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Clinical Review & Education

Review

Updates on Acute Coronary Syndrome


A Review
Alon Eisen, MD; Robert P. Giugliano, MD, SM; Eugene Braunwald, MD

IMPORTANCE Acute coronary syndrome (ACS), the acute manifestation of ischemic heart

Supplemental content at
jamacardiology.com

disease, remains a major cause of morbidity and mortality worldwide and is responsible for
more than 1 million hospital admissions in the United States annually. Considerable research is
being conducted in the field. This review provides a contemporary overview of key new
findings on the pathophysiology, diagnosis, treatment, and prognosis of ACS.
OBSERVATIONS While plaque rupture is the most frequent cause of coronary thrombosis,
studies with optical coherence tomography demonstrate that superficial plaque erosion is
more common than previously thought. High-sensitivity troponin assays (not yet available in
the United States) and cardiac computed tomographic angiography are being increasingly
used in diagnosis and risk stratification of patients with suspected ACS. New data from
long-term dual antiplatelet therapy studies and investigations of anticoagulants provide
important insights into the balance between ischemic and bleeding risks. The added benefit
of percutaneous coronary intervention in noninfarct-related arteries in patients with
ST-segment elevation myocardial infarction has been demonstrated in randomized trials, and
the radial approach has become the standard of care in patients with ACS undergoing
angiography. Promising old and new adjunctive therapies, such as pretreatment with
-blockers, ezetimibe, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors,
are discussed. New guidelines on the management of nonST-segment elevation ACS were
published in the last 2 years, as well as scientific documents on ACS in understudied
populations, such as women and patients with renal dysfunction.
CONCLUSIONS AND RELEVANCE Substantial progress in the prevention, diagnosis, and
management of patients with ACS has been accomplished in recent years. Despite optimal
pharmacological and invasive therapies, the burden of recurrent ischemic events and
mortality remains high, and future research is ongoing to prevent and improve the outcome
of patients with ACS.
JAMA Cardiol. doi:10.1001/jamacardio.2016.2049
Published online July 20, 2016.

Background
Coronary heart disease (CHD) accounted for more than 8 million
deaths in 2013 worldwide.1 Mortality associated with CHD has fallen
steeply in the last decades, but this overall decline has not been
shared equally by all demographic groups.2 While CHD mortality rates
decreased significantly in older patients, they decreased to a lesser
extent in younger adults, particularly in young women.1,2 The decrease in CHD mortality in part reflects the shift in the pattern of acute
coronary syndrome (ACS), with the rise in nonST-segment elevation ACS (NSTE-ACS) and a decline in ST-segment elevation myocardial infarction (STEMI), the latter now accounting for approximately one-third of all ACS events.3 This shift in the last decade might
be due to the ongoing widespread use of high-sensitivity troponin
(hsTn) assays (not yet approved in the United States) and to the
change in the risk factor profile of patients with ACS, including a de-

Author Affiliations: Thrombolysis in


Myocardial Infarction (TIMI) Study
Group, Division of Cardiovascular
Medicine, Brigham and Womens
Hospital, Harvard Medical School,
Boston, Massachusetts (Eisen,
Giugliano, Braunwald); Department
of Medicine, Harvard Medical School,
Boston, Massachusetts (Eisen,
Giugliano, Braunwald).
Corresponding Author: Eugene
Braunwald, MD, Thrombolysis in
Myocardial Infarction (TIMI) Study
Group, 350 Longwood Ave, First
Floor Offices, Boston, MA 02115
(ebraunwald@partners.org).

crease in smoking and in poorly controlled hypertension, younger


age, and widespread use of statins, together with an increase in diabetes mellitus, metabolic syndrome, and chronic kidney disease
(CKD).3
Acute coronary syndrome remains a major cause of morbidity
and mortality worldwide and is responsible for more than 1 million
hospital admissions in the United States annually. In this review, we
report the major findings in the field of ACS, most of which were published in the past 2 years. Out of more than 1000 original articles,
we have selected key studies that we consider to have important
clinical implications.

Pathophysiology
While plaque rupture remains the most common cause of coronary thrombosis, superficial plaque erosion is recognized with

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Updates on Acute Coronary Syndrome

increasing frequency.3 As opposed to lesions associated with


plaque rupture, those that are associated with plaque erosion do
not have thin fibrous caps, abundant inflammatory cells, or a large
lipid core. Rather, these lesions are rich with extracellular matrix,
such as proteoglycans and glycosaminoglycans (Figure 1). A
study4 using optical coherence tomography in 126 patients with
ACS showed that plaque erosion accounted for 31% of all cases.
Patients with plaque erosion presented more frequently with
NSTE-ACS than patients with plaque rupture (61.5% vs 29.1%,
P = .008). In another study 5 in 112 patients with STEMI who
underwent percutaneous coronary intervention (PCI), both optical
coherence tomography and intravascular ultrasound evaluated
the culprit plaque morphology after aspiration thrombectomy.
Plaque rupture was demonstrated in 64% of the patients, plaque
erosion in 27% of the patients, and calcified nodule in 8% of the
patients (Figure 2). Plaque erosion was characterized by eccentric
fibrous plaques, with fewer features of plaque vulnerability.
Figure 1. Main Characteristics of Superficial Erosion and Plaque Rupture
as Causes of Thrombosis in Acute Coronary Syndrome
Thrombus
Lipid
Lumen
Fibrous cap
Matrix
Media

Plaque erosion
Lipid poor
Proteoglycan and glycosaminoglycan rich
Nonfibrillar collagen breakdown
Few inflammatory cells
Endothelial cell apoptosis
Secondary neutrophil involvement
Female predominance
High triglycerides

From the many reports investigating the topic of reperfusion injury, we have selected 3 for highlight in this review. Inflammatory processes have been identified as key mediators of the deleterious effects of reperfusion injury in patients with STEMI. In a novel
randomized study6 in 151 patients with STEMI, treatment with colchicine, an anti-inflammatory agent, was associated with reduced creatinine kinaseMB fraction levels over a period of 72 hours after admission compared with placebo (P < .001) and reduced infarct size
as measured by late gadolinium enhancement with cardiac magnetic resonance (CMR) imaging. The results of preclinical investigations suggest that the inhibition of cyclophilin D, a major component of the mitochondrial permeability transition pore in the inner
mitochondrial membrane, might also have a major role in reperfusion injury. However, in a randomized trial7 of 970 patients with STEMI
who received primary PCI, treatment with intravenous cyclosporine (a cyclophilin D inhibitor) did not improve clinical outcomes compared with placebo and did not prevent adverse left ventricular remodeling at 1 year. The benefits from ischemic preconditioning in
patients with STEMI have long been debated. In the LIPSIA CONDITIONING trial8 (Table 1), a single-center randomized study in 696 patients with STEMI, remote ischemic preconditioning before primary
PCI, together with postconditioning after the PCI, increased myocardial salvage as assessed by CMR within 3 days after the infarction
but did not reduce myocardial infarction (MI) size, microvascular obstruction, or the composite of death, reinfarction, or new heart failure (HF) within 6 months. Therefore, reperfusion injury remains an
area of unmet clinical need.

Plaque rupture
Lipid rich
Collagen poor, thin fibrous cap
Interstitial collagen breakdown
Abundant inflammation
Smooth muscle cell apoptosis
Macrophage predominance
Male predominance
High LDL

Figure reprinted with permission from Libby and Pasterkamp.3 LDL indicates
low-density lipoprotein.

Biomarkers
As hsTn assays became increasingly available in recent years (but not
yet in the United States), several studies examined their clinical implications. Data from 48 594 patients who were admitted for suspected ACS in the SWEDEHEART Registry42 demonstrated that almost 90% of patients had a detectable hsTnT level on admission.
Most patients with detectable hsTnT were not diagnosed as having

Figure 2. Representative Optical Coherence Tomography Images of Underlying Plaque Morphologies in ST-Segment Elevation Myocardial Infarction
A Plaque rupture

Plaque erosion

Calcified nodule

Figure provided by Ik-Kyung Jang, MD, PhD, Massachusetts General Hospital, Boston. sec Indicates seconds.

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Updates on Acute Coronary Syndrome

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Table 1. Trial Acronyms


Acronym

Definition

BRIGHT9

Bivalirudin in Acute Myocardial Infarction vs


Heparin and GPI Plus Heparin

CHAMPION PHOENIX10

Cangrelor vs Standard Therapy to Achieve


Optimal Management of Platelet Inhibition

COMPARE ACUTE11

Comparison Between FFR Guided


Revascularization Versus Conventional
Strategy in Acute STEMI Patients With MVD

COMPLETE12

Complete vs Culprit-Only Revascularization to


Treat Multi-vessel Disease After Primary PCI
for STEMI

CvLPRIT13

Complete vs Lesion-Only Primary PCI

DANAMI-3PRIMULTI14

Third Danish Study of Optimal Acute


Treatment of Patients With STEMI:
Primary PCI in Multivessel Disease

DAPT15,16

Dual Antiplatelet Therapy

EUROMAX17

European Ambulance Acute Coronary


Syndrome (ACS) Angiography

HEAT-PPCI18

How Effective Are Antithrombotic Therapies in


Primary Percutaneous Coronary Intervention

IMPROVE-IT19,20

Improved Reduction of Outcomes: Vytorin


Efficacy International

LIPSIA CONDITIONING8

Effect of Conditioning on Myocardial Damage


in STEMI

MATRIX21,22

Minimizing Adverse Hemorrhagic Events by


Transradial Access Site and Systemic
Implementation of Angiox

MERLIN-TIMI 3623

Metabolic Efficiency With Ranolazine for Less


Ischemia in NonST-Elevation Acute Coronary
SyndromesThrombolysis in Myocardial
Infarction 36

METOCARD-CNIC24-26

Effect of Metoprolol in Cardioprotection


During an Acute Myocardial Infarction

ODYSSEY LONG TERM27

Long-term Safety and Tolerability of Alirocumab


in High Cardiovascular Risk Patients With
Hypercholesterolemia Not Adequately
Controlled With Their Lipid Modifying Therapy

OSLER28

Open-Label Study of Long-Term Evaluation


Against LDL Cholesterol

PARADIGM-HF29

Prospective Comparison of ARNI (Angiotensin


ReceptorNeprilysin Inhibitor) With ACEI
(Angiotensin-Converting Enzyme Inhibitor)
to Determine Impact on Global Mortality and
Morbidity in Heart Failure Trial

PEGASUS-TIMI 5430

Prevention of Cardiovascular Events in Patients


With Prior Heart Attack Using Ticagrelor
Compared to Placebo on a Background of
AspirinThrombolysis in Myocardial
Infarction 54

PRAMI31

Preventive Angioplasty in Myocardial Infarction

PRATO-ACS32

Protective Effect of Rosuvastatin and


Antiplatelet Therapy on Contrast-Induced Acute
Kidney Injury and Myocardial Damage in Patients
With Acute Coronary Syndrome

RIDDLE-NSTEMI33

Randomized Study of Immediate vs Delayed


Invasive Intervention in Patients With
NonST-Segment Elevation Myocardial
Infarction

SCOT-HEART34

Scottish Computed Tomography of the Heart

TASTE

35,36

TOTAL37,38

Thrombus Aspiration in ST-Elevation Myocardial


Infarction in Scandinavia
Trial of Routine Aspiration Thrombectomy With
Percutaneous Coronary Intervention vs PCI
Alone in Patients With ST-Segment Elevation
Myocardial Infarction Undergoing Primary PCI

TRANSLATE-ACS39,40

Treatment With ADP Receptor Inhibitors:


Longitudinal Assessment of Treatment Patterns
and Events After Acute Coronary Syndrome

WOEST41

What Is the Optimal Antiplatelet and


Anticoagulant Therapy in Patients With Oral
Anticoagulation and Coronary Stenting

MI but still had a graded, increased risk of mortality, in particular patients with hsTnT above the 99th percentile upper reference limit.
Using hsTn to rule out an MI in patients presenting with chest pain
in the emergency department has become increasingly common. Patients with chest pain but undetectable hsTnT levels and an electrocardiogram without signs of ischemia (n = 14 636) were shown to be
at minimal risk of MI or death within 30 days (negative predictive value
for MI, 99.8%).43 In another study44 of 1635 patients admitted to the
emergency department with suspected ACS, an early discharge strategy was used in patients with hsTnI levels below the 99th percentile
upper reference limit measured both at presentation and 2 hours later,
a Thrombolysis in Myocardial Infarction (TIMI) risk score of 1 or less,
and no ischemic changes on electrocardiogram. Integrating hsTnI with
the TIMI risk score identified more patients who had low risk of major adverse cardiovascular (CV) events within 30 days and who could
rapidly and safely be discharged for outpatient management. Finally, in a study45 of more than 6000 patients admitted to the emergency department with suspected ACS, hsTnI levels at presentation
below 5 ng/L identified almost two-thirds of patients as being at very
low risk of index MI and subsequent MI or cardiac death within 30 days
(negative predictive value for MI or cardiac death at 30 days, 99.6%).
However, the optimal hsTn level and assay to identify low-risk patients who can safely be discharged from the emergency department deserve further prospective validation.
In 2013, the Society for Cardiovascular Angiography and Interventions (SCAI)46 released an expert consensus document that focused on a new definition of clinically relevant MI after coronary revascularization. Compared with the widely used universal definition
for postprocedural MI (type 4a after PCI and type 5 after coronary
artery bypass graft [CABG] surgery),47 which includes low biomarker thresholds (small degrees of myonecrosis) with uncertain
prognostic importance, the SCAI document introduced a new definition for clinically relevant MI after coronary revascularization (PCI
or CABG) by using much higher threshold levels of biomarker elevation that have been strongly linked to subsequent adverse events
(creatine kinaseMB fraction 10 times the upper limit of normal
or cardiac troponin 70 times the upper limit of normal) (Table 2).
Compared with the universal definition, the SCAI document does
not include symptoms of ischemia or associated angiographic or
imaging complications (Table 2).
C-terminal provasopressin (copeptin), midregional proadrenomedullin (MR-proADM), and midregional proatrial natriuretic peptide (MR-proANP) are biomarkers of hemodynamic stress.23 In the
randomized MERLIN-TIMI 36 trial23 in 4432 patients with NSTEACS, each of these biomarkers predicted CV death and HF at 1 year
and had a prognostic performance at least as good as established
cardiac biomarkers, such as brain-type natriuretic peptide. Future
research is needed to examine the application of these biomarkers
in therapeutic decision making.

Imaging
Coronary computed tomographic angiography (CCTA) is being used
increasingly in clinical practice, while its additive value and the way
to implement it optimally in established or suspected ACS are still
being examined. The SCOT-HEART study34 randomly assigned 4146
patients who were referred for the assessment of suspected

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Table 2. Definitions of Periprocedural Myocardial Infarction (MI)46,47


SCAI Definition of Clinically Relevant MI
After Coronary Revascularization
(PCI or CABG)46
In patients
with normal
baseline
CK-MB

In patients
with elevated
baseline
CK-MB (or
cTn) in whom
the biomarker
levels are
stable or
falling
In patients
with elevated
CK-MB (or
cTn) in whom
the biomarker
levels have
not been
shown to be
stable or
falling

Universal Definition
of Postprocedural MI47

Type 4a: PCI related


MI associated with and occurring
within 48 h of PCI, with elevation
of cardiac biomarker values to >5
times the 99th percentile of the
URL in patients with normal
baseline values (99th percentile
URL) or a rise in cardiac biomarker
values 20% if baseline values are
elevated and area is stable or
falling.
This classification also requires 1
of the following:
a) symptoms suggestive of
myocardial ischemia (ie, prolonged
ischemia 20 min);
b) new ischemic changes on ECG or
new LBBB;
c) angiographic loss of patency of
a major coronary artery or a side
branch, or persistent slow flow or
no flow, or embolization;
The CK-MB (or cTn) rises d) imaging evidence of new loss of
by an absolute increment viable myocardium or new regional
wall motion abnormality.
equal to those levels
Type 5: CABG related
recommended above
MI associated with and occurring
from the most recent
within 48 h of CABG surgery, with
preprocedure level.
elevation of cardiac biomarker
values to >10 times the 99th
percentile of the URL in patients
with normal baseline cardiac
The CK-MB (or cTn) rises biomarker values (99th percentile
by an absolute increment URL).
equal to those levels
This classification also requires 1
recommended above
of the following:
plus new ST-segment
a) new pathological Q-waves and
elevation or depression
new LBBB on ECG,
plus signs consistent
b) angiographic new graft or new
with a clinically relevant native coronary artery occlusion,
MI, such as new-onset or c) imaging evidence of new loss
worsening heart failure
of viable myocardium or new
or sustained
regional wall motion abnormality.
hypotension.
The peak CK-MB
measured within 48 h
of the procedure rises to
10 times the local
laboratory ULN or to
5 times the ULN with
new pathological
Q-waves in 2
contiguous leads or new
persistent LBBB, or in the
absence of CK-MB
measurements and a
normal baseline cTn,
a cTn (I or T) level
measured within 48 h of
the PCI rises to 70
times the local
laboratory ULN or 35
times the ULN with new
pathological Q-waves in
2 contiguous leads or
new persistent LBBB.

Abbreviations: CABG, coronary artery bypass graft; CK-MB, creatine kinaseMB


fraction; cTn, cardiac troponin; ECG, electrocardiogram; LBBB, left bundle
branch block; PCI, percutaneous coronary intervention; SCAI, Society for
Cardiovascular Angiography and Interventions; ULN, upper limit of normal;
URL, upper reference limit.

angina due to CHD to the standard of care alone or to the standard


of care with CCTA. Coronary computed tomographic angiography
better clarified the diagnosis of angina due to CHD, reduced the need
for further stress testing, and increased the use of coronary angiography. During a median follow-up of 1.7 years, the use of CCTA was
associated with a reduction in fatal and nonfatal MI (hazard ratio [HR],
0.62; P = .053). The American College of Radiology and the American College of Cardiology (ACC)48 recommend the use of CCTA in
the emergency department in patients with chest pain and suspected ACS who are at low risk at presentation.
The additive value of CCTA to hsTn assays in the diagnosis and
prognosis of a suspected ACS is under investigation,49 and it is not
clear whether the combination of the 2 methods improves risk stratification and diagnostic accuracy for ACS. Although the use of hsTn
assays increases the sensitivity for the detection of MI and reduces
the time to diagnosis, it may decrease the specificity for the diagnosis of myocardial injury due to obstructive coronary artery disease (CAD).50 Therefore, the additive value of CCTA in addition to
hsTn might be particularly useful in patients in whom hsTn levels are
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not conclusive for ruling in or ruling out an MI. In these patients, the
combined tests may improve triage in the emergency department
and may also serve as a tool for secondary prevention of CV events.
Figure 3 shows a possible implementation of hsTn and CCTA in the
evaluation of patients with suspected ACS.50
In a pilot prospective study51 with a noninvasive technique using
18
F-fluoride positron emission tomography in 40 patients with MI,
the highest coronary uptake was observed in the culprit ruptured
plaque. Moreover, in the 40 patients with stable CAD, 18F-fluoride
uptake appeared to identify coronary plaques with high-risk features on intravascular ultrasound (positive remodeling, microcalcification, and necrotic core). This technique is the first noninvasive
method to identify and localize ruptured and high-risk coronary
plaques. Another novel prospective study52 examined whether highintensity coronary plaques visualized by noncontrast T1-weighted
CMR imaging predicted future coronary events in 568 patients with
suspected or known CAD. Plaque-to-myocardium signal intensity of
1.4 or higher was identified as a significant independent predictor
of future ACS. An observational study53 in 121 patients (85% with
ACS) who underwent coronary arteriography with near-infrared
spectroscopy, an intracoronary technique used to identify lipidrich plaques, demonstrated that large lipid-rich plaques at the nonstented regions in the target artery were associated with major adverse CV and cerebrovascular events. These interesting new imaging
modalities aim to identify vulnerable plaques and might assist in risk
stratification and treatment guidance in the future.

Antiplatelet Therapy
Long-term Dual Antiplatelet Treatment After ACS
Long-term dual antiplatelet treatment after an ACS was examined in
several key trials in recent years. The PEGASUS-TIMI 54 randomized
placebo-controlled trial30 examined the efficacy and safety of adding ticagrelor (90 mg or 60 mg twice a day) to aspirin in 21 162 patients who had experienced an MI 1 to 3 years earlier. Compared with
placebo, both ticagrelor dosages reduced the rate of the primary composite end point (CV death, MI, or stroke) by 15% and 16%, respectively. Similar risk reductions were observed in each of the individual
components of the primary end point (eFigure in the Supplement).
The rates of TIMI major bleeding (but not of intracranial or fatal bleeding) were higher with both dosages of ticagrelor (eFigure in the Supplement). Due to similar efficacy and a better safety profile, 60 mg rather
than 90 mg twice a day of ticagrelor was approved for clinical use in
the United States and Europe in patients beyond 1 year of their MI.
The DAPT trial15 randomized 11 648 patients after coronary
stenting to continue thienopyridine treatment for 30 months or 12
months after PCI. In the 30.7% of patients with MI at presentation
who continued thienopyridine, the rates of the composite of death,
MI, or stroke were reduced compared with those who received placebo after month 12 (3.9% vs 6.8%; HR, 0.56; P < .001), as was stent
thrombosis (0.5% vs 1.9%; HR, 0.27; P < .001), but the rates of moderate or severe bleeding were increased (1.9% vs 0.8%, P = .005).16
The reduction in the composite end point for long-term thienopyridine use was greater for patients with MI compared with those who
were enrolled in the study without MI (eTable 1 in the Supplement).
In the overall DAPT trial,15 extended dual antiplatelet therapy after
drug-eluting stent implantation was associated with an increase in

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Figure 3. Suggested Algorithm for the Use of High-Sensitivity Troponin Assays and Coronary Computed
Tomographic Angiography in the Evaluation of Patients With Suspected Acute Coronary Syndrome (ACS)
in the Emergency Department
Suspected ACS
ECG at
presentation

Normal or nonspecific STT wave abnormalities

hsTn at
presentation
hsTn <ULN

Second hsTn at 3 h/1 h:


no change

hsTn >ULN

Second hsTn at 3 h/1 h:


no change

Second hsTn at 3 h/1 h:


no or no significant change

Very low hsTn


levels*

Pain free, GRACE score <140,


differential diagnoses excluded

Intermediate
hsTn levels*

Workup differential
diagnosis

Low to Intermediate risk of ACS


based on clinical assessment

Diagnosis: NSTEMI (or


alternative diagnosis [eg, stressinduced CM, myocarditis])

CCTA

Diagnosis: nonischemic chest


pain, low risk of ACS
Negative
Outpatient follow-up
stress testing

Second hsTn at 3 h/1 h:


significant increase

Significant stenosis
(high-risk plaque, abnormal
FFR CT, perfusion/
wall motion abnormality)

Invasive angiography
guideline-directed therapies

Figure adapted with permission from


Ferencik et al.50 CCTA indicates
coronary computed tomographic
angiography; CM, cardiomyopathy;
CT, computed tomography;
ECG, electrocardiogram;
FFR, fractional flow reserve;
GRACE, Global Registry of Acute
Coronary Events; hsTn,
high-sensitivity troponin;
NSTEMI, nonST-segment elevation
myocardial infarction; ULN, upper
limit of normal; and URL, upper
reference limit.

Figure 4. Risk of Individual Cardiovascular and Bleeding End Points Comparing Extended Dual Antiplatelet Therapy
(DAPT) vs Aspirin Alone in a Meta-analysis of 6 Trials in 33 435 Patients With a Prior Myocardial Infarction

Source

Risk Ratio (95% CI)

P Value

Major adverse cardiovascular events

0.78 (0.67-0.90)

.001

Cardiovascular death

0.85 (0.74-0.98)

.03

Myocardial infarction

0.70 (0.55-0.88)

.003

Stroke

0.81 (0.68-0.97)

.02

Stent thrombosis (definite/probable)

0.50 (0.28-0.89)

.02

Major bleeding

1.73 (1.19-2.50)

.004

Noncardiovascular death

1.03 (0.86-1.23)

.76

All-cause death

0.92 (0.83-1.03)

.13

Favors
Extended DAPT

0.1

0.5

Favors
Aspirin Alone

1.0

2.5

Nonlog scale x-axis

all-cause mortality. This association was demonstrated in patients


without MI at presentation but not in patients with MI and was attributable to significantly increased noncardiac mortality (cardiac
mortality rates were similar [eTable 1 in the Supplement]). The underlying mechanism of this observation remains unclear.
A clinical prediction score was recently developed from the DAPT
trial54 in an attempt to identify patients who had completed 12
months of dual antiplatelet therapy after coronary stenting without major ischemic or bleeding events and who might benefit from
extended duration of dual antiplatelet therapy. This score requires
further prospective validation before widespread application. In addition, because bleeding in patients after ACS is important in estimating prognosis55 and is associated with reduced quality of life,39
the continued administration of dual antiplatelet therapy should be

Figure reprinted with permission


from Udell et al.56

assessed periodically and weighed individually by balancing the estimated risk of recurrent ischemic events with major bleeding.
In a meta-analysis56 that included 33 435 patients with a prior MI
from 6 randomized clinical trials (mean follow-up, 31 months), extended dual antiplatelet therapy beyond 1 year decreased the risk of
major CV events compared with aspirin alone (6.4% vs 7.5%; risk ratio [RR], 0.85; P = .001) and reduced CV death (RR, 0.85; P = .03)
(Figure 4). Although extended dual antiplatelet therapy was associated with an increase in major bleeding (1.85% vs 1.09%; RR, 1.73;
P = .004), it did not significantly increase intracranial bleeding (RR,
1.34; P = .17) or fatal bleeding (RR, 0.91; P = .75). Most important, extended dual antiplatelet therapy was not associated with non-CV
causes of death, a concern that had been raised in the overall DAPT
trial.15 This meta-analysis56 highlights that patients at high risk (prior

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Figure 5. Therapeutic Window Concept for P2Y12 Receptor Reactivity


<85 VerifyNow-PRU
<16% VASP-PRI
<19 MEA-AU
<31 TEG-MAADP (mm)

Event Risk, %

Bleeding Risk

>208
>50%
>46
>47

Therapeutic
Window

Ischemic Risk

Anticoagulant Therapy
Old age,
anemia, chronic
renal failure, high
BMI, DM, cardiac
marker elevation,
prior ACT, ST, and
CABG

Old age, anemia,


chronic renal
failure, low BMI,
DM, prior bleeding,
triple antithrombotic
therapy, and ticagrelor
or prasugrel therapy

reduced the rate of ischemic complications, including stent thrombosis (adjusted odds ratio, 0.78; P = .005), with no significant increase in severe bleeding. Cangrelor during PCI is approved for clinical use in the United States and Europe.

P2Y12 Receptor Reactivity

Figure reprinted with permission from Tantry et al.57 ACT indicates activated
clotting time; AU, aggregation units; BMI, body mass index; CABG, coronary
artery bypass graft; DM, diabetes mellitus; MAADP, maximal platelet reactivity
and platelet reactivity response to adenosine diphosphate stimulation;
MEA, multiple electrode aggregometry; PRI, platelet reactivity index;
PRU, P2Y12 reaction units; ST, stent thrombosis; TEG, thromboelastography;
and VASP, vasodilator-stimulated phosphoprotein.

MI) may have a preferential benefit from extended dual antiplatelet


therapy by reducing the thrombotic milieu in the coronary bed, which
differs from PCI in patients with stable CAD, in whom dual antiplatelet therapy is prescribed primarily to reduce the rates of stent thrombosis, which is now infrequent in the era of second-generation and
third-generation drug-eluting stents.

On-Treatment Platelet Reactivity Associated With


Ischemia and Bleeding
High on-treatment platelet reactivity to adenosine diphosphate (ADP)
is associated with ischemic events, whereas low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding.57 However, routine testing of platelet function to adjust antiplatelet therapy
in patients with ACS is not supported by evidence from randomized
trials and thus not recommended for routine practice. In a consensus document from an international working group investigating ontreatment platelet reactivity,57 cutoff values for high and low ontreatment platelet reactivity to ADP (Figure 5) that may be used in
future studies and in clinical practice were proposed. In addition, the
authors suggested that, although platelet function testing is not routinely recommended, it may be considered in patients treated with
clopidogrel bisulfate who are at high risk because of current or prior
ACS or stent thrombosis. Personalized antiplatelet therapy based on
a concept of a therapeutic window may improve the balance between greater efficacy and safety, but this approach still deserves further prospective validation.58

The controversy about the comparative safety and efficacy of bivalirudinandheparinhasbeenaddressedinseveralclinicaltrials.Inasinglecenter randomized clinical trial of 1829 patients undergoing primary
PCI (HEAT-PPCI trial),18 patients were treated with either bivalirudin
or unfractionated heparin. At 28 days, the rates of mortality, reinfarction, target vessel revascularization, or stroke were higher with bivalirudin (8.7% vs 5.7%; RR, 1.52; P = .01), with no difference in major
bleeding (Bleeding Academic Research Consortium [BARC] types 3-5;
3.5% vs 3.1%; RR, 1.15; P = .59). The EUROMAX randomized trial17 examinedtheearlyadministrationofbivalirudinvsunfractionatedorlowmolecular-weight heparin in 2218 patients with STEMI who were transported for primary PCI. At 30 days, bivalirudin compared with heparin
regimens reduced the rate of the composite of death or nonCABGrelated major bleeding (5.1% vs 8.5%; RR, 0.60; P = .001). This finding was driven mainly by the reduction in nonCABG-related major
bleeding with bivalirudin. The absolute rates of stent thrombosis were
lowbutwerehigherwithbivalirudintreatment(1.1%vs0.2%,P = .007).
In the BRIGHT trial9 of 2194 patients with acute MI undergoing primary PCI in China, patients were randomly assigned to receive bivalirudin,heparinalone,orheparinplustirofibanhydrochloride.At30days,
bivalirudin treatment resulted in a decrease in the composite of allcause death, reinfarction, ischemia-driven target vessel revascularization, stroke, or bleeding (RR for bivalirudin vs heparin alone, 0.67;
P = .008andRRforbivalirudinvsheparinplustirofiban,0.52;P < .001).
This difference was mainly due to a reduction in bleeding events with
bivalirudin without significant differences in ischemic events.
Finally, in MATRIX,21 a randomized trial that included 7213 patients with an ACS (55.6% with STEMI and 44.4% with NSTE-ACS)
who were planned to undergo PCI, patients received either bivalirudin or unfractionated heparin during the procedure. At 30 days,
major adverse CV events (death, MI, or stroke) occurred in 371 of 3610
patients (10.3%) in the bivalirudin arm and in 391 of 3603 patients
(10.9%) in the heparin arm (RR, 0.94; P = .44). The rate of definite
stent thrombosis was higher in the bivalirudin group (1.0% vs 0.6%,
P = .048), whereas the rate of major bleeding (BARC type 3 or 5) was
lower in the bivalirudin group (1.4% vs 2.5%, P < .001).
Overall, bivalirudin (a relatively expensive drug) appears to reduce bleeding compared with heparin (an inexpensive drug) at the
expense of increased stent thrombosis. These trials should be interpreted with caution because the differential use of glycoprotein
IIb/IIIa inhibitors and operator experience in the randomized arms
of these trials might have influenced both stent thrombosis and
bleeding outcomes.59

Parenteral Antiplatelet Therapy


Cangrelor is an intravenous, direct, reversible, very short-acting (halflife, 3-6 minutes) P2Y12 inhibitor. In the randomized, placebocontrolled CHAMPION PHOENIX trial,10 a total of 11 145 patients
(4802 with ACS) underwent PCI. Compared with clopidogrel administered immediately before or after PCI, cangrelor significantly
E6

Bleeding Risk
A broad variety of bleeding classifications is used in patients with
ACS (eTable 2 in the Supplement), but there is no consensus regarding the optimal one. The prognostic value of BARC-defined bleed-

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ing was examined retrospectively in 2002 patients with STEMI undergoing primary PCI.60 The incidence of BARC types 2, 3, 4, and 5
bleeding was 4.4%, 14.2%, 1.4%, and 0.3%, respectively. In a multivariable analysis, BARC type 3b or 3c bleeding and TIMI major bleeding, but not Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) or International
Society on Thrombosis and Haemostasis (ISTH)defined bleedings, were associated with a doubling of 1-year mortality. Hemoglobin decrease of at least 5 g/dL was the strongest predictor of mortality in both the BARC type 3b or 3c and TIMI major bleeding score
(to convert hemoglobin level to grams per liter, multiply by 10.0).
Triple therapy (aspirin, P2Y12 inhibitor [mainly clopidogrel], and
oral anticoagulant) after acute MI continues to be an ongoing field
of research. The randomized WOEST trial41 demonstrated in 563 patients (25% with NSTE-ACS) receiving oral anticoagulants who were
undergoing PCI that long-term treatment with clopidogrel alone vs
aspirin plus clopidogrel was associated with less bleeding (HR, 0.36;
P < .001) and no increase in ischemic events. There was also a reduction in mortality in the study arm without aspirin (HR, 0.39;
P = .027), although the reason for this finding remains unclear. In another observational study,61 approximately one-quarter of 4959 patients 65 years or older who had atrial fibrillation and were discharged after an acute MI treated with PCI received triple therapy at
discharge (dual antiplatelet therapy and warfarin). Compared with
dual antiplatelet therapy, patients who were treated with triple
therapy had the same rates of death, MI, or stroke at 2 years but had
significantly greater risk of bleeding requiring hospitalization (adjusted HR, 1.61; P < .001) and intracranial bleeding (adjusted HR, 2.04;
P < .01). These results were consistent among subgroups by age, sex,
MI type, and stent type, as well as by the thrombotic risk (CHADS2
score) and by bleeding risk (Anticoagulation and Risk Factors in Atrial
Fibrillation [ATRIA] score). Finally, the results from the observational TRANSLATE-ACS study40 (n = 617) demonstrated that triple
therapy with aspirin, prasugrel, and an anticoagulant was associated with more BARC-defined bleeding events compared with triple
therapy with aspirin, clopidogrel, and an anticoagulant. However, this
finding was driven by patient-reported bleeding that did not require hospitalization. Defining the optimal antithrombotic treatment strategy for patients with acute MI and a history of atrial fibrillation who have been treated with PCI continues to be a conundrum
given the limited evidence from randomized clinical trials. However, the information available at this time points to an increase in
bleeding with triple therapy without a substantial gain of efficacy over
double therapy (an anticoagulant and a single antiplatelet drug).

Invasive Management
Invasive coronary arteriography with intention to proceed to revascularization is recommended for patients with non-STEMI (NSTEMI),
yet the optimal timing of the procedure remains unresolved.62,63 In
a small randomized trial33 of 323 patients with NSTEMI, immediate
coronary arteriography (median, 1.4 hours from admission), followed by PCI when appropriate, was associated with lower rates of
death or MI at 30 days compared with a delayed intervention (median, 61 hours from admission) (4.3% vs 13.0%, P = .008), primarily due to a reduction in the occurrence of new MI in the precatheterization period. The results were consistent at 1 year of follow-up

(6.8% vs 18.8%, P = .002). Further large, randomized trials are


needed to confirm these findings and to examine the long-term effects of an immediate invasive strategy in patients with NSTEMI.
In patients with ACS undergoing invasive management, the radial approach has been used increasingly. The MATRIX randomized
trial22 demonstrated the superiority of radial compared with femoral
arterial access in 8404 patients with ACS with or without ST elevation who were undergoing PCI. Compared with patients with femoral arterial access, patients with radial access had a lower frequency
of death, MI, stroke, or major bleeding events (9.8% vs 11.7%; rate ratio, 0.83; P = .009). This difference was driven by fewer major bleeding events and lower all-cause mortality with radial access. In light of
these results and other evidence of the efficacy and safety of the radial access, this approach will likely become the standard of care in
most patients with ACS undergoing coronary arteriography.
The added benefit of PCI in noninfarct-related arteries that exhibit obstructive lesions in patients with STEMI has long been debated. The PRAMI trial31 randomized 465 patients with STEMI and
multivessel CAD (50% stenosis in at least 1 of the coronary arteries other than the culprit artery). Percutaneous coronary intervention was carried out in half of the patients. The study was prematurely stopped because of a benefit observed with the preventive
PCI strategy. During a mean follow-up of 23 months, the composite
of CV death, nonfatal MI, or refractory angina occurred less frequently in patients who underwent preventive PCI (HR, 0.35;
P < .001). Similarly, the CvLPRIT trial13 demonstrated a 55% reduction in major adverse CV events (all-cause death, MI, HF, or repeat
revascularization) within 12 months in 296 patients with STEMI and
multivessel disease who had complete revascularization at the time
of primary PCI or before hospital discharge. On the basis of these
and other randomized trials, such as the DANAMI-3PRIMULTI trial,14
the prior class III (harm) recommendation with regard to multivessel primary PCI in hemodynamically stable patients with STEMI has
been upgraded and modified to a class IIb recommendation to include consideration of multivessel PCI, either at the time of primary PCI or as a planned, staged procedure.64 Further trials are ongoing (COMPLETE12 and COMPARE ACUTE11) to define the optimum
revascularization for patients with STEMI and multivessel disease.
Another clinical controversy that was addressed recently is routine intracoronary thrombectomy before primary PCI in patients with
STEMI. The TASTE trial35 randomly assigned 7244 patients with STEMI
to undergo manual thrombus aspiration and PCI or to undergo PCI
alone. All-cause mortality rates at 30 days were similar (5.3% vs 5.6%,
respectively; P = .57), as were the rates of death, rehospitalization for
MI, or stent thrombosis after 1 year.36 In the TOTAL trial,37 patients
with STEMI (n = 10 372) were randomized to primary PCI with or without routine manual thrombectomy. At 6 months, the rate of the primary outcome (CV death, MI, cardiogenic shock, or New York Heart
Association class IV HF) was not different between the groups (6.9%
vs 7.0%, P = .86). However, stroke occurring within 30 days was more
common among patients who underwent thrombectomy (0.7% vs
0.3%; HR, 2.06; P = .02). At the 1-year follow-up, the results remained similar.38 Based on these trials, routine intracoronary manual
thrombectomy in patients with STEMI undergoing primary PCI is not
recommended (class III and level of evidence A).64
An interesting report from the CathPCI Registry of the National
Cardiovascular Data Registry on 96 738 admissions of patients undergoing primary PCI for STEMI highlighted the improvement (short-

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Figure 6. Rates of the Composite Cardiovascular End Points


in the ODYSSEY LONG TERM (Left) and OSLER (Right) Trials
4

HR, 0.52 [0.31-0.90]

HR, 0.47 [0.28-0.78]

3.3

Event Rate, %

ening) of the door-to-balloon time in the United States (from a median of 83 minutes in 2005-2006 to 67 minutes in 2008-2009,
P < .001).65 Most important, despite these improvements, inhospital mortality remained unchanged, perhaps reflecting an increase in patients risk during this period.66 Nevertheless, these findings suggest that additional factors may need to be targeted in the
future to achieve better outcomes in patients with STEMI. These include (but are not limited to) reducing the total ischemic time, which
includes the time before hospital admission, and improving inhospital and postdischarge care.

3
2.2
1.7

1.0
1
0

Placebo
(26/788)

Lipid-Modifying Therapies

ODYSSEY LONG TERM

The last 2 years have brought new and exciting evidence with therapies that reduce low-density lipoprotein cholesterol (LDL-C) to lower
levels than those achieved with statins alone. In the randomized
double-blind IMPROVE-IT trial,19 ezetimibe (a drug that reduces intestinal cholesterol absorption) was evaluated in 18 144 patients who
had been hospitalized with an ACS within 10 days. The combination
of simvastatin (40 mg) and ezetimibe (10 mg) was compared with
simvastatin (40 mg) and placebo during a median follow-up of 6
years. Compared with placebo, ezetimibe reduced the median timeweighted average LDL-C level (53.7 vs 69.5 mg/dL, P < .001), and it
reduced the primary CV end point (HR of composite of CV death, nonfatal MI, unstable angina, coronary revascularization 30 days after randomization, or nonfatal stroke, 0.936; P = .016) (to convert
cholesterol level to millimoles per liter, multiply by 0.0259). Myocardial infarction and ischemic stroke were significantly reduced by
13% and 21%, respectively. Lipid-lowering therapy with ezetimibe and
simvastatin was associated with an even greater relative reduction
in the rate of total primary end point events (RR, 0.91; P = .007).20
The IMPROVE-IT trial19 strengthens the LDL-C hypothesis, according to which a lower LDL-C level (even lower than is currently recommended) is safe and effective in improving CV outcomes.
Monoclonal antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have emerged as promising
agents that reduce LDL-C levels significantly and might reduce CV
disease substantially. Two PCSK9 inhibitors, alirocumab and evolocumab, were examined in the ODYSSEY LONG TERM 27 and
OSLER28 projects, respectively67 (Figure 6). Phase 3 clinical trials
with these agents are currently ongoing.

Adjunctive Therapies
The effect of an intravenous -blocker (metoprolol) administered before reperfusion in 270 patients with anterior STEMI without overt
HF (Killip class, 2) was examined in the METOCARD-CNIC randomized trial.24 Compared with placebo, patients who were treated with
metoprolol had a reduced infarct size as measured by CMR 5 to 7 days
after the STEMI and increased left ventricular ejection fraction (LVEF)
(adjusted difference, 2.7%; P = .045). This benefit was even greater
when metoprolol was administered early by the emergency medical services before hospital admission.25 After 6 months, patients pretreated with metoprolol had a lower incidence of severely reduced
left ventricular systolic function (11% vs 27%, P = .006) and fewer
hospitalizations due to HF (HR, 0.32; P = .046).26
E8

Alirocumab
(27/1550)

SOC
Evolocumab
(31/1489) (29/2976)
OSLER-1 and OSLER-2

In the ODYSSEY LONG TERM trial,27 the post hoc cardiovascular end point was a
composite of coronary heart disease death, nonfatal myocardial infarction, fatal
or nonfatal ischemic stroke, and unstable angina requiring hospitalization,
assessed after an average follow-up of 65 weeks. In the OSLER trials,28 the
prespecified cardiovascular end point was a composite of death, myocardial
infarction, unstable angina requiring hospitalization, coronary revascularization,
stroke, transient ischemic attack, and heart failure requiring hospitalization,
assessed after an average follow-up of 11.1 months. Hazard ratios (HRs) are
derived from analyses of Kaplan-Meier event rates. SOC indicates standard of
care. Figure reprinted with permission from Giugliano and Sabatine.67

Patients with ACS are at increased risk for contrast-induced nephropathy. The PRATO-ACS study32 randomized 504 statin-naive
patients with NSTE-ACS intended for an early invasive strategy to
rosuvastatin calcium (40 mg) on admission (followed by 20 mg/d)
or to no statin treatment. Patients treated with rosuvastatin had less
contrast-induced acute kidney injury (6.7% vs 15.1%; adjusted odds
ratio, 0.38; P = .003) as well as fewer adverse CV and renal events
(3.6% vs 7.9%, P = .04). Although this study was small and not
blinded, it highlights the importance of high-potency statins in patients with ACS. Nevertheless, the exact timing of administering highpotency statins during ACS to statin-naive or statin-experienced patients deserves additional study.
Morphine has been a mainstay of treatment in managing pain
during ACS, yet its use is associated with a delayed onset of action
of oral antiplatelet activity due to slower intestinal absorption. Nevertheless, whether morphine use is independently related to worse
clinical outcomes in patients with ACS remains unknown.68,69
Implantable cardioverter-defibrillators (ICDs) are recommended in appropriate patients with an LVEF less than 35% at least
40 days after MI. Among 10 318 post-MI Medicare patients older than
65 years, fewer than 1 in 10 eligible patients with low ejection fraction received an ICD within 1 year after their MI, although ICD implantation was associated with lower risk-adjusted mortality (adjusted HR, 0.64; 95% CI, 0.53-0.78).70 Preventing sudden cardiac
death (SCD) in patients after ACS remains a challenge. In pooled data
from 4 trials in 37 555 patients with NSTE-ACS, SCD accounted for
31.3% of all CV deaths after the ACS (median follow-up, 12.1 months)
and was increased in patients with recurrent MI or any hospitalization during follow-up.71 Reduced LVEF, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior
MI, peripheral artery disease, Asian race, male sex, and high Killip
class were significantly associated with SCD and were used to develop a useful risk-stratification tool.71 Whether these patients should
be managed with ICDs requires further study.

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Table 3. Key Changes to the North American62 and European63


NonST-Segment Elevation Acute Coronary Syndrome (NSTE-ACS)
Practice Guidelines
Source

Key Point

Description

Pathophysiology

Plaque rupture is the most common cause of acute MI in


both sexes.
There is a greater role of microvascular disease and
nonobstructive coronary artery disease in women.
There is an increased prevalence of plaque erosion,
particularly in younger women.
Spontaneous coronary artery dissection is a very rare
cause of acute MI that occurs more frequently in women.

Risk factors

Several risk factors in women increase the risk of acute


MI more so than in men, including hypertension, diabetes
mellitus type 2, depression, and other psychosocial risk
factors.
Depression is more prevalent in women and increases a
womans risk for cardiac death or MI by 50%, particularly
in young and middle-aged women.
Smoking is the most important preventable cause of MI
in women.

Clinical
presentation

First presentation of acute MI is at an older age


compared with men.
Women are more commonly seen with atypical chest
pain and angina-equivalent symptoms (eg, dyspnea,
palpitations, fatigue, weakness, or indigestion).
Women are more likely to have high-risk features at
presentation.
There is a median delay of 2-5 h in presentation with
acute MI.

Treatment

Women are more likely to be undertreated in NSTE-ACS


and in STEMI.
Women have increased bleeding risk in acute MI.
Cardiac rehabilitation is underused and underprescribed.

Outcome

There has been a significant decline in CV death and MI


overall in women in the last decade. However, this decline
is absent in younger women.
The annual rate of CV death in women after MI is still
greater than that in men.
There are higher rates of readmission and recurrent
ischemic events in women in the first year after ACS.

Key Changes

Amsterdam 1. An ischemia-guided strategy is recommended for patients at


low risk (TIMI score 0-1 or GRACE score <109).
et al,62
2. Either clopidogrel or ticagrelor can be used initially with either
2014
an early invasive or ischemia-guided strategy (COR I, LOE B).
Ticagrelor may be preferred over clopidogrel as the initial
treatment (COR IIa, LOE B). In patients treated with ticagrelor, the
preferred aspirin maintenance dosage is 81 mg/d.
3. Use prasugrel only in patients receiving coronary stents (COR I,
LOE B).
4. Bivalirudin is preferred over UFH* + GP IIb/IIIa in patients
undergoing PCI who are at high risk of bleeding (COR IIa, LOE B).
5. There is no benefit of early invasive strategy in women with
low-risk features (COR III).
6. In patients with possible ACS and a normal ECG, normal cardiac
troponins, and no history of CAD, it is reasonable to initially
perform (without serial ECGs and troponins) coronary CT
angiography to assess coronary artery anatomy (COR IIa, LOE A).
Roffi
et al,63
2016

Table 4. Key Points in Acute Myocardial Infarction (MI) in Women73

1. The transradial approach for vascular access is recommended


for coronary angiography and PCI (COR I, LOE A).
2. There is a new algorithm for NSTEMI rule in and rule out based
on high-sensitivity cardiac troponin assessment at presentation
and at 1 h (COR I, LOE B).
3. It is not recommended to administer prasugrel in patients in
whom coronary anatomy is not known (COR III, LOE B).
4. While a 1-y duration of dual antiplatelet therapy in patients
with NSTE-ACS is recommended based on individual patient
ischemic and bleeding risk profiles, dual antiplatelet therapy
duration may be shortened (ie, 3-6 mo) or extended (ie, up to
30 mo) in selected patients if required (COR IIb).
5. A new-generation, drug-eluting stent may be considered over a
bare-metal stent even if short dual antiplatelet therapy is planned
because of increased bleeding risk (COR IIb, LOE B) or in patients
treated with oral anticoagulants (COR IIa, LOE B).
6. In patients undergoing PCI, uninterrupted therapeutic
anticoagulation with VKAs or NOACs should be considered during
the periprocedural phase (COR IIa, LOE C).
7. Direction for managing antiplatelet therapy in patients who are
treated with chronic oral anticoagulants is based on the
CHADS2-VASc and HAS-BLED scores.

Abbreviations: CAD, coronary artery disease; COR, class of recommendation;


CT, computed tomographic; ECG, electrocardiogram; GP IIb/IIIa, glycoprotein
IIb/IIIa; LOE, level of evidence; GRACE, Global Registry of Acute Coronary
Events; NOACs, novel oral anticoagulants; PCI, percutaneous coronary
intervention; NSTEMI, nonST-elevation myocardial infarction;
TIMI, Thrombolysis in Myocardial Infarction; VKAs, vitamin K antagonists;
UFH+, unfractionated heparin.

New Guidelines
During 2014-2015, new guidelines for the management of NSTEACS were published by the ACC and American Heart Association
(AHA)62 and by the European Society of Cardiology.63 Key new recommendations from these guidelines are summarized in Table 3. The
ACC/AHA guideline recognizes that, while an invasive strategy is recommended for most patients with NSTE-ACS, low-risk patients (TIMI
risk score, 1) can benefit substantially from guideline-directed
medical therapy. This guideline also contains expanded recommendations at discharge, such as education about symptoms, risk modification, dual antiplatelet therapy, cholesterol management, and referral to cardiac rehabilitation.
In 2015, the AHA72 published an important document on pharmacotherapy in patients with CKD who are seen with an ACS, a population that is underrepresented in clinical trials and undertreated in
clinical practice. This document highlights that patients with CKD benefit from the evidence-based medications commonly used in ACS and
should not be denied such therapy. However, important consider-

Abbreviations: CV, cardiovascular; NSTE-ACS, nonST-segment elevation acute


coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

ations are necessary to provide the greatest benefit, while limiting the
potential for harm. These considerations include the careful assessment of renal function for adjusting the dose of pharmacotherapy and
the avoidance of medications that are not recommended in patients
with advanced CKD, including aldosterone antagonists, enoxaparin
sodium, fondaparinux sodium, and eptifibatide.
In 2016, the AHA73 also published a scientific statement on acute
MI in women. This document highlights the pathophysiology, risk
factors, clinical presentation, treatment, and outcome of women with
MI (Table 4). It also suggests the following specific measures to improve the outcome of women with MI: (1) increase awareness by the
general public and health care professionals of MI risk and sexspecific symptoms; (2) examine psychosocial risk factors; (3) improve methods to diagnose and treat microvascular CAD, coronary
artery dissection, and spasm; (4) enhance adherence to guidelinebased recommendations; and (5) develop strategies to increase the
inclusion of women of all ages in CV clinical research.
In 2016, the ACC/AHA74 published a focused update on the duration of dual antiplatelet therapy in patients with CAD. In patients
after ACS, a class I recommendation was given to dual antiplatelet
therapy for at least 12 months, whereas a class IIb recommendation was given to dual antiplatelet therapy for longer than 12 months
in patients who have tolerated dual antiplatelet therapy without a
bleeding complication and who are not at high bleeding risk. Notably, these updated guidelines are similar for patients with NSTEACS and STEMI.

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Table 5. Key Unanswered Questions in the Field of Acute Coronary


Syndrome (ACS)
Key Unanswered
Question
Description
Pathophysiology

Will superficial plaque erosion continue to rise to become


the dominant pathophysiology of ACS?
Should patients be treated differently based on their
underlying pathophysiology of ACS?
What are the critical determinants that cause one
vulnerable plaque to cause a clinical event but another
vulnerable plaque to be silent and heal?

Diagnosis

What will be the role of concomitant use of coronary


computed tomographic angiography and high-sensitivity
troponin assays in evaluating patients with suspected ACS?
Will shorter rule-out algorithms with high-sensitivity
troponin assays improve patients outcomes?
What is the role of genetic testing to individualize
treatment and improve patients outcomes?

Acute treatment

To what extent can the total ischemic time be reduced


further in patients with STEMI?
What are the therapeutic targets of reperfusion injury? How
can microvascular circulation after primary PCI be improved?
What is the preferred antithrombotic regimen during PCI?
What is the optimal timing for administering high-potency
statins?
What is the optimal timing and dosing for administering
-blockers? Will -blockers given before primary PCI improve
patients clinical outcomes?
What is the optimal timing of oral antiplatelet
administration in patients with NSTE-ACS who are intended
for an invasive strategy?
What is the role of platelet function testing during the
acute phase of STEMI?
What are the indications for and timing of revascularization
of obstructed noninfarct-related arteries?
What is the role of FFR-guided PCI in patients with
NSTE-ACS?
What are the contemporary benefits of CABG vs PCI in
patients with ACS and multivessel disease?
Will novel pharmacological and mechanical circulatory
support strategies improve survival in patients with
cardiogenic shock after STEMI?
What is the desired hemoglobin level in patients with ACS,
and what is the optimal timing for blood transfusion?

Chronic
treatment

What is the optimal duration and regimen of antiplatelet


therapy after ACS, and how does this differ if an oral
anticoagulant is needed?
Will newer-generation stents allow shortening of the
duration of antiplatelet therapy after ACS?
Can dual antiplatelet therapy after ACS be replaced by a
single potent P2Y12 inhibitor?
What is the role of PCSK9 inhibitors in patients admitted
with ACS?

Prognosis and
secondary
prevention

Can we improve prediction of the risk of sudden cardiac


death after ACS and identify who might benefit more from
prevention strategies?
Can left ventricular remodeling be reduced by the
angiotensin receptor blockerneprilysin inhibitor? Will this
translate into improved survival?
How can the rate of recurrent ischemic cardiovascular
events after ACS be further reduced?
What is the role of cardiac regenerative medicine in
patients with left ventricular dysfunction after MI?

Abbreviations: CABG, coronary artery bypass graft; FFR, fractional flow reserve;
MI, myocardial infarction; NSTE-ACS, nonST-segment elevation acute coronary
syndrome; PCI, percutaneous coronary intervention; PCSK9, proprotein
convertase subtilisin kexin type 9; STEMI, ST-segment elevation myocardial
infarction.

Future Directions
While there has been substantial progress in the prevention, diagnosis, and management of patients with ACS, the burden of recurrent CV ischemic events and mortality remains unacceptably high.75
This situation calls for reappraisal of the mechanisms and risk factors that are associated with these adverse events (Table 5).
E10

Although early reperfusion has substantially reduced the mortality of patients with STEMI, reperfusion is a double-edged sword
because, while it reduces ischemic myocyte necrosis, it also causes
myocardial injury.76 Therapeutic options to reduce reperfusion injury and thus limit infarct size remain elusive but may include remote
ischemicconditioning,exenatide,andanti-inflammatoryagents.77 The
encouraging observations of metoprolol administered before reperfusion(mentionedabove25,26)shouldnowbefollowedupwithaphase
3 trial focused on clinical outcomes in acute STEMI, which could enhance outcome in these patients. Future studies should also examine therapies to reduce ventricular remodeling and HF and to improve survival after MI. Valsartan-sacubitril, the angiotensin receptor
blockerneprilysin inhibitor, is a promising agent that was shown to
reduce CV death and HF hospitalization in patients with chronic HF
and decreased LVEF in the PARADIGM-HF trial.29 A randomized, placebo-controlled trial of this drug in patients after MI with reduced ejection fraction is now in an active planning stage.
Inflammation has an important role in atherogenesis and in the
development of unstable atherosclerotic plaques. Two large placebocontrolled, double-blind trials, both led by Ridker,78,79 are currently testing whether the administration of anti-inflammatory
agents reduces major vascular events in patients after ACS. The Cardiovascular Inflammation Reduction Trial (CIRT)78 is studying lowdose methotrexate, a drug that is widely used in rheumatoid arthritis, which reduces the inflammatory biomarkers, interleukin 6, tumor
necrosis factor, and C-reactive protein. The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS)79 is examining a monoclonal antibody that blocks interleukin 1, a proinflammatory cytokine. The results are eagerly awaited.
If the PCSK9 inhibitors demonstrate clinical benefit in patients
with chronic CAD, a logical next step will be to study their effect when
begun very early after ACS. Their powerful lowering effect of LDL-C
in these patients could prove to be successful in both primary and
secondary prevention of ACS.
It is now evident that vulnerable plaques are dynamic in that
most such plaques appear and disappear without rupture, erosion,
or clinical sequelae.80 Future research should focus on discovering
the critical precipitants of disruption of plaques responsible for ACS
(Figure 7). This investigation should be accompanied by further identifying the vulnerable patients who are at high risk of clinical events.
As the use of long-term antiplatelet therapy to reduce the platelet plug that forms the nidus of coronary thrombi in ruptured or
eroded plaques in patients after ACS has become more widespread, it has become clear that the antithrombotic and hemorrhagic responses to these drugs are not uniform. More advanced
forms of in vitro testing of responses to platelets that will make a
more personalized approach possible in an effort to reduce further
recurrent ischemic events (without incurring an increase in the risk
of major bleeding) are under development.
The most important change in the management of patients with
ACS is likely to come from changing our current population-based
approach to these heterogeneous disorders to a more precise (personalized) approach. In this effort, cardiologists will likely take a page
from the oncologists notebook. Many malignant tumors are now
classified not only by location, size, and histology but also by their
genomic fingerprints. The latter appear to be immensely helpful in
estimating prognosis and developing appropriate therapeutic strategies. In addition to genetic studies, advances in proteomics and

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Figure 7. Nature of the Disrupted Plaque and Possible Targets for Current
and Future Therapies
Lipid-modifying drugs:
Statins
Ezetimibe
PCSK9 inhibitors

Plaque healing (asymptomatic)

Plaque disruption

Antiplatelets,
anticoagulants
Acute thrombosis (ACS)

Anti-inflammatory drugs?

ACS indicates acute coronary syndrome; PCSK9, proprotein convertase


subtilisin kexin type 9.

ARTICLE INFORMATION
Accepted for Publication: May 19, 2016.
Published Online: July 20, 2016.
doi:10.1001/jamacardio.2016.2049.
Author Contributions: Drs Eisen and Giugliano had
full access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Eisen.
Critical revision of the manuscript for important
intellectual content: All authors.
Obtained funding: Braunwald.
Administrative, technical, or material support: Eisen,
Giugliano.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Giugliano reported clinical trials and research support
to his institution from Amgen; honoraria for
continuing medical education lectures from Amgen,
Daiichi Sankyo, and Merck; and consultancies with
Amarin, American College of Cardiology, Amgen,
Boehring Ingelheim, CVS Caremark, Daiichi Sankyo,
Merck, Pfizer, and Stealth Peptides. Dr Braunwald
reported research grant support through his
institution from AstraZeneca, Daiichi Sankyo,
GlaxoSmithKline, Merck, and Novartis; consultancies
with The Medicines Company, Sanofi, and
Theravance; uncompensated consultancy with Merck
and Novartis; and honoraria for lectures from Daiichi
Sankyo, Menarini International, Bayer, and Medscape.
No other disclosures were reported.
Additional Contributions: The images that
constitute Figure 2 were provided by Ik-Kyung Jang,
MD, PhD, Massachusetts General Hospital, Boston.
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