Sean D. Pokorney MD, MBA1, Meena Rao MD, MPH1, Kent R. Nilsson MD1,2MA, Jonathan P.
Piccini, MD, MHS1,3
1 Duke Center for Atrial Fibrillation/Cardiac Electrophysiology Section, Division of Cardiology, Duke University Medical Center, 2 Claude D. Pepper Center Older American Independence Center and 3Duke Clinical Research Institute, Durham, NC .
Corresponding Author: Sean Pokorney, MD, Cardiology Division, Duke University Hospital, 2301 Erwin Rd, DUMC 3845 Durham, NC 27710.
Atrial fibrillation frequently complicates myocardial infarction. Patients with atrial fibrillation complicating
acute coronary syndrome
increased morbidity and mortality relative
to patients that remain
control in the setting of acute coronary syndrome. Stroke prevention should be pursued with oral
anticoagulation therapy, although the majority of patients with atrial fibrillation associated with acute
coronary syndrome receive only antiplatelet therapy. There are several novel oral anticoagulant therapies
but these agents have
not been well
studied in combination with dual antiplatelet
as part of triple therapy is the most conservative
approach until additional
Atrial fibrillation (AF) is the most common arrhythmia
and accounts for one-third of hospitalizations
for rhythm disorders .1 The prevalence
of AF in the United States is 0.89% and increases
with age, such that approximately 70% of cases of
AF are in patients between 65 and 85 years of age
.2 With the aging of the population, the number
of patients with AF is expected to increase
150% by 2050, with more than 50% of patients being
over the age of 80.3-8 The increasing burden
stroke, as patients with AF have a five to seven
fold greater risk than the general population.9,11 Strokes secondary to AF have a worse prog-
nosis than in patients without AF.12,13 Moreover,
an adjusted odds ratio of 1.5 in men and 1.9
in women in the Framingham population.14Each year there are more than one million hospitalizations
the past 10 years, 29% of ACS episodes are STEMI
events .15,16 The incidence of non-STEMI has increased, particularly following the introduction of
highly sensitive troponin .17,18Although mortality
mortality remains significant at 8%.7,19
AF is a known, common complication of ACS.
There are multiple mechanisms for induction of
AF during myocardial infarction (see Figure 1).
Animal models of atrial ischemia have shown that there is an increase in spontaneous atrial ectopic activity and in slowing of atrial conduction, leading to initiation and sustained reentry of AF.20,21 Canines with atrial ischemia develop
gap junction uncoupling that facilitates AF
.22Other infarct related causes of AF include
pericarditis, 23,24 hypoxia, 25,26 sinus node
ischemia, 27 ventricular dysfunction, 28 and
increase in atrial pressure.29 While myocardial
ischemia promotes AF, the ventricular irregularity
caused by AF can initiate or exaggerate
existing subendocardial ischemia by creating
a myocardial oxygen demand mismatch.30
Figure 1: Schematic representation of mechanisms of AF in the setting of ACS.
In the pre-thrombolytic era approximately one in
ten patients with ACS developed AF.31-34 As shown in Table 1, the incidence of AF in the postthrombolytic
era has been more varied, ranging
between 3-25% ,35-36 as has been described in
previous review and systematic review articles
.57,58 At the higher end, a community cohort
study of 3220 patients identified an incidence of
25%, and the majority (54%) of patients developed
AF more than 30-days out from their ACS
event.35 Overall, in the post-thrombolytic era,
the mean incidence of AF complicating ACS, after
adjusting for study size, was 8.8%. One of the limitations
of these observational studies is the unknown
rate of pre-existing, undiagnosed AF. Estimates
11% with a mean of 3.6%, after adjusting for
study size. Lopes, et al. conducted a pooled analysis
trials (GUSTO-I, GUSTO-IIb, GUSTO-III, AS-
SENT-2, ASSENT-3, ASSENT-3 Plus, PURSUIT,
PARAGON-A, PARAGON-B, and SYNERGY). In
table1 a substudy of 40,000 patients for whom baseline
electrocardiograms were available, pre-existing
AF was identified in nearly 1 in 5 patients (18%).49
Table 1: Incidence of AF after ACS in Post-thrombolytic Era
The timing of new-onset AF varies following ACS.
Among 13,858 STEMI patients treated with thrombolytic
onset of AF was 2 days after ACS, 41
which is similar timing as seen in the non-STEMI
population. 37 Madias et al. conducted a single
center study of 517 patients and found that AF developed
days 1, 2, 3, and > 3, respectively. 44
Other studies have suggested a more protracted
evolution of new-onset AF. For example, in the
OPTIMAAL trial, only 28% of those who devel-
oped AF in long-term follow-up (3 years) had AF
at 3 months post-ACS. 48 Similarly, the distribution of onset of AF after ACS in Jabre et al. was
30% within 2 days, 16% between 3 and 30 days,
and 54% greater than 30 days.35 A subgroup
of the CARISMA trial followed post-MI patients
with left ventricular ejection fraction ≤ 40% and
an implantable cardiac monitor for 2 years. Of the
101 patients, 39% had an episode of AF: 16% at 2
months, 32% at 12 months, and 29% at 24 months
after ACS. 59 These disparate data likely reflect
two periods of risk: an acute phase, similar to the
risk observed after cardiothoracic surgery, and a
longer, chronic risk of AF that is related to progressive
heart failure. In support of there being multiple
phases to post-ACS AF, a substudy analysis
of 1131 patients included in the VALIANT study
found a differential response to treatment strategies
for AF based upon time from myocardial in-
Few data are available regarding the type of AF
and subsequent treatment of AF complicating
ACS. Larger studies, such as GISSI-III have shown
that fewer than 25% of patients with AF complicating
ACS return to sinus rhythm prior to hospital
discharge. 40 Long-term follow-up suggests that
the risk of recurrent AF after ACS is substantial.
Asanin et al. followed 320 patients with AF after
ACS for a mean of 7 years (5.5 to 8.5 years) to monitor
in sinus rhythm at discharge of their ACS hospitalization, and 22.5% developed recurrences
of AF. Of note in this study, amiodarone was the
only antiarrhythmic used, and 10% of patients
(more in the recurrence group), received amiodarone.61
There is no data available regarding the impact of direct current cardioversion on patients with AF in the setting of ACS.
Many studies have investigated the risk factors
associated with the development of AF after ACS
(Table 2). Age is the most frequently identified predictive
factor, consistent with the prominent agerelated
incidence of AF in the overall population.
62 Killip classification at presentation is a significant,
independent predictor for the development
of AF in several cohorts, with odds ratios between
1.58 and 5.55, 39, 47, 48, 61 As expected, the presence
of cardiogenic shock (Killip Class IV) carries
the greatest risk. Hypertension, female sex, and
heart rate are also frequently associated with AF
after ACS. 34-51, 53-56 A heart rate > 100 beats
per minute was associated with a 3-fold increased
risk of AF in the OACIS cohort (OR 3.0 [1.94-4.64]).47
Finally, among STEMI patients, delayed revascularization
(> 4 hours from symptom onset)
had a higher incidence of AF .49 Delayed treatment
> 12 hours accentuates risk further (OR 2.19
A single-center study of 1039 patients admitted
with ACS found that patients who developed AF
within 24 hours of ACS had a higher frequency of
proximal RCA lesions (67%) when compared to
those with sinus rhythm. Patients with AF at < 24
hours had the most significant elevation in right
atrial pressure; right ventricular dilation; and incidence
of cardiogenic shock, right ventricular
infarction, and high grade atrioventricular
and decreased left ventricular ejection fraction.55
Table 2: 30-day and 1-year postoperative morbidity and mortality.
Higher body mass index, cardiac arrest, creatine kinase level, prior chronic obstructive pulmonary disease, height, history of hyperlipidemia, left main disease, lower ejecton fraction, left ventricular hyperthophy,non-smoker, North American, and STEMI were all listed in 1 study with a frequency of 5%
AF is associated with higher mortality following
ACS (Table 3). (35-49, 53-56) The increased risk of death is observed in-hospital but persists in longterm
Decreased survival in patients with AF after ACS
was first identified in the 1940s, when mortality at
30 days was 89%.31
By 1975, mortality with AF after
patients without AF.33
Data from the SPRINT
trial in the pre-thrombolytic era showed a higher
long-term (mean 5.5 years) mortality in patients
developing AF after ACS with hazard ratio of 1.28
Eldar et al. completed a prospective
study of 25 Coronary Care Units in Israel (2866 patients)
0.64 (0.44-0.94) and a 1 year OR of 0.69
More recently, the TRACE study randomized patients
with ACS to ACE-inhibition with trandolapril
Patients with AF had a higher mortality
at 2 years with adjusted relative risk of 1.33 (1.191.49).
When examining the relation between AF
and cause-specific death, the relative risk of sudden
cardiac death and death from other causes
were not statistically different at 1.31 (1.07-1.60)
and 1.43 (1.21-1.70), respectively.64
in both cardiac and non-cardiac mortality implies
that the impact of AF on mortality is multifactorial.
As might be expected, patients with recurrence
of AF have worse prognoses. Patients with recurrent
to patients without recurrences (OR of
3.08 [1.45-6.53] and relative risk of 1.52 [1.0-2.31],
respectively) 61. Furthermore, persistent AF at
discharge is associated with a higher adjusted relative
risk of death than paroxysmal AF.
Similar to findings with ventricular arrhythmias
after myocardial infarction, mortality is also affected
mortality at 8-year follow-up compared
to AF within 24 hours of ACS (OR 3.7 [1.84-7.52] vs.
OR 2.5 [1.23-5.00]). 55 There are conflicting data
regarding the relative risks of pre-exisiting versus
new-onset AF. 36, 39, 48, 55
Table 3: Mortality with AF after ACS
HR=Hazard Ratio, OR=Odds Ratio, RR=Relative Risk, N/A=Data Not Available, NSTEMI=Non ST-Segment Elevation Myocar- dial Infraction.
AF complicating ACS is associated with a host of
adverse cardiovascular outcomes, including an in-
creased risk of in-hospital stroke, major bleeding,
re-infarction, heart failure, and ventricular arrhythmias
Multiple studies have documented
increased in-hospital stroke among patients with
AF after ACS. For example, GUSTO-I demonstrated
a statistically significant increase of in-hospital
stroke of 3.1% with AF compared to 1.3% without
AF, and this was driven mainly by ischemic
strokes (1.8% with AF, 0.5% without AF) .42 AF
has also been associated with an increased risk of
acute renal failure after ACS (OR 2.7 [1.2-6.1]) .36
As shown in Table 4, AF consistently is associated
with increased length of stay (range 1.8-4.7 days).
Table 4: Complications Associated with AF after ACS
HR=Hazard Ratio, OR=Odds Ratio, N/A=Data Not Available, CVA=Cerebrovascular Accident, CHF=Congestive Heart Failure, VT=Ventricular Tachycardia, VF=Ventricular Fibrillation.
Prevention of AF after ACS
Many of the risk factors associated with AF after
ACS are modifiable. Optimal management of ACS,
including prompt revascularization, beta-blockade,
optimal afterload reduction, and aggressive
treatment of heart failure are core components of
quality ACS care. These same interventions should
also help minimize the risk of new-onset AF in both the acute and long-term setting.
The GISSI-III trial randomized patients to lisinopril
reduction in AF seen in the treatment arm
(OR 0.76 [0.65-0.89].40 ACE inhibition has also
been shown to decrease arrhythmic death post
MI. 38,65 Randomized data have also shown
that beta-blockade with carvedilol decreased the
frequency of AF post-MI (HR 0.41 [0.25-0.68]), including
new-onset AF (HR 0.51 [0.28-0.93]). 52While disappointing in primary prevention of AF
outside of ACS, statin therapy has been associated
with lower odds of AF after ACS, including data
from the Veterans Administration (adjusted OR of
0.57 [0.39-0.83]). 66,67
Rate & Rhythm Control
Randomized clinical trials have failed to identify
a superior survival advantage with either a rate
versus rhythm control strategy. 68,69 The PIAF
trial compared rate control with diltiazem and
rhythm control with amiodarone in 252 patients to
detect changes in symptoms related to AF. While
there was no symptomatic benefit with rhythm
control in the PIAF trial, there was better exercise
tolerance, as measured by 6 minute walk test .70 The ACC/AHA guidelines for the management of
AF discuss class I indications in the setting of an
acute myocardial infarction: direct-current cardioversion
in the setting of hemodynamic instability
or ongoing ischemia, intravenous amiodarone for
treatment of rapid ventricular response with depressed
ejection fraction, and intravenous beta
blockers or calcium channel blockers for treatment
fraction .1 Vaughan-Williams Class IC
medications have a Class III recommendation (evidence
of harm) due to increased mortality in the
CAST trials. 71,72
The preferred antiarrhythmics for AF post-myocardial
infarction are amiodarone and sotalol (in
the absence of congestive heart failure given its
beta blocking properties). In a subgroup analysis
of VALIANT, patients treated with anti-arrhythmic
higher risk of death than patients treated with
a "rate" control strategy. These findings did not
extend past 45 days. 60 The DIAMOND-MI trial
determined that there was no mortality benefit to
treating patients with dofetilide after myocardial
infarction in the presence of impaired left ventricular
dofetilide in this patient population; therefore,
it is a reasonable second line agent. While
rarely used, Vaughan-Williams class IA agents are
recommended as third line therapy in ACS patients .1
have failed to identify a survival advantage
with antiarrhythmic therapy for the maintenance
of sinus rhythm. 73
Even transient AF after ACS has been associated
with a significantly increased risk of ischemic
stroke (10.2% vs 1.8%) at 1-year.54 The ACC/
AHA guidelines for the management of STEMI
give a class I recommendation to use of oral anticoagulation
AF .74 A consensus document by the
European Society of Cardiology Working Group
on Thrombosis gave a class IIa recommendation
to OAC in combination with aspirin and clopidogrel
for AF patients with NSTEMI .75 Despite
these recommendations, only a minority (13.529%)
follow-up after the ACS event.53 Lopes
et al. conducted an analysis with 23,208 patients
from three IIb/IIIa trials. Only 13.5% of patients
with AF complicating ACS were discharged on
warfarin, and consistent with other observational
studies, warfarin was independently associated
with a lower risk of death or myocardial infarction
(HR 0.29 [0.15-0.98]).50,76.
Jang et al. conducted a study of 362 patients with
AF and ACS who were treated with PCI. The average
1.2. Warfarin was
prescribed to 23% of patients, including warfarin,
aspirin, and clopidogrel (so called "triple therapy"
in 22%) and warfarin and clopidogrel (1%). While
hampered by a small sample size and low statistical
power, there was no statistically significant
difference between the OAC and no OAC groups
in death, stroke, or major adverse cardiac events,
but there was a 5-fold increase in major bleeding
(10.7% in OAC group and 2.2% in non-OAC
group, p = 0.002) 77. A meta-analysis of nine
clinical trials, including 1996 patients on chronic
OAC showed that major adverse cardiovascular
events were significantly reduced in patients taking
more frequent major bleeding at 6-months
(OR 2.12 [1.05-4.29]).78 A second meta-analysis
found that triple therapy was associated with
a significantly lower incidence of ischemic stroke
(OR 0.29 [0.15-0.58]). The triple therapy patients
had a two-fold increase in major bleeding, and the
incidence of death and myocardial infarction were
statistically similar between the two groups.79
Several novel oral anticoagulants have emerged
as alternatives to warfarin. Dabigatran 150 mg
twice daily was found to have superior efficacy
for the prevention of stroke and systemic embolism
with similar risks of major bleeding when
compared to dose-adjusted warfarin in an openlabel
trial. 80 Importantly, when considering
its use in patients with AF after ACS, dabigatran
may be associated with a small increased risk of
MI compared with warfarin. A meta-analysis of 7
trials including 30,514 patients found an increased
risk of MI in those treated with dabigatran (1.2 vs.
0.8%; OR 1.33 [1.03-1.71]).81 A similar trend was
seen when ximelgatran was compared with warfarin
daily was non-inferior to warfarin for the
prevention of stroke and systemic embolization
and the composite of major and non-major clinically
relevant bleeding in the ROCKET AF trial
84. Finally, apixaban was studied in the ARISTOTLE
which showed superiority to warfarin
with respect to stroke or systemic embolism,
along with decreased major bleeding (HR 0.69
[0.60-0.80]). 85 Importantly, all three of the novel
oral anticoagulants lead to significant reductions
in intracranial hemorrhage .80,84,85 Data on
a fourth novel oral agent ,edoxaban, will be forthcoming
these data are not yet
Several studies have investigated the use of novel
oral anticoagulants in the treatment of patients
with ACS (regardless of AF status). Using the
same dose of apixaban as the ARISTOTLE trial,
APPRAISE-2 evaluated the use of apixaban on top
of antiplatelet therapy: aspirin (16% of patients)
or aspirin and clopidogrel (81% of patients) for
the prevention of recurrent ischemic events. In
APPRAISE-2 apixaban increased major bleeding
(HR 2.59 [1.50-4.46]), including more frequent fatal
and intracranial bleeding events. 87 ATLAS
ACS 2-TIMI 51 evaluated the use of rivaroxaban
with antiplatelet therapy (99% on aspirin and 93%
on clopidogrel). Notably, the doses of rivaroxaban
used in ATLAS were much smaller than those used
in ROCKET-AF (2.5 and 5 mg twice daily versus
20 mg daily). Those randomized to low-dose riva-
roxaban had a 16% reduction in the composite efficacy
infarction/stroke). While patients treated with rivaroxaban experienced increased major and intracranial bleeding, there was no excess fatal bleeding
88. Neither of these ACS trials were designed to
investigate the impact of triple therapy on stroke
or survival for AF patients after ACS and/or PCI.
At present the 2011 ACC/AHA guideline update
and a position paper by European Society of Cardiology
cite the lack of data and uncertainty regarding
patients with AF
who undergo PCI.. 89,90 Randomized trials evaluating
combination oral anticoagulation and antiplatelet
therapy after PCI and ACS are needed;
however, the design and execution of these trials
will be challenging. Given the increased risk of
intracranial hemorrhage in APPRAISE-2 and the
differences in dosing and patient populations (AF
versus ACS) across these trials, the devil we know
(warfarin) may be better than the devil we do not
(novel OACs) when prescribing triple therapy.
Until more data are available, the most conservative
approach will be to restrict triple therapy to
the use of warfarin. It is also important to limit
the duration of triple therapy by using bare metal
stents unless there is a significant benefit to drug
eluting stents (class IIa recommendation).75 Finally,
patterns for their dosing and associated
methods of percutaneous coronary access (femo-ral vs radial) will require further investigation.
AF is a common complication of ACS, and it is an
independent predictor of mortality and in-hospi-
tal complications. Despite guideline recommen-
dations and known mortality benefits, oral anticoagulation
remains suboptimal in patients with
AF complicating ACS. While we have a wealth of
data regarding the epidemiology and outcomes
associated with AF after ACS, we have little to no
contemporary clinical trial data to guide therapeutic
While preventing stroke, controlling heart
rate, and improving quality of life remain invio-
lable goals in the treatment of AF, we lack clinical
trials that address the most common therapeutic
choices in each of these treatment strategies after ACS. Despite the obvious challenges to their design,
funding, and completion, randomized trials
dedicated to the management of AF after ACS are
•Jonathan P. Piccini receives research support from Boston Scientific, Johnson & Johnson, and Bayer Healthcare and serves as a consultant to Forest Laboratories, Johnson & Johnson, Medtronic, and Sanofi-Aventis.
•Kent R. Nillson receives research support from Medtronic and receives honoraria from Jansen Pharmaceuticals.
•The remaining authors have no financial disclosures to report
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