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Review
IMPORTANCE Acute coronary syndrome (ACS), the acute manifestation of ischemic heart
Supplemental content at
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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-
Pathophysiology
While plaque rupture remains the most common cause of coronary thrombosis, superficial plaque erosion is recognized with
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E1
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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Definition
BRIGHT9
CHAMPION PHOENIX10
COMPARE ACUTE11
COMPLETE12
CvLPRIT13
DANAMI-3PRIMULTI14
DAPT15,16
EUROMAX17
HEAT-PPCI18
IMPROVE-IT19,20
LIPSIA CONDITIONING8
MATRIX21,22
MERLIN-TIMI 3623
METOCARD-CNIC24-26
OSLER28
PARADIGM-HF29
PEGASUS-TIMI 5430
PRAMI31
PRATO-ACS32
RIDDLE-NSTEMI33
SCOT-HEART34
TASTE
35,36
TOTAL37,38
TRANSLATE-ACS39,40
WOEST41
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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E3
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
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
hsTn at
presentation
hsTn <ULN
hsTn >ULN
Intermediate
hsTn levels*
Workup differential
diagnosis
CCTA
Significant stenosis
(high-risk plaque, abnormal
FFR CT, perfusion/
wall motion abnormality)
Invasive angiography
guideline-directed therapies
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
P Value
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
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
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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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
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.
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.
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
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
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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
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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Key Point
Description
Pathophysiology
Risk factors
Clinical
presentation
Treatment
Outcome
Key Changes
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-
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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Diagnosis
Acute treatment
Chronic
treatment
Prognosis and
secondary
prevention
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).
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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 disruption
Antiplatelets,
anticoagulants
Acute thrombosis (ACS)
Anti-inflammatory drugs?
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.
REFERENCES
1. Roth GA, Huffman MD, Moran AE, et al. Global
and regional patterns in cardiovascular mortality from
1990 to 2013. Circulation. 2015;132(17):1667-1678.
metabolomics will likely expand the current portfolio of biomarkers used to characterize ACS. Proteomic analysis can now be based
on slow off-rate modified aptamer (SOMAmer)based assays with
quantification by microarray-based hybridization.81 This approach
is extremely sensitive, rapid, and automated and can handle more
than 60 analytes. Once validated, these new biomarkers will have
the potential to improve risk stratification and the underlying mechanisms in individual patients and provide the basis of individualized
therapy, including secondary prevention.
Both regional and national systems of care aiming to improve the
outcome of patients with ACS are currently under development and
will likely contribute to better performance.82 With the widespread
use of electronic medical records, it is becoming possible to assess care
in real time and prompt caregivers to consider guideline-approved diagnostic and therapeutic measures. Merger of information gathered
from electronic medical records across multiple health care systems
will also allow a robust assessment of how frequently specific guideline recommendations are being followed and the outcome of such
practices. This enhancement will provide valuable feedback to future writing committees in an effort to improve care based on actual
clinical practice in addition to classic controlled clinical trials.
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