Download Circulation: Cardiovascular Quality and Outcomes Topic Review

Circulation: Cardiovascular Quality and Outcomes
Topic Review
Most Important Outcomes Research Papers on
Anticoagulation for Cardiovascular Disease
Behnood Bikdeli, MD; Aakriti Gupta, MBBS; Purav Mody, MBBS; Julianna F. Lampropulos, MD;
Kumar Dharmarajan, MD, MBA; for the Editor
The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize
the most important manuscripts, as selected by the Editor, that have been published in the Circulation portfolio. The objective of this new
series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes,
and general cardiology audience. The studies included in this article represent the most significant research in the area of anticoagulation for
cardiovascular disease. (Circ Cardiovasc Qual and Outcomes. 2012;5:e65–e74.)
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T
Parenteral Anticoagulants
hrombosis is the leading cause of acute coronary syndromes,
stroke, and venous thromboembolism.1 Accordingly, anticoagulants have been successfully used in each of these settings. 2,3
Since the discovery of unfractionated heparin in the early 1900s,
the number of anticoagulant choices has increased at an accelerating rate. For treatment of acute coronary syndromes, these
include low-molecular weight heparins, fondaparinux, as well as
direct thrombin inhibitors such as bivalirudin.4 While warfarin
and other vitamin K antagonists have long been the dominant
oral anticoagulants, novel oral agents such as dabigatran, rivaroxaban, and apixaban have expanded the number of therapeutic
options.5
All of these agents have potential pros and cons. For example,
unfractionated heparin is relatively inexpensive and easily monitored.
However, it may increase bleeding compared with direct thrombin
inhibitors such as bivalirudin. Analogously, for patients with atrial
fibrillation, warfarin is inexpensive and has a long track record of
preventing thromboembolic events; however, it is subject to multiple
potential food and drug interactions and requires close monitoring
to maintain optimal time in therapeutic range. In contrast, the novel
oral anticoagulants have been shown to be noninferior compared with
warfarin for stroke prevention in atrial fibrillation without the need
for intensive monitoring.6–8 Use of these new agents was also associated with significantly fewer intracranial bleeds and a trend toward
reduced mortality that reached statistical significance for apixaban.8
However, these new options may entail considerable expense, have
no currently available antidote, and lack information on long-term
efficacy and safety. In the Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-LY) trial, concerns were raised about
an increased risk of myocardial infarction in patients taking dabigatran compared with warfarin; this risk was further supported in a subsequent meta-analysis.9
Given the increasing scope of anticoagulant therapy and the
introduction of multiple novel agents in recent years with unique
efficacy and safety profiles, we have chosen to dedicate this series
of Circulation: Cardiovascular Quality and Outcomes clinical
summaries to the topic of therapeutic anticoagulation. We have
included articles on topics such as the efficacy, safety, and costeffectiveness of bivalirudin in acute coronary syndromes, outcomes associated with discontinuation and variable monitoring of
vitamin K antagonist therapy, and indirect comparison of the clinical utility and cost-effectiveness of the novel oral anticoagulants.
Intravenous unfractionated heparin (UFH) and bivalirudin are 2 of the
most commonly used parenteral anticoagulants in patients with acute
coronary syndromes who undergo percutaneous coronary intervention
. UFH was discovered more than 90 years ago and is one of the oldest
drugs still in widespread clinical use.10 It has been shown to improve outcomes in patients with venous thromboembolism11,12 and acute coronary
syndromes.13,14 To its advantage, UFH is inexpensive and can be rapidly
reversed using intravenous protamine sulfate. However, UFH may have
variable pharmacokinetics, as it requires a cofactor for its anticoagulant
activity, is heterogeneous in molecular size, and has variable affinity for
endothelial cells, macrophages, and multiple plasma proteins;4 this variability may contribute to excessive anticoagulation and major bleeding.
In contrast to indirect anticoagulants such as UFH, direct thrombin
inhibitors such as hirudin and bivalirudin directly bind to thrombin and
block its enzymatic activity. Hirudin was the first direct thrombin inhibitor to come into common use after its isolation from the salivary glands
of the medicinal leech, Hirudo medicinalis.15 However, concerns about
its immunogenicity led to the development of additional direct thrombin
inhibitors, including bivalirudin. On the basis of landmark clinical trials in patients with acute coronary syndromes,16,17 bivalirudin has been
licensed as an alternative to UFH in patients undergoing percutaneous
coronary intervention for both ST-elevation myocardial infarction and
non–ST-elevation myocardial infarction/unstable angina. Both clinical
trial data and early real-world experience have shown that bivalirudintreated patients are less likely to suffer major bleeding complications.16–18
The following summaries concern multiple topics pertinent to anticoagulation with UFH or bivalirudin including optimal anticoagulation levels in patients undergoing peripheral vascular interventions,
differences in bleeding complications with UFH relative to bivalirudin, and cost-effectiveness of both agents in patients undergoing
percutaneous coronary intervention.
Bivalirudin Therapy is Associated With Improved
Clinical and Economic Outcomes in ST-Elevation
Myocardial Infarction Patients Undergoing
Percutaneous Coronary Intervention: Results
From an Observational Database
Summary: The authors’ objective was to compare clinical and economic
outcomes in a real-world population of ST-elevation myocardial infarction
Correspondence to The Editor, Circulation: Cardiovascular Quality and Outcomes Editorial Office, 560 Harrison Ave, Suite 502, Boston, MA 02118.
E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org
e65
DOI: 10.1161/CIRCOUTCOMES.112.968701
e66 Circ Cardiovasc Qual Outcomes September 2012
patients undergoing primary percutaneous coronary intervention using
bivalirudin or a combination of heparin+glycoprotein IIb/IIIa inhibitors.
They analyzed 21 316 ST-elevation myocardial infarction admissions from
2004 through 2008 in the Premier Perspective database. Patients receiving
bivalirudin were compared with those receiving heparin+glycoprotein IIb/
IIIa inhibitors and propensity matching was used to account for imbalances
in the baseline characteristics of the 2 groups. The primary outcome was
in-hospital death, and secondary outcomes included rates of bleeding,
transfusion, length of stay, and in-hospital cost. Compared with patients
receiving heparin+glycoprotein IIb/IIIa inhibitors, patients receiving
bivalirudin had fewer in-hospital deaths (3.2% versus 4.0%; P=0.01), less
clinically apparent bleeding (6.9% versus 10.5%; P<0.0001), and less
transfusion (5.9% versus 7.6%; P<0.0001). Patients receiving bivalirudin
also had shorter average length of stay (4.3 versus 4.5 days; P<0.0001)
and lower average in-hospital costs ($18 640 versus $19 967; P<0.0001).
Sensitivity analyses found that mortality and length of stay differences
were the outcomes most sensitive to small unmeasured confounding.
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Conclusion: This real-world analysis of a large nationally represen­
tative dataset provides findings that are consistent with the landmark
Harmonizing Outcomes with Revascularization and Stents in Acute
Myocardial Infarction (HORIZONS-AMI) trial.17 In both studies,
bivalirudin was associated with reduced bleeding rates and better
survival in ST-elevation myocardial infarction patients. A reduction
in bleeding rates may also explain the shorter average length of stay
and hospital costs associated with bivalirudin use in the current Pinto
et al study. It is important to note that mortality differences between
bivalirudin and heparin+glycoprotein IIb/IIIa inhibitors groups were
very sensitive to assumptions related to unmeasured confounding and
that the study was supported by the maker of bivalirudin.18
Bleeding Risk Comparing Targeted Low-Dose
Heparin With Bivalirudin in Patients Undergoing
Percutaneous Coronary Intervention: Results
From a Propensity Score-Matched Analysis
of the Evaluation of Drug-Eluting Stents and
Ischemic Events (EVENT) Registry
Summary: Randomized trials of patients undergoing percutaneous
coronary intervention have shown that bivalirudin is associated with
reduced bleeding compared with unfractionated heparin (UFH). Yet given
the high UFH doses that were administered in some of these studies,19,20
it is unknown whether bleeding differences were driven by excessive
anticoagulation. To address this question, the authors analyzed over 6500
patients in the Evaluation of Drug-Eluting Stents and Ischemic Events
(EVENT) registry. Patients were divided into 3 groups on the basis of the
antithrombotic drug used during percutaneous coronary intervention: (1)
UFH only, (2) UFH+glycoprotein IIb/IIIa inhibitor, and (3) bivalirudin
only. Propensity score matching was used to adjust for 89 measured
covariates. Using guideline definitions,21 UFH-treated groups were
stratified based on the activated clotting time (ACT) achieved (low ACT,
optimal ACT, and high ACT). The primary outcome was a composite
bleeding outcome including access-site bleeding, thrombolysis in
myocardial infarction major or minor bleeding, and transfusion. The
authors also tracked acute and chronic ischemic outcomes (in-hospital
death/myocardial infarction and 12-month death/myocardial infarction/
unplanned revascularization, respectively). The authors consistently
found that bivalirudin use was associated with decreased bleeding relative
to UFH or UFH+glycoprotein IIb/IIIa inhibitor regardless of the level of
ACT achieved. In addition, both acute and chronic ischemic outcomes
were similar between bivalirudin-treated and UFH or UFH+glycoprotein
IIb/IIIa inhibitor patients without regard to the ACT.
Conclusion: Using real-world data, the authors found that relative
to a bivalirudin-based strategy, UFH-based anticoagulation results
in greater bleeding without improved ischemic outcomes in patients
undergoing percutaneous coronary intervention regardless of the
ACT. These findings provide convincing evidence that the favorable
bleeding profile of bivalirudin in randomized controlled trials of
percutaneous coronary intervention is not an artifact of excessive
UFH dosing. Additional analyses demonstrating the interaction
between anticoagulation strategy, ACT, and periprocedural bleeding
risk would have provided further clinically useful information.22
Defining the Optimal Degree of Heparin
Anticoagulation for Peripheral Vascular
Interventions: Insight From a Large, Regional,
Multicenter Registry
Summary: Although unfractionated heparin (UFH) is the most
commonly used antithrombotic agent in percutaneous peripheral
vascular interventions (PVIs), the optimal level of anticoagulation is
unknown. The authors sought to correlate total UFH dose and peak
procedural activated clotting time with postprocedural outcomes in
patients undergoing PVI. They examined 4743 patient records from
the Blue Cross Blue Shield of Michigan Cardiovascular Consortium
PVI Quality Improvement Initiative registry, a prospective multicenter
registry of patients undergoing PVI. Carotid and aortic interventions
were excluded, as were patients who received glycoprotein IIb/IIIa
inhibitors. Over 75% of interventions involved the lower extremity.
Periprocedural and in-hospital outcomes were compared between
patients who received a total UFH dose < or ≥60 U/kg and between
patients who had a peak procedural activated clotting time < or
≥250 seconds. Through the use of a variety of propensity-matched,
multivariate models with and without hierarchical modeling for the
specific physician performing the PVI and the hospital site of care,
the authors found that both postprocedural hemoglobin drop ≥3 g/dL
and transfusion rate were positively associated with a total UFH
dose ≥60 U/kg and a peak procedural activated clotting time ≥250
seconds. Neither procedural success nor in-hospital major adverse
cardiac events were associated with the degree of anticoagulation.
Conclusion: Evidence-based anticoagulation targets are lacking for PVI,
and this was the first large-scale study to evaluate optimal degrees of
anticoagulation using UFH. Although higher degrees of anticoagulation
were unsurprisingly linked to excess bleeding, they were not associated
with reduced in-hospital major adverse cardiac events. One can therefore
question the logic of using more intense anticoagulation. Study findings
also suggest the value of targeting not only activated clotting time as is
often done currently, but also total UFH dose, which is rarely considered.23
Cost-Effectiveness of Targeting Patients
Undergoing Percutaneous Coronary
Intervention for Therapy With Bivalirudin
Versus Heparin Monotherapy According to
Predicted Risk of Bleeding
Summary: Bivalirudin has been shown to reduce the incidence of major
bleeding compared with unfractionated heparin (UFH) in patients
undergoing percutaneous coronary intervention. The authors studied
the cost-effectiveness of substituting bivalirudin for UFH monotherapy
in 81 628 patients from the 2004 to 2006 National Cardiovascular Data
Registry (NCDR) CathPCI Registry. First, a model was used to predict
major bleeding among patients receiving UFH only. Bivalirudin treatment
was assumed to decrease this risk of major bleeding by 33% compared
with UFH alone. Costs were tallied using wholesale drug acquisition
costs plus the costs associated with complications. A decision analytic
Markov model was then created to estimate lost life expectancy associated
with a major bleed, which was predicted to occur in 2.2% of patients.
With these assumptions, bivalirudin treatment was estimated to increase
costs by $571 per patient, yielding cost-effectiveness ratios of $287 473
per bleeding event averted and $1 173 360 per quality-adjusted lifeyear gained. At willingness-to-pay thresholds of $50 000 and $100 000
per quality-adjusted life-year gained, bivalirudin was cost-effective for
patients with a bleeding risk ≥8% (2.5% of patients) and ≥5% (7.9% of
Bikdeli et al Circulation: Cardiovascular Quality and Outcomes Topic Review e67
patients), respectively. Bivalirudin was cost saving only for patients with
a >20% risk of major bleeding (0.16% of CathPCI population). Notably,
the initial bleeding risk model had only moderate ability to predict major
bleeding (c-index 0.69), and cost-effectiveness estimates were sensitive to
bivalirudin’s predicted efficacy in reducing major bleeding.
Conclusion: Routine use of bivalirudin in place of UFH monotherapy
in patients undergoing percutaneous coronary intervention will
increase costs for virtually all patients. However, cost-effectiveness is
achieved in substantially more patients at traditional willingness-topay thresholds of $50 000 and $100 000 per quality-adjusted life-year
gained. This approach can help payers develop informed guidelines
for the use of expensive therapies. Unfortunately, the estimates
from this article are hindered by use of a bleeding model with only
moderate ability to predict major bleeding. In addition, the sensitivity
of cost-effectiveness to the efficacy of bivalirudin raises the question
as to whether alternative bleeding avoidance strategies such as radial
access and closure devices may be more cost-effective.24
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Warfarin
Since its rise from humble beginnings as a rodenticide through its
initial approval by the Food and Drug Administration in 1954 as an
anticoagulant, warfarin has been the gold standard for anticoagulation to
prevent morbidity and mortality in patients with atrial fibrillation or venous
thromboembolism.5,10,11 In recent years, however, this supremacy has
been challenged by novel oral anticoagulants with potentially improved
safety profiles and lower monitoring needs.6–8 Yet, warfarin still remains
the dominant agent in use given its excellent efficacy when optimally
managed, cost advantage (≈4 $/month), and extensive evidence based
regarding its benefits and harms. Increasingly, metrics are being developed
to quantify interinstitutional variation in anticoagulation control and spur
the achievement of increased therapeutic efficacy and reduced harm from
bleeding.25 The following articles describe multiple topics pertinent to
anticoagulation with warfarin including the use of different monitoring
intervals of the international normalized ratio and time in therapeutic
range, the effect of periprocedural interruptions in warfarin therapy, as
well as the impact of cognitive decline on anticoagulation control.
Net Clinical Benefit of Warfarin in Patients With
Atrial Fibrillation: A Report From the Swedish
Atrial Fibrillation Cohort Study
Summary: In patients with atrial fibrillation (AF), risk factors for
bleeding after anticoagulant treatment are largely similar to those that
predict thromboembolic events. In this context, the authors sought to
investigate the net clinical benefit of warfarin therapy among 182 678
patients included in the Swedish Hospital Discharge Register. The
net clinical benefit was defined as number of avoided ischemic
strokes with anticoagulation minus the number of excess intracranial
bleedings. All patients were followed-up for ≈1.5 years and stratified
according to risk scores based on the diagnostic codes in the register.
The CHA2DS2-VASc score was used to measure the stroke risk and the
HAS-BLED score was used to calculate the bleeding risk. Assuming
a weight of 1.5 to compensate for the generally more severe outcomes
with intracranial bleeding, net clinical benefit favored anticoagulation
for almost all AF patients. The exceptions were patients at very low
risk of ischemic stroke with a CHA2DS2-VASc score of 0 and those
with moderately elevated bleeding risk. The results were broadly
similar when using the CHADS2 score, except for patients with very
low embolic risk. The CHA2DS2-VASc was able to identify those
patients (n=6205, 3.9% of all patients) who had no net clinical benefit
or even some disadvantage from anticoagulant treatment.
Conclusion: In this study, the authors demonstrate the superiority of
CHA2DS2-VASc score when compared with CHADS2, as CHADS2
may assign a low risk to many AF patients who are not truly low risk.
When using CHA2DS2-VASc, results show that the risk of developing
ischemic stroke in AF patients without anticoagulation therapy
exceeds that of developing intracranial bleeding with treatment in
almost all patients. The vast majority of patients with AF should
therefore be offered effective thromboprophylaxis.26
Admission International Normalized Ratio
Levels, Early Treatment Strategies, and Major
Bleeding Risk Among Non–ST-SegmentElevation Myocardial Infarction Patients on
Home Warfarin Therapy: Insights From the
National Cardiovascular Data Registry
Summary: The decision to administer antithrombotic therapy to
patients on home warfarin who present with non–ST-segmentelevation myocardial infarction can be complicated by the level of
anticoagulation. Using data from the Acute Coronary Treatment and
Intervention Outcomes Network Registry-Get With the Guidelines
(ACTION Registry-GWTG), the authors stratified 5787 non–STsegment-elevation myocardial infarction patients according to their
admission international normalized ratio (INR) levels. Among these
patients, 46%, 35%, and 19% had subtherapeutic (INR <2), therapeutic
(INR, 2–3), and supratherapeutic (INR >3) INR levels, respectively.
Of those patients with INR ≥2 at admission, 45% were treated with
early heparin in the first 24 hours of hospitalization, 35% and 14%
were respectively prescribed early clopidogrel and glycoprotein IIb/IIIa
inhibitors, and 36% received an early invasive strategy. Higher risk of
major bleeding was noted among patients with therapeutic INR (15%;
adjusted odds ratio: 1.25; 95% confidence interval [CI], 1.03–1.50) and
supratherapeutic INR (22%; odds ratio: 1.60; 95% CI, 1.30–1.97) levels
compared with patients who had subtherapeutic INR levels (12%).
Early use of antiplatelet and antithrombin therapy was associated
with increased bleeding risk (odds ratio: 1.40 [95% CI, 1.14–1.72] for
heparin; 1.50 [95% CI, 1.22–1.84] for clopidogrel; and 1.82 [95% CI,
1.43–2.32] for glycoprotein IIb/IIIa inhibitors). INR level at admission
was not significantly related with the use of heparin, clopidogrel, or
glycoprotein IIb/IIIa inhibitors early therapy and was not associated
with the use of these antithrombotic drugs and bleeding events.
Conclusion: This study reports discrepancies between current
treatment practices and guideline recommendations regarding early
use of antiplatelet treatment in patients on home warfarin who present
with non–ST-segment-elevation myocardial infarction. Results
demonstrated that the early use of antiplatelet and antithrombin
therapy was associated with increased bleeding risk regardless of
admission INR level. In addition, the study demonstrated that higher
INR on admission was associated with increased risk of bleeding.
Although this study was able to characterize the relative harms of
antithrombotic therapy in the setting of oral anticoagulation, it was
limited by its lack of characterization of its relative benefits. This
information will be required to understand the net clinical benefit of
various antithrombotic therapies in this population.27
Ablation of Atrial Fibrillation Under
Therapeutic Warfarin Reduces Periprocedural
Complications: Evidence From a Meta-Analysis
Summary: Periprocedural thromboembolic and hemorrhagic events
are among the most important and insidious complications of
radiofrequency catheter ablation of atrial fibrillation. Although
adequate anticoagulation management during the procedure is
required to reduce thromboembolic risks, the optimal anticoagulation
strategies remain undefined. Recent studies suggest that
radiofrequency catheter ablation of atrial fibrillation performed under
continuous warfarin (CW) may reduce the risk of thromboembolic
events as compared with warfarin discontinuation and periprocedural
heparin bridging. In this systematic review, the authors evaluated
e68 Circ Cardiovasc Qual Outcomes September 2012
the impact of CW compared with warfarin discontinuation on
the periprocedural complications of atrial fibrillation catheter
ablation. From the 9 identified studies, a total of 27 402 patients
were included in the analysis (6400 undergoing ablation with CW).
Analysis showed that CW was associated with a striking decrease of
thromboembolic complications (odds ratio, 0.10; 95% CI, 0.05–0.23;
P<0.001) and in minor bleeding complications (odds ratio, 0.38; 95%
confidence interval, 0.21–0.71; P=0.002) compared with warfarin
discontinuation. CW also did not increase the risk of major bleeding
(odds ratio, 0.67; 95% confidence interval, 0.31–1.43; P=0.30),
including cardiac tamponade (odds ratio, 0.69; 95% confidence
interval, 0.19–2.47; P=0.57).
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Conclusion: In the absence of properly designed randomized trials, this
meta-analysis provides an estimate of bleeding complications related
to 2 commonly used anticoagulation strategies for patients undergoing
radiofrequency catheter ablation of atrial fibrillation and lends support
to continued warfarin anticoagulation. These findings raise questions
about the potential risks and benefits of bridging anticoagulation
strategies in other settings; periprocedural changes in anticoagulation
may introduce more harm than is commonly assumed.28
Bleeding Risk in Very Old Patients on Vitamin K
Antagonist Treatment: Results of a Prospective
Collaborative Study on Elderly Patients
Followed by Italian Centers for Anticoagulation
Summary: Vitamin K antagonist therapy is being widely used to
prevent venous thromboembolism and stroke in patients with atrial
fibrillation. As both venous thromboembolism and stroke risk as
well as the risk for bleeding increase with age, the use of vitamin
K antagonist therapy among the elderly is particularly challenging.
In this large multicenter prospective observational study, the authors
sought to evaluate the quality of anticoagulation therapy and
incidence of bleeding in patients >80 years. This study enrolled 4093
patients aged ≈80 years with a total follow-up of 9603 patient-years.
The median age at the beginning of follow-up was 84 years (range,
80–102 years). Among the bleeding events, 179 (1.87 per 100 patientyears) were major bleeds and 26 (0.27 per 100 patient-years) were
fatal bleeds. Results show that men and patients >85 presented with
higher bleeding rates compared with women and younger patients
(relative risk: 1.4; 95% confidence interval: 1.12–1.72; and relative
risk: 1.3; 95% confidence interval: 1.0–1.65). History of bleeding,
active cancer, and history of falls were independently associated with
bleeding risk in Cox regression analysis.
Conclusion: In this large study of very old patients on vitamin K
antagonist treatment, the rate of major bleeding events was low.
Therefore, age alone should not be a contraindication to treatment
with vitamin K antagonist. To evaluate the quality of anticoagulation
in this study as well as its generalizability to other settings, it would
have been helpful to know patients’ anticoagulation time in therapeutic
range as well as the overall therapeutic range at the study sites.29
The Business Case for Quality Improvement:
Oral Anticoagulation for Atrial Fibrillation
Summary: The authors’ objective was to demonstrate the potential cost
savings from improved international normalized ratio control among
67 077 Veterans Health Administration patients anticoagulated with
warfarin for atrial fibrillation. A simulation model was created that
calculated the number of ischemic strokes, major bleeds, and deaths
based on the percentage of time the international normalized ratio
was in a therapeutic range of 2 to 3. Patients were at high risk of
adverse thrombotic events, as almost 50% had a CHADS2 score
≥3. Improving the time in therapeutic range by 5% prevented 1114
adverse events and reduced costs by $15.9 million over 2 years.
Improving the time in therapeutic range by 10% prevented 2087
events and saved $29.7 million. In sensitivity testing, cost savings
were most sensitive to estimated stroke risk and the estimated stroke
reduction from improved international normalized ratio control.
Conclusion: This study describes an opportunity to simultaneously
save money and improve patient outcomes. A quality improvement
program to enhance anticoagulation control in atrial fibrillation can be
cost saving for the payer, even if only modestly effective in improving
international normalized ratio control. A system such as the Veterans
Health Administration may be able to leverage economies of scale to
create low-cost interventions that improve anticoagulation control and
reap the cost savings of decreased morbidity and mortality from stroke.
Other smaller systems may find this approach more challenging.30
Warfarin Discontinuation After Starting
Warfarin for Atrial Fibrillation
Summary: Appropriate use of warfarin reduces the risk of ischemic stroke
for many patients with atrial fibrillation.31 However, there are several
reasons that may lead to warfarin discontinuation. Using the data from
Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) registry,
the authors determined the independent predictors of prolonged (≥180
days) warfarin discontinuation. Overall, 4188 patients had new initiation
of warfarin therapy (mean age: 71.8 years). Within 1 year after initiation,
26.3% of patients discontinued therapy. Discontinuation rates were lower
for subsequent years (additional 8% during year 2 and 3.6% during
year 3). There were 263 hospitalizations with incident hemorrhage, the
majority of which (65%) resulted in warfarin discontinuation. Among
patients without incident bleeding, multivariable Cox regression found
the following as independent predictors of discontinuation: age <65 years
(adjusted hazard ratio [95% confidence interval]: 1.33 [1.03–1.72]), a
shorter period of time in the therapeutic range for international normalized
ratio (hazard ratio [95% confidence interval]: 1.46 [1.42–1.49]) and lower
CHADS2 risk of stroke (hazard ratio [95% confidence interval]: 2.54
[1.86–3.47] comparing 0 versus 4–6).
Conclusion: In this study, warfarin discontinuation was common, even
among patients without incident hospitalization for bleeding. The greater
rate of discontinuation among low-risk patients (ie, younger patients and
those with lower CHADS2 scores) may reflect clinical decision making
relating to the risk versus benefit of warfarin therapy. Discontinuation
among patients with poor international normalized ratio control is
more concerning and may be correctable if greater attention is given
to improving drug adherence or reducing drug–drug and drug–food
interactions. Novel anticoagulants may be also used as alternatives given
their fewer interactions. Study findings were limited by the data fields
captured by the ATRIA registry and therefore did not fully incorporate
socioeconomic factors, concomitantly prescribed medications, and other
factors that could affect treatment adherence.32
Prompt Repeat Testing After Out-of-Range
INR Values: A Quality Indicator for
Anticoagulation Care
Summary: The authors examined whether the time between an
out-of-range international normalized ratio (INR) value and repeat
INR testing (the follow-up interval) is a potential measure of the
quality of anticoagulation. They studied the records of 104 451
patients attending anticoagulation clinics in the Veterans Health
Administration. For each site of care, the authors computed the
average follow-up interval after low (≤1.5) or high (≥4.0) INR
results as well as average time in therapeutic range for patients
at this location. They found that 57% and 36% of patients had at
least 1 low or high INR, respectively. The site mean follow-up
times after a low INR ranged from 10 to 24 days and from 6 to 18
days after a high INR. Longer follow-up intervals were associated
with worse site-level anticoagulation control after low INR (1.04%
worse anticoagulation control for each additional day until retesting,
Bikdeli et al Circulation: Cardiovascular Quality and Outcomes Topic Review e69
P<0.001) as well as after a high INR (1.12% worse anticoagulation
control for each additional day until retesting, P<0.001). These
relationships were somewhat attenuated but still highly statistically
significant when the proportion of INR values in-range was used as
the dependent variable rather than time in therapeutic range.
Conclusion: The authors demonstrated that anticoagulation sites that
repeat INR testing at a shorter time interval after an abnormal test tend to
provide better quality of anticoagulation as defined by time in therapeutic
range. However, the significance of these findings is attenuated by the
lack of hard data pertaining to outcomes such as rates of incident stroke
embolism. It is striking that the average time to repeat INR testing was
≈2 weeks following documentation of an abnormal value. It is unknown
whether the impact of prolonged time to repeat INR testing is more
important for some patient subgroups relative to others.33
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Risk-Adjusted Percent Time in Therapeutic
Range as a Quality Indicator for Outpatient Oral
Anticoagulation: Results of the Veterans Affairs
Study to Improve Anticoagulation (VARIA)
Summary: The authors sought to document variation in risk-adjusted
percent time in therapeutic range (TTR) for various anticoagulation
management sites used in the Veterans Affairs system. They identified
124 551 patients receiving outpatient oral anticoagulation at 100
Veterans Affairs centers from 2006 to 2008. Patients could have any
indication for anticoagulation with warfarin except valvular heart
disease. The authors calculated TTR for each patient and a mean
TTR for each site of care using the Rosendaal method.34 Expected
TTR was calculated for each patient and each site on the basis of
a number of variables relevant for risk adjustment such as patient
demographics, physical health conditions, mental health conditions,
number of medications taken, number of recent hospitalizations, area
level poverty, and driving distance to the site of care. Risk adjustment
was performed by calculating an observed minus expected (O-E)
score for each site and reclassifying sites based on this risk-adjusted
score. Mean TTR for the entire sample was 58%. Site-observed
TTR varied from 38% to 69%. Site-expected TTR varied from 54%
to 62%. Site risk-adjusted performance ranged from 18% below
expected to 12% above expected. Although risk adjustment did not
alter the ranking of sites by TTR to a significant degree, it did lead
to some reclassification of low, average, and high-performing sites.
Conclusion: Quality of care with regards to warfarin use has routinely
been estimated by calculating the percent of eligible patients receiving
anticoagulation. This study describes a parallel marker of care quality
by calculating risk-adjusted percent time in TTR for patients on
warfarin anticoagulation. Previous studies have illustrated the value
of TTR by demonstrating its impact on clinical outcomes.35 However,
as some patients are more difficult to properly anticoagulate than
others, a true understanding of a hospital’s TTR should account for
differences in case-mix. Doing so can identify hospitals requiring
extra assistance or potentially remedial action.25
Moving the Tipping Point: Decision to
Anticoagulate Patients With Atrial Fibrillation
Summary: With the improved control with time of traditional risk
factors for stroke in patients with atrial fibrillation such as hypertension
and diabetes mellitus as well as the advent of newer oral anticoagulants,
a change in the threshold for initiation of anticoagulant therapy can be
expected. To study this, the authors used a Markov model to identify the
CHADS2 score above which anticoagulation is preferred to maximize
quality-adjusted life-years. The base case was a 69-year-old man with
atrial fibrillation. Assumptions were made regarding predicted stroke
rates, bleeding rates, and neurologic outcomes on the basis of data from
prior studies. Outcomes were compared for 4 anticoagulation strategies:
aspirin only, warfarin only, a novel oral anticoagulant modeled on
dabigatran, or no antithrombotic therapy. The initial analysis was done
using risk of stroke from the original CHADS2 study, and a second
analysis was performed using risk of stroke from the more contemporary
AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) study.
Warfarin was preferred to aspirin for patients with an estimated stroke
rate of at least 1.7%, even when CHADS2 score was 0. However, as
stroke rates had declined in the ATRIA population, warfarin was only
indicated for patients with a CHADS2 score of ≥2. Anticoagulation with
a new, safer agent, modeled on the results of the Randomized Evaluation
of Long-Term Anticoagulation Therapy (RE-LY) trial of dabigatran, led
to a lowering of the threshold for anticoagulation to a stroke rate of 0.9%
per year, that is, a CHADS2 score of <0.
Conclusion: The findings indicate that the threshold for anticoagula­
ting patients with atrial fibrillation may have increased with time as
stroke rates have decreased. However, given the reduced bleeding
associated with use of new oral anticoagulants, the threshold for
anticoagulation initiation has likely been lowered. A limitation of this
study is the lack of incorporation of potential ischemic end points into
the Markov model, as dabigatran has been associated with greater
incidence of myocardial ischemia and infarction.36
Guideline-Discordant Periprocedural
Interruptions in Warfarin Therapy
Summary: The authors sought to determine the frequency and guideline
concordance of periprocedural warfarin interruptions for patients at
a single university hospital. Postal surveys were sent to all patients
followed for >1 year by the University of Michigan Anticoagulation
service. Patients were asked about the number of times they were
requested in the previous year to interrupt warfarin therapy for a medical
or dental procedure or test and the specific indication for each requested
interruption. A total of 1686 of 2133 (79%) subjects responded. The
mean age of respondents was 69 years (SD=14 years) with the majority
being men (56%) and white (93%). Atrial fibrillation was the most
common indication for warfarin therapy (n=966, 57%). At least 1 request
to interrupt warfarin therapy in the previous year was given by 50% of
respondents. Forty-eight percent of requests to interrupt warfarin among
all respondents and 50% of requests to interrupt warfarin among those
taking warfarin for atrial fibrillation were not supported by guideline
statements. Multivariable logistic regression models were unable to
identify specific demographic features or comorbidities that were strong
independent predictors of periprocedural warfarin interruption.
Conclusion: On the basis of the present study, there is a tendency
to halt anticoagulation for several procedures, even when it is not
supported by evidence-based guidelines. This can be dangerous
as it unnecessarily exposes the patients to increased risk of
thromboembolism. More importantly, it represents a potential
target for preventive action by better educating healthcare providers
regarding the most recent periprocedural anticoagulation guidelines.
Of note, study findings are limited by recall bias, absence of data
comparing characteristics of responders versus nonresponders, lack
of data regarding the actual stoppage of warfarin and associated
bridging practices, or the impact of these decisions on event rates.37
Cognitive Function and Anticoagulation Control
in Patients With Atrial Fibrillation
Summary: Atrial fibrillation is an important comorbidity in the aging
population, in whom cognitive dysfunction is common and may impair
appropriate anticoagulation. Using the data from the Atrial Fibrillation
Clopidogrel Trial With Irbesartan for Prevention of Vascular Events
(ACTIVE-W) trial, the authors tested the association between cognitive
dysfunction, appropriate anticoagulation, and ensuing outcomes.
Cognitive function was assessed by the Mini-Mental Status Examination
(MMSE), with values <26 being suggestive of cognitive impairment.
Appropriateness of anticoagulation was assessed using the time in
e70 Circ Cardiovasc Qual Outcomes September 2012
therapeutic range (TTR). Among 2510 participants receiving oral
anticoagulation who had complete data, 171 (6.8%) patients had a MMSE
score <24 and 194 (7.7%) had a score <26. Over a follow-up period of
1.3 years, the median TTR was 65% in the overall cohort and 58% in the
group with MMSE <25. On multivariate analysis, a MMSE score <26
was an independent predictor of lower TTR. Moreover, both vascular
events and bleeding were less common among patients with MMSE
scores ≥26 compared with patients with MMSE<26 (hazard ratio, 0.46;
95% confidence interval, 0.27–0.78; P=0.002 and hazard ratio, 0.56; 95%
confidence interval, 0.37–0.85; P=0.04, respectively). After adjustment
for TTR, the MMSE score was no longer a predictor of bleeding events.
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Conclusion: The authors demonstrate that suboptimal time in TTR
may mediate the relationship between cognitive dysfunction and
increased vascular and bleeding events in patients taking warfarin
for atrial fibrillation. Therefore, when anticoagulation is initiated in
patients with cognitive dysfunction, extra care, such as enrollment
in anticoagulation clinics, involvement of caregivers, and simplified
medication instructions may be warranted to improve anticoagulation
control. Alternatively, if safety remains a concern, novel oral
anticoagulants that have a better safety profile and less need for
monitoring may be considered; however, many of these agents must
be taken twice daily and raise the overall pill burden.38
Novel Oral Anticoagulants
The search for safer alternatives to warfarin has been the focus of
research for decades. Despite being effective at preventing thromboembolic complications, warfarin has several limitations including
interactions with food and medications as well as the need for frequent
laboratory monitoring. These limitations have prompted the introduction of newer anticoagulants that target thrombin and factor Xa,
key enzymes in the coagulation pathway. The initial development of
these drugs was slowed after ximelagatran, a direct thrombin inhibitor
licensed briefly in Europe, was shown to cause fatal hepatotoxicity.39
However, safer agents such as dabigatran, rivaroxaban, and apixaban
have been introduced in recent years, and shown to have promising
advantages over warfarin including lower risk of intracranial bleeding,
no clear interactions with food, fewer interactions with medications,
and no need for frequent laboratory monitoring and dose adjustment.2,6–8
Although some of these drugs have been approved by the Food and
Drug Administration for prophylaxis of venous thromboembolism and
prevention of strokes in patient with nonvalvular atrial fibrillation, they
have been shown to be efficacious in other settings as well.40,41
Despite the associated optimism, transition from warfarin to newer
anticoagulants will likely be gradual given the challenges posed by these
agents in the clinical setting. Because of lack of availability of antidotes
and tests to determine the anticoagulant effect of these agents, concerns
exist about management in patients who bleed while taking these drugs.
Moreover, further information is needed on optimal methods to transition
from warfarin to one of these agents, protocols for periprocedural interruption of anticoagulation, management strategies for patients requiring
urgent procedures, and dosing in settings of chronic disease including
renal failure. Higher cost may also be an obstacle to use. Eventually,
comparative efficacy of these agents with long-term use will be needed.
The following section contains summaries pertaining to issues concerning novel oral anticoagulants including associated periprocedural
bleeding, anticoagulation during cardioversion, cost-effectiveness,
and comparative efficacy.
Periprocedural Bleeding and Thromboembolic
Events With Dabigatran Compared to Warfarin:
Results From the RE-LY Randomized Trial
Summary: In the Randomized Evaluation of Long-Term Anticoagula­
tion Therapy (RE-LY) trial, dabigatran was shown to be noninferior to
warfarin in patients with nonvalvular atrial fibrillation. This subanalysis
was undertaken to compare the periprocedural bleeding risk of patients
treated with dabigatran 110 mg (D110), dabigatran 150 mg (D150), or
warfarin, as the lack of an effective antidote to dabigatran could lead to
increased periprocedural bleeding. Bleeding rates were evaluated from
7 days prior until 30 days after invasive procedures, considering only
the first procedure for each patient. A total of 4591 patients underwent
at least 1 invasive procedure: 24.7% of patients receiving D110; 25.4%
receiving D150; and 25.9% receiving warfarin (P=0.34). Among
patients assigned to either dabigatran dose, the study drug was taken an
average of 49 ([interquartile range 35–85]) hours before the procedure
as compared with 114 (interquartile range 87–144) hours in patients
receiving warfarin (P<0.001). There was no significant difference in
the rates of periprocedural major bleeding between patients receiving
D110 (3.8%), D150 (5.1%), or warfarin (4.6%); (D110 versus warfarin:
relative risk [RR]=0.83, 95% confidence interval [CI]: 0.59–1.17; D150
versus warfarin: RR=1.09, 95% CI: 0.80–1.49). Among patients having
urgent surgery, major bleeding occurred in 17.8% with D110, 17.7%
with D150, and 21.6% with warfarin (D110 versus warfarin: RR=0.82,
95% CI: 0.48–1.41; D150 versus warfarin: RR=0.82, 95% CI: 0.50–
1.35, P=0.44). There was no significant difference in the composite
rate of periprocedural cardiovascular death, ischemic stroke, and
pulmonary embolism between patients receiving D110 (1.2%), D150
(1.5%), or warfarin (1.2%); (D110 versus warfarin: RR=1.05, 95% CI:
0.55–2.01; D150 versus warfarin: RR=1.29, 95% CI: 0.70–2.38).
Conclusion: In this subgroup analysis of RE-LY, the authors
demonstrated that dabigatran was not associated with higher rates
of major periprocedural bleeding as compared with warfarin despite
being interrupted much closer to the actual procedure time. Results
were similar even when urgent surgery was required and planned
drug interruption was not always possible. However, as exclusion
criteria for RE-LY comprised patients with severe renal impairment
and valvular impairment, patients in whom dabigatran has been
prescribed in the real world,42 periprocedural bleeding may be more
common in typical practice and will require rigorous evaluation. Also,
measurement of bleeding in the warfarin arm may be confounded by
a low use of vitamin K and fresh-frozen plasma in this subgroup,
given the open-label nature of this trial.43
Risk of Bleeding With 2 Doses of Dabigatran
Compared With Warfarin in Older and Younger
Patients With Atrial Fibrillation: An Analysis
of the Randomized Evaluation of Long-Term
Anticoagulant Therapy (RE-LY) Trial
Summary: Twice daily dabigatran 150 mg and 110 mg (D150 and
D110 respectively) were shown in the Randomized Evaluation of
Long-Term Anticoagulation Therapy (RE-LY) trial to be effective
treatment strategies for nonvalvular atrial fibrillation. The purpose
of this RE-LY substudy was to report safety results of both doses of
dabigatran compared with warfarin while considering both patient age
and different types of major bleeding. The study cohort included 18 113
patients who were followed for a median of 2 years. Compared with
warfarin, twice daily D110 was associated with a lower risk of major
bleeding (2.87% versus 3.57%; P=0.002), whereas twice daily D150
was associated with a similar risk of major bleeding (3.31% versus
3.57%; P=0.32). There was a significant treatment-by-age interaction,
such that twice daily D110 compared with warfarin was associated
with a lower risk of major bleeding in patients aged <75 years (1.89%
versus 3.04%; P<0.001) and a similar risk in those aged ≥75 years
(4.43% versus 4.37%; P=0.89; P for interaction <0.001), whereas
twice daily D150 compared with warfarin was associated with a lower
risk of major bleeding in those aged <75 years (2.12% versus 3.04%;
P<0.001) and a trend toward higher risk of major bleeding in those aged
≥75 years (5.10% versus 4.37%; P=0.07; P for interaction <0.001).
The interaction with age was evident for extracranial bleeding, but not
for intracranial bleeding, with the risk of the latter being consistently
reduced with dabigatran compared with warfarin irrespective of age.
Bikdeli et al Circulation: Cardiovascular Quality and Outcomes Topic Review e71
Conclusion: Data from these subanalyses of the RE-LY trial indicate an
age-by-treatment interaction for bleeding in patients with atrial fibrillation
at risk of stroke. Although both doses of dabigatran were associated with
lower risk of major bleeding in patients aged <75 years, an increased risk
of extracranial bleeding was noted with the higher dose of dabigatran (150
mg) in patients aged >75 years; though rates of thromboembolic events
were not reported in these age groups. Given that elderly patients may have
various associated risk factors for bleeding including polypharmacy and
renal failure, this finding underscores the added importance of tailoring
dabigatran dosing to bleeding risk in this age group. The Food and Drug
Administration’s decision to favor dabigatran 150 mg even in patients >75
years under the premise that the morbidity of stroke outweighs that of
other nonfatal bleeding may need to be revisited, provided the efficacy
end points of treatment with these agents are known.44
Dabigatran Versus Warfarin in Patients With
Atrial Fibrillation: An Analysis of Patients
Undergoing Cardioversion
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Summary: Given the increased risk of thromboembolic events during
cardioversion in patients with nonvalvular atrial fibrillation, the
authors of this post hoc analysis from the Randomized Evaluation
of Long-Term Anticoagulation Therapy (RE-LY) trial sought to
investigate outcomes associated with cardioversion for patients on
different anticoagulation regimens. Among 18 113 patients with
atrial fibrillation randomized to receive twice daily dabigatran 110
mg (D110), twice daily dabigatran 150 mg (D150), or warfarin, a
total of 1983 cardioversions were performed in 1270 patients (647,
672, and 664 in the D110, D150, and warfarin groups, respectively).
Precardioversion transesophageal echocardiography was encouraged,
particularly in dabigatran-assigned patients. Data from before, during,
and 30 days after cardioversion were analyzed. For patients on D110,
D150, or warfarin, transesophageal echocardiography was performed
before cardioversion in 25.5%, 24.1%, and 13.3% of patients, of which
1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous
treatment with study drug for ≥3 weeks before cardioversion was
lower in D110 (76.4%) and D150 (79.2%) compared with warfarin
(85.5%; P<0.01 for both comparisons). Respective stroke and systemic
embolism rates at 30 days were similar at 0.8%, 0.3%, and 0.6% (D110
versus warfarin, P=0.71; D150 versus warfarin, P=0.40). Rates of
stroke and systemic embolism were also similar in patients who did and
did not undergo transesophageal echocardiography. Major bleeding
rates were respectively 1.7%, 0.6%, and 0.6% (D110 versus warfarin,
P=0.06; D150 versus warfarin, P=0.99).
Conclusion: Cardioversion of patients with nonvalvular atrial fibrillation
in the RE-LY trial appears to be comparably safe and efficacious
whether patients were receiving dabigatran or warfarin. This study
was also the largest cardioversion study to date, and therefore provides
good estimates of thromboembolic complications associated with the
cardioversion procedure. As dabigatran use increases with time, care
must be taken not to apply this study to patients with valvular atrial
fibrillation, for whom novel oral anticoagulants have not been approved
and study of cardioversion safety has not been performed. It is likely
that these patients have a higher incidence of left atrial thrombus and
greater likelihood of thromboembolic complication.45
Myocardial Ischemic Events in Patients
With Atrial Fibrillation Treated With
Dabigatran or Warfarin in the Randomized
Evaluation of Long-Term Anticoagulation
Therapy (RE-LY) Trial
Summary: In this substudy of Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY), the authors report rates of
myocardial infarction (MI), unstable angina, cardiac arrest, cardiac
death, and the prespecified “net clinical benefit” of dabigatran versus
warfarin. “Net clinical benefit” was defined as the combination
of stroke, systemic embolism, MI, major bleeding, and all-cause
death. MI occurred at annual rates of 0.82% and 0.81% with twice
daily dabigatran 110 mg or 150 mg (D110 and D150, respectively)
compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95%
confidence interval [CI] 0.96–1.75 for D110; HR 1.27, 95% CI
0.94–1.71 for D150). Annual rates of a composite of MI, unstable
angina, cardiac arrest, and cardiac death were 3.16% per year with
D110, 3.33% per year with D150, and 3.41% per year with warfarin
(HR 0.93 for D110 versus warfarin, 95% CI 0.80–1.06 and HR 0.98
for D150 versus warfarin, 95% CI 0.85–1.12). Events prespecified as
net clinical benefit occurred at a rate of 7.34% per year with D110,
7.11% per year with D150, and 7.91% per year with warfarin (HR
0.92 for D110 versus warfarin, 95% CI 0.84–1.01 and HR 0.90
for D150 versus warfarin, 95% CI 0.82–0.99). The relative effects
of dabigatran versus warfarin on myocardial ischemic events were
consistent in patients with or without a baseline history of MI or
coronary artery disease.
Conclusion: These data indicate that there may be a nonsignificantly
higher risk of MI with prescription of dabigatran compared with
warfarin in patients with nonvalvular atrial fibrillation. These findings
are particularly concerning as RE-LY was not powered to identify
differences in ischemic outcomes between study arms. Further
study46 has demonstrated a significant risk of myocardial ischemic
events with dabigatran administration. We will need adequately
powered studies to determine whether the net clinical benefit in favor
of dabigatran as shown here truly exists, especially in patients with a
previous history of MI or coronary artery disease.47
Cost-Effectiveness of Dabigatran for Stroke
Prophylaxis in Atrial Fibrillation
Summary: Using results from Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY) and other trials, the authors
developed a Markov decision-analysis model to compare the cost
and quality-adjusted survival of various antithrombotic therapies in a
hypothetical cohort of 70-year-old patients with atrial fibrillation. The
cost-effectiveness threshold was set at $50 000 per quality-adjusted life
year. Assuming the annual costs of warfarin and dabigatran are $545
and $3240, respectively, and that the average risk of major bleeding is
≈3% per year, the most cost-effective therapy depended on stroke risk.
Only aspirin was cost-effective for persons with a CHADS2 score of 0.
Warfarin was cost-effective for persons with a CHADS2 score of 1 or
2 unless bleeding risk was high or anticoagulation control was poor.
Dabigatran 150 mg twice daily was cost-effective unless anticoagulation
control was excellent. Neither dabigatran 110 mg twice daily nor dual
antiplatelet therapy was ever cost-effective.
Conclusion: Although a previous study48 has shown dabigatran to be
a cost-effective choice in the setting of nonvalvular atrial fibrillation,
the current study provides a more detailed analysis by also considering
risk of stroke, risk of bleeding, and adequacy of anticoagulation control.
However, true cost-effectiveness needs to be assessed in the context of
everyday practice, where adherence to dabigatran may be compromised
by its relatively high cost compared with warfarin. As per updated
ACC/AHA guidelines for the management of atrial fibrillation, patients
already taking warfarin with excellent international normalized ratio
control may have little to gain by switching to dabigatran.49,50
Dabigatran and Warfarin in Vitamin K
Antagonist-Naive and -Experienced Cohorts
With Atrial Fibrillation
Summary: Observational and post hoc analyses suggest that patients
who have previously used vitamin K antagonists are more likely to
find a personalized dose that keeps international normalized ratio
in the therapeutic range and minimizes complications. Therefore,
e72 Circ Cardiovasc Qual Outcomes September 2012
in a prespecified substudy, the Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY) investigators determined
whether an interaction existed between previous use of vitamin
K antagonists and outcomes in the main treatment arms. Among
patients naive to vitamin K antagonists, the annual event rates for
stroke or systemic embolism were 1.69%, 1.57%, and 1.07% for
warfarin, dabigatran 110 mg twice daily, and dabigatran 150 mg
twice daily, respectively. Corresponding event rates in vitamin
K-experienced patients were 1.74%, 1.51%, and 1.15%. Similarly,
there was no interaction between previous vitamin K experience and
bleeding events. Major bleeding rates were comparable between
warfarin and dabigatran 150 mg twice daily arms, but were lower
for the dabigatran 110 mg twice daily arm. In all subgroups, rates
of intracranial bleeding were lower with dabigatran compared with
warfarin.
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Conclusion: Previous experience with a vitamin K antagonist did
not influence the benefits of dabigatran relative to warfarin among
subjects in the RE-LY study. Higher dabigatran doses consistently
had greater efficacy in preventing stroke and systemic embolism,
and lower doses had less major bleeding relative to warfarin. Yet,
it is unknown whether study findings are applicable to real-world
practice, as clinical trial subjects would be expected to be more
adherent and capable of medication management than the general
population. In addition, findings should be interpreted with caution in
patient subgroups that were underrepresented in RE-LY, such as those
at high risk of stroke.51
Cost-Effectiveness of Apixaban Compared With
Aspirin for Stroke Prevention in Atrial Fibrillation
Among Patients Unsuitable for Warfarin
Summary: The Apixaban Versus Acetylsalicylic Acid to Prevent
Stroke in Atrial Fibrillation Patients Who Have Failed or Are
Unsuitable for Vitamin-K Antagonist Treatment (AVERROES) trial
showed that apixaban (5 mg twice daily) was superior to aspirin (81–
324 mg daily) for reduction of stroke or systemic embolism without
an increase in rates of major bleeding in patients for whom vitamin
K antagonists were unsuitable. The authors used Markov modeling
to determine the associated costs and quality-adjusted life-years with
treatment due to apixaban versus aspirin. The model was constructed
for a base case of a 70-year-old patient with a CHADS2 score of 2 and
low risk of bleeding. The authors found that 1-year and 10-year total
costs per patient were $3454 and $44 232 for apixaban, and $1805
and $50 066 for aspirin. One-year and 10-year quality-adjusted lifeyears were 0.96 and 6.87 for apixaban, and 0.96 and 6.51 for aspirin.
Besides time, the results were sensitive to several other assumptions
including baseline stroke risk and the monthly costs for management
of major stroke.
Conclusion: For atrial fibrillation patients unsuitable for warfarin
therapy, alternatives include aspirin, aspirin plus a thienopyridine,
or apixaban.52 In this cost-effectiveness analysis, apixaban was
inferior to aspirin at 1 year but was dominant at 10 years among
patients unsuitable for warfarin. The improved cost-effectiveness
of apixaban at 10 years reflects in part the cumulative benefit
of stroke reduction on quality of life and reduction of costs for
management of stroke. The study has several limitations. First, the
authors assigned a cost to apixaban based on that of other novel
oral anticoagulants in the United States. However, this cost may
be too high based on estimates from Europe where the drug is
already approved.34,53 In addition, as the authors have highlighted,
the long-term cost-effectiveness of apixaban should be interpreted
with caution, since AVERROES was terminated with a median
follow-up of 1.1 years and long-term efficacy of apixaban remains
unknown.54
Enoxaparin Versus Dabigatran or
Rivaroxaban for Thromboprophylaxis After
Hip or Knee Arthroplasty: Results of Separate
Pooled Analyses of Phase III Multicenter
Randomized Trials
Summary: Oral anticoagulants are more convenient to use compared with
injectable formulations. Several phase III randomized trials assessed the
efficacy and safety of dabigatran (150–220 mg once daily) and rivaroxaban
(10 mg once daily) for prevention of venous thromboembolism (VTE)
after hip or knee arthroplasty. In this study, the authors conducted a pooled
analysis of these trials, comparing their safety and efficacy with the use of
enoxaparin treatment (30 mg twice daily or 40 mg once daily) for an equal
duration of time. Compared with dabigatran, there was a trend toward
better efficacy for enoxaparin (odds ratio [95% confidence interval]:
0.76 [0.44–1.31]; P=0.02 for heterogeneity). After excluding one of the
studies, efficacy in favor of enoxaparin became statistically significant
and heterogeneity was reduced (odds ratio [95% confidence interval]:
0.49 [0.26–0.49]; P=0.19 for heterogeneity). Bleeding (a composite
of major and clinically relevant nonmajor bleeding) was similar in the
2 groups (odds ratio [95% confidence interval]: 0.90 [0.71–1.15]).
Compared with rivaroxaban, the rate of symptomatic VTE was higher in
patients receiving enoxaparin (odds ratio [95% confidence interval]: 2.04
[1.32–3.17]). However, patients receiving enoxaparin had a lower rate of
bleeding (odds ratio [95% confidence interval]: 0.79 [0.62–0.99]). There
was little evidence suggestive of publication bias.
Conclusion: Novel oral anticoagulants are approved or are in the
process of approval for VTE prophylaxis in several countries. Headto-head comparative effectiveness studies for novel anticoagulants
are unlikely to be conducted in the near future. Therefore, findings
of this study have important implications regarding the choice of
pharmacoprophylaxis in patients undergoing joint arthroplasty
based on the patient’s risks for VTE versus bleeding. Lack of studies
comparing the safety and efficacy of novel oral anticoagulants versus
warfarin for VTE prevention remains a limitation.55
Comparative Efficacy and Safety of
New Oral Anticoagulants in Patients With
Atrial Fibrillation
Summary: Dabigatran, rivaroxaban, and apixaban are 3 novel oral
anticoagulants that were tested against warfarin in 3 large trials for
stroke prevention in atrial fibrillation: Randomized Evaluation of LongTerm Anticoagulation Therapy (RE-LY), Rivaroxaban Once Daily Oral
Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for
Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF), and Apixaban for Reduction in Stroke and Other Thromboembolic
Events in Atrial Fibrillation (ARISTOTLE). The authors provided an
indirect comparison between these new agents with regard to the reduction
of stroke or systemic embolism, and major bleeding. All of the novel
anticoagulants showed numerically superior efficacy for the prevention of
stroke or systemic embolism compared with warfarin, but the difference
reached statistical significance only for dabigatran (150 mg twice daily)
and apixaban (hazard ratio [95% confidence interval]: 0.88 [0.75–1.03],
0.66 [0.52–0.81] and 0.79 [0.66–0.95], for rivaroxaban, dabigatran, and
apixaban, respectively). To explain these findings of differential benefit,
the authors point out that the patients in the ROCKET-AF trial were more
medically complex with higher CHADS2 scores, and higher controlarm event rates as compared with patients in RE-LY and ARISTOTLE.
Accordingly, a separate comparison of all high-risk patients in the 3 trials
was conducted that showed numerically superior efficacy for apixaban
and dabigatran compared with rivaroxaban without clear statistical
differences. In all analyses, apixaban showed significantly lower rates of
major bleeding compared with rivaroxaban and dabigatran.
Bikdeli et al Circulation: Cardiovascular Quality and Outcomes Topic Review e73
Conclusion: This study showed comparable efficacy for dabigatran,
rivaroxaban, and apixaban for stroke prevention in atrial fibrillation
patients, while suggesting a better safety profile for bleeding for apixaban.
Three recent analyses reported slightly better efficacy with dabigatran
compared with rivaroxaban.56–58 However, as the preenrollment risk of
stroke was higher among the rivaroxaban-treated patients in the ROCKETAF trial, one would expect higher event rates in this population. This
study was therefore unique in comparing outcomes across a similarly
high-risk subset of patients in ROCKET-AF, RE-LY, and ARISTOTLE.
Mega-trials comparing the efficacy of new anticoagulants are unlikely to
be conducted in the near future. Accordingly, indirect comparisons such
as this study, individual patient meta-analysis of data, as well as longterm follow-up of patients in the 3 trials, may be helpful.59
Disclosures
Dr Dharmarajan is supported by a National Institutes of Health T32
training grant (2T32HL007854-16A1) from Columbia University,
New York, NY.
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Most Important Outcomes Research Papers on Anticoagulation for Cardiovascular
Disease
Behnood Bikdeli, Aakriti Gupta, Purav Mody, Julianna F. Lampropulos and Kumar
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Circ Cardiovasc Qual Outcomes. 2012;5:e65-e74
doi: 10.1161/CIRCOUTCOMES.112.968701
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