The Year in
Acute Coronary Syndrome
June 2012 – September 2013
• Out of 1.1 million patients with diagnoses of ACS discharged from
U.S.hospitals in 2010, 74% were classified as having Myocardial
• Annual rates of Acute MI have been fairly stable over the past decade,
despite improvements in the management of coronary heart disease
• In ACS pts STEMI ranges from 29-47%,this percent is decreasing
relative to NSTEMI, in part because of temporal change in risk factor
Reduction in classic risk factors such as smoking and HTN,but
increase in DM, metabolic syndrome ,CKD,overall aging of the
Patients with chest pain at rest without elevation of hs-cTn on 2
measurements made 2 to 4 hours apart most likely have non
ischemic chest pain.
Universal definition of MI
(2007) Thygesen et al
1. New target of no more than 120 min from first medical contact to
initiation of fibrinolysis(for those not undergoing PCI).
2. Early initiation of therapeutic hypothermia in survivors of
cardiac arrest, followed by immediate PCI when appropriate.
3. Use of more potent oral antiplatelet drugs (prasugrel or
ticagrelor) as alternatives to clopidogrel and provide specific
advice on how to minimize bleeding, particularly among patients
who require dual antiplatelet therapy (DAPT) in addition to oral
Three important reports.
1.Libby – described an updated model in terms of cellular and
molecular pathways that underlie the pathogenesis of ACS,with a
central role for inflammation,which drives plaque disruption and
This has broadened the approach beyond management of a focal
intracoronary stenosis in ACS.
Mechanisms of acute coronary syndromes and their implications
N Eng J Med 2013;368:2004-13
2. Crea and Liuzzo classified ACS into 3 groups:
Obstructive atherosclerosis with systemic inflammation.
Obstructive atherosclerosis without systemic inflammation.
ACS without obstructive atherosclerosis (Prinzmetal angina,amphetamine
Pathogenesis of acute coronary syndromes.
J Am Coll Cardiol 2013;61:1-11.
3. Falk and a group of cardiac pathologists described 3
common coronary artery plaque morphologies resulting in
disruptive nodular calcifications protruding into the
coronary artery lumen, known as “calcified nodules”).
Update on ACS,the pathologists’ view.
Eur Heart J 2013;34:719-28
• Culprit plaque morphology varies from thrombosis with or without
coronary occlusion to sudden narrowing of the lumen from
• The coronary artery plaque morphologies primarily responsible for
thrombosis are plaque rupture, and plaque erosion.
• Plaque rupture being the most common cause of acute myocardial
infarction, especially in men.
• Autopsy data demonstrate that women <50 years of age more
frequently have erosion, whereas in older women, the frequency of
rupture increases with each decade.
Plaque responsible for thrombosis
• Ruptured plaques are associated with positive (expansive) remodelling
and characterized by a large necrotic core and a thin fibrous cap that is
disrupted and infiltrated by foamy macrophages.
• Plaque erosion lesions are often negatively remodelled with the plaque
itself being rich in smooth muscle cells and proteoglycans with
minimal to absence of inflammation.
• Plaque haemorrhage may expand the plaque rapidly, leading to the
development of unstable angina.
• Plaque haemorrhage may occur from plaque rupture (fissure) or from
• Atherosclerosis is now recognized as an inflammatory disease with
macrophages and T-lymphocytes playing a dominant role.
• Recently at least two subtypes of macrophages have been identified.
M1 is a pro-inflammatory macrophage while M2 seems to play a
role in dampening inflammation and promoting tissue repair.
• A third type of macrophage, termed by us as haemoglobin associated
macrophage or M(Hb) which is observed at site of haemorrhage also
can be demonstrated in human atherosclerosis.
Contributors to vulnerable plaque :
1. Structural determinants of the plaque (size of the necrotic
core,thickness and degree of inflammation within the fibrous
2. Plaque neovascularization
3. Infiltration with hemoglobin stimulated macrophages(increase
the risk of intra plaque hemorrhage).
4. Pattern of calcification (spotty calcification confers higher risk
compared with dense local calcification).
other than revascularization
• To reduce infarct size in patients with STEMI.
• Unloading the left ventricle with left atrial femoral artery bypass
in case of Left anterior coronary artery occlusion, resulted in
further reduction of myocardial infarct size.(an intriguing study in
• Cannot be applied routinely in the catheterization laboratory in all
patients with STEMI.
• Could be lifesaving in patients with large infarctions.
miRNAs discovery is an major advance in biology
Micro- ribonucleic acids (miRNAs):
• Noncoding ribonucleic acid molecules
• 21-23 nucleotide long.
• Regulate the expression of target genes.
3 circulating miRNAs (126,233 and 197) were found to be risk
factors for the development of future MI.
Other have been found to be assosciated with
reduced myocardial salvage,(133a)
more pronounced reperfusion injury,
and left ventricular remodelling after first STEMI.(miRNA 150)
miRNAS can be silenced by specific
antagonists,known as antagomirs,that might be
designed to modify target proteins that predispose
plaques to rupture.
Novel Risk Score in
patients with STEMI
Dynamic TIMI Risk Score
Why this score?
• Most risk scores for ACS,are based on findings at the time of
the patient’s initial presentation.
• They do not take into account events that occur during the
The dynamic TIMI risk score for STEMI includes
6 clinical events occuring after admission
3. Major bleed
4. Congestive Heart Failure or Shock
5. Arrhythmia (VT,VF or AF)
6. Renal failure
Amin et al
3 categories of cTn elevation:
Ischemic myocardial damage(MI)
Nonischemic causes of myocardial damage(myocarditis)
Analytical issues that may be either assay based (calibration
errors) or sample based.
A prospective analysis of 887 unselected patients with acute chest
pain found that a simple algorithm that incorporates
the level of hs-cTn at presentation,
and the absolute change in hs-cTn during the first hour
performed well in separating AMI from non coronary diagnoses.
• Among 2,544 patients presenting with symptoms consistent with
ACS,the combination of
normal hs-cTn at presentation and 2 h later,
no ischemic changes on ECG,and
a TIMI risk score for UA or NSTEMI of 0 or 1
identified approximately 40% of patients in whom the rate of
major adverse cardiac events through 30 days was <1% and who
therefore were good candidates for early discharge.
• Many of these patients may not actually have had ACS.
J Am Coll Cardiol 2013;62:1242-9
In 1,967 patients presenting to ED with chest pain onset within 6
hours demonstrated that a combination of
Negative cTn (not hs),
Copeptin level < 14 pmol/l and
Nondiagnostic echocardiographic findings
could rule out MI in the majority of patients.
CHOPIN trial ,J Am Coll Cardiol 2013;62:150-60
Minor releases of cTn after
• More patients will have detectable levels of cTn after PCI,
are they significant????.
• One analysis concluded that elevations in creatine kinase-MB 3
fold to 5-fold above the upper limit of normal after PCI
correlated with cTn elevations of 50 fold to 100-fold in both
frequency and risk for mortality 1 year after PCI.
Pregnancy assosciated plasma protein-A,
• Zinc binding metalloproteinase found in vulnerable plaques
that cleaves insulin like growth factor -4 from IGF-1and that
causes the destabilization of the fibrous plaque.
MERLIN-TIMI 36 trial
• 3,782 pts with NSTEMI
• Elevated baseline PAPP-A was found to be independently
assosciated with increased risk for CV death or MI at 30 days
(HR:1.62,p=0.006)and 1 yr (HR:1.35,p=0.012).
J Am Coll Cardiol 2012;60:332-8.
Membrane attack complex
• Ischemia mediated changes to myocardial cell surface molecule
expression render the cell membrane a target for the complement
system,leading to the formation of a membrane attack
complex,which leads to cell lysis.
• An analysis of 725 patients with STEMI treated with primary PCI,
elevated concentrations of soluble MAC (a stable nonlytic form
of MAC that can be used to estimate MAC) after multivariate
adjustment were assosciated with
all cause mortality(HR:1.81;p=0.029)and
major adverse CV events (HR:1.70;p=0.006).
• Role in host immunity
• Pathophysiology of immune mediated diseases
• Development of an unstable plaque.
Analysis of 981 pts enrolled in French registry of patients
with MI, low levels of IL-17 were independently
assosciated with increased risk for death or reinfarction at
Eur Heart J 2013;34:570-7
Higher levels of circulating pentraxin-3,a novel inflammatory
marker,were associated with thin-cap vulnerable plaques , as
determined by optical coherence tomography.
Koga et al
• CMR –helpful in risk stratification of patients with suspected
CAD who were followed for 25 months*
• CTA based score
Morphological characteristics of coronary lesions
(stenosis length, plaque volume and attenuation, remodelling
index, presence of spotty calcium)was quite accurate in the
detection of ACS in a cohort of patients with acute chest pain.
• Reduces the mean cost in the ED, shortened lengths of hospital
#Poon et al,JACC,2013;543-52
Catheter based imaging
Optical coherence tomography,
plaque rupture was found to be responsible for the culprit
lesion in 44% of 126 pts, while 36% had plaque erosion;
plaque erosion: more frequently observed in younger patients
whose plaques had thicker fibrous caps and less lipid than those
with plaque rupture.
• Near infrared spectroscopy,which allows the detection of
lipids in the plaques.
Madder et al
• Use of this catheter in patients with STEMI revealed that the lipid
core in culpirt plaques was larger than observed in non culprit
arteries,thereby providing a “biochemical signature of the
Phase 3 clinical trials results with novel antiplatelet drugs.
Bedside monitoring to adjust antiplatelet therapy
Duration of DAPT
Reduction of stent thrombosis
Influence of smoking on antiplatelet inhibition
• Cangrelor reduced the odds of both the primary CV composite
end point of death,MI, ischemia driven revascularization, or
stent thrombosis at 48 hr after randomization by
20% (2,810 pts with NSTEMI)
25% (1,991 pts with STEMI)
• Stent thrombosis reduced by 38% without increasing bleeding
in the overall population,without heterogeneity across the
population stratified by the type of ACS at presentation.
• The benefit of intense but short duration inhibition of P2Y12
to reduce periprocedural complications,particularly MI and
Effect of Prasugrel
• Oral thienopyridine prasugrel did not reduce the composite of
CV death ,MI or stroke among medically managed patients with
NSTEMI compared with clopdiogrel,in the TRILOGY-ACS
• Intensive blockade appears most beneficial in high risk patients
during PCI TRITON TIMI 38 trial.
• 2,440 pts scheduled for coronary stent implantation (30% with prior
MI,27% with non STE ACS) were randomized.
• Strategy of platelet function monitoring using the Verfiy Now assay
followed by intensification of the antiplatelet regimen in patients
with high platelet reactivity,compared with a conventional strategy
with no monitoring or adjustment of antiplatelet regimen.
• Despite increasing the antiplatelet therapy in 1/3 pts in the platelet
montioring group,there were no differences in the primary end
point,the major secondary endpoint of stent thrombosis or any
urgent revascularization or major bleeding.
• Suboptimal cut point for high platelet reactivity.
• Need for even more potent antiplatelet agents in patients with
• Some events cannot be influenced by antiplatelet therapy.
Until more successful strategies are
developed, current ACS guidelines donot
endorse routine testing of platelet function.
Duration of DAPT
• DAPT is recommended for 12 months after ACS whether
STEMI/NSTEMI/UA and whether patients receive intracoronary
stents or not.
• Meta analysis 8,231 pts (61% with ACS) undergoing PCI with
DES from 4RCTs,extended use of DAPT >12 months
significantly increased the risk for TIMI major bleeding by 2.6
fold but did not reduce mortality,MI,or stroke compared with
control (3-12 months of DAPT).
• A very low rate of late stent thrombosis (0.3%) between 12-24
months among patients who received second generation DES
(either zotarolimus or everolimus),95% of whom stopped
clopidogrel at 12 months.
• Interruption of DAPT within the first 90 days after DES
placement is not advised.
HIGH RISK GROUPS (patients undergoing intracoronary stent
placement into a saphenous vein graft are at increased risk
(1.33)for stent thrombosis within the first 3 months, regardless of
stent type, if clopidogrel stopped before day 90after stent
What if DAPT not taken for
1-2 days in first yr
• 1,622 patients in Spanish registry were evaluated(59% ACS) ,29
• Brief 7 days mean interruption was noticed
• Not statistically assosciated with increase in the risk for stent
• 26,000 pts,Intracoronary stents (BMSor DES)
• Treated with DAPT
• After 12 months,patients who were free of major CV events and
bleeding were randomized to either placebo (12 month DAPT
arm )or an additional 18 month of thienopyridine (30 month
DAPT arm ).
• First adequately powered evaluation of the clinical efficacy and
safety of differing durations of DAPT
• Results are anticipated in 2014.
Reduction of stent thrombosis
• TRITON TIMI 38 trial – ACS + stent pts - administration of
prasugrel reduced stent thrombosis by 50%.
• PLATO trial – 11,289 pts ACS + stent – ticagrelor vs
Definite and probable stent thrombosis reduced by 25%
• Benefit was consistent across all patient subgroups and types of
Influence of smoking on antiplatelet inhibition
PARADOX study,Gurbel et al
• Clopidogrel vs Prasugrel
• Inhibition of platelet activation on clopidogrel was lower in
nonsmokers than in smokers.
• Inhibition of platelet activity was greater with prasugrel than
clopidogrel in both smokers and nonsmokers
• Not affected by smoking status of the patient (Prasugrel)
SMOKER’S PARADOX Clinical benefits of clopidogrel are
greater in smokers than in non smokers.
ATLAS ACS 2 TIMI 51 trial
• Oral factor Xa rivaroxaban in addition to standard DAPT in
pts with ACS.
• 7,817 pts with STEMI(>70% PCI)
Use of rivaroxaban 4.7 days after the index event was
• 19% reduction in primary end point compared to placebo.
• Benefit lasted till 30 days.
• 2.5 mg bid reduced CV death.
• Increased major bleeding,ICH.
ACS + Stent pts
• Stent thrombosis reduced by 35%
• Mortality reduction of 44%
European medical agency approval of rivaroxaban
after ACS in 2013.
FDA approval ???
“NO” (for use after ACS)
Is there any benefit of
high dose aspirin?
• Systematic review of literature
• 136 studies
• 2,89,330 pts
No improvement in clinical outcomes with higher >160 mg /day
maintenance doses of aspirin compared with lower doses in
patients with ACS receiving coronary stents or being medically
• An excess of major bleeding of 23/1,000 with these higher doses
of aspirin in medically managed pts.
Am Heart J 2012;164:153-62
HORIZONS AMI trial
• STEMI pts Rx with primary PCI
• Higher doses of aspirin (>200mg/day) increased major
• NOT more effective than low dose aspirin in preventing
recurrent ischemic CV events.
Does the bleeding have an
• 3,560 pts received DAPT after MI
• Less severe forms of bleeding have an negative impact on
the quality of life and may increase the need for re
MI pts with AF
• Requires triple therapy
• 11,480 pts in Denmark were evaluated 2000-2009
• Excess risk for bleeding with triple therapy begins early (<90
days) and continues to 1 yr.
• No improvement in tolerance over time with triple therapy.
Substitution of prasugrel for clopidogrel increases TIMI major
or minor bleeding 3.2 folds.
Patients who require triple therapy generally should
receive low dose aspirin and clopidogrel for the
minimum duration recommended (12 months),
warfarin with a target INR of 2.0-2.5,
and if coronary stenting is indicated ,a BMS.
• Open label
• 573 pts –on oral anticoagulants undergoing coronary stenting.
• Aspirin was not administered in one arm compared with triple
therapy arm (aspirin 80-100 mg/day)
• Risk for any bleeding was less in clopidogrel +OAC arm(19.4% vs
• Secondary end points were also lower with dual therapy (HR :0.60)
• Not conclusive (less no .of events)
• In North Carolina,a statewide STEMI strategy to transport
patients directly to a PCI capable hospital ,the mean time to
reperfusion (by either PCI or fibrinolysis) was reduced by a mean
of 31 min.
• Direct transfer to PCI from ambulance – 20-30 min saved.
• Unavoidable delays (1 in 7 pts)
Delay in providing consent
Difficulty with vascular access
Difficulty in crossing the lesion
Need for intubation
OPTIMAL REPERFUSION STRATEGY
PCI or FIBRINOLYSIS?????
• When delays are expected and primary PCI cannot be
performed within 120 min of first medical contact,
fibrinolytic therapy is recommended.
• The optimal method of reperfusion when the delays are
shorter(60-120 min) is less clear.
Two complication after primary PCI,are risk factors
for subsequent mortality
• Recurrent infarction
• Major bleeding
• Kikkeri et al ,this excess risk persisted beyond 1 year in case of
• In case of bleeding,excess risk returned to normal levels by 1
TRITON TIMI 38 trial
Which is superior BMS or DES ????
Bangalore et al.
Compared with BMS, Sirolimus eluting stents, Paclitaxel
eluting stents,and Everolimus eluting stents were associated
with significantly reduced need for vessel revascularization,
without increasing the risk for stent thrombosis.
Circ Cardiovascul Interven 2013;6:378-90
Palmerini et al.
Analysis of 12,453 pts with STEMI Rx with Stents
The Everolimus eluting stent (a second generation
DES) showed the most favourable safety and
• 1,498 pts with STEMI
Everolimus eluting stents and BMS had similar rates of the
primary composite of death , reinfarction, and any
revascularization at 1 year.
• Rates of repeat target lesion (2.1% vs 5.0%,p=0.003)
• Vessel revascularization (3.7% vs6.8% ,p=0.008) were
signficantly lower in Everolimus eluting stent group.
• 625 pts with STEMI
• Everolimus vs Sirolimus
• Major CV events were lower in Everolimus (4.0 % vs 7.7%,p=0.048)
J Am Coll Cardiol 2012;60:381-7
COMFORTABLE AMI trial
Biolimus eluting stents with a biodegradable polymer reduced the
primary endpoint of major adverse cardiac events at 1 year compared
with BMS (4.3% vs 8.7%,p=0.004)
• Thrombus aspiration reduced both in hospital and longer
term(mean 10 months)adjusted mortality rates.
• Significant reduction in MACE (risk ratio : 0.76),all cause
mortality(risk ratio: 0.71).
• Manual thrombus aspiration vs rheolytic thrombectomy,neither
technique completely removed the thrombus.
ACCF/AHA/ESC STEMI guidelines state that manual
aspiration thrombectomy is reasonable for patients undergoing
primary PCI(Class Iia,Level of evidenceB)
• Intracoronary microparticles (derived from platelets and endothelial
cells) responsible for ongoing thrombosis and microvascular
dysfunction leading to microvascular obstruction.
• Infusion of Exenatide,a glucagon like peptide-1 analogue , beginning
15 min before primary PCI significantly increased myocardial
salvage and reduced infarct size as assessed by MRI compared with
placebo (172 pts with STEMI).
Intracoronary adenosine was shown to improve
ST segment resolution and angiographic
microvascular obstruction in a placebo controlled
trial of 240 pts with STEMI Rx by PCI ,thrombus
REOPEN- AMI study ,J Am Coll Cardiol Intv 2013;6:580-9
• Intracoronary diltiazem and verapamil were more effective than
intracoronary NTG in preventing the no reflow phenomenon,as
assessed by the corrected TIMI frame count,by degree of ST
segment resolution after intervention.
• Ischemic post-conditioning,(brief episodes of ischemia induced by
multiple low pressure coronary artery balloon inflations shortly after
reperfusion) reduced infarct size and myocardial edema(50 pts with
• In NSTEMI pts,undergoing PCI+stent,use of 1-2 doses of
P Selectin antagonist – inclacumab reduced myocardial damage
as assessed by biomarkers.*
EMBRACE STEMI trial #
Bendavia,an IV mitochondrial targeting peptide, with placebo
in 300 pts with anterior STEMI undergoing PCI, whether reduces
*SELECT ACS trial,J Am Coll Cardiol 2013;61:2048-55
#EMBRACE STEMI study;Am Heart J 2013;165:509-14
• Meta-analysis of 6 randomized trials
• 1,054 pts with cardiogenic shock after MI
• IABP did not reduce mortality, HF, reinfarction.
• Confirmed in the IABP SHOCK II trial(606 pts).
• Downgrade the use of IABP – class IIa to class IIb.
Radial access vs femoral access
• 294,469 pts with STEMI
Procedure success was similar
• Median door to balloon time was only 4 min longer
• Bleeding was reduced significantly by 38% with radial compared
with femoral approach.
• US – 1 in 6 PCIs in 2012,More frequently in West Europe.
RIFLE STEACS trial – 1,001 pts with STEMI - radial access
– less rate of primary end points (13.6%vs 21.0%),(hospital stay 5
vs 6 days)
• (1.3% vs 3.2%) STEMI ,but not in NSTEMI pts(1.3% vs 0.8%).
• In UK ,radial access was assosciated with a significantly lower
mortality,major bleeding and site complications.
• $830 lower than femoral access.
• 33% pts had LDL cholesterol>100mg/dl 6 months
after AMI,with fewer than one third achieving levels
• Interruption of statin therapy
• High intensity therapy is useful
Quality of care
• More favourable patient baseline characteristics
• A decrease in time from symptom onset to first medical contact
(240 to 175 min),use of mobile ICUs)
• Increase in the use of reperfusion therapy (49% to 75%),largely
• More frequent use of guideline recommended therapies (statins17%
to 22%),ACE (19% to 28%).
physician order entry
• Reduces death by 41% and rehospitalizations by 32%.
Slow gait speed is a measure of fraility,and among STEMI
pts,independently assosciated with a 41% increase in the hazard
of a CV event for each decline of 0.1m/sec in gait speed.
JAmColl Cardiol 2013;61:1964-72
• An orientation appointment within 10 days of
discharge,rather than standard approach (mean 35 days).
• Improved attendance to 77% (an absolute increase of 18 %
over the standard).