Journal of the American College of Cardiology Vol. 63, No.

3, 2014
Ó 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.041

YEAR IN CARDIOLOGY SERIES

The Year in Acute Coronary Syndrome

Robert P. Giugliano, MD, SM, Eugene Braunwald, MD
Boston, Massachusetts

In this year’s report on acute coronary syndromes (ACS), Indeed, as the sensitivity of cTn measurements has
we have expanded the scope to include ST-segment eleva- increased, the fraction of patients with unstable angina (UA)
tion myocardial infarction (STEMI) in addition to non– (i.e., those with non–ST-segment elevation ACS and no
ST-segment elevation ACS. In this report, we review evidence of myocardial necrosis) is steadily declining (2).
selected highlights across the spectrum of ACS published With the introduction of so-called high-sensitivity cTn
between June 2012 and September 2013. (hs-cTn) into clinical practice in a number of countries
(other than the United States), almost all patients with
ischemic discomfort at rest consistent with ACS have
Background
elevations of hs-cTn and are being reclassified as having
It is estimated that there were over 1.1 million patients with NSTEMI (5). Patients with chest pain at rest without
diagnoses of ACS discharged from U.S. hospitals in 2010, elevation of hs-cTn on 2 measurements made 2 to 4 h
of whom 74% were classified as having myocardial infarction apart most likely have nonischemic chest pain.
(MI) (1). Despite improvements in the management of
coronary heart disease risk factors, the annual rates of acute New Guidelines
myocardial infarction (AMI) have been fairly stable in the
United States over the past decade. The impact of enhanced New guidelines for the management of STEMI were
prevention has been offset by the use of more sensitive released by the American College of Cardiology Foundation
biomarkers of cardiac necrosis, specifically cardiac troponin (ACCF) and American Heart Association (AHA) (6) and
(cTn), to define MI (2), as well as the increase in comor- the European Society of Cardiology (7) during the past year.
bidities that increase the risk for developing ACS, including In addition, the ACCF and AHA published an update of
diabetes, metabolic syndrome, and chronic kidney disease, as the guideline for UA and NSTEMI guideline (8). Key
well as the overall aging of the population. The percent of changes in these guidelines are summarized in Table 2.
patients with ACS classified as having STEMI ranges from Two important updates to the STEMI guideline (6)
29% to 47% in recent databases and registries, depending on include a new target of no more than 120 min from first
the methods used to identify patients and the population medical contact to initiation of fibrinolysis (for those not
being studied (1). This percent is decreasing relative to non- undergoing primary percutaneous coronary intervention
STEMI (NSTEMI), in part because of temporal changes in [PCI]) and the early initiation of therapeutic hypothermia in
the risk factor profile (reductions in “classic” risk factors such survivors of cardiac arrest, followed by immediate PCI
as smoking and hypertension but increases in the afore- when appropriate. Across the ACS spectrum, these updated
mentioned comorbidities) (3). With the broader acceptance guidelines (6–8) now recommend the use of the more potent
of the third universal definition of MI (4) (Table 1), we oral antiplatelet drugs (prasugrel or ticagrelor) as alternatives
expect these trends to continue. to clopidogrel and provide specific advice on how to mini-
mize bleeding, particularly among patients who require
dual-antiplatelet therapy (DAPT) in addition to oral
anticoagulation.
From the TIMI Study Group, Division of Cardiovascular Medicine, Department of
Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts. Dr. Giugliano has received grant support from Amgen, Daiichi-
Sankyo, and Merck to the TIMI Study Group for clinical studies in which he is an
Pathophysiology
investigator; and honoraria for continuing medical education lectures or consulting
from Amgen, Beckman-Coulter, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Three important reports extended the framework for
Lexicon, Merck, Regeneron, and Sanofi. Dr. Braunwald has received grant support understanding the basic mechanisms leading to ACS:
from AstraZeneca, Johnson & Johnson, Beckman Coulter, Daiichi-Sankyo, Merck, 1) Libby (9) described an updated model in terms of cellular
Roche Diagnostics, Sanofi-Aventis, GlaxoSmithKline, and Bristol-Myers Squibb to
the TIMI Study Group for clinical studies in which he is (or was) study chairman; and and molecular pathways that underlie the pathogenesis of
honoraria for continuing medical education lectures or consulting from Amorcyte, ACS, with a central role for inflammation, which drives
The Medicines Company, Medscape, Bayer, Daiichi Sankyo, Menarini International, plaque disruption and thrombosis (Fig. 1). This more
and Sanofi-Aventis.
Manuscript received July 9, 2013; revised manuscript received September 27, 2013, nuanced understanding of the pathophysiology of ACS has
accepted October 21, 2013. broadened our approach beyond management of a focal
202 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

Table 1 Third Universal Definition of Myocardial Infarction

calcification (spotty calcification confers higher risk com-
pared with dense localized calcification). It is hoped that
Definition of myocardial infarction continued work on the pathogenesis of ACS will lead to new
Criteria for acute myocardial infarction diagnostic algorithms and therapeutic targets.
The term acute myocardial infarction (MI) should be used when there is evidence of The search continues for interventions, other than prompt
myocardial necrosis in a clinical setting consistent with acute myocardial
ischemia. Under these conditions any one of the following criteria meets the revascularization, to reduce infarct size in patients with
diagnosis for MI: STEMIs. An intriguing study in swine in which the left

Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac anterior coronary artery was occluded showed that unloading
troponin (cTn)] with at least one value above the 99th percentile upper refer-
ence limit (URL) and with at least one of the following: the left ventricle with left atrial–femoral artery bypass when
- Symptoms of ischemia. added to coronary occlusion resulted in further reduction of
- New or presumed new significant ST-segment–T wave (ST–T) changes or
myocardial infarct size (12). Although this approach cannot
new left bundle branch block (LBBB).
- Development of pathological Q waves in the ECG.
be applied routinely in the catheterization laboratory in all
- Imaging evidence of new loss of viable myocardium or new regional wall patients with STEMI, it could be lifesaving in those with
motion abnormality. large infarctions.
- Identification of an intracoronary thrombus by angiography or autopsy.

Cardiac death with symptoms suggestive of myocardial ischemia and

presumed new ischemic ECG changes or new LBBB, but death occurred before
cardiac biomarkers were obtained, or before cardiac biomarker values would be
Risk Factors
increased.

Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by Several reports published during the past year explored
elevation of cTn values (>5 x 99th percentile URL) in patients with normal genetic risk factors for ACS. Micro-ribonucleic acids
baseline values (99th percentile URL) or a rise of cTn values >20% if the (miRNAs) are noncoding ribonucleic acid molecules, 21 to
baseline values are elevated and are stable or falling. In addition, either (i)
symptoms suggestive of myocardial ischemia or (ii) new ischemic ECG changes 23 nucleotides long, that regulate the expression of target
or (iii) angiographic findings consistent with a procedural complication or (iv) genes. After multivariate adjustment, 3 circulating miRNAs
imaging demonstration of new loss of viable myocardium or new regional wall (126, 233, and 197) were found to be risk factors for the
motion abnormality are required.

Stent thrombosis associated with MI when detected by coronary angiography or development of future MI (13). Other miRNAs have been
autopsy in the setting of myocardial ischemia and with a rise and/or fall of found to be associated with reduced myocardial salvage,
cardiac biomarker values with at least one value above the 99th percentile URL. more pronounced reperfusion injury, and left ventricular

Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by
elevation of cardiac biomarker values (>10 x 99th percentile URL) in patients remodeling after first STEMI (14,15). The discovery of
with normal baseline cTn values (99th percentile URL). In addition, either (i) miRNAs represents a major advance in biology that is likely
new pathological Q waves or new LBBB, or (ii) angiographic documented new to aid in the elucidation of the pathobiology of many
graft or new native coronary artery occlusion, or (iii) imaging evidence of new
loss of viable myocardium or new regional wall motion abnormality. conditions (including ACS), may provide families of new
Criteria for prior myocardial infarction biomarkers, and might open the possibility for the devel-
Any one of the following criteria meets the diagnosis for prior MI: opment of new therapies. For example, miRNAs can be

Pathological Q waves with or without symptoms in the absence of non-ischemic “silenced” by specific antagonists, known as antagomirs,
causes.

Imaging evidence of a region of loss of viable myocardium that is thinned and
that might be designed to modify target proteins that pre-
fails to contract, in the absence of a non-ischemic cause. dispose plaques to rupture.

Pathological findings of a prior MI. New data on hormonal contraceptives and nonsteroidal
Reprinted with permission from Thygesen et al. (4). anti-inflammatory drugs provided new insights regarding
ECG ¼ electrocardiogram.
the increased risk for ACS with these classes of medications.
In an analysis of over 1.6 million women the use of ethinyl
intracoronary stenosis. 2) Crea and Liuzzo (10) classified estradiol was associated with increases in the risk for
ACS into 3 groups (Fig. 2): obstructive atherosclerosis MI (16). A nationwide Danish cohort study of almost
with systemic inflammation, obstructive atherosclerosis with- 100,000 patients alive at 30 days after first MI found that
out systemic inflammation, and ACS without obstructive nonsteroidal anti-inflammatory drugs (prescribed to 44% of
atherosclerosis (e.g., Prinzmetal’s angina, amphetamine- the cohort) within 5 years after the index MI increased the
induced coronary spasm). 3) Falk and a group of cardiac risk for coronary death or nonfatal MI by 30% after 1 year
pathologists (11) described 3 common coronary artery pla- and 41% after 5 years (17). These findings provide addi-
que morphologies resulting in thrombosis (plaque rupture, tional support for the Class III recommendations (i.e.,
plaque erosion, and disruptive nodular calcifications pro- contraindications) for estrogen-containing hormones (6)
truding into the coronary artery lumen, known as “calcified and nonsteroidal anti-inflammatory drugs (6–8) present in
nodules”). These latter investigators described several con- current ACS guidelines.
tributors to the “vulnerable plaque,” including structural Two reports call attention to specific groups of patients
determinants of the plaque (size of the necrotic core, who are at high risk for initial and/or recurrent ACS events.
thickness and degree of inflammation within the fibrous 1) Mild psoriasis was associated with a 30% increase in the
cap), plaque neorevascularization and infiltration with adjusted risk for MI, while severe psoriasis was indepen-
hemoglobin-stimulated macrophages (both of which increase dently associated with increased risk for MI and cardiovas-
the risk for intraplaque hemorrhage), and the pattern of cular (CV) mortality of 70% and 40%, respectively (18).
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 203
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

Table 2 Key Changes to the ACS Practice Guidelines

STEMI (6,7) 1. Use 120 min from first medical contact as the benchmark for fibrinolytic therapy (ACCF/AHA and ESC: Class I, LOE A).
2. Transfer of patients to a PCI-capable hospital for coronary angiography between 3 and 24 h after successful fibrinolysis
(ACCF/AHA: Class IIa, LOE B; ESC: Class IIa, LOE A).
3. Therapeutic hypothermia should be started as soon as possible in comatose patients with STEMI and out-of-hospital cardiac arrest due to
ventricular fibrillation or pulseless ventricular tachycardia (ACCF/AHA and ESC: Class I, LOE B). Immediate angiography with PCI if
appropriate should follow resuscitation (ACCF/AHA and ESC: Class I, LOE B).
4. Use of intra-aortic counterpulsation in patients with cardiogenic shock downgraded from a Class I to Class II recommendation (ACCF/AHA:
Class IIa, LOE B; ESC: Class IIb, LOE B).
5. In patients undergoing PCI, prasugrel or ticagrelor as the second oral antiplatelet agent in addition to aspirin is recommended as an
alternative to clopidogrel (ACCF/AHA: Class I, LOE B), while the ESC prefers the newer agents over clopidogrel (ESC: Class I, LOE A).
6. To limit the risk for bleeding in patients with indications for triple antithrombotic therapy with VKA, aspirin, and a P2Y12 inhibitor, the
duration of triple therapy should be minimized to the extent possible (ACCF/AHA and ESC: Class I, LOE C), and a target INR of 2.0–2.5
might be considered (ACCF/AHA: Class IIb, LOE C).
UA/NSTEMI (ACCF/AHA) (8) 1. Options for the second oral antiplatelet agent include ticagrelor (at admission or at the time of PCI) and prasugrel (at the time of PCI) as
alternatives to clopidogrel (Class I, LOE B).
2. A 600-mg loading dose of clopidogrel is recommended as early as possible before or at the time of PCI (Class I, LOE B).
3. DAPT should be continued for up to 12 months (Class I, LOE B). Continuation of a P2Y12 inhibitor beyond 12 months may be considered in
patients with DES (Class IIb, LOE C).
4. The recommended dose of aspirin is 81 mg in combination with ticagrelor (Class I, LOE B) and after PCI (Class IIa, LOE B).
5. Targeting a lower INR (2.0–2.5) might be reasonable in patients who require VKA in addition to aspirin þ P2Y12 inhibitor (Class IIb, LOE C).

ACCF ¼ American College of Cardiology Foundation; ACS ¼ acute coronary syndrome(s); AHA ¼ American Heart Association; DAPT ¼ dual-antiplatelet therapy; DES ¼ drug-eluting stent(s); ESC ¼ European
Society of Cardiology; INR ¼ international normalized ratio; LOE ¼ level of evidence; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-
segment elevation myocardial infarction; UA ¼ unstable angina; VKA ¼ vitamin K antagonist.

Because corticosteroids and other immunomodulatory for STEMI (21) for the prediction of 1-year mortality.
therapies used to manage psoriasis have either shown no This dynamic score could help clinicians tailor discharge
benefit or the potential for harm early after MI, identifica- medical regimens and guide decisions regarding discharge
tion of the optimal treatment plan for these patients remains location, cardiopulmonary rehabilitation, and timing of
an unmet need. 2) In patients with non–ST-segment ele- follow-up visits.
vation ACS who experienced ventricular tachycardia (VT)
or ventricular fibrillation (VF), either early (within 48 h) or Biomarkers
late (>48 h) after admission, the adjusted hazard ratios
(HRs) for mortality at 1 year were 7.4 and 15, respectively, The ACCF released an expert consensus document (22) that
compared with no VT or VF during the index hospital stay focuses on the practical issues related to elevated cTn levels
(19). These findings are important for 2 reasons. They in clinical practice. A conceptual model proposed 3 cate-
demonstrate that ventricular arrhythmias early after MI may gorizes of cTn elevation: 1) ischemic myocardial damage
not uniformly represent benign reperfusion arrhythmias, as (i.e., MI), 2) nonischemic causes of myocardial damage (e.g.,
previously had been thought. Also, the very high risk for myocarditis), and 3) analytical issues that may be either assay
VT or VF occurring >48 h after admission raises concern based (e.g., calibration errors) or sample based. In Figure 3,
regarding the safety of early discharge for patients who had we highlight the importance of nonischemic causes of cTn
experienced even brief bouts of VT and the need for risk elevation, including both cardiac diagnoses (e.g., congestive
stratification and better therapies to prevent and treat late heart failure) and systemic illnesses (e.g., sepsis), because
ventricular arrhythmias. these are frequently encountered in hospital care and account
We end this section with a brief discussion of a novel for a large number of unnecessary requests for cardiology
dynamic risk score in patients with STEMI (20). Most consultations. It is essential that healthcare providers
risk scores for ACS, such as the TIMI (for a list of trial incorporate the clinical context of an elevated cTn level to
acronyms, see Table 3) risk score for STEMI (21), are based help guide the triage, diagnostic work-up, and treatment
on findings at the time of the patient’s initial presentation. plans for these patients, and not reflexively label all cTn
However, they do not take into account events that occur elevations as indicating MI. In addition, a prospective
during the hospital stay. The dynamic TIMI risk score for analysis of 887 unselected patients with acute chest pain
STEMI (20) includes 6 clinical events occurring after found that a simple algorithm that incorporates ST-segment
admission (reinfarction, stroke, major bleed, congestive elevation, the level of hs-cTn (currently not available in the
heart failure or shock, arrhythmia [VT, VF, or atrial fibril- United States) at presentation, and the absolute change in
lation], and renal failure) that affect the risk for mortality hs-cTn during the first hour performed well (C-statistic ¼
adversely (Table 4). Addition of these clinical events resulted 0.94) in separating AMI from noncoronary diagnoses (23).
in a high discriminatory capacity (C-statistics of 0.76 in As increasingly sensitive cTn assays become available, we
the derivation set and 0.81 in the validation set) and anticipate that most patients will have detectable levels of
improved net reclassification (0.33 in the derivation set, cTn after PCI, but the clinical significance of minor releases
0.35 in the validation set) over the original TIMI risk score of cTn in this setting is unclear. One analysis concluded
204 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

Figure 1 Inflammatory Pathways Pre-Disposing Coronary Arteries to Rupture and Thrombosis

A cross-section of an atheromatous plaque at the bottom of the figure shows the central lipid core containing macrophage foam cells (yellow) and T cells (blue). Arterial smooth
muscle cells (red) present in the intima and media are the source of arterial collagen (triple helical structures). Activated T cells secrete cytokine interferon-gamma, which
inhibits the production of the new, interstitial collagen required to repair and maintain the plaque’s protective fibrous cap (top left). T cells may also activate macrophages in the
intima by expressing CD40 ligand, which engages the CD40 receptor on the phagocyte. This inflammatory signaling causes overproduction of matrix metalloproteinases (MMPs)
1, 8, and 13, which catalyze the initial rate-limiting step in collaged breakdown (top right). CD40 ligation also causes macrophages to overproduce tissue-factor procoagulant.
These multiple consequences of inflammatory signaling each contribute to the instability of the plaque’s fibrous cap. Reprinted with permission from Libby (9).

that elevations in creatine kinase-MB 3-fold to 5-fold above level <14 pmol/l, and nondiagnostic electrocardiographic
the upper limit of normal after PCI correlated with cTn findings could rule out AMI in the majority of patients
elevations of 50-fold to 100-fold in both frequency and risk without serial blood draws (27). These studies highlight how
for mortality 1 year after PCI (24). the incorporation of cTn into a rapid assessment at
Among 2,544 patients presenting with symptoms presentation could help improve efficiency in the diagnosis
consistent with ACS, the combination of normal hs-cTn at and risk stratification of patients with chest pain.
presentation and 2 h later, no ischemic changes on elec- From the many reports describing novel biomarkers asso-
trocardiography, and a TIMI risk score for UA or NSTEMI ciated with clinical outcomes in ACS published during the
(25) of 0 or 1 identified approximately 40% of patients past year, we have selected 4 markers for this year’s review.
in whom the rate of major adverse cardiac events through 1) pregnancy-associated plasma protein–A, a zinc-binding
30 days was <1% and who therefore were good candidates metalloproteinase found in vulnerable plaques that cleaves
for early discharge (26). It is likely that many of these insulin-like growth factor–4 from insulin-like growth factor–1
patients may not actually have had ACS (5). Another study and that causes destabilization of the fibrous plaque, was
in 1,967 patients presenting to emergency departments with measured at baseline in 3,782 patients with non–ST-segment
chest pain onset within 6 h demonstrated that the combi- elevation ACS in the MERLIN–TIMI 36 trial (28). After
nation of negative cTn (not high sensitivity), copeptin multivariate adjustment for baseline cTn I and other risk
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 205
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

Figure 2 A New Pathogenetic Classification of ACS

Simple clinical descriptors provide a framework for understanding the basic mechanisms responsible for coronary instability in homogenous groups of patients with acute
coronary syndromes (ACS) that might help in the search for new diagnostic algorithms and therapeutic targets: 1) patients with obstructive atherosclerosis (ATS) and systemic
inflammation; 2) patients with obstructive atherosclerosis without systemic inflammation; and 3) patients without obstructive atherosclerosis. Reprinted with permission from
Crea and Liuzzo (10).

factors, elevated baseline pregnancy-associated plasma of 725 patients with STEMI treated with primary PCI,
protein–A was found to be independently associated with elevated concentrations of soluble MAC (a stable nonlytic
increased risk for CV death or MI at 30 days (HR: 1.62; form of MAC that can be used to estimate MAC) after
p ¼ 0.006) and 1 year (HR: 1.35; p ¼ 0.012). 2) Ischemia- multivariate adjustment were associated with all-cause
mediated changes to myocardial cell surface molecule mortality (HR: 1.81; p ¼ 0.029) and major adverse CV
expression render the cell membrane a target for the events (HR: 1.70; p ¼ 0.006) (29). 3) Interleukin-17 is
complement system, leading to the formation of a membrane produced by a recently described lineage of CD4þ T cells,
attack complex (MAC), which leads to cell lysis. In an analysis plays a role in host immunity and the pathophysiology of

Table 3 Trial Acronyms

Acronym Definition
ARCTIC Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent
Implantation and of Treatment Interruption Versus Continuation One Year After Stenting
ATLAS ACS 2 Second Trial of Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome
CHAMPION PHOENIX Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition
COMFORTABLE AMI Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction
DAPT Dual Antiplatelet Therapy
EMBRACE-STEMI Evaluation of the Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events–STEMI
EXAMINATION Clinical Evaluation of the Xience-V Stent in Acute Myocardial Infarction
GUSTO Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries
HORIZONS-AMI Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction
IABP-SHOCK II Intraaortic Balloon Pump in Cardiogenic Shock II
MERLIN Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes
PARADOX The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease
PLATO Platelet Inhibition and Patient Outcomes
RIFLE-STEACS Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome
RIVAL A Trial of Trans-Radial Versus Trans-Femoral Percutaneous Coronary Intervention Access Site Approach in Patients With Unstable Angina or
Myocardial Infarction Managed With an Invasive Strategy
TIMI Thrombolysis in Myocardial Infarction
TRILOGY Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes
TRITON Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel
TRIUMPH Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status
TWENTE The Real-World Endeavor Resolute Versus Xience V Drug-Eluting Stent Study in Twente
WOEST What Is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting
XAMI Xience V Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction
206 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

Table 4 Dynamic TIMI Risk Score for STEMI

inflammatory marker, were associated with thin-cap vulner-
able plaques, as determined by optical coherence tomography.
Points
Baseline TIMI risk score for STEMI 0 to 14 possible points
Age, yrs
Imaging
65 to 74 2
There is an increasing effort to identify noninvasive imaging
75 3
modalities to predict acute clinical CV events in patients
Diabetes, hypertension, or angina 1
Systolic blood pressure <100 mm Hg 3
suspected of having coronary artery disease. Coronary mag-
Heart rate >100/min 2
netic resonance angiography was found to be helpful in
Killip class II, III, or IV 2 the risk stratification of patients with suspected CAD who
Weight <67 kg 1 were followed for 25 months (32). Patients with significant
Anterior ST-segment elevation or left bundle 1 luminal narrowing (50% diameter reduction) were at higher
branch block risk for cardiac death, MI, UA, or need for revascularization
Time to treatment >4 h 1
(6.3% vs. 0.3%, p ¼ 0.001) compared with those without
Added index hospitalization events for dynamic score 0 to 15 possible points
significant stenoses.
Recurrent myocardial infarction 1
Building on the prior data supporting a role for computed
Stroke 5
Major bleeding 1
tomographic angiography (CTA) to assist in the rapid triage
Congestive heart failure or shock 3 of patients presenting with acute chest pain to hospital
Arrhythmia 2 emergency departments described in last year’s review (33),
Renal failure 3 Ferencik et al. (34) demonstrated that a CTA-based score
Dynamic TIMI risk score 0 to 29 possible points incorporating morphologic characteristics of coronary lesions
The 6 clinical events after hospital admission (bottom half) are added to the baseline risk factors (stenosis length, plaque volume and attenuation, remodeling
(top half) of the original TIMI risk score for STEMI to yield the dynamic TIMI risk score, which ranges index, presence of spotty calcium) was quite accurate
from 0 to 29 points. Reprinted with permission from Amin et al. (20).
STEMI ¼ ST-segment elevation myocardial infarction. (C-statistic ¼ 0.83) in the detection of ACS in a cohort of
patients with acute chest pain and significant stenosis by
immune-mediated diseases and may play a role in the devel- CTA. A systematic review and meta-analysis of 4 ran-
opment of an unstable plaque. In an analysis of 981 patients domized trials of 1,869 patients undergoing CTA and 1,397
enrolled in a French registry of patients with MI, low levels of managed with usual care showed that CTA reduced the
interleukin-17 were independently associated with increased mean cost in the emergency department and shortened
risk for death or reinfarction at 2 years (HR: 1.40; p ¼ 0.03) lengths of hospital stay (35). Furthermore, in an analysis by
after adjustment for CV risk factors (30). 4) Koga et al. (31) Poon et al. (36), routine CTA of patients presenting with
reported that higher levels of circulating pentraxin 3, a novel chest pain to an emergency department reduced health
expenditures largely because the use of this technique
reduced the incidence of patients’ return to the emergency
department within 30 days.
Two catheter-based imaging techniques are being evalu-
ated for the characterization of coronary plaques in patients
with ACS. Using optical coherence tomography, plaque
rupture was found to be responsible for the culprit lesion in
44% of 126 patients, while 31% had plaque erosion; the
latter was more frequently observed in younger patients
with NSTEMI, whose plaques had thicker fibrous caps and
less lipid than those with plaque rupture (37). An interesting
alternative approach is the use of a catheter designed to
provide near-infrared spectroscopy, which allows the detec-
tion of lipid in the plaques. Madder et al. (38) reported that
use of this catheter in patients with acute STEMI revealed that
the lipid core in culprit plaques was larger than those observed
in nonculprit arteries, thereby providing a “biochemical
signature” of the culprit plaque.
Figure 3 Non-MI Causes of Troponin Elevation
Antiplatelet Therapy
Causes of elevated troponin reflecting direct myocardial damage, other than
myocardial infarction (MI), can be classified into 2 broad groups: 1) cardiac
etiologies and 2) systemic processes. Reprinted with permission from Newby et al.
Antiplatelet therapy is one of the cornerstones of the
(22). management of ACS. From a large body of research, we
have selected 5 areas to highlight in this year’s review.
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 207
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

Phase 3 clinical trial results with novel antiplatelet intensive blockade appears most beneficial in high-risk
drugs. Cangrelor, an intravenous, rapidly acting, potent, patients during PCI (as had been observed with prasugrel
yet reversible P2Y12 inhibitor, was compared with clopi- in the TRITON–TIMI 38 trial [41]), whereas the benefit of
dogrel in the double-blind, double-dummy CHAMPION such therapy over the long term in those patients who are
PHOENIX trial of 11,145 patients (44% of whom had managed medically deserves further prospective evaluation.
ACS) undergoing either urgent or elective PCI (39). Can- A randomized trial of bedside monitoring to adjust
grelor significantly reduced the odds of both the primary antiplatelet therapy. In the ARCTIC trial (42), 2,440
CV composite endpoint of death, MI, ischemia-driven patients scheduled for coronary stent implantation (30%
revascularization, or stent thrombosis at 48 h after ran- with prior MI, 27% with non–ST-segment elevation ACS)
domization by 20% among the 2,810 patients with were randomized to a strategy of platelet-function moni-
non–ST-segment elevation ACS and by 25% among the toring using the VerifyNow assay (Accumetrics, San Diego,
1,991 patients with STEMI, rates that were statistically California), followed by intensification of the antiplatelet
similar to the significant 22% reduction observed in the regimen in patients with high platelet reactivity, compared
overall trial population (Fig. 4). In addition, cangrelor with a conventional strategy with no monitoring or adjust-
reduced the odds of stent thrombosis (by 38%) through ment of the antiplatelet regimen. Despite increasing the
48 h without increasing bleeding in the overall population, antiplatelet therapy in over one-third of the patients in the
without heterogeneity across the population stratified by platelet monitoring group, there were no differences in the
type of ACS at presentation. This trial demonstrated the primary CV composite endpoint (death, MI, stent throm-
benefit of intense but short-duration inhibition of P2Y12 bosis, stroke, or urgent revascularization), the major
to reduce periprocedural complications, particularly MI secondary endpoint of stent thrombosis or any urgent
and stent thrombosis. In contrast, the potent oral thie- revascularization, or major bleeding. Several potential
nopyridine prasugrel did not reduce the composite of CV explanations for the lack of improvement in clinical
death, MI, or stroke among medically managed patients outcomes in ARCTIC and 3 prior similar studies have been
with non–ST-segment elevation ACS compared with offered, including a suboptimal cut point for high platelet
clopidogrel, in the TRILOGY ACS trial (40). These reactivity, a need for even more potent antiplatelet agents in
2 trials (CHAMPION PHOENIX and TRILOGY patients with high reactivity, and the observation that some
ACS), considered in the light of prior studies of potent clinical ischemic events (e.g., procedural complications)
P2Y12 inhibitors in patients with ACS, suggest that more cannot be influenced by antiplatelet therapy. Until more

Figure 4 Primary Efficacy and Safety Results From the CHAMPION PHOENIX Trial by Diagnosis at Presentation

The primary efficacy composite included death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis through 48 h after randomization. The primary
safety endpoint was moderate or severe bleeding according to the GUSTO scale. ACS ¼ acute coronary syndromes; HR ¼ hazard ratio; STE ¼ ST-segment elevation;
STEMI ¼ ST-segment elevation myocardial infarction. Modified with permission from Bhatt et al. (39).
208 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

successful strategies are developed, we agree with the study, reported by Gurbel et al. (48), patients were
recommendations in the current ACS guidelines that do not randomized to clopidogrel or prasugrel in a crossover design.
endorse routine testing of platelet function (6–8). Inhibition of platelet activation on clopidogrel was lower in
Studies exploring shorter duration of DAPT. DAPT is nonsmokers than smokers. Inhibition of platelet activity was
recommended for at least 12 months after ACS, whether it greater with prasugrel than clopidogrel in both smokers and
is secondary to STEMI (6) or non–ST-segment elevation nonsmokers and was not affected by smoking status in
ACS (8) and whether patients receive intracoronary stents or patients receiving prasugrel. These results support the
not. During the past year, new findings regarding the risks so-called smoker’s paradox, in which the clinical benefits
and benefits of prolonged DAPT after the placement of of clopidogrel are greater in smokers than in nonsmokers.
a drug-eluting stent (DES) were reported. In a meta-analysis Oral anticoagulant agents. Two secondary analyses from
including 8,231 patients (61% with ACS) undergoing PCI the ATLAS ACS 2–TIMI 51 trial (49) that evaluated the
with DES from 4 randomized trials, extended use of DAPT oral factor Xa inhibitor rivaroxaban in addition to standard
(>12 months) significantly increased the risk for TIMI therapy (including DAPT) in patients with ACS provided
major bleeding by 2.6-fold but did not reduce mortality, MI, greater insight into the potential role for oral anticoagulation
or stroke compared with control (3 to 12 months of DAPT) after ACS. Among the 7,817 patients with STEMI (>70%
(43). Further support for stopping DAPT >12 months after of whom underwent PCI), the use of rivaroxaban starting on
DES placement come from the TWENTE trial (44), which average 4.7 days after the index event was associated with
showed a very low rate of late stent thrombosis (0.3%) a significant 19% reduction in the composite of CV death,
between 12 and 24 months among patients who received MI, or stroke compared with placebo (49). The benefit began
second-generation DES (either zotarolimus or everolimus), early and was statistically significant at 30 days. Furthermore,
95% of whom stopped clopidogrel at 12 months. However, the very low-dose regimen of rivaroxaban (2.5 mg twice
interruption of DAPT within the first 90 days after DES daily) reduced CV death (2.5% vs. 4.2%, p ¼ 0.006)
placement is not advised. compared with placebo. However, the addition of rivarox-
Certain high-risk subgroups (e.g., patients undergoing aban to DAPT significantly increased major bleeding,
intracoronary stent placement into a saphenous vein graft including intracranial hemorrhage, although rates of fatal
[45]) are at increased risk (adjusted incidence ratio: 1.33) for bleeding were low and not statistically different from placebo.
stent thrombosis within the first 3 months, regardless of stent Among the 9,631 patients with ACS who received stents in
type, if clopidogrel is stopped before day 90 after stent ATLAS ACS 2–TIMI 51 and were treated with DAPT, the
placement. Although interruptions in DAPT were common addition of rivaroxaban compared with placebo significantly
within the first year of a registry enrolling 1,622 patients reduced definite or probable stent thrombosis (as defined by
(59% of whom had ACS) at 29 Spanish hospitals, they the Academic Research Consortium) by 35% (95% confi-
were typically brief (median 7 days) and not associated with dence interval: 7% to 54%; p ¼ 0.017) (50). A mortality
a statistically significant increase in the risk for stent throm- reduction of 44% (95% confidence interval: 11% to 65%) was
bosis (46). The DAPT Study (NCT00977938) enrolled observed in patients who received the lower dose of rivar-
more than 26,000 patients who had received intracoronary oxaban (2.5 mg twice daily) compared with placebo. These
stents (either bare-metal stents [BMS] or DES) and were findings helped shape the European Medicine Agency’s
treated with DAPT. After 12 months, patients who were free approval of rivaroxaban after ACS in 2013; a similar review
of major CV events and bleeding were randomized to either by the U.S. Food and Drug Administration is ongoing.
placebo (12-month DAPT arm) or an additional 18 months
of thienopyridine (30-month DAPT arm). This trial repre- Bleeding
sents the first adequately powered evaluation of the clinical
efficacy and safety of differing durations of DAPT; results are One hundred sixteen years after aspirin was first synthesized,
anticipated in 2014. a consensus on the use of lower dose aspirin for patients with
Reduction of stent thrombosis with ticagrelor. ACS appears to have developed (6–8). A systematic review
Analysis of the TRITON–TIMI 38 trial in patients with of the literature including 136 studies with 289,330 patients
ACS undergoing coronary stent implantation showed that, concluded that there was no improvement in clinical
compared with clopidogrel, the administration of prasugrel outcomes with higher (>160 mg/day) maintenance doses of
reduced stent thrombosis by 50% (41). In the PLATO trial, aspirin compared with lower doses in patients with ACS
which compared ticagrelor with clopidogrel, 11,289 patients receiving coronary stents or being medically managed (51).
with ACS received coronary stents. Definite and probable However, there was an excess of major bleeding of 23
stent thrombosis were also reduced significantly, by 25% per 1,000 with these higher doses of aspirin in medically
(47). As was the case for prasugrel, this benefit was con- treated patients. An analysis from the HORIZONS-AMI
sistent across all patient subgroups and types of stents. trial in patients with STEMI treated with primary PCI
Influence of smoking on antiplatelet inhibition. There concluded that higher dose aspirin (>200 mg/day) increased
have previously been scattered reports on the effects of major bleeding (adjusted HR: 2.80) and was not more
smoking on the action of clopidogrel. In the PARADOX effective than low-dose aspirin in preventing recurrent
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 209
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

ischemic CV events (52). In addition, less severe forms of in North Carolina, an extension of regional coordination to
bleeding, which are also more common with higher doses of the entire state resulted in more rapid diagnosis of STEMI,
aspirin, have a negative impact on the quality of life and may shorter transfer and door-to-device times, and an overall
increase the need for re-hospitalization, as was shown in increase in the use of reperfusion therapy (59). After a
the TRIUMPH study of 3,560 patients receiving DAPT statewide STEMI strategy to transport patients directly to
after MI (53). a PCI-capable hospital (bypassing nearer non-PCI hospitals)
Bleeding complications are particularly elevated in was implemented, the mean time to reperfusion (by either
patients requiring “triple therapy” with aspirin, a P2Y12 PCI or fibrinolysis) was reduced by a mean of 31 min (60).
inhibitor, and a full dose of an oral anticoagulant agent (e.g., To reduce further the time to reperfusion therapy in
patients with ACS and atrial fibrillation). An analysis of patients with STEMI, the emergency department was
nationwide registries in Denmark between 2000 and 2009 bypassed by transferring appropriate patients from the
of 11,480 patients with atrial fibrillation admitted with MI ambulance directly to the catheterization laboratory; this
or for PCI concluded that the excess risk for bleeding with strategy saved 20 to 30 min (61). It is likely that this
triple therapy begins early (within 90 days) and continues approach will be used with increasing frequency as patient
through at least 1 year (54). These findings are important evaluation in ambulances becomes more precise.
because they suggest that there is no improvement in Nevertheless, non-system-related delays that are difficult
tolerance over time with triple therapy, at least through to anticipate (e.g., delays in providing consent, difficulty
1 year of treatment. Although newer, more potent anti- with vascular access or crossing the culprit lesion, the need
platelet therapies, such as prasugrel, have been shown to for intubation) are not uncommon, occurring in 1 of 7
reduce CV events (41), substitution of prasugrel for clopi- patients with STEMI in the National Cardiovascular
dogrel in a small series of 377 patients with DES receiving Data Registry, and are associated with a 6-fold increase in
triple therapy resulted in a 3.2-fold increase in the hazard of mortality (62). When delays are expected and primary PCI
TIMI major or minor bleeding (55). Therefore, we believe cannot be performed within 120 min of first medical
that patients who require triple therapy generally should contact, fibrinolytic therapy is recommended (6–8). The
receive low-dose aspirin and clopidogrel for the minimal optimal method of reperfusion when the delays are shorter
duration recommended, warfarin with a target international (e.g., 60 to 120 min) is less clear.
normalized ratio of 2.0 to 2.5, and, if coronary stenting is Two complications, recurrent infarction and major
indicated, a BMS. bleeding, are risk factors for subsequent mortality after
A novel approach to avoiding triple therapy was tested primary PCI in patients with STEMI. In an analysis of
in the open-label WOEST trial (56), carried out in 573 2,002 patients, Kikkert et al. (63) found that this excess risk
patients with long-term indications for oral anticoagulation persisted beyond 1 year in the case of recurrent MI.
undergoing coronary stenting. In the experimental arm, However, in the case of bleeding, excess risk returned to
aspirin was not administered, and the combination of clopi- normal levels by 1 month. This observation is consistent
dogrel and an oral anticoagulant agent was compared with with results (for bleeding) observed in TRITON–TIMI 38.
triple therapy (aspirin 80 to 100 mg/day plus clopidogrel and Thus, although severe bleeding in patients with ACS
an oral anticoagulant agent). The risk for any bleeding was undergoing PCI certainly adds to early risk, if the bleeding
substantially less with clopidogrel plus an oral anticoagulant episode can be managed, it does not cause irreversible
agent compared with triple therapy (19.4% vs. 44.4%, damage, and the risk declines. However, recurrent infarction
p < 0.0001). Surprisingly, rates of the combined secondary causes irreversible damage to the myocardium and results in
endpoint of death, MI, target vessel revascularization, stroke, persistent elevations of risk.
or stent thrombosis also were lower with dual compared Although early primary PCI with intracoronary stent
with triple therapy (HR: 0.60; 95% confidence interval: implantation remains the gold standard for the treatment of
0.38 to 0.94). However, these data are not very robust given patients with STEMI, 2 new reports compared outcomes
the small number of events (81 events in the entire trial). in patients receiving BMS and DES. In an analysis of
Additional large studies that limit the exposure of patients 28 randomized trials including 14,470 patients with STEMIs
to long-term triple antithrombotic regimens are needed. who were followed for a total of 34,068 patient-
years, Bangalore et al. (64) reported that, compared with
Invasive Management BMS, sirolimus-eluting stents, paclitaxel-eluting stents, and
everolimus-eluting stents were associated with significantly
In this section, we highlight a few of the important publi- reduced need for vessel revascularization, without increasing
cations on the invasive management of ACS and remind the risk for stent thrombosis. Palmerini et al. (65) reported
readers that a dedicated review on interventional cardiology that in an analysis of 12,453 patients with STEMI treated
was recently published in the Journal (57). with stents, the everolimus-eluting stent (a second-generation
Current guidelines for the management of STEMI (6,7) DES) showed the most favorable safety and efficacy profile.
emphasize the importance of well-organized regional sys- Similarly, in the EXAMINATION trial of 1,498 patients
tems (58) to ensure rapid reperfusion therapy. For example, with STEMI, everolimus-eluting stents and BMS had
210 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

similar rates of the primary composite of death, reinfarction, peptide-1 analogue, beginning 15 min before primary PCI
and any revascularization at 1 year; however, the rates of significantly increased myocardial salvage and reduced
repeat target lesion (2.1% vs. 5.0%, p ¼ 0.003) and vessel infarct size as assessed by magnetic resonance imaging
(3.7% vs. 6.8%, p ¼ 0.008) revascularization were signifi- compared with placebo in 172 patients with STEMI and
cantly lower in the everolimus-eluting stent group (66). In TIMI flow grades of 0 or 1 (74). Intracoronary adenosine
the XAMI trial in 625 patients with STEMI randomized to was shown to improve ST-segment resolution and angio-
everolimus-eluting stents versus sirolimus-eluting stents graphic microvascular obstruction in a placebo-controlled
(first-generation DES), the former significantly reduced 3-arm trial of 240 patients with STEMI treated with PCI
major CV events (4.0% vs. 7.7%, p ¼ 0.048) compared and thrombus aspiration (75). In a randomized trial in
with sirolimus-eluting stents (67). Meanwhile in the patients with STEMI undergoing primary PCI, both
COMFORTABLE AMI trial, biolimus-eluting stents with intracoronary diltiazem and verapamil were more effective
a biodegradable polymer reduced the primary endpoint of than intracoronary nitroglycerin in preventing the no-reflow
major adverse cardiac events at 1 year compared with BMS phenomenon (a manifestation of reperfusion injury), as
(4.3% vs. 8.7%, p ¼ 0.004) (68). In patients who are not assessed by the corrected TIMI frame count and by the
candidates for prolonged courses of DAPT (which is degree of ST-segment resolution after the intervention (76).
necessary with DES to prevent late stent thrombosis), Ischemic post-conditioning (i.e., brief repeated periods of
BMS are preferred; however, most other patients would ischemia induced by multiple low-pressure coronary artery
appear to benefit from newer generation DES. balloon inflations shortly after reperfusion) reduced infarct
Results with several adjunctive therapies during primary size and myocardial edema compared with control in a pilot
PCI were reported in the past year. A retrospective analysis trial of 50 patients with STEMI undergoing direct stent
of 2,567 consecutive patients with STEMI undergoing implantation (77). In 544 patients with NSTEMI under-
primary PCI at a single center in the United Kingdom going PCI randomized to 1 of 2 doses of the P-selectin
showed that thrombus aspiration reduced both in-hospital antagonist inclacumab versus placebo, the higher dose
and longer term (mean 10 months) adjusted mortality (20 mg/kg) of inclacumab reduced myocardial damage
rates (69). However, the lack of randomization and the as assessed by release of cardiac biomarkers (78). The
absence of large-scale outcome trials comparing thrombec- EMBRACE-STEMI trial is comparing Bendavia (Stealth
tomy with glycoprotein IIb/IIIa inhibition make it difficult Peptides, Newton Centre, Massachusetts), an intravenous
to know which strategy is preferred. A meta-analysis of 18 mitochondrial targeting peptide, with placebo in 300
trials including 3,936 patients comparing aspiration patients with anterior STEMI undergoing primary PCI
thrombectomy with conventional primary PCI demon- to assess whether limiting reperfusion injury with this agent
strated significant reduction in major adverse cardiac events can reduce infarct size (79). Larger studies are needed with
(risk ratio: 0.76) and all-cause mortality (risk ratio: 0.71) such interventions to determine whether these early benefits
with aspiration thrombectomy (70). However, no differences result in longer term improvement in left ventricular func-
were found in major adverse cardiac events, mortality, tion and reductions in clinical events.
or other individual ischemic events between mechanical A meta-analysis of 6 randomized trials including 1,054
thrombectomy and conventional primary PCI in a meta- patients with cardiogenic shock after MI concluded that
analysis of 7 trials including 1,598 patients (70). Last, intra-aortic balloon counterpulsation did not reduce mor-
a randomized comparison of manual thrombus aspiration tality, heart failure, or reinfarction (80). These findings were
with rheolytic thrombectomy (using high-velocity saline jets subsequently confirmed in the IABP-SHOCK II trial, a
in the distal catheter tip) showed that neither technique randomized, prospective, open-label study of 606 patients
completed removed the thrombus; no difference in residual with cardiogenic shock complicating AMI, which showed
thrombus between the groups was observed using optical no difference in 30-day mortality or other secondary
coherence tomography (71). Both the ACCF and AHA endpoints (81). In the absence of more positive data in the
(6) and the European Society of Cardiology (7) STEMI future, we anticipate that the next update of the STEMI
guidelines state that manual aspiration thrombectomy is guidelines will downgrade the use of balloon counter-
reasonable for patients undergoing primary PCI (Class IIa, pulsation from class IIa to IIb in such patients.
Level of Evidence: B). New data continue to support the use of radial arterial
Although early myocardial reperfusion is a cornerstone of access in patients with ACS. In an analysis of 294,769
therapy for STEMI, reperfusion injury is a common adverse patients with STEMI undergoing PCI in a U.S. database,
effect, and therefore this treatment has been likened to procedural success was similar, median door-to-balloon time
a 2-edged sword (72). Prevention of reperfusion injury in was only 4 min longer, and the adjusted odds of bleeding
AMI remains a major unmet need. New data suggest that were reduced significantly by 38% with a radial compared
intracoronary microparticles (derived from platelets and with a femoral approach (82).
from endothelial cells) are correlated with ongoing throm- In the United States, radial access accounted for 1 in 6
bosis and microvascular dysfunction leading to microvascular PCIs in 2012 (83) and is used more frequently in Western
obstruction (73). Infusion of exenatide, a glucagon-like Europe.
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 211
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

Even more favorable results were observed in the 17% to 22%], angiotensin-converting enzyme inhibitors or
RIFLE-STEACS trial of 1,001 patients with STEMI angiotensin receptor blockers [from 19% to 28%]) before
undergoing primary or rescue PCI. Patients randomized to presentation (91).
radial access had a significantly lower rate of the primary Although adherence to guideline-based therapies during
net adverse composite endpoint of cardiac death, stroke, hospitalization for ACS continues to increase over time,
myocardial infarction, target lesion revascularization, and there is still room for improvement, particularly among
bleeding (13.6% vs. 21.0%), with significant reductions in patients with NSTEMI, who are less likely than those
mortality, bleeding, and hospital stay (5 vs. 6 days) (84). A with STEMI to receive proven therapies at admission and at
similar significant reduction in mortality was observed discharge (92). One of the most successful tools to improve
with radial versus femoral artery access in the subgroup of guideline-based performance measures is the use of
patients with STEMI in the RIVAL trial (1.3% vs. 3.2%), computer-based physician order entry supplemented by
whereas no similar reduction was observed among patients a decision support system. Use of such a computerized
with non–ST-segment elevation ACS in RIVAL (1.3% vs. system resulted in a higher rate of “perfect care,” defined
0.8%) (85). Although radial access was used in only 6.4% as achievement of all 9 performance measures (Table 5)
of patients undergoing PCI for STEMI in the national recommended by the AHA and the American College of
U.S. registry in 2011 (82), we expect this number to climb Cardiology (93), compared with a standard paper order set
rapidly as operators become more familiar with this (89% vs. 61%, p < 0.001) in an analysis of 1,321 patients
approach. with ACS admitted to a single CV center in New Orleans
In a registry of 46,128 patients with STEMI undergoing (94). Referral to outpatient cardiac rehabilitation is the
primary PCI in the United Kingdom, after adjustment for recommendation that is least frequently adhered to among
baseline variables, radial access (compared with femoral the 9 performance measures, despite evidence that comple-
access) was associated with a significantly lower mortality, tion of cardiac rehabilitation is associated with adjusted
major bleeding, and site complications (86). In a registry of reductions in the risks for death of 41% and cardiac rehos-
patients undergoing PCI for ACS or chronic coronary artery pitalization of 32% (95). Another argument for rehabilita-
disease, hospital costs using radial access were, on average, tion is that a slow gait speed is now recognized as a measure
$830 lower than for femoral access, because of a slightly of frailty, and among patients with STEMI, it was inde-
reduced length of hospital stay (87). pendently associated with a 41% increase in the hazard of
a CV event (CV death, MI, or ischemic stroke) for each
Lipids decline of 0.1 m/s in gait speed (96). One approach that
appears to be promising to improve attendance at cardiac
A recent observational registry in 24 U.S. hospitals showed rehabilitation is to schedule an orientation appointment
that 33% of patients had low-density lipoprotein cholesterol within 10 days of discharge, rather than the standard
levels higher than 100 mg/dl 6 months after AMI (i.e., they approach (mean 35 days) (97). This simple, cost-neutral
did not meet the standard goal of <100 mg/dl), with fewer intervention improved attendance to 77% (an absolute
than one-third achieving levels <70 mg/dl (the more increase of 18% over the standard), although larger studies
stringent optional goal) (88). Although no single factor is are needed to determine whether this will translate into
responsible for the low rate of attainment of the goal level of a clinical benefit.
low-density lipoprotein cholesterol in high-risk patients, Additional strategies are also needed to improve long-term
underdosing (89) and interruption (90) of statin therapy are adherence with treatment in the year after ACS. A rando-
2 frequent issues. In a propensity score–matched analysis in mized controlled trial is comparing a 4-step intervention
a cohort of 17,080 patients >65 years of age with MIs (consisting of a pharmacist-led medication reconciliation and
hospitalized in Ontario, Canada, high-intensity statin use tailoring, patient education, closer collaboration between
significantly reduced the rate of repeat hospitalizations for
ACS without increasing the rate of new diabetes (89).
Performance Measures in Patients With
Quality of care. An analysis of 4 nationwide registries Table 5
Acute Coronary Syndromes
spanning 1995 through 2010 described 4 trends that were
responsible for a temporal reduction in mortality in patients 1. Aspirin administration at arrival
2. Aspirin prescription at discharge
with STEMI in France: 1) progressively more favorable
3. Smoking cessation counseling
patient baseline characteristics over time, including declines
4. Beta-blocker prescription at discharge
in age (from 66.2 to 63.3 years) and frequency of prior CV 5. Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker if left
events (from 26% to 17%); 2) a decrease in time from ventricular ejection fraction <40%
symptom onset to first medical contact (from 240 to 175 6. Statin prescription at discharge
min), in part related to greater use of mobile intensive care 7. Referral to cardiac rehabilitation
units; 3) an increase in the use of reperfusion therapy (from 8. Assessment of left ventricular function

49% to 75%), largely primary PCI; and 4) more frequent 9. Door to balloon time <90 min (in patients undergoing primary PCI for STEMI)

use of guideline-recommended therapies (e.g., statins [from Data from Krumholz et al. (93). Abbreviations as in Table 2.
212 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

pharmacists and treating physicians, and a voice messaging passed after first-time myocardial infarction: a nationwide cohort study.
Circulation 2012;126:1955–63.
system) with usual care to determine whether the inter- 18. Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major
vention can improve medication adherence and reduce adverse cardiovascular events: a systematic review and meta-analysis of
healthcare costs (98). observational studies. J Am Heart Assoc 2013;2:e000062.
19. Piccini JP, White JA, Mehta RH, et al. Sustained ventricular tachy-
cardia and ventricular fibrillation complicating non-ST-segment-
Reprint requests and correspondence: Dr. Eugene Braunwald, elevation acute coronary syndromes. Circulation 2012;126:41–9.
Brigham and Women’s Hospital, Department of Medicine, TIMI 20. Amin ST, Morrow DA, Braunwald E, et al. Dynamic TIMI risk score
for STEMI. J Am Heart Assoc 2013;2:e003269.
Study Group, 350 Longwood Avenue, Boston, Massachu- 21. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for
setts 02115. E-mail: [email protected]. ST-elevation myocardial infarction: a convenient, bedside, clinical score
for risk assessment at presentation: an intravenous nPA for treatment of
infarcting myocardium early II trial substudy. Circulation 2000;102:
2031–7.
REFERENCES 22. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012 expert consensus
document on practical clinical considerations in the interpretation of
1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke troponin elevations: a report of the American College of Cardiology
statisticsd2013 update: a report from the American Heart Association. Foundation Task Force on Clinical Expert Consensus Documents.
Circulation 2013;127:e6–245. J Am Coll Cardiol 2012;60:2427–63.
2. Costa FM, Ferreira J, Aguiar C, Dores H, Figueira J, Mendes M. 23. Haaf P, Drexler B, Reichlin T, et al. High-sensitivity cardiac troponin
Impact of ESC/ACCF/AHA/WHF universal definition of in the distinction of acute myocardial infarction from acute cardiac
myocardial infarction on mortality at 10 years. Eur Heart J 2012;33: noncoronary artery disease. Circulation 2012;126:31–40.
2544–50. 24. Tricoci P, Leonardi S, White J, et al. Cardiac troponin after percuta-
3. Boyer NM, Laskey WK, Cox M, et al. Trends in clinical, demographic, neous coronary intervention and 1-year mortality in NSTE ACS using
and biochemical characteristics of patients with acute myocardial systematic evaluation of biomarker trends. J Am Coll Cardiol 2013;62:
infarction from 2003 to 2008: a report from the American Heart 242–51.
Association Get With the Guidelines Coronary Artery Disease 25. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for
Program. J Am Heart Assoc 2012;1:1–18. unstable angina/non-ST elevation MI: a method for prognostication
4. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, and therapeutic decision making. JAMA 2000;284:835–42.
White HD. Third universal definition of myocardial infarction. Eur 26. Cullen L, Muller C, Parsonage WA, et al. Validation of high-
Heart J 2012;33:2551–67. sensitivity troponin I in a 2-h diagnostic strategy to assess 30-day
5. Braunwald E, Morrow DA. Unstable angina: is it time for a requiem? outcomes in emergency-department patients with possible acute coro-
Circulation 2013;127:2452–7. nary syndrome. J Am Coll Cardiol 2013;62:1242–9.
6. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA 27. Maisel A, Mueller C, Neath SX, et al. Copeptin helps in the early
guideline for the management of ST-elevation myocardial infarction: detection of patients with acute myocardial infarction: the primary
a report of the American College of Cardiology Foundation/American results of the CHOPIN trial. J Am Coll Cardiol 2013;62:150–60.
Heart Association Task Force on Practice Guidelines. J Am Coll 28. Bonaca MP, Scirica BM, Sabatine MS, et al. Prospective evaluation of
Cardiol 2013;61:e78–140. pregnancy-associated plasma protein-a and outcomes in patients with
7. Steg PG, James SK, Atar D, et al. ESC guidelines for the management acute coronary syndromes. J Am Coll Cardiol 2012;60:332–8.
of acute myocardial infarction in patients presenting with ST-segment 29. Lindberg S, Pedersen SH, Mogelvang R, et al. Soluble form of
elevation. Eur Heart J 2012;33:2569–619. membrane attack complex independently predicts mortality and
8. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA cardiovascular events in patients with ST-elevation myocardial infarc-
focused update incorporated into the ACCF/AHA 2007 guidelines for tion treated with primary percutaneous coronary intervention. Am
the management of patients with unstable angina/non-ST-elevation Heart J 2012;164:786–92.
myocardial infarction: a report of the American College of Cardi- 30. Simon T, Taleb S, Danchin N, et al. Circulating levels of interleukin-
ology Foundation/American Heart Association Task Force on Practice 17 and cardiovascular outcomes in patients with acute myocardial
Guidelines. J Am Coll Cardiol 2013;61:e179–347. infarction. Eur Heart J 2013;34:570–7.
9. Libby P. Mechanisms of acute coronary syndromes and their impli- 31. Koga S, Ikeda S, Yoshida T, et al. Elevated levels of systemic pentraxin
cations for therapy. N Engl J Med 2013;368:2004–13. 3 are associated with thin-cap fibroatheroma in coronary culprit lesions:
10. Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am assessment by optical coherence tomography and intravascular ultra-
Coll Cardiol 2013;61:1–11. sound. J Am Coll Cardiol Intv 2013;6:945–54.
11. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute 32. Yoon YE, Kitagawa K, Kato S, et al. Prognostic value of coronary
coronary syndromes: the pathologists’ view. Eur Heart J 2013;34: magnetic resonance angiography for prediction of cardiac events in
719–28. patients with suspected coronary artery disease. J Am Coll Cardiol
12. Kapur NK, Paruchuri V, Urbano-Morales JA, et al. Mechanically 2012;60:2316–22.
unloading the left ventricle before coronary reperfusion reduces left 33. Giugliano RP, Braunwald E. The year in non-ST-segment elevation
ventricular wall stress and myocardial infarct size. Circulation 2013; acute coronary syndrome. J Am Coll Cardiol 2012;60:2127–39.
128:328–36. 34. Ferencik M, Schlett CL, Ghoshhajra BB, et al. A computed
13. Zampetaki A, Willeit P, Tilling L, et al. Prospective study on circu- tomography-based coronary lesion score to predict acute coronary
lating microRNAs and risk of myocardial infarction. J Am Coll Cardiol syndrome among patients with acute chest pain and significant coro-
2012;60:290–9. nary stenosis on coronary computed tomographic angiogram. Am J
14. Eitel I, Adams V, Dieterich P, et al. Relation of circulating Cardiol 2012;110:183–9.
microRNA-133a concentrations with myocardial damage and clinical 35. Hulten E, Pickett C, Bittencourt MS, et al. Outcomes after coronary
prognosis in ST-elevation myocardial infarction. Am Heart J 2012;164: computed tomography angiography in the emergency department:
706–14. a systematic review and meta-analysis of randomized, controlled trials.
15. Devaux Y, Vausort M, McCann GP, et al. MicroRNA-150: a novel J Am Coll Cardiol 2013;61:880–92.
marker of left ventricular remodeling after acute myocardial infarction. 36. Poon M, Cortegiano M, Abramowicz AJ, et al. Associations between
Circ Cardiovasc Gen 2013;6:290–8. routine coronary computed tomographic angiography and reduced
16. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. unnecessary hospital admissions, length of stay, recidivism rates, and
Thrombotic stroke and myocardial infarction with hormonal contra- invasive coronary angiography in the emergency department triage of
ception. N Engl J Med 2012;366:2257–66. chest pain. J Am Coll Cardiol 2013;62:543–52.
17. Olsen AM, Fosbol EL, Lindhardsen J, et al. Long-term cardiovascular 37. Jia H, Abtahian F, Aguirre AD, et al. In vivo diagnosis of plaque
risk of nonsteroidal anti-inflammatory drug use according to time erosion and calcified nodule in patients with acute coronary syndrome
JACC Vol. 63, No. 3, 2014 Giugliano and Braunwald 213
January 28, 2014:201–14 The Year in Acute Coronary Syndrome

by intravascular optical coherence tomography. J Am Coll Cardiol implantation and an indication for oral anticoagulation. J Am Coll
2013;62:1748–58. Cardiol 2013;61:2060–6.
38. Madder RD, Goldstein JA, Madden SP, et al. Detection by near- 56. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel
infrared spectroscopy of large lipid core plaques at culprit sites in with or without aspirin in patients taking oral anticoagulant therapy
patients with acute ST-segment elevation myocardial infarction. J Am and undergoing percutaneous coronary intervention: an open-label,
Coll Cardiol Intv 2013;6:838–46. randomised, controlled trial. Lancet 2013;381:1107–15.
39. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibi- 57. Dixon SR, Safian RD. The year in interventional cardiology. J Am Coll
tion with cangrelor during PCI on ischemic events. N Engl J Med Cardiol 2013;61:1637–52.
2013;368:1303–13. 58. Jollis JG, Granger CB, Henry TD, et al. Systems of care for ST-
40. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel segment-elevation myocardial infarction: a report from the American
for acute coronary syndromes without revascularization. N Engl J Med Heart Association’s Mission: Lifeline. Circ Cardiovasc Qual Outcomes
2012;367:1297–309. 2012;5:423–8.
41. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clo- 59. Jollis JG, Al-Khalidi HR, Monk L, et al. Expansion of a regional ST-
pidogrel in patients with acute coronary syndromes. N Engl J Med segment-elevation myocardial infarction system to an entire state.
2007;357:2001–15. Circulation 2012;126:189–95.
42. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust 60. Fosbol EL, Granger CB, Jollis JG, et al. The impact of a statewide pre-
antiplatelet therapy for coronary stenting. N Engl J Med 2012;367: hospital STEMI strategy to bypass hospitals without percutaneous
2100–9. coronary intervention capability on treatment times. Circulation 2013;
43. Cassese S, Byrne RA, Tada T, King LA, Kastrati A. Clinical impact of 127:604–12.
extended dual antiplatelet therapy after percutaneous coronary inter- 61. Bagai A, Al-Khalidi HR, Munoz D, et al. Bypassing the emergency
ventions in the drug-eluting stent era: a meta-analysis of randomized department and time to reperfusion in patients with prehospital ST-
trials. Eur Heart J 2012;33:3078–87. segment-elevation: findings from the Reperfusion in Acute Myocar-
44. Tandjung K, Sen H, Kai Lam M, et al. Clinical outcome following dial Infarction in Carolina Emergency Departments Project. Circ
stringent discontinuation of dual anti-platelet therapy after 12 months Cardiovasc Interv 2013;6:399–406.
in real-world patients treated with second-generation zotarolimus- 62. Swaminathan RV, Wang TY, Kaltenbach LA, et al. Nonsystem
eluting Resolute and everolimus-eluting Xience V stents: two-year reasons for delay in door-to-balloon time and associated in-hospital
follow-up of the randomized TWENTE trial. J Am Coll Cardiol mortality: a report from the National Cardiovascular Data Registry.
2013;61:2406–16. J Am Coll Cardiol 2013;61:1688–95.
45. Sachdeva A, Bavisetty S, Beckham G, et al. Discontinuation of long- 63. Kikkert WJ, Zwinderman AH, Vis MM, et al. Timing of mortality
term clopidogrel therapy is associated with death and myocardial after severe bleeding and recurrent myocardial infarction in patients
infarction after saphenous vein graft percutaneous coronary interven- with ST-segment-elevation myocardial infarction. Circ Cardiovasc
tion. J Am Coll Cardiol 2012;60:2357–63. Intervent 2013;6:391–8.
46. Ferreira-Gonzalez I, Marsal JR, Ribera A, et al. Double antiplatelet 64. Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Outcomes with
therapy after drug-eluting stent implantation: risk associated with various drug-eluting or bare metal stents in patients with ST-segment-
discontinuation within the first year. J Am Coll Cardiol 2012;60: elevation myocardial infarction: a mixed treatment comparison analysis
1333–9. of trial level data from 34,068 patient-years of follow-up from
47. Steg PG, Harrington RA, Emanuelsson H, et al. Stent thrombosis randomized trials. Circ Cardiovasc Intervent 2013;6:378–90.
with ticagrelor versus clopidogrel in patients with acute coronary 65. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Clinical outcomes
syndromes: an analysis from the prospective, randomized PLATO trial. with drug-eluting and bare-metal stents in patients with ST-segment
Circulation 2013;128:1055–65. elevation myocardial infarction: evidence from a comprehensive
48. Gurbel PA, Bliden KP, Logan DK, et al. The influence of smoking network meta-analysis. J Am Coll Cardiol 2013;62:496–504.
status on the pharmacokinetics and pharmacodynamics of clopidogrel 66. Sabate M, Cequier A, Iniguez A, et al. Everolimus-eluting stent versus
and prasugrel: the PARADOX study. J Am Coll Cardiol 2013;62: bare-metal stent in ST-segment elevation myocardial infarction
505–12. (EXAMINATION): 1 year results of a randomised controlled trial.
49. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients Lancet 2012;380:1482–90.
stabilized after a ST-segment elevation myocardial infarction: results 67. Hofma SH, Brouwer J, Velders MA, et al. Second-generation
from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower everolimus-eluting stents versus first-generation sirolimus-eluting
Cardiovascular Events in Addition to Standard Therapy in Subjects stents in acute myocardial infarction. 1-year results of the randomized
With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarc- XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute
tion-51). J Am Coll Cardiol 2013;61:1853–9. Myocardial Infarction) trial. J Am Coll Cardiol 2012;60:381–7.
50. Gibson CM, Chakrabarti AK, Mega JL, et al. Reduction of stent 68. Raber L, Kelbaek H, Ostoijc M, et al. Effect of biolimus-eluting stents
thrombosis in patients with acute coronary syndrome treated with with biodegradable polymer vs bare-metal stents on cardiovascular
rivaroxaban in ATLAS ACS 2-TIMI 51. J Am Coll Cardiol 2013;62: events among patients with acute myocardial infarction: the
286–90. COMFORTABLE AMI randomized trial. JAMA 2012;308:777–87.
51. Berger JS, Sallum RH, Katona B, et al. Is there an association between 69. Noman A, Egred M, Bagnall A, Spyridopoulos I, Jamieson S,
aspirin dosing and cardiac and bleeding events after treatment of acute Ahmed J. Impact of thrombus aspiration during primary percutaneous
coronary syndrome? A systematic review of the literature. Am Heart J coronary intervention on mortality in ST-segment elevation myocardial
2012;164:153–62. infarction. Eur Heart J 2012;33:3054–61.
52. Yu J, Mehran R, Dangas GD, et al. Safety and efficacy of high- versus 70. Kumbhani DJ, Bavry AA, Desai MY, Bangalore S, Bhatt DL. Role of
low-dose aspirin after primary percutaneous coronary intervention in aspiration and mechanical thrombectomy in patients with acute
ST-segment elevation myocardial infarction: the HORIZONS-AMI myocardial infarction undergoing primary angioplasty: an updated meta-
(Harmonizing Outcomes With Revascularization and Stents in analysis of randomized trials. J Am Coll Cardiol 2013;62:1409–18.
Acute Myocardial Infarction) trial. J Am Coll Cardiol Intv 2012;5: 71. Parodi G, Valenti R, Migliorini A, et al. Comparison of manual
1231–8. thrombus aspiration with rheolytic thrombectomy in acute myocardial
53. Amin AP, Bachuwar A, Reid KJ, et al. Nuisance bleeding wih pro- infarction. Circ Cardiovasc Intervent 2013;6:224–30.
longed dual antiplatelet therapy after acute myocardial infarction and its 72. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged
impact on health status. J Am Coll Cardiol 2013;61:2130–8. sword? J Clin Invest 1985;76:1713–9.
54. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of 73. Porto I, Biasucci LM, De Maria GL, et al. Intracoronary microparticles
multiple antithrombotic drugs, including triple therapy, in atrial and microvascular obstruction in patients with ST elevation myocardial
fibrillation patients following myocardial infarction and coronary infarction undergoing primary percutaneous intervention. Eur Heart J
intervention: a nationwide cohort study. Circulation 2012;126: 2012;33:2928–38.
1185–93. 74. Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces reperfu-
55. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, sion injury in patients with ST-segment elevation myocardial infarc-
prasugrel and vitamin K antagonists in patients with drug eluting stent tion. Eur Heart J 2012;33:1491–9.
214 Giugliano and Braunwald JACC Vol. 63, No. 3, 2014
The Year in Acute Coronary Syndrome January 28, 2014:201–14

75. Niccoli G, Rigattieri S, De Vita MR, et al. Open-label, randomized, intervention: are the results of randomized trials achievable in clinical
placebo-controlled evaluation of intracoronary adenosine or nitroprus- practice? J Am Coll Cardiol Intv 2013;6:698–706.
side after thrombus aspiration during primary percutaneous coronary 87. Amin AP, House JA, Safley DM, et al. Costs of transradial
intervention for the prevention of microvascular obstruction in acute percutaneous coronary intervention. J Am Coll Cardiol Intv 2013;6:
myocardial infarction: the REOPEN-AMI study. J Am Coll Cardiol 827–34.
Intv 2013;6:580–9. 88. Martin SS, Gosch K, Kulkarni KR, et al. Modifiable factors associated
76. Huang D, Qian J, Ge L, et al. Restoration of Coronary Flow in with failure to attain low-density lipoprotein cholesterol goal at 6
Patients With No-Reflow After Primary Coronary Intervention of months after acute myocardial infarction. Am Heart J 2013;165:26–33.
Acute Myocardial Infarction (RECOVER). Am Heart J 2012;164: 89. Ko DT, Wijeysundera HC, Jackevicius CA, Yousef A, Wang J, Tu JV.
394–401. Diabetes mellitus and cardiovascular events in older patients with
77. Thuny F, Lairez O, Roubille F, et al. Post-conditioning reduces infarct myocardial infarction prescribed intensive-dose and moderate-dose
size and edema in patients with ST-segment elevation myocardial statins. Circ Cardiovasc Qual Outcomes 2013;6:315–22.
infarction. J Am Coll Cardiol 2012;59:2175–81. 90. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in
78. Tardif JC, Tanguay JF, Wright SS, et al. Effects of the P-selectin routine care settings: a cohort study. Ann Intern Med 2013;158:526–34.
antagonist inclacumab on myocardial damage after percutaneous 91. Puymirat E, Simon T, Steg PG, et al. Association of changes in clinical
coronary intervention for non-ST-segment elevation myocardial characteristics and management with improvement in survival among
infarction: results of the SELECT-ACS trial. J Am Coll Cardiol 2013; patients with ST-elevation myocardial infarction. JAMA 2012;308:
61:2048–55. 998–1006.
79. Chakrabarti AK, Feeney K, Abueg C, et al. Rationale and design of the 92. Somma KA, Bhatt DL, Fonarow GC, et al. Guideline adherence after
EMBRACE STEMI study: a phase 2a, randomized, double-blind, ST-segment elevation versus non-ST segment elevation myocardial
placebo-controlled trial to evaluate the safety, tolerability and efficacy infarction. Circ Cardiovasc Qual Outcomes 2012;5:654–61.
of intravenous Bendavia on reperfusion injury in patients treated with 93. Krumholz HM, Anderson JL, Bachelder BL, et al. ACC/AHA 2008
standard therapy including primary percutaneous coronary intervention performance measures for adults with ST-elevation and non-ST-
and stenting for ST-segment elevation myocardial infarction. Am elevation myocardial infarction: a report of the American College of
Heart J 2013;165:509–14. Cardiology/American Heart Association Task Force on Performance
80. Cassese S, de Waha A, Ndrepepa G, et al. Intra-aortic balloon coun- Measures (Writing Committee to Develop Performance Measures for
terpulsation in patients with acute myocardial infarction without ST-Elevation and Non-ST-Elevation Myocardial Infarction) devel-
cardiogenic shock. A meta-analysis of randomized trials. Am Heart J oped in collaboration with the American Academy of Family Physi-
2012;164:58–65. cians and American College of Emergency Physicians endorsed by the
81. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support American Association of Cardiovascular and Pulmonary Rehabilitation,
for myocardial infarction with cardiogenic shock. N Engl J Med 2012; Society for Cardiovascular Angiography and Interventions, and Society
367:1287–96. of Hospital Medicine. J Am Coll Cardiol 2008;52:2046–99.
82. Baklanov DV, Kaltenbach LA, Marso SP, et al. The prevalence and 94. Milani RV, Lavie CJ, Dornelles AC. The impact of achieving perfect
outcomes of transradial percutaneous coronary intervention for ST- care in acute coronary syndrome: the role of computer assisted decision
segment elevation myocardial infarction: analysis from the National support. Am Heart J 2012;164:29–34.
Cardiovascular Data Registry (2007 to 2011). J Am Coll Cardiol 2013; 95. Martin BJ, Hauer T, Arena R, et al. Cardiac rehabilitation attendance
61:420–6. and outcomes in coronary artery disease patients. Circulation 2012;126:
83. Feldman DN, Swaminathan RV, Kaltenbach LA, et al. Adoption of 677–87.
radial access and comparison of outcomes to femoral access in percu- 96. Matsuzawa Y, Konishi M, Akiyama E, et al. Association between gait
taneous coronary intervention: an updated report from the National speed as a measure of frailty and risk of cardiovascular events after
Cardiovascular Data Registry (2007–2012). Circulation 2013;127: myocardial infarction. J Am Coll Cardiol 2013;61:1964–72.
2295–306. 97. Pack QR, Mansour M, Barboza JS, et al. An early appointment to
84. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial Versus outpatient cardiac rehabilitation at hospital discharge improves atten-
Femoral Randomized Investigation in ST-Segment Elevation Acute dance at orientation: a randomized, single-blind, controlled trial.
Coronary Syndrome: the RIFLE-STEACS (Radial Versus Femoral Circulation 2013;127:349–55.
Randomized Investigation in ST-Elevation Acute Coronary 98. Lambert-Kerzner A, Del Giacco EJ, Fahdi IE, et al. Patient-centered
Syndrome) study. J Am Coll Cardiol 2012;60:2481–9. adherence intervention after acute coronary syndrome hospitalization.
85. Mehta SR, Jolly SS, Cairns J, et al. Effects of radial versus femoral Circ Cardiovasc Qual Outcomes 2012;5:571–6.
artery access in patients with acute coronary syndromes with or without
ST-segment elevation. J Am Coll Cardiol 2012;60:2490–9.
86. Mamas MA, Ratib K, Routledge H, et al. Influence of arterial access Key Words: biomarkers - coronary stent(s) - myocardial infarction -

site selection on outcomes in primary percutaneous coronary plaque rupture - platelets - thrombosis - troponin.