CCS guidelines.[13] The majority of internal medicine residents reported a high subjective comfort level with prescribing OAC,
and 95% had started at least one patient on OAC in the prior 3 months. Despite these high self-reported levels of comfort and
experience, residents consistently chose warfarin over any combination of NOACs in our clinical scenarios. Our findings appear to
be combination of a knowledge gap, an apparent preference for warfarin due to a high degree of concern regarding perceived
adverse events and anticoagulant reversibility and the potential of resident modelling of attending physicians.

A similar prescribing trend for warfarin was recently demonstrated for Canadian internists, where 68% of all OAC prescriptions in
2013 were for warfarin, with 57% for warfarin in the first half of 2014.[14] The authors did not stratify the prescriptions based on
indications; however, they estimated at least 59% of prescriptions among all specialties were for AF.[14] OAC prescriptions for AF
indications are likely higher in an internist practice compared with the majority of other specialties, although further research is
needed on this subject. This prescribing trend by attending internists may partly be responsible for our studies trend of residents
favouring warfarin through resident modelling. Furthermore, attending physicians from various specialties have been shown to
have similar significant knowledge gaps, with up to one-third reporting they would prescribe antiplatelet agents as opposed to
OAC for a patient with a CHA2DS2-VASc of 3.[17] Coinciding with these findings, NOAC uptake has been shown to be quite rapid
overall in both Canada and the USA, with a recent US study demonstrating 62% of patients started on OAC from 2010 to 2013 for
NVAF received a NOAC.[1820]

The major exception to this trend was found in scenario 1. Residents were asked to assess a 76-year-old male with CHF and
hypertension for appropriate OAC in the setting of NVAF. First-year residents continued to favour warfarin; however, as seniority
progressed, NOACs became the preferred option of choice, with third-year residents choosing NOACs the most. It should be
noted, however, that only 15.2% of third-year residents exclusively chose a NOAC. This implies a knowledge gap is at least
partially responsible for our observed results and one still exists at the end of core internal medicine training. Subjective comfort
with prescribing OAC was highest among PGY-3s and may also have contributed to the observed higher percentage of NOAC
choices. Comfort level, however, was not stratified into the use of warfarin versus NOACs and, therefore, this assumes a higher
subjective comfort level equates to increased comfort with NOACs in relation to warfarin.

When faced with any additional clinical co-morbidity (ie, history of GIB, ICH or CKD), residents of all levels of training favoured
warfarin. This likely reflects in part residents' number one reported consideration when choosing OAC being the risk of adverse
events, in combination with potential knowledge gaps as highlighted below.

In a patient with a remote history of a GIB while on ASA, deemed low risk of recurrence by expert opinion, >95% of all residents
correctly chose OAC, but warfarin was strongly favoured, regardless of PGY year. However, when faced with a GIB in a patient
currently on a NOAC, the majority of residents continued a NOAC over switching to warfarin (50.8% vs 41.8%). These varying
results may reflect the current rapidly evolving state of evidence relating to GIB risk and NOACs. A meta-analysis of the four
landmark NOAC trials in 2014 found an increased GIB risk (RR 1.25), while a meta-analysis later the same year involving the four
landmark NOAC AF trials, combined with an additional NOAC AF trial and the NOAC trials for VTE, found no increased risk of
major GIB.[10,21] This finding persisted when analysed by indication, that is, AF alone.[21] Residents slightly favoured apixaban
(7.2% compared with 1.7% for dabigatran and 2.7% for rivaroxaban for exclusive choices), possibly reflecting the Aristotle trial
and the trend towards lower rates of GI haemorrhage, although this did not reach statistical significance.[6] Despite these
and the trend towards lower rates of GI haemorrhage, although this did not reach statistical significance.[6] Despite these
potentially conflicting meta-analyses results, the overall favourable riskbenefit profile of NOACs has resulted in their guideline
recommendation for our scenarios.[13]

Interestingly, in the scenario of a patient with a history of ICH, with again expert opinion of low rebleed risk, internal medicine
residents only prescribed OAC 66.2% of the time. This percentage did increase with training level, with 73.7% of third-year
resident recommending OAC; however, warfarin remained the OAC of choice, with NOACs being chosen exclusively only 21% of
the time. This is in contradiction to the results from the landmark NOAC trials and subsequent meta-analysis, which showed a
significantly lower rate of ICH compared with warfarin.[47,10,21] ASA was chosen by just over 25% of residents, despite recent
evidence showing no statistical difference in rates of ICH between warfarin and ASA, but a relative risk reduction of 70% for
ischaemic strokes.[22] This result likely reflects both a knowledge gap and lack of familiarity with such patients.

In patients with CKD with an eGFR=3059 mL/min/1.73 m2 (Stage 3), the CCS guidelines suggest reduced dose NOACs as up to
80% of dabigatran, 33% of rivaroxaban and 25% of apixaban are renally cleared.[23] Patients with stage 3 CKD were included in
the landmark NOAC trials, with no increase in adverse events.[47] For patients with stage 4 and 5 CKD (eGFR<29 mL/min/1.73
m2), there is minimal or no randomised control trial data available and therefore expert opinion suggests avoidance of NOACs in
this situation.[23] Resident choices did not align with this, as warfarin was chosen in the vast majority of cases (56.3% vs 10.6%
for exclusive choices), again reflecting a potential knowledge gap.

The majority of residents felt the availability of a reversal agent for the NOACs would lead them to no longer prescribe warfarin,
despite ranking availability of a reversal agent at the lower end of factors to consider when choosing OAC. This finding is difficult
to interpret as residents reported concern for adverse events as their main consideration when choosing OAC, yet consistently
chose warfarin over NOACs, despite evidence suggesting lower rates of ICH, major bleeding and overall mortality.[10,11] The
clinical benefit of reversal agents is unclear, as INR reversal with prothrombin complex concentrate in the setting of ICH results in
similar outcomes for ICH of patient's not on warfarin, with high rates of morbidity and mortality.[24] Reversal agents for the NOACs
are in the late stages of development, with idarucizumab, a reversal agent for dabigatran recently receiving approval in the USA.
[2527] Our results suggest approval of these agents in Canada may lead to a shift towards residents favouring NOACs over
warfarin, even though the ability to reverse the anticoagulant effect of NOACs may be more of a perceived benefit over a clinical
one.

NOACs are shown to have improved cost-effectiveness compared with warfarin long term when assessed in the context of both
the American and Canadian healthcare systems.[28,29] Factors such as lack of routine monitoring and reduced costs associated
with fewer complications (ie, ICH) account for this improved cost-effectiveness.[30] Despite this, perceived increased cost is a
major reason for restricted access to NOAC therapy and may play a role in physician OAC preference.[30] Residents in our survey
ranked cost as a less important factor when choosing a form of OAC. This reflects either awareness of NOACs improved cost-
effectiveness or a lack of consideration for cost when choosing NOACs. Either way, consideration of cost does not appear to
account for the preference for warfarin found in our study.

Implementation of guideline-based management can be a difficult task. Camm et al[30] have identified significant barriers to
implementing the 2012 European Society of Cardiology AF guidelines and developed best-practice strategies for guideline
implementation. Three key areas were identified: practical, educational and access. The significant knowledge gap identified in
our study suggests resources should be focused on educational avenues for both attending physicians and residents to improve
adherence to the CCS guidelines.

Limitations

Our study has several limitations. The response rate was 60%; however, results are accurate at 4 percentage points at the 95%
confidence level. Additionally, while our subgroup analysis of internal medicine residents involved a high response rate, with 518
responses, split almost equally over the 3 years of core internal medicine training, there was a slightly higher percentage of PGY-
1s (38%) and this may have contributed in part to the high rates of warfarin use reported due to a larger knowledge gap earlier on
in training. This trend persists, however, throughout core internal medicine training, with minimal improvement. We believe this
reflects an actual knowledge gap, beyond the slightly higher contribution of junior resident responses. Another major limitation of
survey-based studies, such as ours, is self-reported data and the fact that this may not align with clinical practice.

Conclusion

In conclusion, we found significant incongruence between Canadian NVAF guidelines and the OAC choices of Canadian internal
medicine residents. Progression through core internal medicine residency training appears to have minimal effect on this. Given
the fact that 95% of residents reported starting at least one patient on OAC in the preceding 3 months prior to our study, we feel
these results reflect a very significant knowledge gap. A knowledge gap that requires improvement to avoid the morbidity and
mortality associated with inadequate anticoagulation and the inappropriate predisposition towards warfarin and its less favourable
side-effect profile.

Sidebar 1
Main Messages

In the rapidly evolving world of oral anticoagulation for non-valvular atrial fibrillation, the prescribing choices of Canadian
internal medicine trainees had not previously been studied.

Throughout all years of core internal medicine training, significant incongruence exists between residents reported choices
and the Canadian Cardiovascular Society guidelines.

Warfarin was consistently and inappropriately favoured over the non-vitamin K antagonist oral anticoagulants in a variety of
clinical scenarios.

Sidebar 2
Current Research Questions

What are the optimal methods for improving atrial fibrillation (AF) guideline adherence among internal Medicine residents?

How much of a role does resident modelling of attending physicians play in predicting resident guideline adherence?

What are the resident adherence rates for other major cardiovascular guidelines?

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Funding
Bayer, Inc. provided an unrestricted educational grant.

Provenance and peer review

Not commissioned; externally peer reviewed.

Postgrad Med J. 2017;93(1100):308-312. 2017

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