Download Stroke Prevention in Atrial Fibrillation

Cardiac Arrhythmia
Cardiac Arrhythmia
Chapter 1
Stroke Prevention in Atrial Fibrillation
Todd Mendelson1 and David Lin1*
1
Hospital of the University of Pennsylvania, USA
Corresponding Author: David Lin, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA, Email:
[email protected]
*
First Published April 24, 2016
Copyright: © 2016 Todd Mendelson and David Lin.
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
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Atrial fibrillation (AF) is one of the most common
arrhythmias in the United States and a significant cause
of morbidity. Using historical data from the Framingham
Study, prevalence has been estimated to be up to 12%
[1]. More recently, the ARIC study has evaluated the incidence of atrial fibrillation based on race and found it
is more incident in whites than blacks. From their data,
the cumulative risk of AF at age 80 is 21% for white men,
17% in white women, and 11% in African-American men
and women [2]. Based on estimates from Olmsted County
data, the number of people in the United States with atrial
fibrillation will reach 10 million by the year 2050 [3]. As
risk factors (such as hypertension, diabetes, obesity and
sleep apnea) for atrial fibrillation become more common
and as the population continues to age, atrial fibrillation
will continue to be a common arrhythmia.
Thrombo-embolic stroke is a dreaded complication
of this common arrhythmia. Early attempts to quantify
the risk of stroke led to the commonly used CHADS2 risk
stratification system [4]. This scoring system was an advancement in the risk evaluation of stroke due to its ease
of use; however, it was criticized for adjudicating many
people to the intermediate risk group. Therefore, another
group added/updated the CHADS2 score to include vascular disease to improve the ability of clinicians to evaluate use of oral anticoagulation [5]. The CHA2DS2-Vasc
scoring system is the most widely used method for clinicians to determine the risk of stroke in patients with atrial
fibrillation and, in fact, is the guideline recommended
method [6]. Yet it is important to keep in mind that these
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risk calculators are specifically for non-valvular atrial fibrillation and do not include other potential mediators of
thrombo-embolism such as thyroid disease. Furthermore,
whether these risk calculators still apply after successful
AF ablation remains a question to be answered. Recent
studies have shown enhanced hypercoagulability in hyperthyroidism and atrial fibrillation (above atrial fibrillation alone or hyperthyroidism alone) [7].
Warfarin is the oldest of the anticoagulants used to
prevent stroke in atrial fibrillation and remains the gold
standard for stroke prevention in AF. As is well known, it
was first developed as a pesticide in the 1940s and was approved for use in humans by the FDA in the 1950s. Since
then, it has been studied multiple times as a strategy to
prevent stroke in atrial fibrillation. In fact, a Cochrane review of patients with atrial fibrillation and no prior history of stroke, found that warfarin compared to placebo
prevented 25 strokes for every 1000 patients treated with
warfarin [8]. There have not been many recent advances in warfarin; however, it remains one of the dominant
strategies to prevent stroke in atrial fibrillation. There
were attempts to analyze genetic variation in response to
warfarin [9]; however, when used in a prospective clinical
trial, there was no clinical benefit [10]. Perhaps the biggest
advance in warfarin has been the ability for patients to use
home monitoring with excellent time in therapeutic range
[11]. For the forseeable future, warfarin will likely continue to be the anticoagulant of choice for patients with
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valvular heart disease and end-stage renal disease (ESRD)
not yet on dialysis.
The past several years have seen the rise of a new
generation of oral anticoagulants which were initially referred to as novel oral anticoagulants; however, as time
has gone by, the utilization of these agents have increased
as the novelty has worn off. The two main classes of anticoagulants are direct thrombin inhibitors and Factor Xa
inhibitors (whereas warfarin is a vitamin K antagonist).
The overall class has some advantages over warfarin. First,
there is no monitoring of anticoagulant level needed. Second, the onset of action and time to achieve a therapeutic level is on the order of hours rather than days. Third,
there are fewer dietary and drug interactions as compared
to warfarin. They are limited though as none has been
studied in patients with ESRD not yet on dialysis. There
has been only one study evaluating a novel oral anticoagulant in patients with mechanical valves; and it showed
harm with the novel anticoagulant compared with warfarin [12]. Therefore, it is unlikely that others will be tested
in the near future. The guidelines continue to endorse the
newer anticoagulants for patients with non-valvular atrial
fibrillation.
Dabigatran (Pradaxa) is a direct thrombin inhibitor
that was first approved in Europe for DVT prophylaxis
is orthopedic surgery patients. In the fourth quarter of
2010, the U.S. Food and Drug administration approved
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dabigatran for the prevention of stroke in patients with
non-valvular atrial fibrillation. After oral administration,
dabigatran reaches peak concentration in a few hours (depending on whether or not it is taken with a fatty meal).
The elimination half-life is 12-17 hours. The elimination is
renal and so dose reduction is recommended for patients
with impaired renal function. The standard dose is 150 mg
twice a day if CrCl>30 mL/min. If CrCl is 15-30 mL/min,
then a dose of 75 mg twice a day is recommended [13].
There is no data regarding CrCl<15mL/min. The clinical trial leading to approval of dabigatran was the Randomized Evaluation of Long-term Anticoagulant Therapy
(RE-LY) trial [14]. The trial randomized approximately
18,000 patients to either dabigatran or warfarin. The trial was designed as a non-inferiority trial with the upper
bound of non-inferiority being 1.46. The follow up time
was 2 years and the primary outcome was stroke or systemic embolism. The dabigatran arm consisted of two different doses (110 mg or 150 mg). The trial showed that the
150 mg arm compared to the warfarin arm had lower rates
of stroke and systemic embolism; however, similar rates
of hemorrhage. Interestingly, the 110 mg dose showed
similar rates of stroke/embolism, but lower rates of hemorrhage compared to warfarin. Nonetheless, the approved
dose for atrial fibrillation in the U.S. is 150 mg twice a day
(or 75 mg twice a day for renal impairment). The most
common side effect seen in the trial was dyspepsia (11%
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incidence). From approval in October 2010 through August 2012, there were 3.7 million prescriptions dispensed
according to an FDA statement [15].
Rivaroxaban (Xarelto) is a direct factor Xa inhibitor
that was also first approved for an orthopedic indication.
The U.S. FDA approved rivaroxaban in November 2011
for stroke prevention in patients with non-valvular atrial
fibrillation. The absorption of rivaroxaban varies depending on whether or not the medication was ingested with
(out) food. Therefore, the manufacturer recommends taking rivaroxaban with food [16]. The half-life of the drug
is 5 to 9 hours, though, the inhibition of factor Xa lasts for
approximately 24 hours; therefore, the medication is dosed
once a day. The standard dose is 20 mg daily and there is
a lower dose (15 mg) for those with CrCl between 15 and
50 mL/min. The clinical trial supporting use of rivaroxaban in non-valvular atrial fibrillation was the ROCKETAF
trial [17]. The study randomized approximately 14,000
patients to either warfarin or rivaroxaban (20 mg) and
measured the primary outcome of stroke or systemic embolism. The median follow up time was just under 2 years
(707 days) and the trial was designed as a non-inferiority
trial. The trial showed that rivaroxaban was not inferior to
warfarin for the prevention of stroke or systemic embolism. The risk of major bleeding between groups was similar; however, there was a lower rate of fatal bleeding and
intracranial bleeding in the rivaroxaban group. The most
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common adverse event was epistaxis which was more
common in the treatment group. Currently, rivaroxaban
is the only once daily medication amongst the oral factor
Xa or direct thrombin inhibitors.
Apixiban (Eliquis) was the second direct factor Xa inhibitor to arrive to the U.S. market. It was approved by
the FDA in 2012 for stroke prevention in atrial fibrillation.
In contrast to the two prior drugs, apixiban was first approved for atrial fibrillation and subsequently for DVT/PE
prevention and treatment. The half-life is approximately
12 hours and the absorption is independent of food coadministration [18]. There are two doses available: the
standard dose is 5 mg twice a day. For patients with two of
the three following conditions, the recommended dose is
2.5 mg twice a day: age ≥ 80 years, weight ≤ 60 kg, serum
creatinine ≥ 1.5 mg/dL. The major clinical trial leading
to approval of apixaban was the ARISTOTLE trial [19].
The trial randomized approximately 18,000 to apixiban or
warfarin and was designed as a non-inferiority trial. The
primary endpoint was ischemic or hemorrhagic stroke or
systemic embolism. The median follow up was 1.8 years.
The study showed that apixiban was not inferior to warfarin with respect to the primary endpoint. One of the secondary endpoints was mortality and it showed the warfarin group had a statistically significantly higher mortality
rate. However, the rates were low and it just barely met
statistical significance. As a general summary, the new
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anticoagulants seem to have similar efficacy with regard
to stroke prevention and have a slightly more favorable
bleeding profile compared to warfarin [20].
Even newer oral anticoagulants are currently in the
pipeline. Edoxaban is another direct factor Xa inhibitor
which is dosed once a day. In the ENGAGE-AF TIMI 48
trial, subjects were randomized to low-dose edoxaban (30
mg), high-dose edoxaban (60mg), or warfarin [21]. In
keeping with the prior trials, the rates of stroke or systemic
embolism were similar (non-inferior) between edoxaban
and warfarin. There was also the same signal toward less
risk of bleeding in the factor Xa inhibitor. It was approved
by the FDA in January 2015. Another direct factor Xa inhibitor betrixaban is a little earlier in the pipeline as the
most recent data is a phase 2 clinical trial [22]. Bextrixaban is predominantly metabolized by the liver (in contrast
to the others which are predominantly metabolized by
the kidneys). The small phase 2 trial showed similar rates
of bleeding compared to warfarin and that the medication was well tolerated. It is also being studied for DVT
prophylaxis and is on fast-track for FDA approval for that
indication.
Perhaps the most novel medication on the scene regarding novel anticoagulants is the first approved reversal
agent. One of the major criticisms of the novel oral anticoagulants was the lack of reversibility. Idarucizumabwas
studied in the RE-VERSE AD trial [23]. Idarucizumab
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(Praxbind) is a monoclonal antibody fragment which
has two orders of magnitude more affinity for dabigatran
than thrombin does. There is a single, standard 5 gram
IV dose. The FDA approved the drug in the fall of 2015.
While idarucizumab is specific to dabigatran (a direct
thrombin inhibitor), there is another drug in the pipeline
which looks to be an anti-factor Xa inhibitor. Andexanet
Alfa is a recombinant factor Xa decoy protein which can
bind the factor Xa inhibitors. In the ANNEXA-A and the
ANNEXA-R, andexanet alfa was evaluated for its ability
to reverse both apixaban and rivaroxaban [24]. There is
an ongoing phase 3 trial of this drug and it is yet to be
approved by the FDA. The ANNEXA 4 trial is set to finish in 2022 (according to ClinicalTrials.gov). Nonetheless,
there is an approved dabigatran reversal agent available
and there is a factor Xa inhibitor reversal agent in phase
3 trials.
In addition to the evolution of anticoagulants, there
has also been an evolution in non-pharmacologic stroke
prevention. As is commonly agreed upon today, the left
atrial appendage is felt to be the site of origin of most
thrombi that go on to systemic embolism in atrial fibrillation. The earliest cited reference to this theory is from the
late 1960s [25]. One of the first discussions of techniques
to prevent stroke in rheumatic mitral stenosis dates back
to the early 1950s [26]. In the modern era, Blackshear and
Odell reviewed outcomes of left atrial appendage obliteration in non-rheumatics and found some promising evi10
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dence [27]. It is in this background, that many surgeons
who are performing MAZE procedures to prevent atrial
fibrillation will now over-sew or exclude the left atrial appendage (with the goal to reduce stroke). There are many
echocardiographic studies that question the efficacy of left
atrial appendage exclusion [28] and find that certain techniques are more efficacious than others [29]. Nonetheless,
for patients undergoing cardiac surgery and have a history of atrial fibrillation, one option to decrease the risk
of stroke is to exclude the left atrial appendage at the time
of surgery.
As the role of left atrial appendage exclusion has become entrenched as a method for stroke prevention, there
has been a race to develop percutaneous methods to
achieve this goal, thereby potentially eliminating the need
for open-heart surgery for left atrial appendage ligation.
There have been descriptions of using cardiac plugs, suture devices, and umbrella devices. The premise is based
on sealing the left atrial appendage from communicating
with the left atrium proper. One of the first was studied
in Europe; however, the device is no longer on the market [30]. There have been Amplatzer devices as well which
have been explored in two generations [31,32]. There is a
technique to ligate the appendage via a percutaneous epicardial approach with a snare/suture device [33,34]. This
technique has been widely performed off label (as the device is not approved by the FDA for left atrial appendage
closure) and a recent report questioned the safety of the
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technique [35].
Currently, in the United States, there is only one FDA
approved device for the indication of percutaneous left
atrial appendage exclusion to prevent stroke in the setting
of atrial fibrillation. There have been two trials evaluating
the safety and efficacy of the Watchman Device [36,37].
In the PROTECT-AF study, patients were randomized to
warfarin or left atrial appendage occlusion. The results
showed that the device was non-inferior to warfarin with
respect to the combined endpoint of stroke, systemic embolism, or cardiovascular death [37]. There were some
safety concerns and so the FDA required a second study
to evaluate the safety of the device. In the PREVAIL trial,
the non-inferiority of the device compared to warfarin
and the study showed improvement with regard to safety
of the device [36]. Currently, the device is implanted in
patients who have a contra-indication to long-term anticoagulation and have a high risk of systemic embolism. Of
note, patients are recommended to stay on warfarin for at
least several weeks post-implantation.
Regarding stroke prevention, one common scenario
surrounds patients asking about continuation of anticoagulation after ablation of atrial fibrillation. There have been
no randomized clinical trials evaluating the need for ongoing anticoagulation after atrial fibrillation has been successfully eliminated. There has been a single large, multiple center review of outcomes [38]. It showed that the risk
of ongoing anticoagulation may be greater than the risk of
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stroke. The future direction of stroke prevention research
in atrial fibrillation will likely include these two final issues. Are there non-pharmacologic, durable methods to
prevent stroke? Does left atrial appendage ligation and
ablation effectively mitigate stroke risk? Further clinical
trials will shed light on this very important clinical question.
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