Antithrombotic Therapies in Acute Coronary Syndrome

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Antithrombotic Therapies in
Acute Coronary Syndrome
By Steven P. Dunn, Pharm.D., FAHA, BCPS-AQ Cardiology; and Hasan Kazmi, Pharm.D., BCPS
Reviewed by Paul P. Dobesh, Pharm.D., FCCP, BCPS-AQ Cardiology; and Ola Adejuwon, Pharm.D., BCPS, BCCCP, BCNSP
1. Distinguish the types of myocardial infarction that can occur in critically ill patients.
2. Evaluate the acute use of antiplatelet and anticoagulant therapies for patients with ischemic heart disease.
3. Develop appropriate management of chronic antithrombotic pharmacotherapies for ischemic heart disease in critically
ill patients.
4.Demonstrate appropriate management of antithrombotic toxicities and adverse effects in patients with ischemic
heart disease.
ACS Acute coronary syndrome
BMS Bare metal stent
CABG Coronary artery bypass grafting
DAPT Dual antiplatelet therapy
DES Drug-eluting stent
GPI Glycoprotein IIb/IIIa inhibitor
NSTE ACS Non–ST-segment elevation acute
coronary syndrome
PCI Percutaneous coronary
STEMI ST-segment elevation myocardial
UA Unstable angina
UFH Unfractionated heparin
Table of other common abbreviations.
CCSAP 2017 Book 1 • Cardiology Critical Care
Acute coronary syndrome (ACS) continues to contribute to the significant morbidity and mortality related to cardiac disease, which
remains the leading cause of death in the United States. About 15.5
million Americans have coronary heart disease with over 900,000
coronary events each year, which accrue over $200 billion in direct
and indirect costs (Mozaffarian 2016). Endogenous thrombosis
pathways, including activation of the clotting cascade and platelet
aggregation, are a key component of the pathophysiology of ACS.
Specifically, platelets serve critical roles as “first responders” to
injured vascular endothelium by interacting with subendothelial constituents, leading to platelet adhesion, activation, and aggregation
and resulting in platelet-mediated thrombosis. Platelet activation
also promotes inflammatory cytokine release as well as clotting
cascade activation, which often initiates and accelerates hemodynamically significant clot formation within the coronary lumen.
Therefore, optimal inhibition of thrombosis is paramount in the treatment of ACS. Acute coronary syndrome is recognized as a spectrum
of disease, including unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation
myocardial infarction (STEMI), but appropriate inhibition of thrombosis is indicated in all phases of ACS.
Recognizing ACS events in critically ill patients is complicated
for many different reasons. These may include ECG monitoring,
which is less sensitive and specific; lack of patient responsiveness
Antithrombotic Therapies in Acute Coronary Syndrome
to ischemic chest pain as the result of continuous analgesia
or altered mental status; and complications of myocardial
infarction (MI), such as arrhythmia or hypotension, which are
relatively nonspecific in a critically ill patient with a broad differential diagnosis (Klouche 2014).
Objective markers of myocardial necrosis, such as cardiac biomarkers, are also difficult to interpret in critically
ill patients. Plasma troponin concentration, a standard for
the diagnosis of MI, is unreliable in critically ill patients
because of the assay’s extreme sensitivity in distinguishing
myocardial ischemia caused by coronary thrombosis from
a wide range of pathologies. More than 60% of critically ill
patients may have a detectable plasma troponin concentration (Hamilton 2012). Transient cardiac biomarkers in
critically ill patients can greatly confuse the specific diagnosis and cause harm from misapplied therapies. For example,
one group of investigators identified that of 171 patients
admitted to an ICU, 42.1% had elevated troponin I concentrations, but only 22.2% of all patients had an MI (Lim 2006).
To this end, key stakeholders from leading cardiovascular
societies in the United States and worldwide have developed
a universal definition of MI to delineate the specific causes
of myocardial ischemia, which is now in its third iteration
(Table 1-1).
A critically ill patient population appears likely to have
a high prevalence of type 2 infarcts, or infarcts related to a
disruption between myocardial oxygen supply and demand,
usually because of concomitant illness or medical stress
(Ammann 2003; Lee 2015). Antithrombotic therapy is unlikely
to be of significant value in these patients, and care to ensure
the appropriate source of ischemia is paramount among the
medical professionals caring for the patient. The gold standard diagnosis of myocardial ischemia related to coronary
thrombosis remains cardiac catheterization. However, catheterization may not be feasible in critically ill patients for
reasons such as instability and bleeding risk, which makes
the actual diagnosis significantly more difficult to ascertain.
Identifying the source of myocardial ischemia before applying treatment, likely in consultation with a cardiologist, is vital
to achieving optimal outcomes.
Readers of this chapter are presumed to be familiar
with the following:
• General treatments and approaches to the
management of acute coronary syndrome
• Coronary and cardiac anatomy and physiology
Patients with ACS of suspected coronary thrombotic origin
need urgent evaluation and management of their ischemia.
In particular, patients with STEMI need immediate reperfusion. Earlier reperfusion has been associated with improved
clinical outcomes, including surrogate markers of myocardial perfusion, reinfarction, and mortality; early reperfusion is
recommended in the current guidelines (Fibrinolytic Therapy
Trialists’ (FTT) Collaborative Group 1994; O’Gara 2013). Various
modalities to treat ACS have evolved, prioritizing early and
effective reperfusion. Common reperfusion strategies include
fibrinolysis, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG) surgery. These are termed
an early invasive strategy in the guidelines. If an early invasive
strategy is not pursued, an ischemia-guided strategy is indicated (Amsterdam 2014).
The specific interaction between the reperfusion strategy
and the optimal antithrombotic therapy depends on the overarching treatment strategy used and the diagnosis of STEMI
compared with non–ST-segment elevation acute coronary
syndrome (NSTE ACS) (Figure 1-1). Treatment may be different
depending whether the patient is in the pre-, peri-, or postprocedural stage of care. When the time of initial presentation
to the time of revascularization is very short (e.g., primary PCI
for STEMI), there is little to no distinction between pre- and
peri-procedural management. However, other scenarios may
have distinct periods of pre- versus peri-procedural management (e.g., PCI for NSTE ACS).
• Pharmacologic properties of various anticoagulant
and antiplatelet therapies
Table of common laboratory reference values.
• O’Gara PT, Kushner FG, Ascheim DD, et al. 2013
ACCF/AHA guideline for the management of
ST-elevation myocardial infarction: a report of the
American College of Cardiology Foundation/
American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol
• Amsterdam EA, Wenger NK, Brindis RG, et al. 2014
AHA/ACC Guideline for the Management of
Patients with Non-ST-Elevation Acute Coronary
Syndromes: a report of the American College of
Cardiology/American Heart Association Task Force
on Practice Guidelines. J Am Coll Cardiol
• Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA
Guideline Focused Update on Duration of Dual
Antiplatelet Therapy in Patients With Coronary
Artery Disease: a report of the American College of
Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines. J Am Coll Cardiol
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-1. Universal Definition of MI and Antithrombotic Therapies
Considerations for
Antithrombotic Therapies
Spontaneous MI: Related to coronary plaque rupture, ulceration, or erosion
leading to thrombus formation and subtotal or total coronary occlusion
Indicated by guidelines
Ischemic imbalance: Myocardial necrosis from a condition other than coronary artery
disease contributed to an imbalance between myocardial oxygen supply and demand
Not indicated and may be harmful in
some scenarios
Sudden death: Patients with ECG changes and symptoms of myocardial ischemia but
unable to confirm biomarkers because the patient died
Procedural infarction: Related to thrombosis induced by PCI (type 4a) and stent
thrombosis (type 4b)
Possible benefit
Cardiac surgery infarction: Infarction related to cardiac bypass grafting surgery
Possible benefit-risk from surgical
MI = myocardial infarction; N/A = not applicable; PCI = percutaneous coronary intervention.
Information from Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation
Acute Coronary
(urgent revascularization)
Primary PCI
Rescue PCI
• DAPT to facilitate
(aspirin and
• Anticoagulation to
fondaparinux, or
• Pre-procedure or
therapy (aspirin plus
either oral P2Y12
inhibitors, cangrelor, or
GP llb/llla inhibitors)
• Intra-procedure
(bivalirudin or heparin)
• Post-procedure DAPT
Delayed PCI or
• Pre-procedure or
antiplatelet therapy
(aspirin plus either
oral P2Y12 inhibitors,
cangrelor, or GP Ilb/
llla inhibitors)
• Intra-procedure
(bivalirudin, enoxaparin,
or heparin)
• Post-procedure DAPT
• Offset of antiplatelet
and anticoagulant
therapy for surgery
• Pre-procedure or
antiplatelet therapy
(delayed PCI)
• Intra-procedure
• Post-procedure DAPT
(delayed PCI)
• DAPT unless
• Anticoagulation for
specified duration (at
least 48 hours) unless
Figure 1-1. Antiplatelet and antithrombotic therapy for acute coronary syndrome. This figure depicts general
recommendations for the two major strata of acute coronary syndrome regarding antiplatelet and antithrombotic
therapy. Usefulness and duration of antiplatelet therapy depend greatly on the modality of reperfusion and whether an
ischemia-guided strategy is chosen.
CABG = coronary artery bypass grafting; DAPT = dual antiplatelet therapy; NSTE ACS = non–ST-segment elevation acute coronary
syndrome; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction.
Information from: Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with NonST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol 2014;64:e139-228; and O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline
for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
with placebo. In addition, 30-day mortality was reduced with
DAPT (Sabatine 2005). No data exist with newer P2Y12 inhibitors for fibrinolytic therapy. Therefore, the choice of P2Y12
inhibitor for fibrinolysis should be limited to clopidogrel at a
loading dose of 300 mg, followed by 75 mg daily; patients older
than 75 should receive 75 mg daily only because of their exclusion in CLARITY and concern for greater risk of bleeding.
Fibrinolysis was the initial reperfusion strategy for STEMI,
which consisted of administering a fibrinolytic agent to
reestablish coronary perfusion. Its benefits in reducing morbidity and mortality in patients with STEMI when given within
12 hours of symptom onset are well established (Fibrinolytic
Therapy Trialists’ (FTT) Collaborative Group 1994; Pinto
2011). Until the advent of PCI, fibrinolysis was the most common approach to early reperfusion for patients with STEMI.
Percutaneous coronary intervention is superior to fibrinolysis if reperfusion can be attained within 120 minutes from
first medical contact (Huynh 2009; Keeley 2003; Pinto 2011).
Thus, fibrinolysis is now generally reserved for patients with
STEMI presenting to hospitals without PCI capabilities who
cannot be transferred to another PCI-capable hospital within
120 minutes from first medical contact. These patients are
often transported to a PCI-capable facility after fibrinolysis to
undergo angiography for evaluation of reperfusion success
and evaluation of the coronary anatomy, generally before hospital discharge. After fibrinolysis, if patients have cardiogenic
shock or acute heart failure or if reperfusion has failed (lack
of major ST resolution and absence of reperfusion arrhythmias), guidelines recommend urgent transfer for rescue PCI
(O’Gara 2013). Absolute and relative contraindications to fibrinolysis in MI are listed in Table 1-2. Critically ill patients may
be more likely than most populations to have these complicating issues.
Antithrombotic therapy plays an important role in facilitating and sustaining reperfusion in patients receiving
fibrinolytic therapy for STEMI. The guidelines recommend
unfractionated heparin (UFH), enoxaparin, or fondaparinux
(O’Gara 2013). Compared with UFH, enoxaparin decreases the
recurrence of MI and urgent revascularization, but possibly at
the cost of increased nonfatal major bleeding (Antman 1999).
Although the net clinical benefit favors the use of enoxaparin,
individual patients should be considered to weigh the risks of
bleeding versus the ischemic benefits. Although the guidelines prefer no particular anticoagulant, fondaparinux should
be used with caution in this setting. Despite data showing
improved outcomes in patients receiving fibrinolysis alone,
patients who subsequently undergo PCI may have worse procedural outcomes and are at risk of catheter thrombosis if not
given another anticoagulant at the time of PCI (see section on
peri-procedural anticoagulation that follows) (Yusuf 2006).
Dual antiplatelet therapy (DAPT) is also indicated for
patients receiving fibrinolytic therapy for STEMI. Aspirin
reduced vascular mortality in combination with streptokinase
in the ISIS-2 trial (ISIS-2 Collaborative Group 1988). In CLARITY,
use of clopidogrel in addition to aspirin and standard fibrinolytic therapy was associated with greater arterial patency and
reduced 30-day adverse cardiovascular outcomes compared
CCSAP 2017 Book 1 • Cardiology Critical Care
Primary PCI
Having shown superiority to fibrinolysis in achieving arterial
patency and mortality, PCI is now the preferred modality for the
treatment of STEMI, with a goal of achieving coronary reperfusion within 90 minutes of institutional presentation (Keeley
2003; O’Gara 2013). Percutaneous coronary intervention techniques have evolved over the past 2 decades, starting with
balloon angioplasty alone, progressing to bare metal stents
(BMS), and now in the current era of drug-eluting stents (DES).
The choice of using BMS versus DES often depends on various interventional factors and the ability to continue prolonged
DAPT. However, DES are generally considered superior because
of their reduced risk of in-stent restenosis. Another significant
advancement in cardiac catheterization is the choice of access
site. Traditionally, the coronary vessels have been accessed by
the femoral artery because of ease of access. However, radial
artery access has gained popularity because of the lower and
less consequential risks associated with bleeding episodes,
given that the radial artery is more compressible and bleeding is more easily attenuated. In the United States, adoption
of radial artery access has increased from 2% in 2008 to 16%
in 2012 (Feldman 2013). A radial approach decreases not only
major bleeding but also mortality (Valgimigli 2015b; Ferrante
2016)). This has important implications because it affects the
interpretation of bleeding outcomes when comparing various
antithrombotic regimens in studies of patients undergoing PCI.
Pre-procedural antithrombotic therapy is largely used with
the goals of successful clot stabilization and facilitation of
intra-procedural success. Aspirin therapy (81–325 mg) is the
recommended initial treatment for all phases of ACS, including
STEMI, as well as before cardiac catheterization (Amsterdam
2014). This provides a baseline level of platelet inhibition and
generally has been included as part of PCI procedures since
their inception. In critically ill patients, non–enteric-coated
aspirin products, ideally crushed, are recommended either
orally or through feeding tubes because of their superior onset
of action. If oral access is not available, aspirin suppositories can be considered, though they are less preferable, given
the significant delay (up to 4 hours) in onset of action compared with crushed oral dosage forms. Using pre-procedural
P2Y12 inhibition to more completely inhibit platelet-driven
thrombosis is controversial. Although this “preloading” is
generally thought to facilitate PCI efficacy and is guideline
recommended, the superiority of earlier P2Y12 inhibition has
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-2. Absolute and Relative Contraindications to Fibrinolysis in STEMI
Absolute Contraindications
Time Interval
Prior intracerebral hemorrhage
Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Prior ischemic stroke
Previous 3 mo
Suspected aortic dissection
Can be ruled out with
ED imaging studies
Active bleeding or bleeding diathesis
Significant closed-head or facial trauma
Previous 3 mo
Intracranial or intraspinal surgery
Previous 2 mo
Prior receipt of streptokinase
Previous 6 moa
Relative Contraindications
Time Interval
History of chronic, severe, poorly controlled hypertension
Hypertension on presentation (SBP > 180 mm Hg or DBP > 110 mm Hg)
Known other intracranial pathology not covered in absolute contraindications
Traumatic or prolonged (> 10 min) CPR
Major surgery
Previous 3 wk
Recent internal bleeding
Previous 2–4 wk
Noncompressible vascular punctures
Active peptic ulcer
Oral anticoagulant therapy at presentation
With planned readministration of streptokinase.
CPR = cardiopulmonary resuscitation; DBP = diastolic blood pressure; SBP = systolic blood pressure.
Information from: O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation
myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
not been conclusively proven by a well-designed trial, even
with use of a faster-acting oral P2Y12 inhibitor. Cangrelor, an
intravenous P2Y12 inhibitor with rapid onset and a significantly shortened half-life, is an attractive alternative to oral
agents in the pre-procedural STEMI setting. Unfortunately,
all evidence to date for cangrelor has focused on the intraand post-procedural settings. In addition, recovery of platelet
function after receiving oral P2Y12 inhibitor therapy occurs
over a minimum of several days, regardless of drug choice.
This presents challenges if the patient requires urgent surgical revascularization because performing surgery under the
exposure of these agents increases surgical complications.
CCSAP 2017 Book 1 • Cardiology Critical Care
However, patients with STEMI rarely (less than 5% of cases)
undergo surgical revascularization (Gu 2010). Gastric access
is required for P2Y12 inhibitors; no experience with alternative
dosage forms exists, though crushed dosage forms appear
to confer faster pharmacodynamic onset, leading to reduced
platelet reactivity compared with whole tablets as soon as 30
minutes post-dose with prasugrel (Rollini 2016).
Patients with STEMI undergoing primary PCI also benefit from anticoagulant therapy, though given the very short
goal interval between presentation and coronary reperfusion,
most of these therapies are relegated to the intra-procedural setting. However, systems of care may be developed to
Antithrombotic Therapies in Acute Coronary Syndrome
transition some intra-procedural therapies to be given in the
pre-procedural setting so that the catheterization team can
focus on site access and coronary reperfusion.
in patients with NSTE ACS receiving anticoagulation either
while waiting for PCI or while receiving ischemia-guided therapy only (Table 1-3).
Anticoagulant therapy for intra-procedural cardiac catheterization has evolved considerably in the past 2 decades.
Historically, UFH was the agent used in conjunction with
glycoprotein IIb/IIIa inhibitors (GPIs); it typically has been given
as an intravenous bolus with potential repeat intravenous
bolus doses to achieve target activated clotting time (ACT)
goals. However, the introduction of bivalirudin has shifted this
paradigm, with much controversy over which agent is better
Almost all patients with STEMI (more than 95%) undergo PCI
for rapid revascularization (Gogo 2007; Gu 2010). Introducing
a catheter into the coronary arteries can be highly thrombogenic and requires aggressive adjunctive antithrombotic
treatment. As such, drug selection, dosing, and routes of
administration can vary considerably compared with those
Table 1-3. Pharmacologic Properties and Dosing of Anticoagulants Used in ACS
of Action
AT-mediated inhibition of
factors II and X
AT-mediated inhibition of
factors X > II
AT-mediated inhibition
of factor X
Direct thrombin (II)
Fibrinolysis, NSTE ACS, or
ischemia-guided therapy:
• 60 unit/kg bolus (max
4000 units) + 12 units/
kg/hr infusion (initial
max 1000 units/hr),
titrated to therapeutic
aPTT for 48 hr or until
• ≤ 75 yr: 30 mg IV bolus, then 15 min
later 1 mg/kg SC q12hr (max 100 mg
for first two doses, give first dose with
initial IV dose)
• >75 yr : No bolus, 0.75 mg/kg SC q12 hr
(max 75 mg for first two doses)
• CrCl < 30 mL/min/1.73 m2: 30 mg
IV bolus (omit if > 75 yr) and 1 mg/kg
SC q24hr (give first dose with initial
IV dose with max of 100 mg)
• Duration is for index hospitalization up
to 8 days, or until revascularization
• 2.5 mg IV x 1, then
2.5 mg SC daily starting
the next day for index
hospitalization up
to 8 days, or until
• 0.15–2 mg/kg/hr
infusion, titrated
to aPTT goal
• 0.75 mg/kg IV
bolus + 1.75 mg/
kg/hr infusion
PCI with planned GPI:
• 50–70 units/kg IV bolus
to achieve therapeutic
PCI without planned GPI:
• 70–100 units/kg
IV bolus to achieve
therapeutic ACT
NSTE ACS/ischemia-guided therapy :
1 mg/kg SC q12hr for duration of
hospitalization or until revascularization
Primary PCI:
• 0.5–0.75 mg/kg IV bolus if no
anticoagulation previously
0.3 mg/kg IV if last SC dose was > 8 hr
before PCI, or only one SC dose given
NSTE ACS/ischemiaguided therapy :
• 2.5 mg SC daily
for duration of
hospitalization or until
• Not recommended
without additional
anticoagulant with
anti-II activity
aPTT, anti-Xa, and/or ACT
(200–250 s during PCI
with GPI or 250–300 s
without GPI), Hgb, Hct, Plt
Renal function, Hgb, Hct, Plt, anti-Xa
(as indicated)
Renal function, Hgb, Hct
PTT and/or ACT
as indicated, renal
function, Hgb, Hct
IV : Immediate
SC: 2 hr
IV: Immediate
SC: 2 hr
1–2 hr
IV : 6 hr
SC: 12 hr (longer with renal dysfunction)
17–21 hr (longer with
renal dysfunction)
1–3 hr based on
renal function
ACS = acute coronary syndrome; ACT = activated clotting time; aPTT = activated PTT; anti-Xa = anti-factor Xa; AT = antithrombin; GPI =
glycoprotein IIb/IIIa inhibitor; IV = intravenous(ly); NSTE ACS = non–ST-segment elevation acute coronary syndrome; PCI = percutaneous
coronary intervention; q = every; SC = subcutaneous(ly); UFH = unfractionated heparin.
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-4. Landmark Studies Comparing Bivalirudin with UFH for PCI
Pertinent Baseline
End Points
Incl.: NSTE
Three arms:
1) UFH or
2) Bivalirudin +
3) Bivalirudin
alone ±
bailout GPIIb/
• Composite of death,
MI, unplanned
• Major bleeding
• Net benefit (composite
+ major bleeding)
UA 41%
PCI 55%
ASA 98%,
clopidogrel 63%
Radial access:
Arm 1: 47% UFH,
47% enoxaparin
• Arm 2 vs. 1: noninferior in
composite, major bleeding, and
net clinical outcome
• Arm 3 vs. 1: noninferior in
composite; superior in bleeding
(3.0% vs. 5.7%, RR 0.53, p<0.001)
and net clinical outcome (10.1%
vs. 11.7%, RR 0.86, p=0.015)
Excl: NSTE
Two arms:
1) UFH +
universal GPI
2) Bivalirudin +
• Major bleeding
• Net adverse clinical
events (major bleeding
or MACE)
GPI use in 7.2% of
bivalirudin arm,
clopidogrel 98%
• Major bleeding: bivalirudin 4.9%
vs. 8.3%, RR 0.60 (p<0.002)
• Net events: 9.2% vs. 12.1%, RR
0.76 (p=0.005)
• All-cause mortality: 2.1% vs. 3.1%,
RR 0.66 (p=0.047)
• Acute stent thrombosis: 1.3% vs.
0.3%, RR 4.3 (p<0.001)
4 (2011)
with definite
planned PCI
Excl: STEMI,
Two arms:
1) UFH +
2) Bivalirudin
• Composite of death,
large recurrent MI,
urgent TVR, major
30-day bleeding
• Major bleeding
88% DES
99% femoral access
• No difference in composite
• Major bleeding UFH 4.6% vs.
2.6%, RR 1.84 (p=0.02)
Excl: NSTE
Two arms:
1) Bivalirudin +
GPI+ post PCI
bivalirudin x
4 hr
2) UFH/
+ provisional
• Composite: death
or major non-CABG
• Net events (MACE +
non-CABG bleeding)
Clopidogrel 40%,
prasugrel 30%,
ticagrelor 30%
UFH 90%,
enoxaparin 8.5%
GPI use: 11.5% vs. 69%
Radial access: 46%
• Composite: bivalirudin 5.1% vs.
8.5%, RR 0.60 (p=0.001)
• MACE: 6.0% vs. 5.5%, RR 1.09
• Net events: 6.6% vs. 9.2%, RR
0.72 (p=0.02)
• Major bleeding: 2.6% vs. 6.0%,
RR 0.43 (p<0.001)
• Acute stent thrombosis: 1.1% vs.
0.2%, RR 6.11 (p=0.007)
Two arms:
1) Bivalirudin
GPI allowed)
2) UFH
GPI allowed)
• MACE (death, CVA,
reinfarction, unplanned
• Major bleeding
Clopidogrel 11%,
prasugrel 28%,
ticagrelor 62%
Radial access 80%
GPI: UFH group 15% vs.
bivalirudin group 13%
• MACE: Bivalirudin 8.7% vs. 5.7%,
RR 1.54 (p=0.01)
• Major bleeding: 3.5% vs. 3.1%
Two arms:
1) Bivalirudin
+ prasugrel
GPI allowed)
2) UFH +
GPI allowed)
• Composite: death,
MI, unplanned
revascularization, stent
thrombosis, stroke,
major bleeding
Trial stopped early for
low recruitment
GPI use: Bivalirudin
3.0 % vs. UFH 6.1%
Femoral access: 99%
• Composite: Bivalirudin 15.6% vs.
14.5% (p=0.680)
• Bleeding: 14.1% vs. 12.0%
(Continued )
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-4. (Continued)
Pertinent Baseline
End Points
Two arms:
• MACE: Composite of
1) Bivalirudin +
all-cause death, MI,
stroke up to 30 days
GPI (group
• Net events: Major
non-CABG bleeding +
randomized to
MACE up to 30 days
receive post
• Post-PCI infusion
PCI bivalirudin
outcome: Composite
x 4 hr vs.
of urgent TVR,
definite stent
2) UFH +
thrombosis, or net
adverse clinical events
up to 30 days
Clopidogrel 46%,
prasugrel 24%,
ticagrelor 13%
GPI use: 4.6% vs. 26%
Radial access: 50%
• MACE: bivalirudin 10.3% vs.
10.9% (p=0.44, note: UFH +
planned GPI rate was 8.1%)
• Net events: 11.2% vs. 12.4%
(p=0.12, note: UFH + planned
GPI rate was 10.6%)
• Post PCI infusion: infusion
11.0% vs. no infusion 11.9%
• Major bleeding: 1.4% vs. 2.5%,
RR 0.55 (p<0.001)
• Death: 1.7% vs. 2.3%, RR 0.71
Excl: Prior
Three arms:
1) Bivalirudin +
post PCI
infusion (30
min – 4 hr)
2) UFH
3) UFH +
Clopidogrel 100%
Radial access 78.5%
• Arm 1 vs. 2: 8.8% vs. 13.2%, RR
0.67 (p=0.008)
• Arm 1 vs. 3: 8.8% vs. 17.0%, RR
0.52 (p<0.001)
• No differences in MACE
• Bleeding: 4.1% vs. 7.5% vs.
12.3% (p<0.001)
• Net events: MACE + or
any bleeding
• Any bleeding
CABG = coronary artery bypass grafting; DES = drug-eluting stent; UA = unstable angina.
(Table 1-4). Each agent has drug-specific characteristics that
may influence its use. Although rare, heparin carries a risk
of heparin-induced thrombocytopenia (HIT) in 0.1%–5% of
patients. Bivalirudin has more consistent anticoagulant effects
and, unlike UFH, can bind clot-bound thrombin, an important
substrate for platelet activation and fibrin formation. Therefore,
bivalirudin would be expected to inhibit a larger pool of thrombin compared to UFH. However, it requires a continuous infusion
intra-procedurally, needs dose-adjustment for renal dysfunction, and is significantly more expensive than UFH.
Bivalirudin and UFH are two of the most extensively studied
adjunctive anticoagulants for primary PCI. The HORIZONS-AMI
study with bivalirudin established efficacy and safety in PCI
therapy in patients with STEMI, which showed bivalirudin to be
noninferior to UFH with respect to ischemic outcomes (despite
an increase in acute stent thrombosis) while reducing major
bleeding outcomes (Stone 2008). Because HORIZONS-AMI
is almost a decade old, clinicians have questioned whether
its results are still valid. Percutaneous coronary intervention
treatments have rapidly evolved over the past 15 years, potentially affecting the study’s applicability to current practices.
Some important variables to consider when comparing studies include the types of stents used, radial versus femoral
access, use of GPIs, and use, choice, and dosage of P2Y12 inhibitors. Some recent studies using contemporary PCI practices
CCSAP 2017 Book 1 • Cardiology Critical Care
have provided similar results to HORIZONS-AMI (see Table 1-3)
(Kastrati 2011; Valgimigli 2015a; Steg 2013; Han 2015).
In contrast, other recent studies have challenged the superiority of bivalirudin over UFH, causing much debate. The
HEAT-PPCI (n=1812) trial compared bivalirudin with UFH with
provisional GPI use for either arm in patients with STEMI undergoing primary PCI (Shahzad 2014). Most patients received
ticagrelor (62%) or prasugrel (28%), and 81% had a radial artery
approach. The groups had similar GPI use (13% vs. 15%). The
outcomes differed from previous studies in that ischemic
events were more common with bivalirudin (8.7% vs. 5.7%,
RR 1.54, p=0.01), and the incidence of major bleeding did not
differ between the two groups, possibly because of the more
stringent bleeding definition used in the trial. Although previous studies with bivalirudin in subsets of troponin-positive
patients have trended toward worse outcomes compared with
heparin plus GPI (Stone 2006; Kastrati 2011), this study defied
the prevalent view that bivalirudin is superior in PCI. Possible
reasons for the discordant results include low use of GPIs (possibly because of the high use of newer P2Y12 inhibitors) and
more access by the radial artery.
However, other contemporary studies with similar patient
populations argue that bivalirudin continues to decrease
bleeding (Steg 2013; Han 2015; Valgimigli 2015a). The BRAVE-4
Antithrombotic Therapies in Acute Coronary Syndrome
compared bivalirudin plus prasugrel with UFH plus clopidogrel
in patients with STEMI undergoing PCI. The study was terminated early because of slow recruitment (n=548 of planned
1240). All patients underwent femoral arterial access, and GPI
use was low (3% vs. 6%). The study was unable to show differences in ischemic or bleeding outcomes, although it was
underpowered. These newer data challenge the idea that
bivalirudin improves patient outcomes. However, newer practices such as use of radial access and decreased GPI, as well
as newer P2Y12 inhibitor use may lead to outcomes with UFH to
be more similar to those of bivalirudin and provide an overall
more attractive and cost-effective treatment.
Other options for anticoagulation in the PCI setting include
enoxaparin and fondaparinux. Enoxaparin dosing is different
for patients with STEMI, who are generally taken emergently to
the catheterization laboratory (see Table 1-3). Data describing
this strategy used a high rate of radial artery access. Thus, the
safety outcomes of enoxaparin in patients with STEMI receiving
PCI with femoral artery access are less well known. Otherwise,
considerations for enoxaparin are the same as previously
described. Fondaparinux has also been compared with UFH
in patients with STEMI, with no difference in overall outcomes
(Yusuf 2006). However, there was an increase in guidewire catheter thrombosis, which led the STEMI guidelines to recommend
against fondaparinux as a sole agent in PCI (O’Gara 2013).
Intra-procedural antiplatelet therapy is also important to
ensure successful PCI outcomes. Historically, this has been
accomplished rapidly and completely with the use of GPIs,
which prevent platelet aggregation and significantly attenuate platelet-driven thrombosis (Table 1-5). Typical regimens
Table 1-5. Pharmacologic Properties of Antiplatelet Therapy Used for ACS
of Action
162–325 mg
(acute); 81–325
mg (chronic)
of ACS (all
A2 production
phases) and
~1–2 hr;
~5 days
gastric adverse
20 min if
effects, allergic
renal excretion
Platelet turnover
– irreversibly
of stent
binds to
300–600 mg
P2Y12 inhibitor
of ACS (all
(acute); 75 mg
– requires
phases) and
daily (chronic)
to active
of stent
(600 mg)
Platelet turnover ~5–7 days
– irreversibly
binds to
~6 hr
(300 mg)
~3–5 days
~2 hr
(75 mg daily)
60 mg (acute);
Reduce to
~30 min
Platelet turnover ~5–10 days
P2Y12 inhibitor
of ACS
10 mg daily
5 mg daily if
– irreversibly
– requires
binds to
with PCI,
< 60 kg
to active
of stent
P2Y12 inhibitor
Treatment of
ACS with or
180 mg (acute); 90 Avoid use in
mg BID (chronic)
without PCI;
~30 min
Hepatic by
severe hepatic
uric acid
with strong
of stent
~3–5 days
(Continued )
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-5. (Continued)
of Action
P2Y12 inhibitor
PCI: 30 mcg/kg IV
2 min (bolus)
~1 hr
bolus, 4 mcg/kg/
therapy for
min infusion for
at least 2 hr
Bridge to surgery:
0.75 mcg/kg/min
Eptifibatide GPI
180 mcg/kg IV
Reduce infusion
bolus (max 22.6
to 1 mcg/kg/
therapy for
mg) x 2 for PCI,
min if CrCl
followed by 2
< 50 mL/min;
(max 15 mg/
Bleeding, Plt
Primarily renal
~4–8 hr
Primary renal
~4–8 hr
12–24 hr
hr) infusion for
18-24 hr (operator
25 mcg/kg
Reduce to 0.075
IV bolus followed
mcg/kg/min if
therapy for
by 0.15 mcg/kg/
CrCl < 60 mL/
min for 18–24
Bleeding, Plt
hr (operator
0.25 mg/kg IV/IC
bolus, followed
therapy for
by 0.125 mcg/
kg/min (max 10
Bleeding, Plt
mcg/min) for
12 hr
BID = twice daily; ESRD = end-stage renal disease.
include an intravenous bolus at the time of PCI and a postprocedural course to prevent acute stent thrombosis and
allow for oral P2Y12 inhibitor onset. Recently, the advent of
high-dose bivalirudin and more rapidly acting oral P2Y12
inhibitors has largely supplanted the routine use of procedural GPI through improved safety indices. Today, much GPI
use is therefore through so-called “bailout” (i.e., non-planned
use), though this approach has not been prospectively evaluated. These uses are largely procedural phenomena such as
slow-reflow of an occluded coronary artery (implying distal
or microvascular occlusion), high-risk interventions, or large
clot burden at the operator’s discretion.
Continuous intravenous cangrelor during PCI offers an
attractive alternative to pre-procedural (or later) P2Y12 inhibitor
preloading as a reversible and short-acting P2Y12 inhibitor. In
the CHAMPION-PHOENIX trial, intravenous cangrelor reduced
CCSAP 2017 Book 1 • Cardiology Critical Care
a composite end point of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours compared with
clopidogrel (4.7% vs. 5.9%, p=0.005), the benefit for which persisted up to 30 days post-procedure (Table 1-6) (Bhatt 2013).
Cangrelor also reduced procedural thrombotic events, including stent thrombosis, compared with clopidogrel when both
therapies were given at the time of PCI. Various bleeding indices were also increased with cangrelor relative to clopidogrel,
some of which were statistically different. Of importance,
intravenous cangrelor must be carefully transitioned to an
oral P2Y12 inhibitor. There is a competitive pharmacodynamic
interaction such that thienopyridine P2Y12 inhibitors must be
given after cangrelor is discontinued and no sooner because
the active metabolite generated by these compounds is
unstable and may be metabolized before the offset of cangrelor (Steinhubl 2008). Ticagrelor may be used irrespective of
Antithrombotic Therapies in Acute Coronary Syndrome
Table 1-6. Landmark Studies of Antiplatelet Agents in ACS with PCI
1. Aspirin +
Clopidogrel 300 mg
loading dose
followed by 75 mg
daily for 3–12 mo
2. Aspirin + Placebo
• Composite: death,
nonfatal MI, stroke
• Bleeding (as
defined by trial)
~67% with ECG
Only ~36% receiving
(PCI + CABG) and
~20% receiving PCI
• Composite: Clopidogrel 9.3% vs.
11.4% (p<0.001)
• Major Bleeding (trial-defined):
Clopidogrel 3.7% vs. 2.7%
Excl: High risk
of bleeding,
age > 75
1. Clopidogrel 300 mg
followed by 75 mg
daily until at least
hospital discharge
or day 8
2. Placebo
• Composite:
occluded infarctrelated artery,
death, recurrent
• TIMI major
~47% receiving
~30% receiving LMWH
~93% received
• Composite: Clopidogrel 15.0% vs.
21.7% (p<0.001)
• TIMI major bleeding (30 days):
Clopidogrel 1.9% vs. 1.7% (p=0.80)
Excl: STEMI,
high risk of
incl oral
1. Clopidogrel 600 mg
(at least 2 hr before
PCI) + placebo and
2. Clopidogrel 600 mg
(at least 2 hr before
PCI) + abciximab
and intra-procedural
• Composite:
death, MI, urgent
target vessel
(30 day)
• TIMI major
bleeding (30 day)
~25% with prior MI
~50% receiving DES
• Composite: Abciximab 8.9% vs.
11.9% (p=0.03)
• Composite (troponin-negative):
Abciximab 4.6% vs. 4.6% (p=0.98)
• TIMI major bleeding: Abciximab
1.4 % vs. 1.4% (p=NS)
Incl: All patients
with ACS
intended for PCI
Excl: Bleeding
1. Prasugrel 60 mg
followed by 10 mg
daily x 15 mo
2. Clopidogrel 300 mg
followed by 75 mg
daily x 15 mo
• Composite: death,
MI, stroke
• TIMI major
bleeding (nonCABG related)
23% with diabetes
99% of patients
received PCI
~47% with DES
• Composite: Prasugrel 9.9% vs.
12.1% (p<0.001)
• TIMI major bleeding (non-CABG):
Prasugrel 2.4% vs. 1.8% (p=0.03)
Incl: All patients
with ACS
strong CYP3A4
1. Ticagrelor 180 mg
followed by 90 mg
BID x 12 mo
2. Clopidogrel 300–
600 mg followed
by 75 mg daily x
12 mo
• Composite: death,
MI, stroke
• Major bleeding (as
defined by trial)
~60% receiving PCI
~18% receiving DES
~4% receiving CABG
• Composite: Ticagrelor 9.8% vs.
11.7% (p<0.001)
• Mortality: Ticagrelor 4.5% vs. 5.9%
• Non-CABG TIMI major bleeding:
Ticagrelor 2.8% vs. 2.2%, p=0.03
Incl: PCI, both
elective and all
1. Cangrelor 30 mcg/
kg followed by
4 mcg/kg/min for
2 hr
2. Clopidogrel
300–600 mg
• Composite:
death, MI,
stent thrombosis
at 48 hr
• GUSTO severe
bleeding at 48 hr
~57% elective PCI
~17% STEMI
~74% received 600
mg clopidogrel
~55% received DES
• Composite: Cangrelor 4.7% vs.
5.9% (p=0.005)
• Stent thrombosis: Cangrelor 0.8%
vs. 1.4% (p=0.01)
• GUSTO severe bleeding: Cangrelor
0.2% vs. 0.1% (p=0.44)
• Any blood transfusion: Cangrelor
0.5% vs. 0.3% (p=0.16)
• ACUITY major bleeding: Cangrelor
5.2% vs. 3.1% (p<0.0001) (femoral);
1.5% vs. 0.7% (p=0.04) (radial)
End Points
LMWH = low-molecular-weight heparin.
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
cangrelor administration because of its longer half-life relative to the active metabolites of the thienopyridines.
enoxaparin, fondaparinux, and bivalirudin (see Table 1-3).
Unfractionated heparin has been shown to reduce ischemic
outcomes compared with no anticoagulant therapy, albeit
inconsistently (Oler 1996). In lower-risk patients not receiving
immediate revascularization, UFH should be continued for up
to 48 hours or until PCI is performed (Amsterdam 2014; O’Gara
Enoxaparin is an attractive anticoagulation option that
does not require routine monitoring. The SYNERGY trial
compared enoxaparin with UFH in over 10,000 patients with
NSTE ACS intended to have early invasive management
and provided some salient clinical pearls (Ferguson 2004).
Overall, enoxaparin did not reduce the rates of death and MI,
but it did increase major bleeding. However, this may have
been influenced by patients who received UFH before randomization. Subanalyses suggested that enoxaparin was
superior in patients who did not receive UFH before study
enrollment. Crossover from one agent to another worsened
efficacy and safety outcomes in both arms and should be
avoided. Some concerns with enoxaparin use include dose
adjustments in renal dysfunction and possibly patients
with morbid obesity, as well as evaluating the need for an
additional intravenous dose before PCI, depending on the
precise time when the last subcutaneous dose was given,
which may not always be known.
Two other possible anticoagulant options include
fondaparinux and bivalirudin. In OASIS-5, the synthetic polysaccharide factor Xa inhibitor, fondaparinux, at a low dose
(2.5 mg daily) was compared with enoxaparin in over 20,000
patients with NSTE ACS and showed noninferiority in ischemic outcomes while lowering major bleeding (OASIS-5
Investigators 2006). However, the greatest concern with
fondaparinux is an increase in procedural cardiac catheter
thrombosis. Guidelines recommend that if fondaparinux is
initially selected, another adjunct anticoagulation with antifactor II activity be used during PCI (O’Gara 2013). Data from
the FUTURA/OASIS-8 trial generally supports the use of
standard dose procedural unfractionated heparin (85 units/
kg or 60 units/kg if using GPI titrated to goal ACT range)
compared with lower doses of heparin (FUTURA/OASIS-8
Trial Group 2010). Bivalirudin, a direct thrombin inhibitor, is
capable of binding to both free and clot-bound thrombin.
Although it has not been formally studied in NSTE ACS outside the PCI setting, bivalirudin can be used in place of UFH
and low-molecular-weight heparin in patients with a history
of HIT.
Non–ST-segment elevation acute coronary syndromes can
be classified as UA or NSTEMI and are treated with either
an “early invasive strategy” or an “ischemia-guided strategy.” In an early invasive strategy, the decision is made to
perform coronary angiography and PCI, typically within
24 hours of hospital admission, whereas an ischemia-guided
strategy (also known as a conservative strategy or medical
management) uses optimizing medications to decrease further ischemia, reduce angina, and prevent complications of
ischemic heart disease, such as arrhythmias and myocardial
remodeling (Amsterdam 2014). Both strategies use antiplatelet and anticoagulant agents to treat ACS.
Early Invasive Strategy
Antithrombotic therapies in patients with NSTE ACS parallel therapies in patients with STEMI in many ways. Stable
patients with NSTE ACS undergoing an early invasive strategy typically do not receive an emergency PCI, in contrast to
patients with STEMI. This creates a defined pre-procedural
period in which the patient receives various antithrombotic
therapies before undergoing PCI. As with STEMI, aspirin therapy (81–325 mg) is the recommended initial treatment before
cardiac catheterization (Amsterdam 2014). The P2Y12 inhibitors are also recommended, though using pre-procedural
P2Y12 inhibition to more completely inhibit platelet-driven
thrombosis remains controversial, despite the extended preprocedural window. The superiority of earlier P2Y12 inhibition
has not been thoroughly demonstrated to be of value in clinical trials of patients with NSTE ACS (Montalescot 2014;
Steinhubl 2002). Recovery of platelet function is also a more
significant issue in NSTE ACS, regardless of drug choice,
because the presence of multivessel disease in patients
with NSTE ACS may exceed 70% of cases, though fewer than
20% will actually undergo CABG (Parikh 2010; Gogo 2007).
Regardless of the timing of P2Y12 inhibitor administration,
the guidelines state that it is reasonable to consider ticagrelor or prasugrel over clopidogrel in patients with NSTE ACS,
given their improved ischemic outcomes (Amsterdam 2014;
Wallentin 2009; Wiviott 2007). Use of intravenous antiplatelet agents such as “upstream” GPIs (i.e., pre-procedural
GPI use outside the cardiac catheterization laboratory) for
NSTE ACS should be limited, given evidence for no additional
benefit with increased bleed risk (Giugliano 2009). No data
currently exist with cangrelor in the pre-procedural setting
Patients with ACS also benefit from parenteral anticoagulant therapy up until revascularization. Options include UFH,
CCSAP 2017 Book 1 • Cardiology Critical Care
Peri-procedural management of antithrombotic therapies
in NSTE ACS is very similar to management of STEMI. All
patients should have received aspirin and possibly a P2Y12
inhibitor if preloaded before PCI. If the patient was not given
a P2Y12 inhibitor, one should be given unless angiography
identifies the need for CABG surgery. As with STEMI, GPIs are
Antithrombotic Therapies in Acute Coronary Syndrome
typically only used in a bailout setting because the perceived
need for aggressive intra-procedural antiplatelet therapy
may be diminished by P2Y12 inhibitor preloading. However,
the ISAR-REACT 2 trial, in which patients with NSTE ACS
undergoing PCI with clopidogrel preloading received either
abciximab or placebo, showed superiority in reducing
adverse cardiovascular outcomes with the planned use of
GPIs (see Table 1-6).
Anticoagulant therapy is indicated in PCI, typically at
higher doses to provide more intense antithrombotic therapy during the procedure. Options for anticoagulants include
UFH, enoxaparin, fondaparinux, and bivalirudin. If enoxaparin was chosen as the anticoagulant before PCI, it may be
used as the sole anticoagulant peri-procedurally, though the
timing of dosing needs attention. If the prior subcutaneous
dose was given 8–12 hours before PCI or only a single subcutaneous dose was given, an extra 0.3-mg/kg intravenous
dose should be given at the time of PCI (Amsterdam 2014).
Although fondaparinux is an option for NSTE ACS, its use
alone is not recommended for PCI because of a higher risk of
catheter thrombosis (OASIS-5 Investigators 2006).
Evidence for bivalirudin stems from the ACUITY study,
in which it was compared with either UFH or enoxaparin
in patients with NSTE ACS undergoing PCI (Stone 2006).
Bivalirudin showed superiority to UFH/enoxaparin for the
primary outcome, a combined bleeding/ischemic outcomes
end point. However, this was driven primarily by decreased
bleeding because ischemic outcomes were numerically
higher in bivalirudin, though still meeting a generous prespecified noninferiority margin of 25%. Of note, the major
bleeding definition was very liberal, likely affecting the
results. Newer data from ISAR-REACT 4 show decreased
bleeding with bivalirudin versus heparin with abciximab
using a more stringent definition, though it was underpowered to detect a potential worsening of ischemic outcomes
with bivalirudin (Kastrati 2011).
with MI-associated mechanical complications (e.g., ventricular septal rupture, papillary muscle rupture).
Antithrombotic therapy from the onset of ACS to surgery,
if necessary, involves balancing ischemic risks from further myocardial necrosis and complications of MI compared
to bleeding risk during surgery. Additionally, some time-allowance for testing to ensure appropriate risk stratification for
surgical candidacy is often necessary. In general, parenteral
anticoagulants are continued up until the time of surgery
with a period of offset immediately before surgery to allow
for safe incision. This strategy is not necessarily evidence
based but is commonly applied, despite no proven benefit
to the patient and possible risk. Antiplatelet bridging is
more complex, though recent drug approvals provide further
options. However, few data exist describing the risk of thrombosis in an unrevascularized patient awaiting CABG, and no
data regarding the patient populations to target. Many surgeons consider operating under the exposure of oral P2Y12
inhibitors to be contraindicated and appropriate offset commensurate with their pharmacodynamic effect is warranted
(5–7 days). However, platelet function recovery can be variable.
Some data exist with timing surgery respective to normalized
platelet function may serve to shorten the time to operation
with minimal risk of bleeding compared with the label recommendations (Mahla 2012). Another option would be the
use of continuous intravenous cangrelor. This therapy was
investigated in the BRIDGE trial, in which patients receiving
at least 72 hours of thienopyridine therapy and requiring nonemergency CABG surgery received 0.75 mcg/kg/minute or
placebo until the time of surgery (Angiolillo 2012). Patients
in the study (n=210) had no greater bleeding events than did
patients receiving placebo. Reversible GPIs (i.e., eptifibatide)
have also been used as bridging agents, though they may
be associated with a greater risk of bleeding with more prolonged use.
CABG Surgery
After PCI, most patients are monitored closely for bleeding
in an institutional setting. Current guidelines recommend
cessation of anticoagulation at the end of PCI to reduce
bleeding complications, with the exception of any compelling indications, such as recent venous thromboembolism
or hypercoagulable state, patients with mechanical valves
at high risk of thrombosis, and those requiring mechanical
circulatory support (Amsterdam 2014; Levine 2011). Smaller
studies of UFH have shown significantly increased bleeding
with continuation of heparin after PCI (Rabah 1999). However,
there has been interest in continuing bivalirudin after PCI to
try to decrease the stent thrombosis seen in the aforementioned trials. Most patients in EUROMAX received post-PCI
bivalirudin for at least 4 hours; nevertheless, there was an
increased risk of acute stent thrombosis. However, BRIGHT
continued bivalirudin as well (median duration 180 minutes),
and there was no increased risk of acute stent thrombosis in
Post-PCI Antithrombotic Therapy
Some patients with ACS will require cardiac surgery for definitive coronary revascularization. Coronary artery bypass
grafting surgery involves using an artery or vein from the
patient and creating an anastomosis from the aorta distal to
a coronary lesion in order to restore blood flow to that area of
the myocardium. Even though the CABG surgery rates have
declined recently, it remains a common approach to cardiac
revascularization (Epstein 2011). The guidelines recommend
CABG surgery over PCI in various clinical scenarios. Although
each decision is complex and patient-specific, some common indications for CABG surgery include patients with 50%
or greater stenosis of the left main coronary artery, 70% or
greater stenosis of three major coronary arteries, and 70%
or greater stenosis of the proximal left anterior descending
artery plus another major coronary artery. Coronary artery
bypass grafting surgery is also recommended in patients
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
the bivalirudin arm. Neither of these studies compared postPCI bivalirudin with a control group. The MATRIX uniquely
compared post-PCI bivalirudin with placebo but found no difference in acute stent thrombosis or bleeding between the
two arms. A possible explanation is that BRIGHT used full
PCI doses (1.75 mg/kg/hour) post-PCI, whereas EUROMAX
and MATRIX allowed for lower doses (0.25 mg/kg/hour). For
patients deemed at high risk of acute stent thrombosis who
received bivalirudin during PCI, continuing high-dose bivalirudin or using a GPI could be considered.
Antiplatelet therapy is a critical component of postprocedure success. Regardless of what specific procedure
is performed or if an ischemia-guided strategy is chosen, all
patients with ACS are recommended to receive 12 months of
DAPT (Levine 2016). This is largely to reduce the risk of recurrent MI (secondary prevention), though newer agents may
also reduce cardiovascular mortality. Patients who receive
PCI with stent placement receive more strict guidance for
minimum durations of DAPT because of the risk of in-stent
thrombosis, which likely will produce an emergency coronary
occlusion, if occurring. The minimum duration of DAPT for a
patient receiving a BMS is 1 month, though up to 12 months
is both beneficial and generally recommended. Patients postDES placement will receive a minimum of 12 months of DAPT
with a lesser recommendation to continue beyond 12 months
at the cardiologist’s discretion because some patients continue to be at risk of late in-stent thrombosis for years after
DES placement (Levine 2016). Others may be at prolonged
risk of bleeding events with lengthened treatment. To address
this disparity, the DAPT trial was the largest trial examining
the population-level recommended duration and randomized over 20,000 patients to 12 or 30 months of DAPT after
PCI (Mauri 2014). Overall, the population risk of adverse cardiovascular events was reduced with 30 months of DAPT,
whereas the rate of moderate or severe bleeding events and
mortality increased. However, the mortality increase may be
explained through excessive cancer-related mortality in the
extended-treatment arm. This suggests that some patients or
subgroups will benefit from extended therapy but that no uniform population-level recommendation can be applied.
Other studies examine short-term interruptions or premature discontinuation, like those that critically ill patients
may have because of surgery or other factors. The SENS trial
showed that of 194 patients post-DES who required discontinuation of DAPT for procedures, only 4 (2.2%) had significant
cardiovascular events (Kim 2009). Similarly, in the DATE registry, 823 patients (not including higher-risk PCI procedures)
discontinued P2Y12 inhibitor therapy after 3 months (Hahn
2010). Cardiovascular outcomes and stent thrombosis events
were less than 0.5% at 12 months. Although intriguing, further
data are needed regarding whether a short-term interruption
or premature discontinuation in a low-risk patient is safe
before any definitive recommendation can be made. The risks
to the patient (cardiovascular outcomes/events vs. bleeding)
CCSAP 2017 Book 1 • Cardiology Critical Care
should be determined on a patient-specific basis. Because
this may depend on procedural factors, consultation with an
interventional cardiologist to determine the appropriate duration of DAPT is highly recommended. Risk scores may also
aid in decision-making (Baber 2016; Kereiakes 2016).
Ischemia-Guided Strategy
Antiplatelet therapies benefiting patient populations in an
ischemia-guided strategy are not significantly different
from those in other ACS settings that receive revascularization. These patients still benefit from DAPT for up to 1 year
post-event. The usefulness of more potent P2Y12 inhibitors in
addition to aspirin in patients with ACS who do not receive
PCI is inconsistent. This was shown in the TRILOGY-ACS trial,
in which prasugrel failed to improve ischemic outcomes compared with clopidogrel in this patient population (Roe 2012).
However, ticagrelor had benefit over clopidogrel in PLATO,
regardless of management strategy, and is preferred to clopidogrel in the guidelines for an ischemia-guided strategy
(Amsterdam 2014; Wallentin 2009).
Parenteral anticoagulant agents also provide value in an
ischemia-guided strategy. Options include intravenous UFH
at a 60 units/kg bolus with an initial infusion of 12 units/kg/
hour titrated to a therapeutic aPTT or anti-Xa, enoxaparin
1 mg/kg subcutaneously every 12 hours, and fondaparinux
2.5 mg subcutaneously daily. Unfractionated heparin is recommended to be continued for 48 hours, whereas enoxaparin
and fondaparinux are recommended to be continued for the
duration of the hospital stay. If, however, the decision is
later made to undergo PCI, these agents should be discontinued afterward. Guidelines do not give any preference to
one agent over another (Amsterdam 2014). Enoxaparin has
been compared with UFH in various studies, showing a significant reduction in ischemic outcomes (Antman 1999; Cohen
1997; Blazing 2004). However, most of these studies were
conducted before modern-era P2Y12 inhibitors, which limits
them. Fondaparinux was studied in the previously mentioned
OASIS-5 trial, which included both patients who underwent
an early invasive strategy and those who underwent an
ischemia-guided strategy. Fondaparinux was noninferior to
enoxaparin with a decreased incidence of bleeding, though
this may be related to the lower-intensity dosing strategy in
the fondaparinux arm.
The management of chronic antithrombotic pharmacotherapy prescribed for coronary artery disease in a patient
who presents with unrelated critical illness is complex.
Dual antiplatelet therapy may increase the risk of bleeding
when various diagnostic or invasive procedures are indicated. Dual antiplatelet therapy may also increase the risk
Antithrombotic Therapies in Acute Coronary Syndrome
of major and life-threatening bleeding events, resulting in
critical illness. Balanced against this, critically ill patients
are at greater risk of ischemic coronary events which lead to
greater risk of mortality if they occur. Premature cessation
of DAPT increases the risk of coronary events. In addition,
the contribution of DAPT to various procedural risks is
largely unknown and may be overstated. The appropriate
management, therefore, must balance the risk of bleeding
with the thrombosis events in the specific patient. However,
several population-level studies provide greater insight into
treating the individual patient.
The principal factors that aid the clinician in assessing
the risk of coronary thrombosis are whether a stent or several stents were placed in a coronary artery, the type of stent
(BMS vs. DES), and the duration from the index event, with
earlier times conferring higher risk. Lesser, but potentially
important factors include the specific location of the stent
in an artery, the myocardial territory affected, procedural
factors such as the use of overlapping stents, bifurcation
lesions, and the length of stent chosen. Ideally, all antithrombotic therapy prescribed for either secondary prevention or
prevention of coronary stent thrombosis should be continued
in a critically ill patient in the absence of contraindications.
The consequences of stent thrombosis tend to be quite
severe, resulting in death or MI in over 60% of patients (Cutlip
2001). However, when faced with higher bleeding risk scenarios or critical illness related to bleeding events, several
additional scenarios may be considered. In the absence of
coronary stents, DAPT used for secondary prevention likely
can be temporarily held or at least minimized to aspirin only
to provide a balance of protection versus bleeding risk. In
a patient with coronary stents, P2Y12 inhibitors can generally be temporarily held after 1 month after BMS placement
and 12 months after DES placement. Because very late stent
thrombosis still occurs with DES, some patients may be recommended for lifetime DAPT. It is therefore recommended
to engage cardiologists in this discussion, if possible, even
if stent placement occurred more than 12 months earlier.
In a patient with a high risk of bleeding or an active bleeding event, guidelines generally suggest discontinuing DAPT
after 2 weeks of therapy post-BMS and 6 months of DES therapy may be safe, though again, these decisions should be
made in concert with cardiology consultation (Levine 2016).
A patient for whom DAPT must be discontinued secondary to life-threatening bleeding should receive consultation
with cardiology to determine the best course of action. Use
of aspirin-only regimens in these scenarios may provide the
best balance of bleeding versus protection. In the STARS
trial, electively placed, older-generation coronary stents protected with aspirin only (325 mg/day) produced a 30-day
event rate of adverse cardiovascular effects of 3.6% (Leon
1998). Although inferior to a regimen containing DAPT, this
may provide an acceptable approximation of risk if faced
with a catastrophic bleeding scenario.
CCSAP 2017 Book 1 • Cardiology Critical Care
Although coronary thrombosis can be catastrophic, the negative effects of bleeding associated with antithrombotic
therapy should not be underestimated. Although previously
seen as simply an undesired adverse effect, bleeding has
been shown to be associated with increased morbidity and
mortality, and is now regarded as an important clinical outcome (Steg 2011). Some possible explanations for this include
prolonged cessation of antiplatelet therapy, endogenous prothrombotic rebound, and increased sympathetic response
resulting in myocardial ischemia. Risk factors for bleeding
include older age, female sex, lower body weight, invasive procedures, renal insufficiency, and history of bleeding. Newer
oral P2Y12 agents, GPI, triple therapy with DAPT and an anticoagulant, and antithrombotic agents not adjusted for renal
dysfunction all increase the risk of bleeding.
Strategies to reduce the risk of bleeding should include
carefully selected patients for invasive procedures, consideration for delaying procedures in patients with lower ischemic
risk and high bleed risk (e.g., non-urgent CABG surgery
for patient who just received a P2Y12 inhibitor). Procedural
techniques can reduce bleeding risk, such as radial artery
approaches to PCI versus femoral approaches. As mentioned
previously, the radial artery approach to PCI access site
decreases the incidence of bleeding and is quickly becoming
more prevalent in select centers. This selection of access site
may also influence post-PCI decisions as they relate to the
risk of bleeding. For example, the risk of continuing anticoagulation post-PCI may be higher in someone who underwent
a femoral artery approach versus a radial artery approach.
Antithrombotic medications clearly affect bleeding risk,
and many considerations need to be made to minimize that
risk. Appropriate selection, dosing, and duration of antithrombotic medications are fundamental to reducing bleeding risks.
The P2Y12 inhibitors may have varying efficacy and safety in
different populations, such as the increased risk of bleeding of prasugrel over clopidogrel without improved efficacy
in patients with NSTE ACS treated with an ischemia-guided
strategy (Roe 2012). Thus, proper selection of agents can help
minimize unnecessary risk of excess bleeding. For patients
with a high risk of bleeding undergoing PCI, either the use of
bivalirudin or the avoidance of GPI may be warranted. Triple
antithrombotic therapy with aspirin, a P2Y12 inhibitor, and
an anticoagulant significantly increases the risk of bleeding
and should be avoided, when possible. Many antithrombotic
medications need dose adjustments or drug avoidance
based on renal function (see Table 1-3) or other variables
such as age and weight (prasugrel, apixaban). All current
guidelines prefer aspirin 81 mg to higher doses as this has
been shown to have equal efficacy with reduced GI bleeding
Antithrombotic Therapies in Acute Coronary Syndrome
the duration of DAPT can decrease bleeding and
should be considered. Finally, patients at risk of GI
bleeding (e.g., history of GI bleed, GI ulcers, triple
antithrombotic therapy) may benefit from a proton pump
inhibitor given with antithrombotic therapy (Amsterdam
2014; Vaduganathan 2016). Although some concerns may
exist with a pharmacodynamic drug interaction between
omeprazole and clopidogrel, clinical outcomes have not been
affected (Bhatt 2010; Dunn 2013). Any decision to interrupt
or discontinue antithrombotic therapies needs to weigh carefully the risks of ischemic complications versus the risks of
bleeding. For mild to moderate bleeds, if the patient is still in
the guideline-recommended period of mandatory DAPT, both
drugs should be continued with supportive management for
the acute bleed. Major bleeding may require interruption of
DAPT, regardless of the timing of stent placement. For all
bleeds, supportive care and specific interventions should be
made to promote hemostasis, if available (e.g., fluids, blood
products, endoscopic GI repair, manual pressure of an access
site, topical vasoconstrictors and packing of epistaxis) (Steg
of thrombocytopenia (Gore 2009; Wang 2009). They have
also shown increased mortality in patients who develop
thrombocytopenia, as well increased bleeding and reinfarction. Thus, monitoring platelets in these patients is critical/
necessary. Various antithrombotic medications can lead to
The GPIs are most likely to cause thrombocytopenia. It can
occur in up to 0.4%–5.2% of patients undergoing PCI with abciximab, whereas eptifibatide and tirofiban have a lower incidence
of 0.5%–3.2% (Matthai 2010). However, the true incidence of
thrombocytopenia with all GPIs is often confounded by heparin use. Although use of these agents has decreased, it is
prudent to recognize their adverse effects. Thrombocytopenia
occurs early after initiating the drug, and platelets should be
monitored 2–4 hours afterward. If thrombocytopenia is present, drug discontinuation is recommended to prevent profound
thrombocytopenia. Patients who have experienced this should
not be reinitiated on a GPI in the future, if possible. Should
there be an acute indication, a different GPI should be used
to avoid the risk of repeat thrombocytopenia. Thienopyridines
such as ticlopidine, clopidogrel, and prasugrel have been associated with thrombocytopenia as well. Ticlopidine was rarely
used because of its higher incidence of adverse effects, which
include thrombotic thrombocytopenic purpura, a microangiopathic hemolytic anemia, and has been removed from the U.S.
market. Clopidogrel and prasugrel can also cause thrombotic
thrombocytopenic purpura, but it is very rare.
Other Severe Adverse Effects
Registries of patients with ACS have shown the incidence of
thrombocytopenia as 1.6%–13%, depending on the definition
Patient Care Scenario
M.A. is a 69-year-old woman found in her bathroom
after a fall; she appears to have a head injury. Her medical
history consists of hypertension, type 2 diabetes, dyslipidemia, coronary artery disease with two DES placed in
her mid-right coronary artery 4 months ago, and arthritis.
On arrival at the ED, she seizes and is intubated for airway
protection. A CT scan of her head reveals a large intracranial hemorrhage (ICH). An emergency neurosurgery
consult is placed. Which one of the following is the most
appropriate urgent management of M.A.’s stent antithrombotic therapy?
A. Discontinue both aspirin and clopidogrel.
B. Continue aspirin, but discontinue clopidogrel.
C. Continue clopidogrel, but discontinue aspirin.
D. Continue both aspirin and clopidogrel, given her
recent stent placement.
Although interrupting DAPT is highly discouraged
within the first 6–12 months of DES placement, it must be
considered in severe circumstances. An ICH is a devastating major bleed because it cannot be compressed and can
cause rapid, permanent damage if not controlled. There
are few data to guide clinicians in these situations, and
management is based largely on expert opinion (ideally
with both an interventional cardiologist and a neurosurgeon). In less severe non-ICH bleeds and when duration
of DAPT is complete or near-complete, continuing aspirin
only and discontinuing the P2Y12 agent can be considered. The decision is more challenging in more severe
bleeds, or if stents were recently placed, and should be
made on a patient-specific basis. When the ICH has led
to seizures and intubation, discontinuing both agents is
necessary. Discontinuing DAPT will likely increase the
risk of stent thrombosis. However, continuing antithrombotic therapy poses a definite, real risk of an exacerbating
the life-threatening bleed. In conjunction with a neurosurgery or neurology consultation, if it appears clinically
and radiologically that the ICH has stabilized, reinitiating
aspirin and sequentially (if indicated) the P2Y12 inhibitor
can then be considered.
1. Flower O, Smith M. The acute management of intracerebral hemorrhage. Curr Opin Crit Care 2011;17:106-14.
2. Okada T, Nakase T, Sasaki M, et al. Do the antithrombotic therapy at the time of intracerebral hemorrhage influence clinical
outcome? Analysis between the difference of antiplatelet and anticoagulant agents and clinical course. J Stroke Cerebrovasc
Dis 2014;23:1781-8.
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Heparin-induced thrombocytopenia is another rare form of
thrombocytopenia that may occur in any patient exposed to
heparin products. Endogenous platelet factor 4 (PF4) binds
to heparin in the plasma. Heparin-induced thrombocytopenia
can occur when these PF4-heparin complexes form antibodies
that then bind to platelets, causing platelet activation, aggregation, clot formation, and consumptive thrombocytopenia.
Acute coronary syndrome registries have reported a 0.3%
incidence in patients with ACS (Gore 2009). The incidence
is likely higher in cardiac surgery patients because of large
amounts of intraoperative heparin exposure and PF4 release
ranging from 1%–3% (Matthai 2010). Heparin-induced thrombocytopenia is characterized by a decline in platelets to
less than 150,000/mm3 or a 50% decrease from baseline,
occurring 5–14 days after heparin exposure. Unlike GPIassociated thrombocytopenia in which the platelet nadir is
typically 20,000/mm3, HIT platelet nadirs are typically closer
to 50,000/mm3. This platelet reduction can also occur within
1 day if patients have had exposure within the past 100 days.
Although these timelines may overlap with thrombocytopenia
occurring with thienopyridines, severe bleeding associated
with GPI-associated thrombocytopenia usually does not
occur in HIT and can help distinguish the diagnosis as well
as the timing and nadir of the platelet decrease. Although
laboratory testing may help diagnose HIT, it is ultimately a
clinical diagnosis. If suspicion is high, all heparin products
must be discontinued (including low-molecular-weight heparin, heparin flushes, and heparinized catheters), and a direct
thrombin inhibitor should be initiated to prevent thromboses. A complete discussion of the evaluation and treatment
of HIT is beyond the scope of this chapter, but bivalirudin use
is preferred with a history of HIT or if HIT is suspected and
anticoagulation is indicated because of the clinical trial data
associated with bivalirudin in patients with ACS.
with both agents (Cattaneo 2012; Wallentin 2009; Bhatt
2013). These studies have shown that dyspnea with ticagrelor may occur within 24 hours to 7 days after initiation, and in
the clinical trials, it occurred in about 15%–38% of patients
(Sanchez-Galian 2015; Cattaneo 2012). Although the dyspnea is typically mild to moderate, it can be severe enough
to require drug discontinuation in up to 4% of patients. If
needed, discontinuation of ticagrelor typically occurs in the
first 1–2 weeks (Bonaca 2015). There are no well-defined recommendations for ticagrelor-induced dyspnea, though most
cases do not require drug discontinuation. All other causes
of dyspnea must first be ruled out. It may be challenging to
distinguish dyspnea of cardiac etiology versus drug-induced
dyspnea in a patient with a recent MI. If dyspnea is thought
to be the result of a specific disease process, the presence
or absence of other clinical features may help narrow the etiology. Currently, no treatments exist for ticagrelor-induced
dyspnea. If identified, ticagrelor may need to be discontinued
and replaced with another P2Y12 inhibitor.
Bradycardia and other bradyarrhythmias have also been
identified in ticagrelor-treated patients, presumably because
of an adenosine-related effect. In the PLATO trial, ticagrelor-treated patients receiving continuous ECG monitoring
(n=2866) had a greater frequency of asymptomatic pauses
of more than 3 seconds (5.8% vs. 3.6%, p=0.01) within the
first week of treatment but not at 30 days (Wallentin 2009).
There was no significant difference in symptomatic events.
The implications for these events are unclear, though ticagrelor should be considered in the differential for a patient with
ventricular pauses or bradyarrhythmias, particularly within
the first week of treatment. Ticagrelor also induces hyperuricemia, possibly through reduced uric acid clearance or
increased production by adenosine, with potential implications for patients with a history of gout or other hyperuricemic
disorders (Zhang 2015).
Other Adverse Effects
Ticagrelor and cangrelor cause some unique adverse drug
reactions, such as dyspnea and bradycardia, as a result of their
structural relationship with adenosine. Dyspnea is a common
symptom of many disease states and can potentially be a
warning sign for disease exacerbation. In the cardiac patient,
dyspnea of heart failure may be a presenting sign of worsening ischemia or progressive heart failure. Clinicians must be
prudent in assessing the cause of dyspnea, as it may allow
for an opportunity to intervene before a patient decompensates. Unfortunately, dyspnea has a very broad differential
diagnosis with many triggers, including non–disease-related
triggers. The mechanism of P2Y12 inhibitor–induced dyspnea
is controversial. Some argue that ticagrelor prevents adenosine reuptake and promotes adenosine-induced dyspnea,
though this theory has been debated (van den Berg 2015). The
incidence and consequence of dyspnea related to ticagrelor and cangrelor is not well defined. Since it was identified,
many studies have described an increased risk of dyspnea
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic therapy for critically ill patients with ACS is
complex and involves many branching decision points. Even
defining a true ACS compared with myocardial ischemia from
preexisting critical illness is complex and not always easily
definable. Management of chronic antithrombotic therapy in
critically ill patient populations is equally complex. Guidelines
recommend minimum durations of DAPT for secondary prevention of ACS as well as prevention of stent thrombosis if
a patient receives PCI. However, patients may receive longterm or lifelong DAPT at their cardiologist’s discretion. A
patient-centered approach underscores the need for good
communication between intensivist teams and cardiologists
to determine the best management options for a given patient.
Finally, DAPT therapy and other anticoagulants are
associated with adverse effects, including bleeding, thrombocytopenia, and other toxicities. Familiarity with identifying
Antithrombotic Therapies in Acute Coronary Syndrome
with non-ST-segment elevation acute coronary syndromes
who receive tirofiban and aspirin: a randomized controlled
trial. JAMA 2004;292:55-64.
Practice Points
In determining the optimal antithrombotic therapy for a
critically ill patient with ACS, practitioners should consider the following:
Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of
ticagrelor in patients with prior myocardial infarction.
N Engl J Med 2015;372:1791-800.
• Try to classify the potential infarct according to the universal definition. If thought to be a type 2 infarct (supply/
demand imbalance), consider withholding antithrombotic
therapy, particularly if there is a potential for harm.
• Choice and type of antithrombotic therapy depend on the
revascularization modality (if any) and patient-specific
• Chronic antithrombotic therapy prescribed for ACS may
be withheld in certain scenarios in critically ill patients,
but consider involving a cardiologist in this determination,
especially if the patient has a history of coronary stents.
• Antithrombotic therapy is associated with various toxicities,
especially bleeding. Management of bleeding and recent
history of coronary stenting is complex, and treatment decisions should largely be made on a patient-specific basis.
Cattaneo M, Faioni EM. Why does ticagrelor induce
dyspnea? Thromb Haemost 2012;108:1031-6.
Cohen M, Demers C, Gurfinkel EP, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin
for unstable coronary artery disease. Efficacy and Safety
of Subcutaneous Enoxaparin in Non-Q-Wave Coronary
Events Study Group. N Engl J Med 1997;337:447-52.
CURRENT-OASIS 7 Investigators, Mehta SR, Bassand JP,
et al. Dose comparisons of clopidogrel and aspirin in acute
coronary syndromes. N Engl J Med 2010;363:930-42.
Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the
modern era: a pooled analysis of multicenter coronary
stent clinical trials. Circulation 2001;103:1967-71.
and managing these episodes as well as the risks of discontinuing therapy is paramount in ensuring optimal patient
Dunn SP, Steinhubl SR, Bauer D, et al. Impact of proton
pump inhibitor therapy on the efficacy of clopidogrel
in the CAPRIE and CREDO trials. J Am Heart Assoc
Epstein AJ, Polsky D, Yang F, et al. Coronary
revascularization trends in the United States, 2001-2008.
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Ammann P, Maggiorini M, Bertel O, et al. Troponin as a risk
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Feldman DN, Swaminathan RV, Kaltenbach LA, et al.
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Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/
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patterns of coronary revascularization strategies for
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Antithrombotic Therapies in Acute Coronary Syndrome
CRUSADE Quality Improvement Initiative). Am J Cardiol
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Montalescot G, van ’t Hof AW, Lapostolle F, et al. Prehospital
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CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
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coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis
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Zhang N, Zhang Z, Yang Y, et al. Ticagrelor-related gout: an
underestimated side effect. Int J Cardiol 2015;192:11-3.
Steg PG, van ’t Hof A, Hamm CW, et al. Bivalirudin started
during emergency transport for primary PCI. N Engl J Med
Steinhubl SR, Berger PB, Mann JT III, et al. Early and
sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled
trial. JAMA 2002;288:2411-20.
Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning
patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for
patients with acute coronary syndromes. N Engl J Med
Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin
during primary PCI in acute myocardial infarction. N Engl J
Med 2008;358:2218-30.
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome
Self-Assessment Questions
Questions 1–3 pertain to the following case.
transferred to the CCU for closer monitoring. J.M.’s ECG is
consistent with diffuse ST depression and slight ST-elevation
(non-STEMI criteria) in aVR, suggestive of disease in the left
main coronary artery. Troponin is elevated at 1.5 ng/mL. His
home drugs include aspirin 81 mg daily, metformin 1000 mg
twice daily, metoprolol 50 mg twice daily, and phenytoin
300 mg at bedtime. J.M. received enoxaparin 1 mg/kg subcutaneously x 1 dose in the ED. His vital signs include blood
pressure 100/60 mm Hg and heart rate 72 beats/minute.
M.J. is a 56-year-old man with a medical history significant
for coronary artery disease; he had a percutaneous coronary intervention (PCI) with stent placement to the proximal
left circumflex sometime in the past 12 months after having
stable angina symptoms refractory to medical therapy. M.J.
presents at the ED today with a several-week history of coffee-ground emesis and dark, tarry stools. This morning, he
felt dizzy and had presyncopal events together with chest
pain. His hemoglobin is 5.3 g/dL on admission, blood pressure is 80/60 mm Hg, and heart rate is 95 beats/minute. M.J.
is admitted to the medical ICU for further treatment. His ECG
is significant for ST depressions in the anterolateral leads.
His first troponin is 1.25 ng/mL, which increases to 2.5 ng/mL
6 hours later. His home drugs include aspirin 325 mg daily,
clopidogrel 75 mg daily, lisinopril 5 mg daily, and metoprolol
tartrate 25 mg twice daily.
4. According to the universal definition of MI, which one of
the following types of infarction is most consistent with
J.M.’s presentation?
5. The team is concerned that J.M. may have left main coronary disease, given his ECG findings, and therefore may
require urgent cardiac surgery if identified through coronary angiography. Given this concern, which one of
the following antiplatelet regimens is most appropriate while J.M. awaits cardiac catheterization (expected
within 1 hour)?
According to the universal definition of MI, which one of
the following types of infarction is most consistent with
M.J.’s presentation?
A. Continue his aspirin therapy only.
B. Administer 60 mg of prasugrel, followed by 10 mg
C. Administer 180 mg of ticagrelor, followed by 90 mg
twice daily.
D. Initiate cangrelor at 0.75 mcg/kg/minute continuous
intravenous infusion.
2. M.J. is given a medical diagnosis of, and meets the
criteria for, a non–ST-segment elevation myocardial
infarction (NSTEMI). Which one of the following would be
the most appropriate anticoagulation therapy to promote
clot stabilization until reperfusion and/or further testing
modalities can be initiated for M.J.?
Give unfractionated heparin (UFH).
Give enoxaparin.
Give fondaparinux.
Anticoagulation therapy is not necessary.
A. Discontinue all anticoagulation, given his potential
for upcoming cardiac surgery.
B. Administer UFH (60-unit/kg bolus, followed by
12 units/kg/hour infusion) immediately on arrival at
the critical care ICU.
C. Continue therapeutic enoxaparin with the next dose
12 hours from his first dose in the ED.
D. Change to fondaparinux 2.5 mg subcutaneously
daily (first dose the following day) to reduce his risk
of bleeding.
3. Which one of the following best describes the optimal
management of M.J.’s chronic dual antiplatelet therapy
(DAPT) in the acute setting?
Discontinue clopidogrel and continue aspirin.
Discontinue aspirin and clopidogrel.
More information is needed about the patient’s stent.
Continue both aspirin and clopidogrel.
Questions 4–6 pertain to the following case.
J.M., a 65-year-old man with a history of tobacco abuse,
hypertension, type 2 diabetes, peripheral arterial disease, and
seizure disorder secondary to traumatic brain injury, presents to the ED with persistent chest pain. In the ED, his chest
pain is fairly refractory to continuous nitroglycerin, and he is
CCSAP 2017 Book 1 • Cardiology Critical Care
Which one of the following is the most appropriate action
regarding J.M.’s anticoagulation therapy?
A 59-year-old woman presents for an emergency
appendectomy after complaints of abrupt-onset abdominal pain. She has a history of coronary artery disease,
including stenting of her left circumflex artery 8 months
ago with drug-eluting stent (DES) placement (specific
stent unknown). In addition, she has a medical history
Antithrombotic Therapies in Acute Coronary Syndrome
of hypertension, tobacco abuse, and obesity. Her home
drugs include aspirin 81 mg daily, clopidogrel 75 mg
daily, atorvastatin 40 mg daily, and paroxetine 20 mg
daily. Her surgery is relatively uncomplicated, and she is
admitted to the surgical ICU postoperatively for monitoring. Which one of the following is best to recommend for
this patient’s antiplatelet therapy in the acute post-surgical setting?
B. Continue heparin and initiate cangrelor at 0.75 mcg/
C. Discontinue heparin and initiate eptifibatide at
2 mcg/kg/minute.
D. Discontinue heparin and initiate therapeutic
bivalirudin, titrated to therapeutic aPTT.
10. K.L.’s dynamic chest pain continues after the procedure.
The team is trying to expedite his surgery. In the interim,
they wish to initiate some antiplatelet therapy as a bridge
to surgery. Which one of the following is best to recommend for K.L.?
A. Discontinue both aspirin and clopidogrel because of
the risk of bleeding.
B. Discontinue aspirin and clopidogrel, and initiate
cangrelor at 0.75 mcg/kg/minute.
C. Continue her home aspirin and clopidogrel if
surgical risk is not prohibitive.
D. Discontinue clopidogrel but continue aspirin
11. Your hospital receives a call for potential transfer from
a rural hospital. A 68-year-old man presented to the ED
with complaints of nausea, vomiting, and diaphoresis.
His medical history includes hypertension (reportedly
well controlled with current blood pressure 135/75 mm
Hg and heart rate 90 beats/minute) and dyslipidemia. Fifteen minutes after being seen by paramedics, his ECG
showed ST elevations in leads V2–V5. He was immediately given aspirin, enoxaparin, and nitroglycerin. The
ED physician at the outside hospital consults with your
cardiologist about potentially transferring the patient for
cardiac catheterization versus giving fibrinolytic therapy.
The patient has no known contraindications for fibrinolytics. The patient’s estimated travel time is 55 minutes.
Which one of the following is best to recommend for
this patient?
Questions 8–10 pertain to the following case.
K.L. is a 45-year-old man admitted with acute onset substernal
chest pain. His medical history is consistent with end-stage
renal disease on hemodialysis, type 2 diabetes, peripheral
arterial disease with a femoral-popliteal bypass, hypertension, tobacco abuse, and carotid artery disease. K.L.’s ECG is
significant for ST-segment depression in anterolateral leads
with reciprocal changes in inferior leads. His initial troponin
is 2.6 ng/mL, and he is placed on the cardiac ICU because of
refractory chest pain. Given his other atherosclerotic disease
and related risk factors, the cardiology team is concerned
that K.L. may have multivessel coronary disease that would
be best managed with cardiac bypass surgery. However, he is
scheduled for cardiac catheterization tomorrow morning for
a definitive diagnosis and potential PCI, should he have treatable disease. K.L. has received aspirin from the ED.
A. Give clopidogrel 300 mg now plus tenecteplase;
then have the patient transferred to your center for
cardiac catheterization.
B. Give clopidogrel 600 mg now plus tenecteplase;
then have the patient transferred to your center for
cardiac catheterization.
C. Give clopidogrel 300 mg and have the patient
immediately transferred to your center for cardiac
D. Give clopidogrel 600 mg and have the patient
immediately transferred to your center for cardiac
8. Which one of the following is the best option to initiate
for K.L.’s anticoagulation therapy?
K.L. has coronary disease in three discrete arteries, best
treated with coronary artery bypass grafting (CABG) surgery. He undergoes a workup regarding his candidacy
for surgery. A few days later, he develops thrombocytopenia with a greater than 50% drop in platelet count
from a baseline of 300,000/mm3 to 128,000/mm3. The
team sends laboratory monitoring, including platelet
factor 4 and serotonin release assay, which will have a
minimum of 48 hours’ turnaround. Which one of the following is the most appropriate action regarding K.L.’s
Questions 12 and 13 pertain to the following case.
G.G. is a 44-year-old man who presents to your ED with the
chief concern of crushing chest pain. He has ST elevations
in leads V3 and V4 and receives a diagnosis of a STEMI.
His medical history includes hypertension; he is otherwise
healthy. G.G. is given aspirin 325 mg once and heparin 5000
units intravenously once, and he is taken emergently to the
cardiac catheterization laboratory for a primary PCI.
A. Discontinue heparin, begin enoxaparin at 1 mg/kg
subcutaneously every 12 hours.
CCSAP 2017 Book 1 • Cardiology Critical Care
Initiate eptifibatide at 2 mcg/kg/minute.
Load with 180 mg of ticagrelor x 1.
Load with 60 mg of prasugrel x 1.
Initiate cangrelor at 0.75 mcg/kg/minute.
Antithrombotic Therapies in Acute Coronary Syndrome
12. Which one of the following is the best anticoagulation
strategy to recommend for G.G.?
the incidence of moderate or severe bleeding using the
GUSTO scale. Outcomes are as follows:
Enoxaparin 1 mg/kg subcutaneously once
Fondaparinux 2.5 mg intravenously once
Bivalirudin 180 mcg/kg double bolus
No anticoagulant needed unless the ACT is below
13. G.G. received 60 mg of prasugrel during PCI as well as
bailout abciximab for slow flow after revascularization. Two hours after arriving at your ICU, he continues
to bleed from his access site. A CBC is normal except
for a platelet count of 26,000/mm3. G.G.’s baseline platelet count on admission was within normal limits. Which
one of the following drugs most likely caused G.G.’s
14. A 76-year-old man presents to your hospital for an
inguinal hernia repair. He has a medical history of hypertension, dyslipidemia, and remote MI treated with a
DES several years earlier (unknown vessel and no longer taking P2Y12 inhibitor). On postoperative day 1, the
patient develops chest pain. An ECG shows ST depressions in leads V1–V3. The patient is given aspirin,
clopidogrel, and heparin. He then experienced pulseless
ventricular tachycardia. Cardiopulmonary resuscitation
is initiated, and the patient is successfully resuscitated
and transferred to your ICU. He then has hematemesis
and hypotension, prompting the team to hold clopidogrel. Three days later, the patient has no longer had any
bleeding, and his hemoglobin and hemodynamics are
stable. An EGD reveals friable mucosa but no obvious
signs of bleeding. Which one of the following is best to
recommend regarding this patient’s P2Y12 therapy in the
acute setting?
(95% CI)
p value
19 (0.4)
(definite or
n (%)
65 (1.4)
< 0.001
events, n
211 (4.3)
285 (5.9)
< 0.001
severe or
n (%)
119 (2.5)
73 (1.6)
Using number needed to treat (NNT) versus number needed
to harm (NNH), which one of the following best depicts the
risk-benefit of continued DAPT when comparing stent thrombosis events (definite or probable) with the incidence of
GUSTO severe or moderate bleeding?
A. Risk-benefit is about equal.
B. Risk is significantly greater than benefit.
C. Benefit is significantly greater than risk.
D. Not enough information is provided.
Questions 16–18 pertain to the following case.
J.W. is a 63-year-old man (weight 80 kg) with a medical history of alcohol abuse, cirrhosis, GI bleed (1 year ago), and
poor adherence to medical care. He is admitted to the medical
ICU with altered mental status, hyperammonemia, jaundice,
and fluid overload. On day 2 of admission, he has complaints
of chest pressure and is found to have ST-segment depressions in leads V1–V4. The decision is made to pursue an
ischemia-guided strategy for treatment of non–ST-segment
elevation acute coronary syndrome (NSTE ACS).
Hold clopidogrel therapy, given the recent GI bleed.
Reinitiate clopidogrel.
Change to prasugrel therapy.
Initiate cangrelor therapy while awaiting a final
decision on oral P2Y12 therapy.
16. Which one of the following is the most appropriate antiplatelet regimen to recommend for J.W.?
15. The DAPT trial examined the benefit and risk of 12 months
of DAPT (aspirin plus clopidogrel or prasugrel) versus
30 months of DAPT in patients receiving PCI with
DES. Patients received the guideline-recommended
12-month minimum duration and were then randomized
to receive continued thienopyridine versus placebo up to
30 months. The primary end points of the trial were definite or confirmed stent thrombosis, a composite of major
adverse cardiovascular events (death, MI, stroke), and
CCSAP 2017 Book 1 • Cardiology Critical Care
Aspirin 81 mg plus ticagrelor 90 mg twice daily
Aspirin 81 mg plus prasugrel 10 mg daily
Aspirin 81 mg plus clopidogrel 75 mg daily
No antiplatelet therapy at this time
17. Which one of the following is the most appropriate UFH
regimen to recommend for J.W.?
Antithrombotic Therapies in Acute Coronary Syndrome
A. A 6400-unit intravenous bolus followed by
1440 units/hour for 48 hours
B. A 6400-unit intravenous bolus followed by
1440 units/hour for 8 days
C. A 4800-unit intravenous bolus followed by
960 units/hour for 48 hours
D. A 4800-unit intravenous bolus followed by
960 units/hour for 8 days
18. Which one of the following would best attenuate J.W.’s
risk of bleeding?
A. Initiate pantoprazole continuous infusion at 8 mg/
B. Initiate pantoprazole 40 mg orally daily.
C. Separate out administration times of antithrombotic
D. Give lower doses of one or more antithrombotic
19. A 55-year-old man has a medical history of STEMI
(3 days ago) with an asymptomatic left ventricular ejection fraction 24 hours after the event of 40%, tobacco
abuse, hypertension, and diabetes. He had two DESs
placed and is awaiting hospital discharge on the acute
care floor on aspirin 81 mg, ticagrelor 90 mg twice daily,
atorvastatin 80 mg once daily, carvedilol 12.5 mg twice
daily, and lisinopril 5 mg twice daily. During morning
rounds, your team receives a page that the patient is
feeling short of breath. A 12-lead ECG is unchanged from
his baseline. Cardiac biomarkers are negative. His lungs
are clear to auscultation, and chest radiography is clear
without evidence of edema or infectious processes. His
Sao2 is 99%, and his respiratory rate is 28 breaths/minute. A bedside arterial blood gas fails to identify evidence
of CO2 retention. Which one of the following is the most
likely cause of this patient’s symptoms?
A. Ischemic heart disease
D. Acute decompensated heart failure
20. Which one of the following is most likely to result in
patient harm secondary to medical error?
A. Administration of ticagrelor on an every-12-hour
versus twice-daily schedule
B. Coadministration of clopidogrel with a proton pump
C. Administration of a loading dose of clopidogrel
during a cangrelor infusion in PCI
D. Administration of 600 mg of clopidogrel instead of
300 mg for a loading dose
CCSAP 2017 Book 1 • Cardiology Critical Care
Antithrombotic Therapies in Acute Coronary Syndrome

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