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CHAPTER 5 Atrial Fibrillation
Table 5.2 Outcomes of the RE-LY Trial
Outcome Dabigatran
110 mg
Dabigatran
150 mg
Warfarin RR Dabiagtran 110 mg
Versus Warfarin
RR Dabigatran 150 mg Versus
Warfarin
Stroke or systemic embolism 1.53 1.11 1.69 0.90; 0.74–1.11 ( p = 0.3) 0.65; 0.52–0.81 ( p < 0.001)
Ischemic stroke 1.34 0.92 1.20 1.11; 0.89–1.40 ( p = 0.35) 0.76; 0.60–0.98 ( p = 0.03)
Hemorrhagic stroke 0.12 0.10 0.38 0.31; 0.17–0.56 ( p < 0.001) 0.26; 0.14–0.49 ( p < 0.001)
Major bleed 2.71 3.11 3.36 0.80; 0.70–0.93 ( p = 0.003) 0.93; 0.81–1.07 ( p = 0.32)
Intracranial hemorrhage 0.23 0.3 0.74 0.31; 0.20–0.47 ( p < 0.001) 0.40; 0.27–0.60 ( p < 0.001)
GI hemorrhage 1.12 1.51 1.02 1.10; 0.86–1.41 ( p = 0.43) 1.50; 1.19–1.89 ( p < 0.001)
Life-threatening hemorrhage 1.22 1.45 1.8 0.68; 0.55–0.83 ( p < 0.001) 0.81; 0.66–0.99 ( p = 0.04)
Acute myocardial infarction 0.82 0.81 0.64 1.29; 0.96–1.75 ( p = 0.09) 1.27 (0.94–1.71) ( p = 0.12)
Mortality 3.75 3.64 4.13 0.91; 0.80–1.03 ( p = 0.13) 0.88; 0.77–1.00 ( p = 0.051)
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CHAPTER 5 Atrial Fibrillation
the prevention of stroke and systemic embolism, while causing similar rates of
bleeding. Conversely, low-dose dabigatran caused 20 percent less major bleed-
ing than warfarin while maintaining equivalent effi cacy in stroke prevention.
Both the 110-mg and 150-mg doses were associated with signifi cant reductions
in hemorrhagic strokes and intracranial hemorrhage compared to warfarin. As
intracranial bleeding is one of the most feared consequences of anticoagu-
lant therapy, this is an important benefi t. Warfarin was better tolerated than
dabigatran, with dyspepsia the primary driver of drug discontinuation. This is
could be due to the compound’s tartaric acid core, which may also explain the
trend toward increasing gastrointestinal hemorrhage with dabigatran although
the gastrointestinal bleeds were not confi ned to the upper gastrointestinal
tract. There was also a trend toward increasing rates of myocardial infarction
with dabigatran, although this did not reach statistical signifi cance and was
less prominent when newly identifi ed events were considered.
32
This trend
must also be interpreted in the context that warfarin is protective against
myocardial infarction
33
and that the overall net clinical benefi t of dabigatran is
favorable compared to warfarin.
34
Rivaroxaban
ROCKET-AF
35
assessed rivaroxaban, an oral Factor Xa inhibitor, against warfarin
for the prevention of stroke and systemic embolism. The patient cohort enlisted
in ROCKET-AF was at higher risk for that compared to other randomized con-
trol trials of new oral anticoagulants in stroke prevention for AF (86 percent of
the population of the CHADS
2
score of 3 or greater). It is also notable that the
TTR was only 55 percent, which is less favorable compared to the other trials.
Rivaroxaban (a 20-mg once-daily compound, in contrast to the other new
anticoagulants) was non-inferior to warfarin for the primary effi cacy end-
point of stroke and systemic embolism (Table 5.3). Overall rates of bleeding
were similar in the two groups, although rivaroxaban was associated with a
Table 5.3 Outcomes of the ROCKET-AF Trial
Outcome Rivaroxaban Warfarin HR Rivaroxaban Versus
Warfarin
Stroke or systemic
embolism
1.7 2.2 0.79; 0.66–0.97 ( p < 0.001)*
Ischemic stroke 1.34 1.42 0.94; 0.75–1.17 ( p = 0.581)
Hemorrhagic
stroke
0.26 0.44 0.59; 0.37–0.93 ( p = 0.024)
Major bleeding 3.6 3.4 1.04; 0.90–1.20 ( p = 0.58)
Intracranial
hemorrhage
0.5 0.7 0.67; 0.47–0.93 ( p = 0.02)
Critical bleeding 0.8 1.2 0.69; 0.53–0.91 ( p = 0.007)
Fatal bleeding 0.2 0.2 0.50; 0.31–0.79 ( p = 0.003)
Decrease in Hb
>2 g/dL
2.8 2.3 1.22; 1.03–1.44 ( p = 0.02)
Transfusion 1.6 1.3 1.25; 1.01–1.55 ( p = 0.04)
Mortality 1.87 2.21 0.85; 0.70–1.02 ( p = 0.073)
*Based on an ‘on treatment’ analysis—this was not signifi cant for intention to treat analysis.
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CHAPTER 5 Atrial Fibrillation
Table 5.4 Outcomes of the ARISTOTLE Trial
Outcome Apixaban Warfarin HR Apixaban Versus
Warfarin
Stroke or systemic
embolism
1.27 1.60 0.79; 0.66–0.95 (p = 0.01)
Ischemic stroke 0.97 1.05 0.92; 0.74–1.13 (p = 0.42)
Hemorrhagic stroke 0.24 0.47 0.51; 0.35–0.75 (p < 0.001)
Major bleeding 2.13 3.09 0.69; 0.60–0.80 (p < 0.001)
Intracranial
hemorrhage
0.33 0.80 0.42; 0.30–0.58 (p < 0.001)
Gastrointestinal
bleeding
0.76 0.86 0.89; 0.70–1.15 (p = 0.37)
Any bleeding 18.1 25.8 0.71; 0.68–0.75 (p < 0.001)
Mortality 3.52 3.94 0.89; 0.80–0.998 (p = 0.047)
signifi cant reduction in fatal and intracranial bleeding. Interestingly, the number
of patients suffering a decrease in hemoglobin or requiring a blood transfusion
was increased in the rivaroxaban group. The two drugs were equally well toler-
ated. Some have proposed that rivaroxaban should fi nd favor in AF patients
who have suffered an acute coronary syndrome (ACS), seeing as it was shown
to be of benefi t in ACS when given in a very-low-dose 2.5-mg twice-daily regi-
men in the ATLAS ACS 2–TIMI 51 trial.
36
However, the dosing for ACS and AF
is different, and there has been no study comparing the effect of the AF dose of
rivaroxaban for the indication of ACS when added to dual antiplatelet therapy.
Recommendations in this regard are therefore speculative.
Apixaban
Apixaban is an oral Factor Xa inhibitor that was compared to warfarin for the
prevention of stroke and systemic embolism in ARISTOTLE.
37
Although the
rates of ischemic stroke were similar for the two therapies, a substantial reduc-
tion in hemorrhagic stroke meant apixaban was superior to warfarin for the
prevention of all-cause stroke and systemic embolism (Table 5.4). There was
also less major bleeding with apixaban, which was also the better-tolerated
therapy. Signifi cantly, apixaban is the only new oral anticoagulant that has been
shown to demonstrate a mortality benefi t over warfarin. As with dabigatran,
apixaban is given in a twice-daily dosing (5 mg twice daily).
Other new oral anticoagulants
The three new agents discussed above have all completed phase III randomized
control trials and have already been—or soon will be—approved and incor-
porated into guidelines for the prevention of stroke and systemic embolism
in AF. Looking further afi eld, there are other agents in development that will
potentially add to the selection of safe and effective alternatives to warfarin.
The ENGAGE AF TIMI-48 study is a phase III non-inferiority trial currently
under way evaluating edoxaban against warfarin for the prevention of stroke
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CHAPTER 5 Atrial Fibrillation
and systemic embolism.
38
Betrixaban has completed phase II development and
is interestingly being co-developed with an antidote.
39
Results for these two
new agents and others are expected in the coming years, as the fi eld continues
to move forward at pace.
Practical considerations
The emergence of the new oral anticoagulants should trigger a landscape shift
for stroke prevention in AF: rather than deciding between superior anticoagula-
tion with warfarin and inferior antiplatelet therapy with aspirin, clinicians will
soon have an array of effective therapies to choose from. While this represents
a major advance in the fi eld of cardiovascular medicine, it also represents a
major challenge for the prescribing physicians.
Patients unwilling and unable to take warfarin should clearly be offered treat-
ment with a new agent. Since warfarin’s benefi t is dependent on excellent anti-
coagulant control with a high TTR, patients with erratic INRs should also be
considered for a new drug; there is evidence to suggest patients with a low TTR
derive the greatest benefi t from new anticoagulants.
How to best to identify those who would do well on warfarin, with a high
TTR? One way is to use a new clinical score which can assess the probability
of good TTR based upon several clinical characteristics, called the SAMe-TT
2
R
2
score, which includes female Sex, Age (<60 years), Medical history (at least 2
of the following: hypertension, diabetes, coronary artery disease/myocardial
infarction, peripheral arterial disease, congestive heart failure, previous stroke,
pulmonary disease, hepatic or renal disease), Treatment (interacting drugs eg
amiodarone for rhythm control) [all 1 point], as well as current Tobacco use
(2 points) and Race (non-Caucasian; 2 points) (Table 5.5).
40
The SAMe-TT
2
R
2
score (SAMe-TT
2
R
2
) can help predict poor INR control
and aid decision making by identifying those AF patients that would do well on
VKA (SAMe-TT
2
R
2
score = 0-1), or conversely, those who would do less well
Table 5.5 The SAMe-TT
2
R
2
Score for Predicting Patients That
Would do Well on VKAs, with High Time in Therapeutic Range
Acronym Defi nitions Points
SSex (female) 1
AAge (less than 60 years) 1
MMedical history* 1
e
TTreatment (interacting Rx eg. amiodarone for rhythm
control)
1
TTobacco use (within 2 years) 2
RRace (non Caucasian) 2
Maximum points 8
*2 of the following: hypertension, diabetes, myocardial infarction, peripheral artery disease,
congestive heart failure, previous stroke, pulmonary disease, hepatic or renal disease.
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CHAPTER 5 Atrial Fibrillation
(ie. SAMe-TT
2
R
2
score ≥2 or more) and require additional interventions to
achieve acceptable anticoagulation control or be more suitable for NOACs.
An important common benefi t of all new oral anticoagulants is that they
offer substantially reduced rates of intracranial hemorrhage (Table 5.6).
Offering comparisons between the new drugs is problematic and generally
speculative, as they are separate compounds that have been studied in separate
trials with differing designs and in differing populations. However, some tentative
conclusions can be drawn. The propensity of dabigatran to cause dyspepsia and
the increased signal for gastrointestinal hemorrhage with high-dose dabigatran
might make this an unwise choice in patients with established gastrointestinal
disorders. Rivaroxaban was also associated with more gastrointestinal bleeding
than warfarin, so apixaban may be the safest option for the group of patients
considered to be at high risk for gastrointestinal bleeding. Rivaroxaban has a small
advantage over the other new drugs by offering a once-daily dosing regimen.
Dabigatran and rivaroxaban must both be used with caution in patients with
renal insuffi ciency, and reduced dosing is recommended (110 mg or 75 mg twice
daily for dabigatran and 15 mg daily for rivaroxaban). Apixaban was given at a
reduced dose of 2.5 mg twice daily for patients with renal insuffi ciency (although
less than 5 percent of the study population received this dosage). Patients with
severe renal impairment or those on renal replacement therapy were excluded
from all three trials, so it may be prudent for clinicians to treat this group with
warfarin until further evidence is available to guide use with new anticoagulants.
Several specifi c clinical scenarios represent a challenge to clinicians when
using the new anticoagulants, owing to our relatively limited clinical experience
with them and scarce scientifi c data. The issues of perioperative bridging, labo-
ratory measures of anticoagulant activity, transitioning between anticoagulants,
and managing overdose and hemorrhage are all areas with limited evidence—
although clinicians are advised to drawn on expert consensus documents to
help inform their management here.
41,42
Upstream therapy
There is a body of evidence that suggests that perpetual atrial remodeling is the
primary driver of AF. This remodeling process causes electrical and structural
transformation, as well as interacting with changes related to aging in the heart
and the progression of underlying chronic cardiac disease.
43
Upstream thera-
pies refer to drugs targeting the underlying anatomical and pathophysiological
Table 5.6 Who Should Be Treated with a New Oral
Anticoagulant?
• Patients who are unwilling or unable to take warfarin
• Patients taking drugs known to interact with warfarin
• Patients with a history of intracranial bleeding
• Patients na ıïve to anticoagulation
• Patients with a low TTR for reasons other than poor compliance
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CHAPTER 5 Atrial Fibrillation
substrate of AF; they target underlying risk factors for the development of AF
as well as aiming to reduce the fi brosis and infl ammation that leads to the pro-
gression of the disorder. Upstream therapies therefore have the potential of
acting both against the formation of AF (primary prevention) and the deteriora-
tion of AF (secondary prevention). Common examples of upstream therapies
include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), aldosterone antagonists, and statins.
ACE inhibitors and ARBs
Angiotensin II has arrhythmogenic properties by stimulating infl ammation, acti-
vation of oxidative stress, atrial hypertrophy, and atrial fi brosis. ACE inhibitors
and ARBs can inhibit these effects. Meta-analyses of large trials of heart failure
with left ventricular systolic dysfunction demonstrated that patients treated
with ACE inhibitors and ARBs had a signifi cant reduction in the risk of AF.
44
This benefi t was also present for the reduction in risk of recurrent AF after
cardioversion when an ACE inhibitor or ARB was administered alongside a
traditional antiarrhythmic agent. However, a placebo-controlled study with
candesartan did not show any benefi t in maintenance of sinus rhythm when a
traditional antiarrhythmic agent was not co-administered.
45
One meta-analysis
46
demonstrated a signifi cant risk reduction in incident AF for patients with hyper-
tension, although other studies have had less convincing results. Most notably,
the GISSI-AF study
47
showed no benefi t of valsartan when added to standard
medical therapy for patients with paroxysmal or recently cardioverted AF. The
ACTIVE-I arm of the ACTIVE trial investigated whether the administration of
irbesartan at a dose of 300 mg once daily to patients with AF would reduce
cardiovascular events.
48
Over 9,000 patients were included and followed for
4 years. The addition of irbesartan was not associated with any reduction in
cardiovascular events.
Aldosterone antagonists
There is evidence that aldosterone plays a role in the development and progres-
sion of AF; as well as being the end point of the renin-angiotensin-aldosterone
system, patients with primary hyperaldosteronism have a 12-fold increased risk of
AF compared to patients with hypertension. Although there are animal models
suggesting aldosterone antagonists can reduce fi brosis and development of AF,
no human studies have been reported as yet. A substudy of the EMPHASIS-HF
trial reported on the incidence of new AF in patients with systolic dysfunction
treated with eplerenone.
49
There was a signifi cant reduction in new-onset AF in
patients treated with eplerenone (HR: 0.58, 95 percent CI 0.35–0.96; p = 0.034).
The reduction in cardiovascular events with eplerenone for patients with sys-
tolic dysfunction was consistent for patients with and without AF.
Omega-3 fatty acids
There is experimental evidence to suggest that omega-3 fatty acids reduce
atrial electrical and structural remodeling, although the clinical data have been
confl icting.
50
There were initial reports that claimed treatment with omega-3
fatty acids was associated with a reduction in postoperative AF, but this was
not reproduced in randomized controlled trials.
51
There is also limited evidence
suggesting omega-3 fatty acids may reduce AF recurrence after pulmonary vein
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CHAPTER 5 Atrial Fibrillation
isolation or cardioversion, but the evidence is insuffi cient to make specifi c rec-
ommendations on their use in this context currently.
Statins
Statins possess a number of properties that are felt to be protective against
AF: reduction in infl ammation, reduction in endothelial dysfunction, antioxi-
dant effect, prevention of atherosclerosis, and improved lipid profi le.
50
Some
data suggest that statins can protect against the occurrence of AF in patients
with impaired left ventricular systolic function and also patients with permanent
pacemakers.
52
A systematic review has also pointed to the benefi t statins may
have in preventing AF after surgery,
53
a pro-infl ammatory state. The evidence
for statins as secondary prevention in patients known to have AF is less sup-
portive of their use in this context (i.e., after cardioversion or ablation).
Conclusion
AF is an increasing problem, and this trend is likely to continue. The supe-
rior treatment and survival of previously fatal cardiac conditions has meant
the burden of AF will grow in the future and reach epidemic levels. For myriad
reasons, AF leads to a hypercoagulable state and predisposes to thromboem-
bolic disease. The most severe sequela of this is stroke, and management of AF
patients must prioritize adequate thromboprophylaxis to prevent stroke. This
has traditionally taken the form of warfarin, although this effective therapy has
been chronically underused.
An unmatched period of progress in AF research has yielded major advances
in the treatment of this condition. A deeper understanding of thrombotic risk
associated with the arrhythmia has informed the formation of better stroke risk
stratifi cation schemata and enabled the identifi cation of the truly low-risk patient
for whom there is no net clinical benefi t of anticoagulation—these patients
do not require any antithrombotic therapy. For all remaining AF patients who
warrant effective thromboprophylaxis, clinicians now have an increased array
of therapeutic options. As a group the new oral anticoagulants are at least as
effective as warfarin at preventing stroke and cause substantially less intrac-
ranial hemorrhage. All available safety data are reassuring, but the true safety
and effi cacy of these agents will only be established with long-term longitudinal
surveillance programs. There may be further additions to the group of new oral
anticoagulants, with several drugs being tested in trials and expected to report
in the coming months and years. Further to this, our understanding of the avail-
able agents will deepen and the management of challenging clinical scenarios
such as operative bridging and hemorrhage will become better defi ned. There
will also be renewed focus on the area of upstream therapy, with the aim to
prevent or mitigate the progression of AF.
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