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Utilization of MRI and MRA for Cardiac Thrombus Chapter | 8 119
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Four-chamber cine image Four-chamber delayed enhancement image
CASE B Iron-overload cardiomyopathy with small apical thrombus not recognized on cine image, but clearly detected on delayed enhancement image.
Three-chamber cine with thrombus at
the apex
Three-chamber delayed enhancement
images demonstrating thrombus
Three-chamber delayed
enhancement with resolution
of thrombus after anticoagulation
Four-chamber delayed enhancement showing thrombus Four-chamber delayed enhancement with resolution of
thrombus after anticoagulation
CASE C Nonischemic cardiomyopathy with thrombus seen on cine and delayed enhancement images that resolved on a follow-up scan, with anti-
coagulation revealing evidence of noncompacted myocardium.
120 Cardiovascular Thrombus
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Right-atrial thrombus with TI 340 ms Right-atrial thrombus with TI 600 ms
CASE D Right-atrial thrombus in a patient with atrial fibrillation whose dabigatran was reversed after a traumatic fall. The thrombus shows typical
appearance with variable TI. TI, inversion time.
ATRIAL FIBRILLATION
Using CMRI to evaluate the left atrium and left-atrial appendage for thrombus is an active area of interest. In 2003 Ohyama
et al. performed transesophageal echocardiograms and CMRI on 56 patients with nonrheumatic persistent atrial fibrillation
and a history of cardioembolic stroke. The MRI techniques used did not include contrast or delayed enhancement imaging
but they did establish that left-atrial appendage thrombus could be visualized. In their study 16 thrombi were seen by
transesophageal echocardiography (TEE) and all were detected on MRI [14].
A common indication for MRA is the evaluation of pulmonary venous anatomy in atrial fibrillation patients prior to
pulmonary vein isolation procedures. Pulmonary vein visualization is with a contrast-enhanced 3D MRA, which includes a
3D reconstruction of the left atrium and left-atrial appendage with an in-plane resolution of 1.5 mm. Typically, this is
PICTURE 2 No reflow in the inferior wall.
Utilization of MRI and MRA for Cardiac Thrombus Chapter | 8 121
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combined with a transesophageal echocardiogram to rule out left-atrial or left-atrial appendage thrombus. Studies are now
investigating the diagnostic performance of CMRI with delayed enhancement imaging for assessment of left-atrial and leftatrial appendage thrombus at the time of pulmonary venogram. Additional images obtained include cine images of the left
atrium and left-atrial appendage in two orthogonal views and “ single-shot” delayed enhancement images approximately
10 min after gadolinium administration with a long TI (600 ms) to null avascular tissue [15]. On cine imaging a left-atrial
or left-atrial appendage thrombus appears as a mass distinct from the wall or pectinate muscle. On contrast-enhanced MRA
it appears as a filling defect, and on long TI delayed enhancement images, the thrombus is a dark mass.
In a 2016 study using the aforementioned sequences, Kitkungvan et al. compared 261 patients undergoing TEE and
CMRI within 7 days prior to pulmonary vein isolation procedure [15]. TEE detected clot in nine patients. As expected,
some of these were not visualized on CMRI cine ima ging or MRA. Cine imaging in CMRI is a gated image and not
surprisingly performs even less well when patients are in atrial fibrillation at the time of the study. Delayed enhancement
CMRI detected all of the thrombi. The single-shot approach used in the study is a rapid acquisition without breath holding
and is unaffected by the underlying rhythm, making it ideally suited to atrial fibrillation patients. Typically, anticoagulant
use is high in patients undergoing pulmonary vein isolation procedures, so detection of thrombus in these patients is
relatively rare. Large numbers of patients will be needed to fully validate MRI/MRA for this indication.
CONCLUSION
CMRI is an important imaging tool for detecting cardiac thrombus. Because of its ability to identify characteristic scar
patterns, it is increasingly used in the routine evaluation of ischemic and nonischemic cardiomyopathy. With its high
spatial resolution and ability to characterize tissue, associated thrombi are being accurately identified. Not unexpectedly, its
use in identifying thrombus in other routine scans such as those performed in the setting of atrial fibrillation is being
actively investigated.
REFERENCES
[1] Aboix A, Alio J. Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Curr Cardiol Rev 2010;6(3):150e61.
[2] Delewi R, Zijlstra F, Piek J. Left ventricular thrombus formation after acute myocardial infarction. Heart 2012;98:1743e9.
[3] https://www.med-ed.virginia.edu/courses/rad/cardiacmr/index.html.
[4] Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed enhancement cardiovascular magnetic resonance assessment of nonischaemic
cardiomyopathies. Eur Heart J 2005;26:1461e74.
[5] Kim RJ, Wu E, Rafael A, Chen E, Parker M, Simonetti O, Klocke F, Bonow R, Judd RM. The use of contrast-enhanced magnetic resonance imaging
to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445e53.
[6] Weinsaft J, Kim H, Crowley AL, Klem I, Shenoy C, Van Assche L, Brosnan R, Shah D, Velazquez E, Parker M, Judd RM, Kim RJ. LV thrombus
detection by routine echocardiography, insights into performance characteristics using delayed enhancement CMR. JACC Cardiovasc Imag
2011;4(7):702e12.
[7] Sirachi MB, Junor C, Rodriguez LL, et al. Clinical, imaging, and pathologic characteristics of left ventricular thrombus: a comparison of contrast
enhanced magnetic resonance imaging, transthoracic echocardiography and transesophageal echocardiography with surgical and pathological
validation. Am Heart J 2006;152:75e84.
[8] Weinsaft J, Kim H, Shah D, Klem I, Crowley AL, Brosnan R, James O, Patel M, Heitner J, Parker M, Velazquez E, Steenbergen C, Judd RM,
Kim RJ. Detection of left ventricular thrombus by delayed-enhancement cardiovascular magnetic resonance, prevalence and markers of patients with
systolic dysfunction. J Am Coll Cardiol 2008;52:148e57.
[9] Waller B, Grider L, Rohr T, McLaughlin T, Taliercio C, Fetters J. Intracardiac thrombi: frequency, location, etiology and complications: a
morphologic review. Clin Cardiol 1995;18. 477e479 and 530e534.
[10] Delewi R, Nijveldt R, Hirsch A, Marcu CB, Robbers L, Hassell ME, et al. Left ventricular thrombus formation after acute myocardial infarction as
assessed by cardiovascular magnetic resonance imaging. Eur J Radiol 2012;81:3900e4.
[11] Pazos Lopez P, Pozo E, Siqueira M, Garcia-Lunar I, Cham M, Jocobi A, Macaluso F, Fuster V, Narula J, Sanz J. Value of CMR for the differential
diagnosis of cardiac masses. JACC Cardiovasc Imag 2014;7:896e905.
[12] Hamilton S, Henry T, Little B, Lerakis S, Stillman A. Case based review of T1 and T2 mapping techniques. Radiographics 2014;34(6).
[13] Casper T, El Ghannudi S, Ohana M, et al. Magnetic resonance evaluation of cardiac thrombi and masses by T1 and T2 mapping: an observational
study. Int J Cardiovasc Imag 2016:1e9.
[14] Ohyama H, Hosomi N, Takahashi T, Mizushige K, Osaka K, Kohno M, Koziol J. Comparison of magnetic resonance imaging and transesophageal
echocardiography in detection of thrombus in the left atrial appendage. Stroke 2003;34:2436e9.
[15] Kitkungvan D, Nabi F, Ghosn M, Dave A, Quinones M, Zogbhi W, Valderrabano M, Shah D. Detection of LA and LAA thrombus by CMR in
patients referred for pulmonary vein isolation. JACC Cardiovasc Imag 2016;9(7):809e18.
Chapter 9
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Acute Myocardial Infarction: STEMI and
NSTEMI
Kalpa De Silva1, Divaka Perera1and Peter O’Kane
1
Guy’s & St. Thomas’ Hospital, London, United Kingdom;2Royal Bournemouth Hospital, Bournemouth, Dorset, United Kingdom
2
INTRODUCTION
The pathogen esis that underlies acute myocardia l infarction (MI) is complex and multifactorial. Rupture or erosion of a
coronary artery atheroma exposes flowing blood to the prothrombotic contents of the plaque, resulting in platelet
activation and subsequent thrombus formation. If this process results in reduced coronary blood flow, the patient may
present with an acute coronary syndrome (ACS). Total thrombotic occlusion generally results in ST-segment elevation
MI (STEMI), whereas incomplete occlusion (or extensive collateralization) is mo re likely to present as non-STEMI
(NSTEMI) or unstable angina without evidence of myonecrosis (collectively non-ST-segment elevation ACS [NSTEACS]). Percutaneous coronary intervention (PCI) is the mainstay of revascularization in all forms of ACS, by
providing rapid mechanical restoration of coronary flow and therefore myocardial perfusion. Although this provides a
method of mechanically improving the patency of the epicardialarterybytreatingunderlyingcoronarystenosesor
regions of vulnerable plaque, the coexistent thrombus that is often present remains a harbinger of persistent ischemia
and increased infarct siz e an d is causal in acute stent th romb osis. Moreover, the frequent ly o bser ve d a ngio gra phi c
phenomena of “slow flow” (delayed transit of dye through coronary arteries) and “ no reflow” (absent transit of dye
through coronary arteries) are predominantly secondary to thrombotic debris causing microvascular obstruction, which
correlates with the size of infarction and adversely affects mortality. Although there a re technical aspects of PCI during
ACS that can potentially reduce the thrombotic burden, there remains the possibility that PCI itself can mechanically
embolize thrombotic material, which can adversely affect the patient’s outcome. Adjunctive pharmacological treatment
pre- and post-revascularization, or in patients managed conservatively, may be of equal if not greater importance in
influencing prognosis [1 e3] .
Pathophysiological Importance of Intracoronary Thrombus in Acute Myocardial Infarction
Angiographically detected intracoronary thrombus in the setting of primary PCI (PPCI) for STEMI is associated with an
adverse prognosis and leads to a higher incidence of in-hospital and long-term adverse cardiac events. The presence of
intracoronary thrombus impairs both epicardial and microvascular compartments of the myocardial circulation, by
spontaneous or PCI-induced occlusion of the epicardial vessel or its branches, or distal emboli zation of plaque and
thrombotic components into the microvasculature. Percutaneous intervention in the STEMI setting is causa l in increasing
rates of distal embolization, with data derived from PPCI cohorts showing that it leads to 6%e18% distal embolization
rate [4e10]. Furthermore, patients with distal embolization, compared with those without , showed lower procedur al
success rates with higher slow/no-reflow rates, lower left-ventricular ejection fraction (LVEF), and larger enzymatic
infarctions, with increased in-hospital and late mortality rates [5,11].
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00009-0
Copyright © 2018 Elsevier Inc. All rights reserved.
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ANTIPLATELET THERAPY IN ACUTE CORONARY SYNDROME
Refinement of the utilization of oral and intravenous antiplatelet agents has been the foundation for the significant
reduction in mortality in patients presenting with ACS since the late 1990s. Timely initiation of antiplatelet therapy is a
critical component of the successful management of ACS [1,3]. The individual agents and the data to support their use in
clinical practice will be discussed in the next sections.
Aspirin
Acetylsalicylic acid was introduced into medi cal practice in 1897 when Felix Hoffmann, a chemist at the German Bayer
Company, formulated a pure and stable form by mixing acetic and salicylic acids. Having been used to treat inflammatory
conditions, its antiplatelet effects were not recognized for another 70 years. Perhaps surprisingly, given that other
contemporary therapies are available, aspirin remains the cornerstone of antiplatelet therapy for both stable patients with
coronary heart disease and those with ACS.
Aspirin is administered as soon as an ACS is suspected at an oral loading dose of 300e325 mg (or 250e500 mg
intravenously), followed by 75e100 mg daily. Higher daily doses have been associated with greater bleeding without
evidence of improved efficacy [12]. Aspirin has been shown to reduce 30-day mortality in ACS by w25%, and the risks of
nonfatal reinfarction and stroke by w50% [13,14]. Aspirin is typically continued indefinitely in patients with established
coronary artery disease (in the absence of significant bleeding complications).
Aspirin primarily interferes with the biosynthesis of cyclic prostanoids, thromboxane A
other prostaglandins. Arachidonic acid released from membrane and other phospholipid pools is oxygenated and cyclized
by the enzyme cyclooxygenase (COX), which ultimately leads to formation of TXA
, a potent aggregator of platelets and
2
vasoconstrictor. Aspirin selectively and irreversibly inhibits COX by acetylation of serine 529, thereby inhibiting TXA
formation and in turn platelet aggregation. However, platelets are also activated through alternative pathways such as
adenosine diphosphate (ADP) and thrombin, through the P2Y
receptor- and PAR receptor-initiated pathways, respec-
12
tively, even in the presence of aspirin [15,16].
The adjunctive use of a second antiplatelet agent to inhibit ADP-mediated platelet aggregation is especially critical in
ACS patients undergoing PCI, as it has been shown to provide more effective platelet inhibition and to reduce ischemic
events in NSTE-ACS [17,18] and STEMI [19e21]. Thus the P2Y
receptor antagonists clopidogrel, prasugrel, and
12
ticagrelor are routinely used and have been shown to complement aspirin in reducing ischemic events in ACS patients
managed invasively [18,22,23]. As the potency of P2Y
has increased, the question as to the added efficacy of aspirin
12
following PCI in ACS has been questioned. The Ticagrelor with Aspirin or Alone in High-Risk Acute Coronary
Intervention (TWILIGHT) trial as of this writing is recruiting over 9000 patients, aiming to determine whether a single
anti-platelet (SAPT) regime with Ticagrelor only is as efficacious as dual anti-platelet therapy (DAPT) of Ticagrelor and
aspirin in terms of ischaemic and bleeding endpoints. The results are not expected until the final quarter of 2018 but may
provide important insights into the future rationale of DAPT in this setting.
(TXA2), prostacyclin, and
2
2
Clopidogrel
Clopidogrel, a thienopyridine derivative, inhibits platelet activation mediated by ADP by blocking the P2Y12receptor,
thereby reducing ischemic events. As a sole agent in patients with atherosclerotic vascular disease, clopidogrel was slightly
more effective than aspirin in reducing the composite risk of vascular death, MI, or ischemic stroke in the CAPRIE trial
[17]. The CURE trial [24] confirmed the additive value of clopidogrel to aspirin in reducing the composite end point of
death from cardiovascular causes, MI, or stroke in patients with ACS treated conservatively or with PCI for refractory
ischemia. In this trial clopidogrel principally reduced the rate of non-Q-wave MI, while increasing the risk of mild to
moderate bleeding. However, clopidogrel did not significantly increase life-threatening or fatal bleeding, and the rates of
all-cause mortality were similar in patients treated with aspirin alone or aspirin plus clopidogrel. On the basis of the CURE
trial, DAPT with aspirin and clopidogrel became the standard of care in ACS.
However, a ltho ugh clopidogrel remains the most widely used P2Y
extent to which clopidogrel reduces ADP-mediated platelet activation limits its utility in many patients. Clopidogrel is a
prodrug and requires a two-step conversion to generate the active metabolites, which are principally generated through
hepatic metabolism. Genetic polymorphisms of the cytochrome P450 pathway that diminish clopidogrel conversion may
be present in up to 40% of patients [25,26], although both loss- and gain-of -fun ct ion alleles have been descri bed [27].
receptor inhibitor, substantial variability in the
12
Acute Myocardial Infarction: STEMI and NSTEMI Chapter | 9 125
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Altered platelet reactivity on clopidogrel may result in either an increased risk of stent thrombosis and MI in patients
who are hyporesponders [28] or an increased risk of bleedinginpatientsinwhoseplatelets are excessively inhibited
[18,24]. The role of platelet function testing (PFT) to assess the variability in response to clopidogrel, to tailor
antiplatelet therapy, has been assessed in several studies. However, the data accumulated as of this writing have
not demonstrated improved clinical outcomes with routine PFT, which is thus reserved for use in selected high-risk
cases [29].
Concerns about hyporesponders to clopidogrel led to pharmacodynamic assessment of clopidogrel dosing, which
suggested that there was an advantage in loading with 600 mg rather than 300 mg [30]. In the Antiplatelet Therapy for
Reduction of Myocardial Damage During Angioplasty (ARMYDA-2) study, patients receiving a 600-mg loading dose of
clopidogrel 4e8 h before the procedure showed a 52% relative risk reduction (RRR) of the study composite end point
(death, MI, or target vessel revascularization) at 30 days, compared with patients receiving a 300-mg loading dose. The
benefit of the ARMYDA-2 study was entirely due to a reduction in periprocedural MI, and no bleeding excess was
reported, but this study was not powered to show differences in hard clinical end points. The first trial to assess clinical
outcomes, CURRENT OASIS 7, tested whether a double-dose regimen of clopidogrel (600 mg followed by 150 mg
maintenance from day 2 to day 7, and then 75 mg maintenance) was superior to a standard-dose regimen of clopidogrel
(300 mg loading followed by 75 mg maintenance) in preventing cardiovascular (CV) death, MI, or stroke at 30 days in
patients with ACS who were treated with an early invasive strategy. For the study, 25,086 patients were recruited, wi th no
significant difference observed at 30 days for the primary objective, which occurred in 4.2% of individuals receiving the
double-dose regimen compared with 4.4% of those who received the standard doses (hazard ratio [HR] 0.94, 95% CI
0.83e1.06, P ¼ .3). Indeed, in the analysis of the results from the subgroup of 17,263 patients with ACS who underwent
PCI, the double-dose regimen led to a nominal 25% decrease in CV events (3.9% vs. 4.5%; HR 0.85, 95% CI 0.74e0.99,
P ¼ .039). However, the P value for interaction was .03 and did not meet the prespe cified criteria (P ¼ .01) for these
results to be considered statistically significant. Therefore, the only statistically significant benefit was the 32% reduction in
the risk of stent thrombosis (1.6% vs. 2.3%; HR 0.68, 95% CI 0.55e0.85, P ¼ .001). Interestingly, although the success of
clopidogrel at a standard-dose regimen against placebo in the CURE trial was driven by the benefit obtained in a population
mostly medically treated, a similar cohort of patients in CURRENT OASIS 7 did not benefit from higher doses of
clopidogrel. These results suggest that the dose of clopidogrel should not be the same for patients with ACS treated with or
without PCI. Such a hypothesis seems to be confirmed by the good clinical results obtained with prasugrel in the Trial to
Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON) [22] and with
ticagrelor in the Platelet Inhibition and Patient Outcomes (PLATO) PCI trial [23], showing that platelet inhibition should
be more aggressive in patients with ACS undergoing PCI.
Prasugrel
Similar to clopidogrel, prasugrel is a thienopyridine and a prodrug requiring conversion to an active metabolite before
binding to and inhibiting the platelet P2Y
bypasses several critical cytochrome P450 enzymes, most importantly, the CYP2C19 allele), rather than the two-step
conversion process required to metabolize clopidogrel. Therefore prasugrel inhibits ADP-induced platelet aggregation
more rapidly, more consistently, and to a greater extent than even high doses of clopidogrel in patients [25,26] and in those
undergoing PCI [31]. Prasugrel efficacy is also not affected by external conditions and medications that interfere with
clopidogrel metabolism, such as cigarette smoking and certain proton pump inhibitors [32].
The TRITON TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with
Prasugrel Thrombolysis in Myocardial Infarction-38) trial compared prasugrel with clopidogrel in 13,608 patients
presenting with ACS in whom PCI was planned and who were followed for 6e15 months [22]. Compared with clopidogrel, prasugrel significantly reduced the rates of MI (9.7% vs. 7.4%; P < .001), urgent target-vessel revascularization
(3.7% vs. 2.5%; P < .001), and stent thrombosis (2.4% vs. 1.1%; P < .001). However, this antiischemic advantage came at
the cost of excess major bleeding (2.4% vs. 1.8%; P ¼ .03), including life-threatening (1.4% vs. 0.9%; P ¼ .01) and
fatal (0.4% vs. 0.1%; P ¼ .002) bleeding. There were no significant differences between the agents in cardiac mortality or
all-cause mortality. On the basis of this trial the European Society of Cardiology (ESC) recommended prasugrel in
clopidogrel-naive pa tients as an adjunct to PPCI for STEMI and in high-risk NSTE-ACS patients undergoing PCI,
particularly those with diabetes mellitus or previous stent thrombosis. Contraindications to its use include patients with
previous stroke or transient ischemic attack (TIA) (in whom an increased risk of intracranial bleeding was evident), and
caution is recommended in patients ages over 75 years or in those with low body weight (<60 kg), in whom a lower daily
receptor. However, prasugrel metabolism requires only a single step (and
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dose of 5 mg may be considered. Prasugr el should be discontinued 7 days prior to major surgery (vs. 5 days for clopidogrel). Post hoc analysis of the TRITON TIMI-38 outcome data through 12 months (its licensed indication in Europe),
rather than 15 months as reported in the original report, demonstrated a persistence of absolute risk reduction in ischemic
events (2.7%) and stent thrombosis (1.2%) (P < .001), with no significant incre ase in bleeding [33].
In contrast to its benefits in patients with ACS undergoing PCI, prasugrel has not been demonstrated to provide incremental utility compared with clopidogrel in NSTE-ACS patients managed medically (i.e., without revascularization). In
the TRILOGY ACS trial, among patients presenting with NSTE-ACS who were managed medically, the use of either 5 or
10 mg of daily prasugrel showed no benefit in reducing the primary end point of CV death, MI, or stroke compared with
clopidogrel, with an excess in thrombolysis in myocardial infarction (TIMI) minor bleeding in the prasugrel-treated arm
(3.3% vs. 2.1%, P ¼ .02) [34].
Ticagrelor
Ticagrelor is a cyclopentyltriazolopyrimidine (as opposed to clopidogrel and prasugrel, which are thienopyridines), and is a
direct-acting and reversible oral inhibitor of the platelet P2Y
intestinal tract, and reaches its peak concentration in w1.5 h. Its main metabolite, AR-C124910XX, is formed rapidly via
CYP3A4 by dehydroxyethylation at position 5 of the cyclop entane ring. Ticagrelor has been shown to provide more rapid
and consistent inhibition of platelet function than clopidogrel [35,36].
Among 18,624 patients w ith ACS (STEMI and NSTE-ACS) randomized in the PLATO trial [23], ticagrelor reduced
ischemic and vascular end points compared with clopidogrel in patients treated both invasively and medically.
The primary composite end point of death from vascular causes, MI, or stroke occurred in 9.8% of patients
receiving ticagrelor v ersus 11.7% of those receiving clopidogrel (HR 0.84, 95% CI 0.77d0.92, P < .001). Unl ike
prasugrel in the TRITON TIMI-38 trial, ticagrelor use in PLATO resulted in a reduction in the rate of cardiac mortality
(4.0% vs. 5. 1%; P ¼ .001) and all-cause mortality (4.5% vs. 5.9%; P < .001). Although there were no significant
differences in the rates of overall major bleeding between the ticagrelor and the clopidogrel groups (11.6% and 11.2%,
respectively; P ¼ .43) , ticagrelor was associated with a hig her rate of major bleeding not r el ated to coronary artery
bypass graft (CABG) (4.5% vs. 3.8%, P ¼ .03). Compared with clopidogrel, ticagrelor resulted in more instances of fatal
intracranial bleeding but fewer instances of fatal bleeding from other sources. Moreover, ticagrelor was effective in
patients with prior stroke or TIA, the elderly, and those of low body weight, and is thus not contraindicated in these
subgroups. However, a significant interaction was present in the PLATO trial between ticagrelor and chronic aspirin
dose, such that all patients treated with ticagrelor should be maintained on 100 mg of daily aspirin for optimal ischemic
efficacy (Table 9.1) [37].
receptor. Ticagrelor is absorbed quickly from the gastro-
12
Intravenous P2Y12Inhibitors
Clopidogrel, prasugrel, and ticagrelor are oral agents, and as such have a number of limitations, including delayed
absorption and onset of action in ACS, due to gastric hypoperfusion and r educed motility, an effect that may be
exacerbated by narcotic analgesics such as morphine [38e40]. In contrast, cangrelor is an intravenous, fast-acting
(3e5 min for full effect), potent (inhibits >95% o f ADP-induced p lat elet aggregation), and direct-acti ng platelet
ADP P2Y
within 1 h of infusion discontinuation. The CHAMPIONePHOENIX trial [41] assessed the efficacy of cangrelor (bolus
plus 2-h infusion) in 11,145 patients und erg oi ng elective or urgent PCI, compared with a clopidogrel loading dose (300
or 600 mg) in the periprocedural period. The primary 48-h end point of death, MI , ischemia-d ri ven repeat revascul ar ization, or stent thrombosis was significantly reduced by cangrelor, and stent thrombosis was reduced by 38% (0.8% vs.
1.4%, respectively, odds ratio [OR] 0.62, 95% CI 0.43e0.90, P ¼ .01). There were a number of limitations of the trial,
including that there was no mandate to treat with oral antiplatelet therapy upstream of the angiogram, which is
considered routine practice in the ACS setting. Furthermore, clopidogrel was used as the antiplatelet of choice, often at a
dose of 300 mg rather than 600 mg, rather than a comparison against the more potent P2Y
meta-analysis of three randomized PCI trials of cangrelor versus clopidogrel, in which 69% of patients had ACS, found a
19% RRR in periprocedural death, MI, ischemia-driven revascularization, or stent thrombosis (cangrelor 3.8% vs.
clopidogrel 4.7%; OR 0.81, 95% CI 0.71, 0.91, P ¼ .007) [42]. Can gr elor use has resulted in an increase in minor, but
not major, bleeding and no increase in thrombocytopenia [43,44]. In contrast to the increased rates of bleeding reported
with overdosing of glycopro tei n IIb/IIIa inhibitors (GPIs), unintentional cangrelor overdosing (definedasanexcessof
inhibitor that has a short plasma half-life (<10 min), allowing for complete reversal of platelet function
12
. That aside, a subsequent
12
TABLE 9.1 Summary of Studies on Duration of Dual Antiplatelet Therapy Following an Acute Coronary Syndrome
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No. of Patients in Each
Treatment Group Primary End Point Design and Randomization
ARTICInterruption,
2014
DAPT, 2014 12 months (n ¼ 4941);
DES-LATE,
2013
EXCELLENT,
2012
ISAR-SAFE,
2014
ITALIC,
2014
OPTIMIZE,
2013
PRODIGY,
2012
RESET, 2012 3 months (n ¼ 1059);
SECURITY,
2014
12 months (n ¼ 624);
18e24 months (n ¼ 635)
36 months (n ¼ 5020)
12 months (n ¼ 2514);
36 months (n ¼ 2531)
6 months (n ¼ 722);
12 months (n ¼ 721)
6 months (n ¼ 1997);
12 months (n ¼ 2003)
6 months (n ¼ 1997);
12 months (n ¼ 941)
3 months (n ¼ 1563);
12 months (n ¼ 1556)
6 months (n ¼ 751);
24 months (n ¼ 750)
12 months (n ¼ 1058)
6 months (n ¼ 682);
12 months (n ¼ 717)
Death, myocardial infarction, stent
thrombosis, cerebrovascular accident,
or target vessel revascularization
Death, myocardial infarction, stent
thrombosis, cerebrovascular accident,
or bleeding
Cardiac death, myocardial infarction,
or cerebrovascular accident
Cardiac death, myocardial infarction,
or cerebrovascular accident
Death, myocardial infarction, stent
thrombosis, cerebrovascular accident,
or bleeding
Death, myocardial infarction,
cerebrovascular accident, target vessel
revascularization, or bleeding
Death, myocardial infarction,
cerebrovascular accident, or major
bleeding
Death, myocardial infarction, or
cerebrovascular accident
Cardiac death, myocardial infarction,
stent thrombosis, target vessel
revascularization, or major bleeding
Cardiac death, myocardial infarction,
cerebrovascular accident, stent
thrombosis, bleeding
Superiority, randomization at
discontinuation of DAPT
Superiority, randomization at
discontinuation of DAPT
Superiority, randomization at
discontinuation of DAPT
Non-inferiority, randomization at
discontinuation of DAPT
Non-inferiority, randomization at
discontinuation of DAPT
Non-inferiority, randomization at
the time of the PCI
Non-inferiority, randomization at
the time of the PCI
Superiority, randomization
1 month after PCI
Non-inferiority, randomization at
the time of the PCI
Non-inferiority, randomization at
the time of the PCI
Follow-up
Duration After
Randomization
(Median)
17 months Superiority of
18 months Superiority of
24 months Superiority of
12 months Non-inferiority shown
9 months Non-inferiority shown
12 months Non-inferiority shown
12 months Non-inferiority shown
24 months Superiority of
12 months Non-inferiority shown
12 months Non-inferiority shown
Results of the
Primary End Point
>12 months DAPT not
shown
30 months DAPT
shown
24 months DAPT not
shown
24 months DAPT not
shown
Acute Myocardial Infarction: STEMI and NSTEMI Chapter | 9 127
DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.
De Silva K, James S, Gershlick A, Stone G. Bleeding associated with the management of Acute Coronary Syndromes. Heart BMJ, 2017. PMID: 28087588.
128 Cardiovascular Thrombus
https://t.me/med1917
20% of the bolus dose) does not lead to an increased rate of major bleeding complications [43]. Cangrelor has received
US FDA and European Commission authorization for the compound to be commercialized [44]. Further studies are
required to establish the potential role of cangrel or in ACS patients treated with either ticagrelor or prasugrel. Despite the
favorable data, cangrelor utilization in real-world clinical practice has been limited, and formalizing a precise role for
this agent wi thin the ACS PCI pathway rem ains to be determined.
Intravenous Glycoprotein IIb/IIIa Inhibitors
GPIs, including abciximab, eptifi batide, and tirofiban, act at the final common pathway of platelet aggrega tion and have
been shown to reduce ischemic event rates when administered with heparin in patients undergoing PCI for NSTE-ACS or
STEMI. A previous systematic review of early (relatively small) clinical trials suggested that abciximab in STEMI may
reduce 30-day mortality by approximately 30% without increasing hemorrhagic stroke or life-threatening bleeding [45]
(although major bleeding, thrombocytopenia, and transfusions were increased with GPI use). However, most trials of GPI
were performed a decade or more ago during the clopidogrel era and before the introduction of the more potent P2Y
receptor inhibitors prasugrel and ticagrelor, and intravenous cangrelor.
Early studies such as the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial
also examined whether upstream administration of GPIs at the time of first medical contact (rather than initiation in the
catheterization laboratory) might improve clinical outcomes in patients with STEMI undergoing PCI. Upstream GPI versus
catheter-lab administration of abciximab had no significant effect on the primary end point of death, recurrent MI, or heart
failure, but significantly increased the risk of bleeding [46].
For tirofiban there are two studies of early versus late therapy in patients with ACS. The randomized, double-blind
Continuing Tirofiban in Myocardial Infarction Evaluation (On-TIME) trial provided tirofiban given either prehospital or
in the catheter lab in 507 patients with acute MI treated at a PCI center. The tirofiban was administered a median of only
59 min earlier in the prehospital cohort, which perhaps could explain the results. The investigators did not find that early
initiation of tirofiban led to significantly improved initial TIMI 3 flow of the infarct-related artery (IRA). Despite better
patency (TIMI 2 or 3 flow), a lower prevalence of thrombus or fresh occlusion, and a better myocardial perfusion in the
IRA pre-PCI, no beneficial effect on post-PCI angiographic or clinical outcome was found, compared with initiation of
tirofiban in the catheterization laboratory.
A follow-up larger study of 984 patients, the On-TIME -2 trial, using high-dose tirofiban versus placebo, did
demonstrate a significant benefit of upstream compared with downstream provisional administration on the primary
surrogate end point ST-segment resolution (STR) and on the primary composite clinical end point of death, recurrent MI,
urgent target vessel reintervention, or thrombotic bailout. Moreover, the clinical benefit was related predominantly to a
reduction in the perceived need for bailout tirofiban.
In NSTE-ACS, several randomized trials have not shown an additive benefit of routine upstream treatment with GPI in
patients undergoing angiography and PCI, and bleeding was increased [47e50]. Thus, GPI agents are not recommended
for upstream use, and their use in the catheter lab has progressively declined since 2013. Nonetheless, in both NSTE-ACS
and STEMI, the use of GPI as a bailout therapy in cases of refractory large thrombus or slow or no reflow after PCI is
considered reasonable (class IIa level of evidence C classification by the ESC), although bleeding is increased in this
setting, especially when femoral access has been used. The efficacy and utility of bailout GPI therapy has never been
formally assessed in a randomized trial setting (a difficult undertaking), although anecdotal experiences and expert opinion
support its use in this setting [51]. Thus, whereas routine use of GPIs in combination with oral P2Y
out of favor (principally because of excess bleeding and uncertain efficacy in the contemporary era), it remains an option
for selective use as a bailout strategy during PCI complicated by refractory thrombosis.
inhibitors has fallen
12
12
ANTICOAGULATION
Anticoagulation with unfractionated heparin (UFH), which inhibits both factor IIa and factor Xa, has historically bee n
recommended for all ACS patients; it may be discontinued immediately after successful PCI or for up to 5 days in
medically treated patients. In the pre-PCI era, heparin was reported to modestly reduce major adverse coronary event
(MACE) rates in patie nts with ACS, although no large-scale randomized trials were completed [52]. In the contemporary
era there are four choices of anticoagulation to consider in the acute setting for NSTE-ACS prior to invasive management:
UFH, low-molecular-weight heparins (LMWH), fondaparinux, and bivalirudin.
Acute Myocardial Infarction: STEMI and NSTEMI Chapter | 9 129
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Subcutaneous enoxaparin (the most widely used LMWH) has theoretical advantages over UFH, although its longer
half-life and lack of a readily available test to measure its effect on coagulation may complicate management in patients
undergoing PCI. In the initial medical management of NSTE-ACS the use of enoxaparin was shown in the SYNERGY trial
to have superior efficacy compared with intravenous UFH, with reduced rates of MI (risk ratio [RR] ¼ 0.83; 95% CI 0.70,
0.99) and repeat revascularization (RR ¼ 0.88; 95% CI 0.82, 0.95), with similar bleeding (RR ¼ 1.00; 95% CI 0.80, 1.24),
although switching between these agents should be avoided [53e55]. In comparison with subcutaneous enoxaparin,
subcutaneous fondaparinux (a factor Xa inhibitor) has been shown to result in less major bleeding and lower long-term
mortality in patients with NSTE-ACS and STEMI managed conservatively [56,57]. However, in the OASIS 5 trial the
dose of the comparator LMWH was considered by some to be unreasonably high, perhaps artificially favoring fondaparinux [37]. Moreover, because of a risk of catheter-related thrombus during PCI, full-dose UFH or bivalirudin is required
in addition to fondaparinux if PCI is performed [58,59]. Fondaparinux is thus not recommende d in ACS patients undergoing PCI. Finally, the studies demonstrating a benefit of fondaparinux compared with LMWH were performed in an
era in which patients with NSTE-ACS were typically treated conservatively or generally not taken to the catheterization
laboratory for 5e7 days. In the current era most patients with NSTE-ACS undergo angiography and revascularization
within 24e72 h. As such, intravenous UFH prior to catheterization is a more practical recommendation. Fondaparinux use
varies markedly across Europe, and it is still used during initial medical stabilization of NSTE-ACS in the United
Kingdom. Fondaparinux is not used for ACS in the United States, but in the United Kingdom fondaparinux has become the
agent of choice in ACS largely because of lower cost compared with LMWH.
Bivalirudin has been used for many years, having emerged as an alternative antithrombotic agent in PCI for N STEACS and STEMI, particularly in patients at high ischemic risk and/or high risk of bleeding. UFH and LMWH are
indirectly acting antithrombin inhibitors, which work by binding to antithrombin III, causing a conformatio nal change
that results in its activation t hrough an increase in the flexibility of its reactive-site loop [60]. The activated antithrombin
III then inactivates thrombin and other proteases involved in blood clotting. However, there are a number of pharmacologic limitations to UFH and LMWH use, including variable pharmacokinetics and pharmacodynamics, leading to
frequent under- or overdosing. Heparins also secondarily (and perhaps paradoxically) activate platelets and bind
nonspecifically to other proteins, including platelet factor 4, which may result in heparin-induced thrombocytopenia. In
contrast, bivalirudin is a small (20-amino-acid)-molecule direct thrombin (factor II) inhibitor, which has a more
predictable pharmacokinetic and pharmacodynamic profile, has a shorter half-life (25 min vs. 60e90 min for UFH and
4 h or more for LMWH), has intrinsic antiplatelet activity, and does not cause thrombocytopenia, providing an alternative with a number of theoretical advantages over UFH [61].
Observational data from the mid-1990s reported reduced bleeding and ischemic complicat ions with bivalirudin
compared with UFH [62,63]. Subsequent randomized trials in ACS patients, in both NSTE-ACS (ACUITY and ISARREACT 4) and STEMI (HORIZONS-AMI), in which bivalirudin was co mpa red with UFH plus GPI, demo nstr ated
reduced bleeding and thrombocytopenia with comparable MACE with bivalirudin, with lower all-cause mortality [64].
However, with the advent of potent oral P2Y
receptor inhibitors, GPIs are less frequently used in Europe, and the
12
bleeding advantage with bivalirudin versus UFH alone is probably of lesser magnitude than with bivalirudin versus UFH
plus GPI. Moreover , because of its short half-life, stopping bivalirudin at the end of the PCI pro ced ur e was associated
with an approximate 1% increase in acute (<24 h) ste nt thromb osis in patie nts wit h STEMI in the HORIZONS- AMI
trial, although mortality was reduced at 30 days with bivalirudin (2.1% vs. 3.1%, P ¼ .04), a difference that persisted
to 3 years [65]. An increase in acute stent thrombosis after discontinuation of bivalirudin has not been observed in
NSTE-ACS.
Several additional studies have ignited a debate around bivalirudin use. HEAT-PPCI (Unfractionated Heparin vs.
Bivalirudin in Primary Percutaneous Coronary Intervention) [66] was a single-center UK trial comparing heparin only
versus bivalirudin in consecutive STEMI patients undergoing PPCI. Unlike all other bivalirudin trials, bleeding was
not decreased with bivalirudin in this trial, and the overall efficacy outcome favored UFH because of more reinfarctions
(2.7% vs. 0.9%, P ¼ .004) and stent thromboses (3.4% vs. 0.9%, P ¼ .001) with bivalirudin. However, the duration of
bivalirudin use was very short and the activated clotting time with bivalirudin was low compared with other studies,
questioning the generalizability of the findings from this study. Following publication of HEAT-PPCI and the discussions
that followed, bivalirudin use in the United Kingdom dropped dramatically and it is no longer in routine use in the majority
of interventional centers. Most interventional cardiologists have adopted UFH for PPCI therapy with a GPI use of
approximately 15% as observed within the trial itself.
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