REVIEWS

Antithrombotic therapy for patients

with STEMI undergoing primary PCI
Francesco Franchi, Fabiana Rollini and Dominick J. Angiolillo
Abstract | Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the
cornerstone of pharmacological treatment to optimize clinical outcomes in patients with
ST‑segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary
intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect
thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the
direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include
glycoprotein IIb/IIIa inhibitors and the P2Y12-receptor inhibitor cangrelor. Dual antiplatelet
therapy with aspirin and an oral P2Y12-receptor inhibitor is pivotal for the acute and long-term
treatment of patients with STEMI undergoing PPCI. Prasugrel and ticagrelor provide a more
prompt, potent, and predictable antiplatelet effect compared with clopidogrel, which translates
into better clinical outcomes. Therefore, these agents are the first-line treatment in PPCI. However,
patients can still experience adverse ischaemic events, which might be in part attributed to
alternative pathways triggering thrombosis. Thrombin has an important role, suggesting the need
for strategies directly targeting circulating thrombin or other factors of the coagulation cascade,
such as oral anticoagulants (rivaroxaban), and the thrombin receptor on the platelet membrane
(vorapaxar). In this Review, we provide an overview of currently available antithrombotic therapies
used in patients with STEMI undergoing PPCI, results from pivotal clinical trials and their
implications for guidelines, as well as recommendations for clinical practice.

University of Florida College
of Medicine-Jacksonville,
Division of Cardiology-ACC
Building 5th floor, 655 West
8th Street, Jacksonville,
Florida 32209, USA.
Correspondence to D.J.A.
dominick.angiolillo@
jax.ufl.edu
doi:10.1038/nrcardio.2017.18
Published online 23 Feb 2017
Acute ST‑segment elevation myocardial infarction
(STEMI) is a major cause of morbidity, mortality, and dis‑
ability worldwide. Currently, STEMI comprises 25–40%
of myocardial infarction (MI) presentations1–4. The goal of
STEMI treatment is reperfusion, aimed to achieve an early
and complete recanalization of the infarct-related artery.
Indeed, timely reperfusion with primary percutaneous
coronary intervention (PPCI) is considered the treat‑
ment of choice in this setting1–4. Over the past 30 years,
the manage­ment of patients with STEMI has evolved
substantially in terms of reperfusion strategies, adjunc‑
tive antithrombotic therapy, technical approaches, and
development of coordinated systems of care, which have
led to marked improvements in short-term and long-term
outcomes1–4. Both in‑hospital and 1‑year mortality from
STEMI (5–6% and 7–18%, respectively) have decreased
significantly, but cardiovascular outcomes could still
be improved1–4.
Atherosclerotic plaque rupture or erosion followed
by arterial thrombosis and formation of an occlusive
thrombus is the major determinant leading to STEMI5–7.
The main elements involved in this process are cellular
(platelets) and plasma (coagulation) factors7–9. Therefore,
antithrombotic therapy, including antiplatelet and anti‑
coagulant agents, is the cornerstone of pharmacological
treatment to optimize clinical outcomes in patients with
STEMI undergoing PPCI1–4,9. In this Review, we provide
an overview of currently available antithrombotic thera­
pies used in the setting of patients with STEMI under‑
going PPCI, including describing the rationale for use,
pharmacological characteristics, pivotal clinical trial
data, and guidance for selecting the appropriate regimen
in the early phase of management, primarily focusing on
adjunctive therapies for PPCI.
Rationale for antithrombotic therapy in STEMI
Injury to the arterial vessel wall exposes the subendo­
thelial layer and leads to recruitment and activation of
platelets, as well as generation of excessive levels of throm‑
bin. Following adhesion, platelets release many activat‑
ing factors, mainly thromboxane A2, ADP, and thrombin,
which activate intraplatelet signalling pathways leading to
enhanced interactions among adherent platelets and fur‑
ther recruitment and activation of circulating platelets7–9.

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REVIEWS

Key points unfractionated heparin (UFH) and low-molecular-­weight

• Antithrombotic therapy is the cornerstone of pharmacological treatment to optimize
clinical outcomes in patients with ST‑segment elevation myocardial infarction (STEMI)
undergoing primary percutaneous coronary intervention (PPCI)
• Anticoagulant therapy is mandatory in PPCI and includes heparins and bivalirudin,
which have different pharmacological and clinical profiles; the choice between these
agents is mainly on the basis of bleeding risk profile
• Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the
P2Y12-receptor inhibitor cangrelor, which can provide immediate platelet inhibition
until the full antiplatelet effect of oral agents is achieved
• Dual antiplatelet therapy with a combination of aspirin and one of the new-generation
P2Y12-receptor inhibitors prasugrel or ticagrelor is the recommended first-line
treatment in patients undergoing PPCI
• In the absence of data supporting superiority of one agent over the other, the choice
between prasugrel and ticagrelor should take into consideration contraindications
and patient characteristics; clopidogrel should be used when both prasugrel and
ticagrelor are contraindicated or not available
• Agents targeting thrombin-mediated effects on platelet activation, namely vorapaxar
and rivaroxaban, have been developed and can be used in selected patients with
STEMI to reduce long-term atherothrombotic events
The final step for all these signalling pathways is the
conversion of the platelet glycoprotein IIb/IIIa receptor
into its active form, which binds to soluble adhesive sub‑
strates, including fibrinogen and von Willebrand factor,
and leads to platelet aggregation and formation of an
occlusive thrombus mediated by platelet–fibrin inter­
action7–9. Vascular injury also exposes subendothelial
tissue factor, which activates the coagulation cascade
leading to thrombin generation7–9. Thrombin converts
fibrinogen to fibrin, an essential component of arterial
thrombus, and is one of the most potent platelet activ­
ators by binding to protease-activated receptors (PARs)
on the platelet membrane10–13. Notably, only a modest
amount of thrombin is produced as a result of the coagu­
lation cascade, whereas the surface of activated platelets is
the main source of c­ irculating thrombin10–13.
Several classes of anticoagulant and antiplatelet
agents targeting mediators and receptors promoting
thrombosis are currently approved for the early manage‑
ment of patients with acute STEMI, and are available for
either intravenous or oral administration1–4 (FIG. 1). The
following sections provide details on the pharmacology
and clinical trial development of these different classes
of antithrombotic agents.
Intravenous antithrombotic therapies
The acute phase of STEMI is characterized by a high
prothrombotic milieu and an increased risk of throm‑
botic complications, which, in addition to the need to
reduce the time from hospital admission or first med‑
ical contact to coronary angiography, underscores the
need for fast-acting, intravenous antithrombotic thera‑
pies providing effective blockade of thrombin-mediated
effects and important platelet signalling pathways1–9.
Anticoagulant therapy
Anticoagulant therapy is mandatory in PPCI. Anticoagu­
lant drugs available for parenteral use are ­indirect throm‑
bin (factor IIa) and factor Xa inhib­itors, which include
heparin (LMWH); the direct thrombin inhibitor bivali‑
rudin; and the direct factor Xa inhibitor fondaparinux.
These agents have different mechanisms of action, bind‑
ing specificity, pharmaco­kinetic and pharmacodynamic
consistency, risks of heparin-induced thrombocytopenia
(HIT), effects on platelet function, and half-lives (TABLE 1).
Because of the high rate of catheter thrombosis recorded
in the OASIS‑6 trial14, fondaparinux is not recommended
as background a­ nticoagulant for PPCI and, therefore,
is not discussed1–4.
Unfractionated heparin. UFH is a sulfated polysacchar­
ide with a molecular weight range of 3,000–30,000 kDa
(mean 15,000 kDa)15. Its major anticoagulant effect is
based on inactivation of thrombin and activated factor X
(factor Xa) through an antithrombin-­dependent mech‑
anism. The heparin–antithrombin complex inactiv­ates
not only thrombin but also factors Xa, IXa, XIa, and
XIIa. Major limitations of UFH use include its vari­able
pharmacokinetic profile with high intrapatient and
inter­patient variability, and the increased risk of HIT15.
HIT is a serious, potentially lethal, immuno­logically
mediated adverse reaction to UFH and, less commonly,
to LMWH, which occurs in 0.1–5.0% of patients receiv‑
ing heparin therapy, with variability according to patient
population and type of heparin exposure. Up to 50% of
patients with HIT develop thrombotic complications,
and mortality is from 5–10% up to 20–30% in those
who develop thrombotic complications. The treatment
for this condition includes termination of heparin ther‑
apy (both UFH and LMWH), use of alternative anti‑
coagulants (the direct thrombin inhibitors bivalirudin
or argatroban) to prevent thrombotic complications,
and platelet transfusion in severely thrombocytopenic
patients with bleeding16.
Although no placebo-controlled trials have evalu‑
ated the use of UFH in PPCI, intravenous UFH titrated
to target-recommended activated clotting times is a
famili­ar and extensively practised strategy for anti‑
coagulant therapy at the time of PCI for STEMI1–4.
Dosage should follow standard recommendations for
PCI, t­ aking into account the use of glycoprotein IIb/IIIa
inhibitors (GPIs; 70–100 U/kg bolus with no GPI use
planned, and 50–70 U/kg bolus with GPI use planned)
to achieve therapeutic activated clotting times
(250–300 s without GPIs use, and 200–250 s with GPI
use)1–4. UFH ­currently has a class I indication for anti‑
coagulation ­during PPCI in both the ACC/AHA and
ESC guidelines1–4.
Low-molecular-weight heparin. LMWHs are derived
from UFH by chemical or enzymatic depolymerization
and are about one-third the molecular weight of UFH
(mean molecular weight 4,000–5,000 kDa)15. The lower
molecular weight compared with UFH translates into
a reduced capacity to bind to protein and cells and to a
more predictable dose–response profile, a longer plasma
half-life, and a lower incidence of HIT15. Like UFH,
LMWHs produce their anticoagulant effect by enhanc‑
ing antithrombin activity. Coagulation monitoring is

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generally not needed, and dosing is weight-adjusted15.
The major limitation of LMWHs is that they have pre‑
dominantly renal clearance, and their use is generally
not recommended in patients with creatinine clearance
of <30 ml/min, owing to increased risk of bleeding17,18.
Different LMWHs are approved for use in Canada,
Europe, and the USA. However, the most extensively
tested in the setting of PCI is enoxaparin, which was
also compared with UFH in patients undergoing PPCI
in the ATOLL trial19. In this trial, patients (n = 910)
with STEMI were randomly assigned to receive an
intra­venous bolus of 0.5 mg/kg enoxaparin (followed
by an additional 0.25 mg/kg bolus in the event of a
prolonged procedure or thrombotic complications)
or UFH before PPCI19. Patients who received any anti‑
coagulant before randomization and those requiring
crossover from one drug to the other were excluded.
Enoxaparin did not significantly reduce the incidence
of the primary end point (a composite of death, com‑
plication of MI, procedure failure, or major bleeding at

Endothelium
Necrotic core

Tissue Blood stream

factor

Plaque
rupture

Heparin

Activated Nonactivated platelets

XII XIIa platelets
• Rivaroxaban
XI XIa • Heparin
• Clopidogrel
IX IXa VIIa VII • Prasugrel
• Ticagrelor
Tissue ADP • Cangrelor
VIIIa factor • Bivalirudin TXA2
• Heparin Vorapaxar
X Xa X
P2Y12 TP Aspirin
Va receptor receptor
Thrombin COX1
Prothrombin (II) Thrombin (IIa) Arachidonic
PAR1 acid
receptor
Fibrinogen (I) Fibrin (Ia)
V
GP (IIb/IIIa) Platelet
receptor
Fibrinogen (I)

vWF vWF receptor

• Abciximab
Collagen Collagen receptor • Eptifibatide
Fibrin • Tirofiban

Figure 1 | Mechanism of thrombus formation during ST‑segment elevation myocardial infarction, and targets of
Nature Reviews | Cardiology
currently available antithrombotic agents. After plaque rupture, adhesion of platelets to the subendothelium during
the rolling phase is mediated by the interaction between the glycoprotein (GP) Ib/V/IX receptor complex located on the
platelet surface and von Willebrand factor (vWF), and between collagen exposed at the site of vascular injury and platelet
collagen receptors. Binding of collagen to these receptors triggers intracellular mechanisms that induce the release of
activating factors, mainly thromboxane A2 (TXA2), ADP, and thrombin. These factors enhance the interactions among
adherent platelets and promote further recruitment and activation of circulating platelets. Platelet activation by these
mediators has as the final pathway the conversion of the platelet GP IIb/IIIa receptor, the main receptor mediating platelet
aggregation, into its active form. Activated GP IIb/IIIa receptors bind to fibrinogen and vWF, leading to platelet aggregation
and thrombus formation mediated by platelet–platelet interactions. Vascular injury also exposes subendothelial tissue
factor, which forms a complex with factor VIIa and sets off a chain of events that culminates in formation of the
prothrombinase complex. Prothrombin is converted to thrombin, which subsequently converts fibrinogen to fibrin,
generating a fibrin-rich clot, and further activates platelets by binding to protease-activated receptors (PAR1) on the
platelet membrane. However, only a modest amount of thrombin is produced as a result of the coagulation cascade, and
the surface of activated platelets is the main source of circulating thrombin. Antiplatelet and anticoagulant agents work by
inhibiting key receptors and factors involved in this cascade of events. COX, cyclooxygenase; TP, thromboxane prostanoid.

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Table 1 | Pharmacological properties of parenteral anticoagulants and indication in PPCI

Property Unfractionated Enoxaparin Fondaparinux Bivalirudin
heparin
Administration route Intravenous Intravenous, Subcutaneous Intravenous
subcutaneous
Factor Xa:IIa inhibition 1:1 3–4:1 Only Xa Only IIa
Action independent of No No No Yes
antithrombin
Nonspecific binding Yes Partial No No
Variable PK/PD measures Yes Yes (<unfractionated No No
heparin)
Inhibits fibrin-bound thrombin No No No Yes
Effect on platelets Activation Activation Activation Inhibition
Half-life ~60 min 90–120 min* 17 h 25 min
Risk of HIT Yes Yes Low No
(<unfractionated
heparin)
Indication in PPCI Class I Class IIa‡ Class III ACC/AHA: class I;
ESC: class IIa
Dose in PPCI 70–100 U/kg bolus 0.5 mg/kg NA 0.75 mg/kg
without GPIs§; 50–70 U/ intravenous bolus intravenous bolus;
kg bolus with GPIs§ 1.75 mg/kg/h infusion
Reversal agent Protamine sulfate No Recombinant No
factor VIIa
*After intravenous administration of 0.5 mg/kg. ‡Only in European guidelines; not recommended in US guidelines. §Further boluses
needed to maintain therapeutic activated clotting time. GPI, glycoprotein IIb/IIIa inhibitor; HIT, heparin-induced thrombocytopenia;
NA, not applicable; PD, pharmacodynamic; PK, pharmacokinetic; PPCI, primary percutaneous coronary intervention.

30 days) compared with UFH (28% versus 34%; relative
risk [RR] 0.83, 95% CI 0.68–1.01, P = 0.06). However,
enoxaparin led to a significant 41% relative reduction
in the composite main secondary end point of death,
recurrent acute coro­nary syndrome (ACS), or urgent
revasculariza­tion (7% versus 11%; P = 0.015), as well
as other secon­d ary end points, without increasing
the risk of major bleeding (5% versus 5%; P = 0.79).
Of note, crossover between anticoagulants or simultan­
eous administration of both was associated with worst
outcomes19. On the basis of the neutral results of the
ATOLL trial, the ACC/AHA guidelines do not give any
recommendation for the use of enoxaparin in PPCI1,2.
However, on the basis of a potential benefit in the
secon­dary end point, the ESC guidelines give a class IIa
indication for enoxaparin in this setting3,4.
Bivalirudin. The direct thrombin inhibitor bivalirudin
is a synthetic derivate of hirudin. The drug is a poly­
peptide of 20 amino acids that binds to thrombin at both
the active site and the fibrinogen-binding site (exosite 1)
without the need for a cofactor15,20. Administered by
intravenous infusion, bivalirudin has a linear dose–
response profile, which translates into an immediate
(2–15 min) and predictable anticoagulant effect, with no
need for routine coagulation monitoring and rapid offset
of anticoagulant effects after stopping the infusion15,20.
Only 20% of bivalirudin clearance is dependent on the
kidneys, and its half-life increases from 25 min to 1 h in
patients with severe kidney disease, and 3.5 h in patients
undergoing haemodialysis15,20.
Several clinical trials support the efficacy and safety
of bivalirudin compared with heparin plus routinely or
provisionally administered intravenous GPIs in patients
undergoing PCI, including for ACS20–22. However, the
benefit of bivalirudin use in patients with STEMI under‑
going PPCI has been the subject of debate. Clinical trials
of bivalirudin versus heparin in PPCI are summarized
in TABLE 2 and FIG. 2.
In the HORIZONS‑AMI trial23, patients (n = 3,602)
with STEMI undergoing PPCI were randomly assigned
to receive either bivalirudin with a provisional GPI, or
UFH plus routine GPIs. Compared with heparin plus
GPIs, bivalirudin significantly reduced the risk of net
adverse clinical events at 30 days (9.2% versus 12.1%;
RR 0.76, 95% CI 0.63–0.92, P = 0.005), mainly driven by
a 40% reduction in major bleeding (4.9% versus 8.3%;
RR 0.60, 95% CI 0.46–0.77, P <0.001). Although major
adverse cardiovascular events (MACE) were similar
between the two treatments, bivalirudin use led to a four‑
fold increase in the rate of acute (≤24 h) stent thrombosis
(1.3% versus 0.3%; P <0.001), with no differences in the
rate of subacute (>24 h−30 days) stent thrombosis23. Of
note, at 1‑year and 3‑year follow‑up, results were con‑
sistent with the 30‑day analysis, and bivalirudin use was
associated with a reduction in cardiac and all-cause mor‑
tality24,25. Interestingly, a post-hoc analysis of this trial sug‑
gested that a UFH bolus administered before bivalirudin
administration might be associated with an attenuated
risk of acute stent thrombosis without increasing major
bleeding26,27, which was supported by registry data on
almost 3,000 patients with STEMI undergoing PPCI28.

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The EUROMAX trial29 was designed to investi‑
gate whether the benefit of bivalirudin over heparin
in PPCI persisted in the setting of a more contempor­
ary approach characterized by prehospital adminis‑
tration of antithrombin therapy, optional use of GPIs,
and use of radial access and of the more potent P2Y12-
receptor inhibitors prasugrel and ticagrelor. In the trial,
patients (n = 2,218) with STEMI transported for PPCI
were randomly assigned to receive either bivalirudin or
hep­arin plus optional GPIs, initiated in the ambulance
or in a hospital without PPCI capacity. Compared with
heparin plus optional GPIs, bivalirudin significantly
reduced the risk of death or non-CABG-related major
bleeding at 30 days (5.1% versus 8.5%; RR 0.60, 95% CI
0.43–0.82, P = 0.001) and the composite of death, re‑­
infarction, or non-CABG major bleeding (6.6% versus
9.2%; P = 0.02), mainly driven by a 57% reduction in
major bleeding (2.6% versus 6.0%; P <0.001). Although
no differences in mortality were observed, bivalirudin
use was associ­ated with a sixfold increase in the rate of
acute stent thrombosis (1.1% versus 0.2%; P = 0.007).
This increase occurred despite prolonged bivalirudin
infusion after PCI (in 93% of patients, of whom 22.5%
received the PCI dose) and the use of prasu­g rel or
ticagre­lor in half of the patients29. However, the risk of
stent thrombosis seemed to be mitigated by prolong‑
ing the bivalirudin infusion at the PCI dose30. Of note,
a prespecified, post-hoc analysis showed that bivaliru‑
din reduced the composite end point of death or major
bleeding compared with either heparin plus bailout
GPIs or heparin plus routine upstream GPIs31. However,
these data should be considered as hypothesis-­
generating. A pooled analysis of 5,800 patients from
the HORIZONS‑AMI and EUROMAX trials confirmed
a 26% reduction in net adverse outcomes and a 47%
reduction in major bleeding, with a significant sixfold
increase in the risk of acute stent thrombosis, mainly in
the first 4 h after PPCI32.
In the HEAT‑PPCI trial33, patients (n = 1,812) with
STEMI undergoing PPCI were randomly assigned to
receive either bivalirudin or UFH. Only provisional
use of GPIs (abciximab) was allowed in both groups.
Bivalirudin use compared with UFH use significantly
increased the incidence of MACE (8.7% versus 5.7%;
RR 1.52, 95% CI 1.09–2.13, P = 0.02), mainly driven by a
significantly higher rate of re‑infarction, with no signifi­
cant difference in major bleeding (3.5% versus 3.1%;
P = 0.59). Bivalirudin use was associated with a more
than threefold increase in the rate of acute stent throm‑
bosis (2.9% versus 0.9%; P = 0.007). Of note, the rate of
acute stent thrombosis with bivalirudin was twofold to
threefold higher than in any previous study, possibly
related to the fairly short duration of infusion, which
was stopped immediately at the end of PCI33.
In the BRIGHT trial34, patients (n = 2,194) with acute
MI undergoing emergency PCI (87.7% with STEMI
undergoing PPCI) were randomly assigned to receive
either bivalirudin, heparin alone, or heparin plus GPI.
Bivalirudin use resulted in a decrease in 30‑day net
adverse clinical events compared with either heparin
alone (difference −4.3%; RR 0.67, 95% CI 0.50–0.90,
P = 0.008) or heparin plus tirofiban (difference −8.1%;
RR 0.52, 95% CI, 0.39–0.69, P <0.001). These results
were primarily owing to a reduction in bleeding events
with bivalirudin compared with heparin and hep‑
arin plus tirofiban (4.1% versus 7.5% versus 12.3%;
P = 0.001), without significant differences in MACE or
stent thrombosis. Moreover, acute stent thrombosis was
not increased with bivalirudin in this trial (0.3% in each
group), possibly owing to the routine use of a prolonged
postprocedural bivalirudin infusion at PCI dose. In the
subgroup of 1,925 patients with STEMI undergoing
PPCI, results were consistent with the overall trial popu­
lation for the primary end point, MACE, acute stent
thrombosis, and bleeding. Results were also consistent
at the 1‑year follow-up34.
In the BRAVE‑4 trial35, patients with STEMI under‑
going planned PPCI were randomly assigned to a strat‑
egy based on prasugrel plus bivalirudin or clopidogrel
plus UFH. The trial was terminated early owing to slow
recruitment after 548 patients (out of the 1,240 planned)
were randomized. No significant difference in the pri‑
mary outcome (a composite of MACE or major bleed‑
ing at 30 days) was observed between the two strategies
(15.6% versus 14.5% in the bivalirudin and UFH groups,
respectively), although the results should be interpreted
with caution because the trial was underpowered.
In the MATRIX trial36, patients (n = 7,213) with an
ACS for whom PCI was anticipated were randomly
assigned to receive either bivalirudin or UFH. The
rates of MACE and net adverse clinical events were not
signifi­cantly lower with bivalirudin than with UFH,
despite a significant reduction in major bleeding, all-
cause death, and cardiac death. Although patients
treated with bivalirudin had a modestly higher inci‑
dence of definite 30‑day stent thrombosis, the rate of
acute (≤24 h) stent thrombosis was similar between
treatment groups. Moreover, bivalirudin infusion after
PCI did not significantly decrease the rate of urgent
target-­vessel revascularization, definite stent thrombosis,
or net adverse clinical events compared with no infu‑
sion36. In the subgroup of patients (n = 4,010, 56%) with
STEMI, the use of bivalirudin did not reduce the rate
of MACE compared with the use of UFH (5.9% versus
6.5%; RR 0.90, 95% CI 0.70–1.16, P = 0.43), nor the rate
of net adverse clinical events (7.0% versus 8.2%; RR 0.84,
95% CI 0.67–1.05, P = 0.13). Consistent with the overall
trial population, bivalirudin use was associated with a
reduction in BARC 3 or 5 bleeding (1.7% versus 2.8%;
P = 0.019), and all-cause and cardiovascular death com‑
pared with UFH, with no significant difference in acute
stent thrombosis (0.9% versus 0.5%; P = 0.10). Of note,
bivalirudin seemed to be safer and more effective than
heparin in the subgroup of patients with STEMI and
chronic kidney disease and in those with previous use
of UFH37. However, these results should be interpreted
with caution as they derive from a post-hoc analysis and
need to be considered as hypothesis-generating.
Overall, results of these large-scale clinical trials,
as well as data from several meta-analyses, show that
bivali­rudin compared with heparin yields similar rates
of MACE and net adverse clinical events at 30 days,

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Table 2 | Major clinical trials of bivalirudin versus heparin in PPCI

Feature HORIZONS-AMI23 EUROMAX29 HEAT-PPCI33 BRIGHT34 MATRIX-STEMI37
Trial design
Patient 3,602 STEMI undergoing 2,218 STEMI 1,812 STEMI 2,194 acute MI 4,010 STEMI
population PPCI transported for PPCI undergoing PPCI undergoing emergency PCI undergoing PPCI*
(87.7% STEMI)
Type of heparin UFH UFH or enoxaparin UFH UFH UFH
Heparin dose‡ 60 U/kg with subsequent UFH: 100 U/kg 70 U/kg 100 U/kg in heparin-only 70–100 U/kg without
boluses targeted to ACT without GPI or group; 60 U/kg in heparin GPI or 50–70 U/kg with
of 200–250 s 60 U/kg with GPI. plus tirofiban group GPI
Enoxaparin: 0.5 mg/kg
GPI use in Routine Routine or bailout Bailout Bailout (5.6% of patients) in Routine or bailout
heparin group (97.7% of patients) (69% of patients) (14% of patients) heparin-only group; routine (25.9% of patients)
(100%) in heparin plus
tirofiban group
GPI use in Bailout (7.5% of patients) Bailout Bailout Bailout Bailout
bivalirudin (11.5% of patients) (14% of patients) (4.4% of patients) (4.6% of patients)
group
Post-PCI None (but could be 4 h after PCI at None 30 min−4 h after PCI Patients randomized 1:1
bivalirudin continued at low doses if 0.25 mg/kg/h; (mean 180 min) at PCI dose to receive or not receive
infusion clinically indicated) continuation of post-PCI infusion
PCI dose was also (full dose for up to 4 h
permitted (22.5%) or reduced dose of
0.25 mg/kg/h for ≥6 h)
P2Y12-receptor Clopidogrel 300–600 mg Clopidogrel (50%), Clopidogrel (11%), Clopidogrel 300–600 mg Clopidogrel (29%),
inhibitor prasugrel (30%), prasugrel (27%), prasugrel (31%),
or ticagrelor (20%) or ticagrelor (62%) or ticagrelor (30%)
Radial access No 47% of patients 81% of patients 78% of patients 50% (randomized 1:1 to
radial versus femoral)
Primary end NACE (major bleeding Death or Efficacy: MACE NACE (MACE [all-cause MACE (death, MI, or
point or MACE [death, non-CABG-related (all-cause death, death, reinfarction, stroke) at 30 days;
reinfarction, TVR major bleeding at CVA, reinfarction, ischaemia-driven TVR, or NACE (MACE or major
for ischaemia, and 30 days or additional stroke] or any bleeding) at bleeding) at 30 days
stroke]) at 30 days; unplanned TLR) at 30 days
non-CABG-related major 28 days. Safety: major
bleeding at 30 days bleeding at 28 days
Bleeding Protocol-defined§ Protocol-defined|| BARC type 3–5 BARC BARC type 3 or 5
definition
Study results
Primary end NACE: bivalirudin 9.2% Bivalirudin 5.1% MACE: bivalirudin Bivalirudin 8.8% versus MACE: bivalirudin 5.9%
point(s) versus heparin 12.1% versus heparin 8.5% 8.7% versus heparin heparin 13.2% versus versus heparin 6.5%
(P = 0.005); non-CABG- (P = 0.001) 5.7% (P = 0.02); major heparin plus tirofiban 17.0% (P = 0.43); NACE:
related major bleeding: bleeding: bivalirudin (P <0.001) bivalirudin 7.0% versus
bivalirudin 4.9% versus 3.5% versus heparin heparin 8.2% (P = 0.13)
heparin 8.3% (P <0.001) 3.1% (P = 0.59)
MACE Bivalirudin 5.4% versus Bivalirudin 6.0% See primary end Bivalirudin 5.0% versus See primary end point
heparin 5.5% (P = 0.95) versus heparin 5.5% point heparin 5.8% versus heparin
(P = 0.64) plus tirofiban 4.9% (P = 0.83)
Major bleeding See primary end point Bivalirudin 2.6% See primary end BARC type 3–5: Bivalirudin 1.7% versus
versus heparin 6.0% point bivalirudin 0.5% versus heparin 2.8% (P = 0.019)
(P <0.001) heparin 1.5% versus heparin
plus tirofiban 2.1% (P = NA)
Acute stent Bivalirudin 1.3% versus Bivalirudin 1.1% Bivalirudin 2.9% Bivalirudin 0.3% versus Bivalirudin 0.9% versus
thrombosis heparin 0.3% (P <0.001) versus heparin 0.2% versus heparin 0.9% heparin 0.3% versus heparin heparin 0.5% (P = 0.10)
(≤24 h) (P = 0.007) (P = 0.007) plus tirofiban 0.3% (P = NA)
Bivalirudin dose was 0.75 mg/kg bolus followed by 1.75 mg/kg/h for the duration of PCI in all studies. *The MATRIX trial included 7,213 patients with ACS for whom PCI was
anticipated, of whom 4,010 had STEMI (56%) and 3,203 (44%) had non‑ST‑segment elevation ACS; results of the STEMI subgroup are reported here. ‡Initial bolus dose;
subsequent UFH boluses were to be administered to maintain target ACT. §Major bleeding: intracranial or intraocular haemorrhage; bleeding at the access site, with a
haematoma that was ≥5 cm or that required intervention; a decrease in the haemoglobin level of ≥4 g/dl without an overt bleeding source or ≥3 g/dl with an overt bleeding
source; reoperation for bleeding; or blood transfusion. ||Major bleeding: intracranial, retroperitoneal, or intraocular bleeding; access-site haemorrhage requiring
radiological or surgical intervention; a reduction in the haemoglobin level of >4 g/dl without an overt source of bleeding; a reduction in the haemoglobin level of >3 g/dl
with an overt source of bleeding; reintervention for bleeding; or use of any blood-product transfusion. ACS, acute coronary syndrome; ACT, activated clotting time;
BARC, Bleeding Academic Research Consortium; CVA, cardiovascular accident; GPI, glycoprotein IIb/IIIa inhibitor; MACE, major adverse cardiovascular events;
MI, myocardial infarction; NA, not available; NACE, net adverse clinical events; STEMI, ST‑segment-elevation myocardial infarction; PCI, percutaneous coronary
intervention; PPCI, primary percutaneous coronary intervention; TLR, target-lesion revascularization; TVR, target-vessel revascularization; UFH, unfractionated heparin.

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and reduces major bleeding, with a signal towards a a MACE

reduction in all-cause and cardiac mortality, at the price
of an increased risk of acute stent thrombosis22,29,33–35,37–39.
Currently, bivalirudin, with or without previous hep­arin
therapy, has a class I (level of evidence B) recommenda‑
tion in the ACC/AHA guidelines1,2. The ESC guidelines
give a class IIa recommendation, also specify­ing that a
1.75 mg/kg/h infusion should be administered for up
to 4 h after the procedure3,4. In patients at high risk of
bleeding, preferential use of bivalirudin mono­therapy
compared with UFH plus GPIs is given a class  IIa
recom­m endation in the ACC/AHA guidelines 1,2.
Of note, the different levels of recommendations in
these guidelines might be owing to the timing of publi‑
cation relative to the clinical trials described above. The
ACC/AHA guidelines were published before the results
of the EUROMAX and HEAT‑PPCI trials were available,
whereas the ESC guidelines incorporated the results of
these trials, which led to a downgrading of bivalirudin
from a class I recommendation to the current class IIa.
Whether the results of the BRIGHT and MATRIX trials
will lead to further changes in the guidelines is currently
not known.
Antiplatelet therapy
Intravenous antiplatelet drugs include the cyclo­
oxygenase (COX) 1 inhibitor aspirin (not approved by
the FDA for parenteral use); the GPIs abciximab, eptifi­
batide, and tirofiban; and the P2Y12-receptor inhibitor
cangrelor. Given that aspirin is primarily used in an oral
formulation, details on this drug are given in the section
on oral antiplatelet therapy.
Glycoprotein IIb/IIIa inhibitors. GPIs can be classified
into two groups: small (eptifibatide, tirofiban) and non-
small (abciximab) molecules, which are characterized
by different pharmacological properties (TABLE 3). They
target the final pathway of platelet aggregation, com‑
peting with von Willebrand factor and fibrinogen for
glycoprotein IIb/IIIa receptor binding and provide fast
and potent antiplatelet effects40. GPIs have been shown
to improve ischaemic outcomes in patients with STEMI
or non-STEMI undergoing PCI, and most clinical trials
of GPIs in STEMI have studied abciximab40–43. However,
recent trials also support the benefit of eptifibatide and
tirofiban (used at high-bolus dose), which yield similar
outcomes to abciximab44,45. Nevertheless, the clinical
benefit of GPIs was mainly shown in the era of b ­ alloon
angioplasty, before routine use of dual antiplatelet ther‑
apy (DAPT), the advent of new stent technologies, radial
artery interventions, thrombus aspiration, and direct
thrombin inhibitors. In these trials, GPI therapy was
associated with a reduction in MACE at the expense of
increased bleeding and thrombocytopenia40–45. To date,
the administration of GPIs is an accepted treatment
option in patients undergoing PPCI. However, the
development of alternative treatment strategies with a
more favourable safety profile has reduced their role,
and available data support selective (that is, bail-out
in the event of large residual thrombus) rather than
routine use40.
HORIZONS-AMI23
EUROMAX29
HEAT-PPCI33
BRIGHT34*
MATRIX-STEMI37†
b Major bleeding
HORIZONS-AMI23
EUROMAX29
HEAT-PPCI33
BRIGHT34*
MATRIX-STEMI37†
0.0 0.5 1.0 1.5 2.0
Bivalirudin better Heparin better
Figure 2 | Ischaemic and bleeding outcomes in the
Nature Reviews | Cardiology
major clinical trials comparing bivalirudin versus
heparin in ST‑segment elevation myocardial infarction
(STEMI). The graphs show relative risk with the 95%
confidence intervals of bivalirudin versus heparin on
a | major adverse cardiovascular events (MACE) and
b | major bleeding. MACE and major bleeding are as
defined in each study protocol. Follow‑up was 30 days for
each trial, with the exception of HEAT-PPCI for which it was
28 days. *Data are reported for the comparisons between
bivalirudin versus heparin plus bailout glycoprotein IIb/IIIa
inhibitors. ‡The MATRIX trial included 7,213 patients with
acute coronary syndrome for whom percutaneous
coronary intervention was anticipated, of whom 4,010
(56%) had STEMI and 3,203 (44%) non‑ST‑segment
elevation acute coronary syndrome. The results of the
STEMI subgroup are reported here.
Intracoronary administration of GPIs, which could
potentially allow a rapid achievement of local platelet
inhibition resulting in improved myocardial perfusion,
has been tested in several small studies and shown to be
associated with some benefits, as compared with intra‑
venous administration, but these results have not been
confirmed in large-scale clinical trials46–49. Currently, the
ACC/AHA guidelines give a class IIa recommendation
for GPIs at the time of PPCI (abciximab, double-bolus
eptifibatide, or high-bolus-dose tirofiban) in selected
patients with STEMI receiving UFH (with or without
stenting or clopidogrel pretreatment), and a class IIb
indication for intracoronary abciximab1,2. The ESC
guidelines instead give a class IIa recommendation for
GPIs for bailout use only (for example, in the event of
evidence of no‑reflow or thrombotic complications)3,4.
Several studies have also investigated whether early,
upstream use of GPIs as a facilitating strategy to early
reperfusion can improve clinical outcomes in STEMI50.
However, results were not consistent, and a clear benefit
of this approach has not been demonstrated. A detailed
description of pharmacoinvasive approaches for STEMI

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Table 3 | Pharmacology of glycoprotein IIb/IIIa inhibitors

Feature Abciximab Eptifibatide Tirofiban
Trade name ReoPro Integrilin Aggrastat
Molecule Fragment antigen binding (Fab)7E3 Synthetic peptide Nonpeptide mimetic
Molecular weight (Da) ~50,000 ~800 ~500
Stoichiometry (drug to ~1.5:1 >>100:1 >>100:1
glycoprotein IIb/IIIa)
Binding Noncompetitive Competitive Competitive
Half-life (h) • Plasma: 10–15 • Plasma: 2.0–2.5 • Plasma: 2.0–2.5
• Biologic: 12–24 • Biologic = plasma • Biologic = plasma
PCI dosing • Bolus: 250 µg/kg • Bolus: 180 µg/kg* plus • Bolus: 25 µg/kg
• Infusion: 0.125 µg/kg/min (12 h) 180 µg/kg (after 10 min) • Infusion: 0.15 µg/kg/
• Infusion: 2 µg/kg/min (12–24 h)‡ min (up to 18 h)
Renal adjustment No • Bolus: 180 µg/kg • Bolus: 25 µg/kg
• Infusion: 1 µg/kg/min (12–24 h) • Infusion: 0.075 µg/
kg/min (up to 18 h)
*Started immediately before PCI. ‡Started immediately after the first bolus. PCI, percutaneous coronary intervention. Reprinted
from Muñiz-Lozano, A. et al. Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice. Ther. Adv.
Cardiovasc. Dis. 7 (4), 197–213 (2013).

goes beyond the scope of this Review, and is described
elsewhere51. Both the ACC/AHA and ESC guidelines
give a class IIb (level of evidence B) recommendation
for upstream use of GPIs1–4. In particular, upstream
use of a GPI (versus in‑lab use) might be considered
in high-risk patients undergoing transfer for PPCI,
on the basis of the benefit shown in a post-hoc analysis
of the FINESSE trial52.
Cangrelor. Cangrelor is an analogue of ATP and the only
intravenous P2Y12-receptor inhibitor currently available
for clinical use. It directly and reversibly binds to the
P2Y12 receptor in a predominantly competitive ­manner
without the need to be metabolized53,54. Cangrelor is
characterized by a linear dose-dependent pharmaco­
kinetic profile, which leads to very stable pharma‑
codynamic effects, and achieves very potent platelet
inhibition reaching steady-state concentrations within
a few minutes53,54. Its very short half-life (3–5 min)
allows a fast offset of action, with platelet aggregation
returning to baseline levels within 30–60 min from
infusion termination53,54. The unique pharmacological
properties of cangrelor, along with the central role of
the ADP receptor in platelet activation and in amplifi‑
cation of other platelet signalling pathways, make this
agent a very attractive option in the setting of PPCI.
In addition, cangrelor is not affected by renal function
and thus, unlike small-molecule GPIs, does not require
dose adjustment in patients with kidney disease, which
is often unknown at the time of presentation in patients
with STEMI53,54.
Cangrelor was approved for clinical use on the basis of
the results of the CHAMPION PHOENIX trial55, which
tested the hypothesis that addition of cangrelor to DAPT
(aspirin plus clopidogrel) in patients under­going PCI
could reduce the occurrence of acute ischaemic events in
P2Y12-receptor inhibitor-naive patients across the spec‑
trum of coronary artery disease manifestations (stable
angina, non‑ST‑segment elevation ACS, and STEMI).
After angiography, patients (n = 11,145) were randomly
assigned to receive either cangrelor (30 μg/kg bolus fol‑
lowed by 4 μg/kg/min infusion for 2–4 h) or clopidogrel
loading dose (300–600 mg before or immediately after
PCI, as per institutional standard). In the cangrelor
group, patients received 600 mg of clopidogrel at the
end of infusion. Adjunctive cangrelor therapy signifi‑
cantly reduced by 22% the composite of death from any
cause, MI, ischaemia-driven revascularization, and stent
thrombosis at 48 h (4.7% versus 5.9%; P = 0.005), mainly
driven by a 20% reduction in the rate of MI. Cangrelor
also led to a significant 38% reduction in the rate of the
main secondary efficacy end point of stent thrombosis55.
Intraprocedural stent thrombosis, which was shown to
be associated with an increase in adverse outcomes at
48 h and 30 days, was also ­significantly reduced by the
use of cangrelor56.
The rate of severe bleeding at 48 h was not signifi‑
cantly increased by cangrelor according to the GUSTO
criteria, as well as with other definitions of bleeding.
However, the rate of major bleeding according to the
more sensitive ACUITY criteria was significantly
higher in patients treated with cangrelor, mainly owing
to higher incidence of haematoma at the site of vascu‑
lar access. Overall, the net rate of adverse clinical events
(ischaemic plus bleeding events) was significantly
reduced by the use of cangrelor. The clinical benefit of
adjunctive cangrelor therapy was consistent at 30 days55.
Of note, in the subgroup of patients receiving bivaliru‑
din (19% of the trial population), cangrelor compared
with clopidogrel significantly reduced ischaemic events
as well as stent thrombosis to the same magnitude as in
the main trial, with a trend for reduced stent thrombosis
in the first 2 h (REF. 57). An exploratory pooled analysis of
patient-level data from the three phase III CHAMPION
trials compared the ischaemic and bleeding risk of GPIs
versus cangrelor in patients undergoing PCI. Cangrelor
was associated with a similar ischaemic risk and a trend
towards a lower risk-adjusted risk of severe bleeding

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compared with clopidogrel plus GPIs58. In the STEMI
subgroup of the CHAMPION PHOENIX trial55 (18% of
the overall trial population), cangrelor showed a con‑
sistent 25% reduction in the primary end point (2.8%
versus 3.7%; OR 0.75, 95% CI 0.46–1.25, P = 0.98 for
interaction) at the expense of an 84% increase in major
bleeding, which was also consistent with the overall trial
population (P = 0.93 for interaction).
Cangrelor (30 μg/kg bolus plus 4 μg/kg/min infu‑
sion initiated before PCI and continued for ≥2 h or for
the duration of PCI, whichever is longer) is currently
approved for clinical use by the FDA and the European
Medicines Agency (EMA) as an adjunct to PCI for
reducing the risk of periprocedural MI, repeat coro‑
nary revascularization, and stent thrombosis in patients
who have not been treated with an oral P2Y12-receptor
antagonist and are not being given a GPI59,60. Although
no specific recommendations are available for patients
with STEMI, cangrelor has been endorsed in the ESC
guidelines for patients with non‑ST‑segment elevation
ACS (class IIb, level of evidence A)61. To date, the clinical
profile of cangrelor compared with GPIs and in addi‑
tion to the more potent oral P2Y12 inhibitors prasugrel
and ticagrelor has yet to be tested. Although switching
from cangrelor to clopidogrel has been tested in large-
scale clinical trials55,62, the transition between cangrelor
and other oral antiplatelet agents has been investigated
in a few small pharmacodynamic studies63–69. Data
available so far suggest that clopidogrel and prasugrel
should be administered immediately after discontinu­
ation of cangre­lor infusion to avoid a pharmacodynamic
interaction, because these agents compete for the same
ADP-binding site on the P2Y12 receptor63–68. By con‑
trast, ticagrelor is a noncompetitive ADP antagonist
and can, therefore, be administered before, during, or
after cangre­lor infusion63,69. No drug interaction has
been described when transitioning from any oral P2Y12-
receptor inhibitor to cangrelor, which can, therefore,
be started at any time63–69.
Oral antithrombotic therapies
Oral antithrombotic therapy is the cornerstone of the
acute and long-term treatment of patients with STEMI.
Several classes of antithrombotic, both antiplatelet and
anticoagulant, agents available for oral administration
are currently approved for clinical use for the manage‑
ment of patients with STEMI (TABLE 4). These agents
include COX1 inhibitors (aspirin); P2Y12-receptor
antagonists (clopidogrel, prasugrel, ticagrelor, and
ticlopidine); PAR1 inhibitors (vorapaxar); and fac‑
tor Xa inhibitors (rivaroxaban)1–4,9. The use of aspirin in
combin­ation with a P2Y12-receptor antagonist is com‑
monly known as standard DAPT. Other oral therapies
have been tested in addition to standard DAPT and are,
therefore, described as adjunctive therapies.
Standard dual antiplatelet therapy
Aspirin. Aspirin irreversibly inhibits COX1 and thereby
blocks the production from arachidonic acid of throm‑
boxane A2, a vasoconstrictor and highly potent stimu‑
lant of platelet activation70,71. Aspirin is rapidly absorbed
in the upper gastrointestinal tract and is associated
with measurable platelet inhibition within 60 min.
The plasma half-life of aspirin is approximately 20 min,

Table 4 | Pharmacological properties of oral antithrombotic therapy for STEMI

Feature Aspirin Clopidogrel Prasugrel Ticagrelor Vorapaxar Rivaroxaban*
Target COX1 P2Y12 receptor P2Y12 receptor P2Y12 receptor PAR1 Factor Xa
Type of blockade Irreversible Irreversible Irreversible Reversible Reversible Reversible
Dose 150–325 mg 600 mg 60 mg LD; 10 mg 180 mg LD; 90 mg 2.08 mg once-daily 2.5 mg twice-daily MD
LD; 81–100 mg LD; 75 mg once-daily MD twice-daily MD MD
once-daily MD once-daily MD
Prodrug No Yes Yes No‡ No No
Onset of action 60 min 2‑8 h 30 min−4 h§ 30 min−4 h§ >12 h|| 2–4 h
Offset of action 7–10 days 7–10 days 7–10 days 3–5 days 4–8 weeks 12 h
Drug interactions NSAIDs CYP2C19 No CYP3A inhibitors CYP3A inhibitors CYP3A4 inhibitors or
inhibitors or inducers, drugs or inducers, drugs inducers, P‑glycoprotein
using P‑glycoprotein using P‑glycoprotein transporter inhibitors
transporter transporter
Timing of Immediately At presentation At presentation At presentation or at After stabilization¶ After stabilization
administration after or at time or at time time of PPCI (>24 h after admission)
presentation of PPCI of PPCI
Contraindications Hypersensitivity Hypersensitivity, Prior CVA, high Prior ICH, high risk Prior ICH or Prior CVA, CrCl
active risk of bleeding, of bleeding, severe CVA, high risk <15 ml/min, high risk of
pathological hypersensitivity hepatic dysfunction, of bleeding, bleeding, severe hepatic
bleeding hypersensitivity hypersensitivity dysfunction, treatment
with other anticoagulant,
hypersensitivity
*Approved only by the European Medicines Agency; not approved by the FDA for this use. ‡Although most ticagrelor-mediated antiplatelet effects are direct,
approximately 30–40% are attributed to an active metabolite (AR‑C124910XX). §Depending on clinical setting. ||If administered without a loading dose. ¶2 weeks
after the acute event according to European Medicines Agency; no timing prespecified by the FDA. COX, cyclooxygenase; CrCl, creatinine clearance; CVA,
cerebrovascular accident; CYP, cytochrome P450; ICH, intracranial haemorrhage; LD, loading dose; MD, maintenance dose; NSAID, nonsteroidal anti-inflammatory
drug; PAR, protease-activated receptor; PPCI, primary percutaneous coronary intervention; STEMI, ST‑segment elevation myocardial infarction.

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and peak plasma levels are achieved 30–40 min after
ingestion of uncoated aspirin70,71. In the ISIS‑2 trial72,
aspirin therapy was associated with a significant
reduction in vascular mortality in patients with sus‑
pected acute MI, either as a stand-alone therapy or
in combination with streptokinase. Aspirin is the
established first-line therapy in patients with STEMI,
and non-enteric-coated aspirin (150–325 mg) should
be administered promptly after presentation (class I
recommendation) and then continued indefinitely
irrespective of the treatment strategy 1–4. The aspi‑
rin loading dose should preferably be given orally
including chewing, to ensure complete inhibition
of thromboxane A2-dependent platelet aggregation.
An  intravenous formulation is available in some
­countries, and can be used in patients who are unable to
swallow. Current evidence suggests the use of low-dose
aspirin (≤100 mg) following the initial loading dose73,74.
However, aspirin specifically targets COX1, and is not
effective in reducing platelet activation mediated by
other pathways involved in arterial thrombosis, which
exposes patients to residual thrombotic risk in both the
acute and long-term phases, underscoring the need for
adjunctive therapies8,9. P2Y12-receptor inhibitors are
the standard-of‑care therapy to be used in combination
with aspirin, also known as DAPT9.
P2Y12-receptor inhibitors. ADP exerts its effects on
platelets through the purinergic G‑protein-coupled
P2Y12 and P2Y1 receptors, with the former having the
major role in platelet activation and aggregation9,75. The
combination of a P2Y12-receptor antagonist and aspirin
can produce a degree of platelet inhibition higher than
that achieved by each single agent76, and this synergistic
effect has been shown to be beneficial in several clin‑
ical trials that tested antiplatelet regimens in patients
with ACS, including those with STEMI9,77–86 (TABLE 5).
Therefore, DAPT with aspirin and a P2Y12-receptor
inhibitor is the mainstay of the early and long-term
treatment of patients with STEMI1–4,9. The first avail‑
able P2Y12-receptor inhibitor was the first-generation
thienopyridine ticlopidine, which in combination with
aspirin was superior to both aspirin alone and aspirin
plus warfarin for prevention of thrombotic events in
patients undergoing PCI77–80. However, its use has been
largely abandoned owing to its frequent adverse effects,
including life-threatening haematological disorders,
and because of the better clinical outcomes achieved
with clopidogrel87,88.
Clopidogrel. The second-generation thienopyridine
clopidogrel is the most widely used P2Y12-receptor
inhibitor89–91. Clopidogrel is a prodrug that requires
metabolic transformation to exert its antiplatelet
effect. After intestinal absorption, ~85% of clopidogrel
is hydrolysed by carboxylase to an inactive metabo­
lite. The remaining ~15% is rapidly metabolized by
hepatic cytochrome P450 (CYP) isoenzymes, mainly
CYP2C19, in a two-step oxidation process which leads
to the gener­ation of a highly unstable active metabolite
that binds to the P2Y12 receptor in a competitive (irre‑
versible) ­manner9. Several clinical trials have shown
the benefit of DAPT with aspirin and clopidogrel in a
broad spectrum of coronary artery disease manifesta‑
tions, including in patients with STEMI81–84 (TABLE 5).
The CLARITY trial83, conducted in patients (n = 3,491)
with STEMI treated with fibrinolytic therapy and then
undergoing urgent angiography, showed that clopi‑
dogrel (300 mg loading dose, followed by 75 mg per
day) in addition to aspirin significantly reduced the
incidence of thrombotic events before angiography
compared with placebo (21.7% versus 15.0%; OR 0.64,
95% CI 0.53–0.76, P <0.001). In the COMMIT trial84,
patients (n = 45,852) with acute MI, mainly STEMI, were
randomly assigned to receive either clopidogrel (75 mg
per day) or matching placebo, plus aspirin. Clopidogrel
therapy significantly reduced thrombotic events (9.2%
versus 10.1%; OR 0.91, 95% CI 0.86–0.97, P = 0.002),

Table 5 | Major clinical trials of oral antithrombotic therapy in ACS including STEMI
Trial Setting Treatment groups Primary end point Results*
CLARITY 83
3,491 STEMI Aspirin plus clopidogrel plus FA Occluded infarct-related 15.0% vs 21.7%; OR 0.64,
vs aspirin plus FA artery, death, or recurrent MI 95% CI 0.53–0.76, P <0.001
before angiography
COMMIT84 45,852 acute MI (39,755 STEMI) Aspirin plus clopidogrel vs aspirin Death, reinfarction, or stroke 9.2% vs 10.1%; OR 0.91,
at 28 days 95% CI 0.86–0.97, P = 0.002
TRITON-TIMI 38 13,608 ACS undergoing PCI Aspirin plus prasugrel vs aspirin Cardiovascular death, 9.9% vs 12.1%; HR 0.81,
(REF. 85) (3,534 STEMI) plus clopidogrel nonfatal MI or nonfatal 95% CI 0.73–0.90, P <0.001
stroke at 14.5 months
PLATO86 18,624 ACS (7,544 STEMI) Aspirin plus ticagrelor vs aspirin Death from vascular causes, 9.8% vs 11.7%; HR 0.84,
plus clopidogrel MI, or stroke at 12 months 95% CI 0.77–0.92, P <0.001
TRA 2oP-TIMI 50 26,449 with prior MI, ischaemic Standard APT plus vorapaxar vs Cardiovascular death, MI, 9.3% vs 10.5%; HR 0.87,
(REF. 108) stroke, or PAD (9,248 with standard APT plus placebo or stroke at 36 months 95% CI 0.80–0.94, P <0.001
STEMI as qualifying event)
ATLAS ACS 2- 15,526 patients with recent DAPT plus rivaroxaban 5.0 mg vs Cardiovascular death, 8.8% vs 9.1% vs 10.7%;
TIMI 51 ACS (7,817 STEMI) DAPT plus rivaroxaban 2.5 mg vs nonfatal MI or nonfatal HR 0.84, 95% CI 0.74–0.96,
(REF. 115) DAPT plus placebo stroke at 24 months P = 0.008‡
*Results are reported for the main trial. ‡Combined rivaroxaban groups versus placebo. ACS, acute coronary syndrome; APT, antiplatelet therapy; DAPT, dual
antiplatelet therapy; FA, fibrinolytic agent; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STEMI, ST‑segment
elevation myocardial infarction.

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and death from any cause (7.5% versus 8.1%; OR 0.93,

95% CI 0.87–0.99, P = 0.03). On the basis of these data,
clopidogrel has been for many years the standard of
care, in addition to aspirin, in patients with STEMI9.
Clopidogrel (300–600 mg loading dose and 75 mg daily
maintenance dose) is currently recommended (class I)
for the treatment of patients with STEMI. Available data
also suggest that a 600 mg loading dose should be pre‑
ferred in patients undergoing PPCI1–4. In patients with
STEMI treated with fibrinolytics, clopidogrel is also the
only P2Y12-receptor inhibitor currently recommended
and should be administered as a 300 mg loading dose
followed by 75 mg per day in patients aged ≤75 years,
and 75 mg per day without a loading dose in patients
aged >75 years1–4.
Concerns have grown about the heterogeneous
nature of individuals’ response to clopidogrel. Several
factors have been associated with clopidogrel response
variability, including genetic (CYP polymorphisms),
clinical (poor absorption, drug–drug interactions, ACS,
diabetes mellitus, obesity, chronic kidney disease), and
cellular (accelerated platelet turnover or upregulation
of P2Y 12 pathway) factors 92,93. Importantly, several
pharmaco­dynamic studies have shown that approx­
imately 30–40% of patients have high platelet reactivity
while on treatment with clopidogrel, which translates
into higher rates of cardiovascular events, including
stent thrombosis92,93. These findings underscore the
need for more potent antiplatelet agents, especially for
patients with high prothrombotic milieu such as those
with STEMI, which has led to the clinical development
of prasugrel and ticagrelor.
Prasugrel. Prasugrel is a third-generation thienopyri‑
dine. Prasugrel is a prodrug and, after intestinal absorp‑
tion, requires a single-step oxidation process through
hepatic CYP to generate its active metabolite, which irre‑
versibly binds to the P2Y12 receptor9. The active metabo‑
lites of prasugrel and clopidogrel have the same potency,
but the metabolic conversion of prasugrel is more effi‑
cient, leading to higher bioavailability94. These pharma‑
cological properties translate into faster onset of action,
enhanced platelet inhibition, and lower i­nterindividual
variability compared with clopidogrel95.
In the TRITON-TIMI 38 trial85, patients (n = 13,608)
with moderate-to‑high-risk ACS scheduled for PCI were
randomly assigned to receive either prasugrel 60 mg
loading dose followed by 10 mg daily maintenance dose,
or clopidogrel 300 mg loading dose followed by 75 mg
daily maintenance dose, in addition to aspirin. In the
trial, coronary anatomy had to be defined before ran‑
domization in all patients, with the exception of those
with STEMI. Prasugrel significantly reduced the primary
efficacy end point (a composite of cardiovascular death,
nonfatal MI, or nonfatal stroke) by 19% compared with
clopidogrel over a median follow‑up of 14.5 months,
mainly driven by a reduction in nonfatal MI. Prasugrel
also led to a significant 52% reduction in the rate of
stent thrombosis, and a 34% decrease in the need for
urgent target-vessel revascularization. Although this
effect was hampered by significantly increased rates
TRITON96
TRITON PPCI97
PLATO102
PLATO PPCI103
TRA 2°P110
ATLAS-ACS115*
0.0 0.5 1.0 1.5 2.0
Alternative Aspirin and
treatment better clopidogrel better
Figure 3 | Ischaemic outcomes in theReviews
Nature ST‑segment
| Cardiology
elevation myocardial infarction (STEMI) subgroups
of major clinical trials on novel oral antithrombotic
agents. Risk reduction of novel antithrombotic agents
versus dual antiplatelet therapy with aspirin and
clopidogrel in post-hoc analyses on the STEMI subgroups
of clinical trials performed in patients with acute coronary
syndromes. Major adverse cardiovascular events are the
primary end point of each trial. *Results are reported
for the comparison between rivaroxaban 2.5 mg
versus placebo.
of non-CABG-related major bleeding, CABG-related
major bleeding, life-threatening bleeding, and fatal
bleeding, the net clinical benefit was still in favour of
prasugrel-treated patients. Importantly, use of prasugrel
had a neutral effect in patients with low body weight
(<60 kg) and elderly patients (aged ≥75 years), and a net
harm in patients with a history of stroke or transient
ischaemic attack85.
In the subgroup of patients (n = 3,534) with STEMI
undergoing PCI, prasugrel reduced the primary end
point at 30 days compared with clopidogrel (6.5% ver‑
sus 9.5%; HR 0.68, 95% CI 0.54–0.87, P = 0.002), with
an effect that was consistent with the main trial popu­
lation (P = 0.769 for interaction)96,97 (FIG. 3). The main
secondary end point of cardiovascular death, MI, or
urgent target-vessel revascularization at 30 days, as well
as stent thrombosis, were also significantly reduced.
Non-CABG-related major bleeding was similar in the
clopidogrel and prasugrel groups, but no interaction was
noted between presenting syndrome and the bene­fits of
prasugrel (P = 0.4091 for interaction). All these effects
persisted up to 15 months. Of note, patients with STEMI
were divided into two strata in the trial: those enrolled
within 12 h of onset of symptoms (PPCI), and those
enrolled between 12 h and 14 days after symptom onset
(secondary PCI). No significant benefit with prasu­
grel over clopidogrel was shown for patients receiving
PPCI, and the effects seen in patients with STEMI as
a whole were mainly driven by patients who received
secondary PCI. However, the effects on the primary
end point were consistent between primary and sec‑
ondary PCI at 15 months (P = 0.15 for interaction), with
a tendency towards a difference in treatment effect at
30 days (P = 0.06 for interaction). This trend was attenu­
ated after periprocedural MI events were excluded from
the analysis. In addition, the magnitude of the risk
reduction achieved by prasugrel in patients treated with

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REVIEWS

PPCI for the primary end point at 30 days was similar
to that achieved in the whole trial population (HR 0.80,
95% CI 0.60–1.08, P = 0.144), with a significant reduc‑
tion in rates of stent thrombosis96,97. Prasugrel (60 mg
loading dose and 10 mg daily maintenance dose) is cur‑
rently a class I recommendation in patients with STEMI
undergoing reperfusion with PPCI, and can be admin‑
istered in this setting even before coronary anatomy has
been established1–4.
Ticagrelor. The cyclopentyltriazolopyrimidine ticagre­
lor is not a prodrug and does not require metabolic
activation, although approximately 30–40% of its
antiplatelet effects are attributed to an active metabo‑
lite (AR‑C124910XX) generated through the hepatic
CYP3A system. Ticagrelor does not bind directly to the
platelet ADP-binding site on the P2Y12 receptor. The
drug reversibly binds in a noncompetitive manner to
a distinct site on the receptor, thereby preventing via
allosteric modulation ADP activation of the P2Y12 path‑
way9. Ticagrelor is rapidly absorbed after oral adminis‑
tration and, because of its half-life of 7–12 h, requires
twice-daily administration. Compared with clopidogrel,
ticagrelor achieves a more prompt, potent, and predict‑
able antiplatelet effect, with a faster offset of action98.
Moreover, ticagrelor also has non‑P2Y 12-mediated
effects; in particular, the drug increases plasma levels
of adenosine owing to inhibition of cellular uptake99.
These effects might contribute to the overall benefits of
ticagrelor, but have also been suggested to contribute to
its nonbleeding adverse effects, such as higher incidence
of dyspnoea (15–22% of ticagrelor-treated patients) and
ventricular pauses86,100,101.
The efficacy and safety of ticagrelor in ACS were evalu­
ated in the PLATO trial86, in which patients (n = 18,624)
with ACS were randomly assigned to receive either tica‑
grelor (180 mg loading dose followed by 90 mg twice-
daily maintenance dose) or clopidogrel (300–600 mg
loading dose followed by 75 mg daily maintenance
dose) in addition to aspirin. Compared with clopi‑
dogrel, ticagrelor significantly reduced the primary
end point (a composite of death from vascular causes,
MI, or stroke) by 16% at 12 months, including a signifi­
cant 21% reduction in cardiovascular death and a 16%
reduction in MI. Ticagrelor treatment also significantly
reduced the rate of definite or probable stent thrombosis.
Although protocol-defined major bleeding was similar
between groups, non-CABG-related major bleeding
and fatal intracranial haemorrhage were ­significantly
increased with ticagrelor86.
In the subgroup of patients (n = 7,544) with ST‑
segment elevation ACS intended for reperfusion with
PPCI, ticagrelor reduced the incidence of the primary
end point at 12 months compared with clopidogrel
(10.8% versus 9.4%; HR  0.87, 95%  CI 0.75–1.01,
P = 0.07), with an effect that was consistent with the
overall trial results (P = 0.29 for interaction) (FIG. 3).
Ticagrelor also reduced rates of MI, all-cause mortal‑
ity, and definite stent thrombosis, without increasing
the risk of bleeding. However, this subgroup included
patients initially or ultimately treated conservatively102.
In a post-hoc subgroup analysis of patients (n = 4,949)
with STEMI treated with PPCI within 12 h of admission
(excluding those initially medically managed), ticagrelor
led to a 9% relative reduction in the incidence of the
primary end point compared with clopidogrel (7.9% ver‑
sus 8.6%; HR 0.91, 95% CI 0.75–1.12, P = 0.38) (FIG. 3),
which was consistent with the overall PLATO popula‑
tion (P = 0.40 for interaction). Ticagrelor also reduced
the rates of stent thrombosis in this subgroup, with‑
out increasing the risk of major bleeding103. This lack
of increased rate of haemorrhagic events with ticagre‑
lor, which is consistent with the STEMI subgroup of the
TRITON-TIMI 38 trial, could be owing to the younger
age and low bleeding risk of this population. Ticagrelor
(180 mg loading dose and 90 mg twice-daily mainten­ance
dose) is currently recommended (class I) for the treat‑
ment and prevention of secondary ­atherothrombotic
events in patients with STEMI u ­ ndergoing PPCI1–4.
Adjunctive antithrombotic therapy
DAPT primarily targets pathways associated with
thromboxane A2 and ADP-mediated platelet activ­
ation8,9. Therefore, other pathways, such as thrombin-­
mediated platelet activation remain unaffected, which
might account for the residual risk of atherothrombotic
events13,104. Given that levels of thrombin are known
to be elevated after an ACS, and thrombin is the most
potent platelet activator, targeting thrombin-mediated
effects has been an important area of clinical investiga‑
tion13,105. Two different approaches can be pursued to
block thrombin effects: indirect modulation by block‑
ade of the platelet PAR, and direct inhibition of either
thrombin or other upstream coagulation factors13,104.
Vorapaxar. PARs are a family of G‑protein-coupled
receptors, and PAR1 and PAR4 are expressed on human
platelets. Of these, PAR1 has the principal role of mediat‑
ing platelet activation at low concentrations of thrombin,
whereas PAR4 is activated only at high concentrations13.
The only PAR1 antagonist that has completed phase III
clinical investigations and is available for clinical use is
vorapaxar (TABLE 4). Vorapaxar is a synthetic tricyclic
3‑phenylpyridine that is an analogue of himbacine. After
oral administration, vorapaxar is rapidly absorbed with
high bioavailability and a long half-life106. Vorapaxar
was tested in two large-scale, phase III clinical trials:
the TRACER trial107, which was conducted in patients
with non‑ST‑segment elevation ACS and did not show
a favourable balance between efficacy and bleeding with
vorapaxar in acute management (and, therefore, will not
be discussed further), and the TRA 2°P‑TIMI 50 trial108.
The TRA 2°P‑TIMI 50 trial108 was a secondary pre‑
vention trial designed to investigate the efficacy and
safety of vorapaxar in reducing atherothrombotic events
in patients with established atherosclerosis receiving
standard antiplatelet therapy, including aspirin and/or
a thienopyridine (mainly clopidogrel) (TABLE 5). Patients
were eligible for the study if they had a history of MI
or ischaemic stroke (within the previous 2 weeks to
12 months), or symptomatic peripheral arterial dis‑
ease. Patients (n = 26,449) were randomly assigned to

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receive either vorapaxar 2.5 mg daily or placebo. After a
median follow‑up of 30 months, vorapaxar significantly
reduced the primary end point (death from cardio‑
vascular causes, MI, or stroke) by 13% compared with
placebo, driven by a 17% reduction in the rate of MI,
at the expense of a significant increase in moderate or
severe bleeding and a twofold increase in intracranial
bleeding108. In patients with previous stroke, vorapaxar
was associated with higher rates of major bleeding
and intracranial haemorrhage, with no improvement
in ischaemic outcomes109. Patients with previous MI
(n = 17,779) derived an increased benefit in the pri‑
mary end point with vorapaxar compared with placebo
(8.1% versus 9.7%; P <0.0001), which was consistent
across timing and types of MI. In particular, in patients
with previous STEMI (n = 9,248), vorapaxar led to a
significant 27% reduction in the risk of cardiovascular
death, MI, or stroke (FIG. 3). Despite a higher incidence
of bleeding events, intracranial and fatal bleeding were
not significantly increased by vorapaxar in patients with
previous MI, with an overall reduction in the net clin­
ical outcome. The outcome improvement achieved with
vorapaxar was even more pronounced after excluding
patients at high risk of bleeding (previous stroke, body
weight <60 kg, or aged >75 years)110. The efficacy and
safety of vorapaxar in combination with prasugrel
and ticagrelor has not been tested.
Vorapaxar (2.08 mg once-daily maintenance dose) is
currently approved by the FDA111 and EMA112 for the
reduction of thrombotic events in patients with previ‑
ous MI or peripheral arterial disease. In patients with
previous MI, the EMA specifies that the drug should
be initiated 2 weeks after the acute event, in line with
TRA 2°P‑TIMI 50 trial inclusion criteria, whereas no
timing is specified by the FDA.
Rivaroxaban. Several clinical trials have tested the effi‑
cacy and safety of various non-vitamin K antagonist
oral anticoagulants in patients with ACS104,113. However,
only rivaroxaban met the primary end point in phase III
clinical testing and is currently available for clinical use
in this setting104,113.
Rivaroxaban is an oral factor Xa inhibitor that is
­rapidly absorbed and reaches a maximum plasma con‑
centration in 2–4 h, with a half-life of approx­imately
5–13 h (REF. 104) (TABLE 4). The ATLAS ACS-TIMI 51
trial114 tested the clinical effects of rivaroxaban (2.5 mg
or 5.0 mg twice daily) compared with ­placebo in patients
(n = 15,526) with a recent (>24 h but <7 days) ACS
receiving standard antiplatelet therapy with aspirin and a
thienopyridine (mainly clopidogrel) (TABLE 5). Both doses
of rivaroxaban were similarly effective in reducing ischae‑
mic events after a median follow‑up of 13.1 months, but
this efficacy was offset by a dose-­dependent increase
in non-CABG-related major bleeding, including intra­
cranial haemorrhage, which was lower with the 2.5 mg
dose. Notably, the 2.5 mg dose was associ­ated with a
significant reduction in cardio­vascular death and all-
cause death compared with ­placebo. In the subgroup of
patients with STEMI (n = 7,817), rivaroxaban reduced
the incidence of ischaemic events, with an effect that was
evident as early as 30 days, with no significant difference
between the two dosing regimens (8.7% with rivaroxa­
ban 2.5 mg, 8.2% with rivaroxaban 5 mg, and 10.6% with
placebo). Also in this subgroup, rivaroxaban 2.5 mg led
to a signifi­cant reduction in cardio­vascular and all-
cause death compared with placebo (FIG. 3). However,
rivaroxaban treatment was still associated with a dose-­
dependent increase in major bleeding, including intra­
cranial haemorrhage, but with no significant increase in
fatal bleeding115. The clinical profile of low-dose rivaroxa­
ban as an adjunctive therapy to prasugrel or ticagrelor
is currently unknown. The phase II GEMINI ACS‑1
trial116 is ongoing to test the safety of low-dose rivaroxa­
ban in addition to P2Y12 inhib­ition with clopidogrel or
ticagrelor (without aspirin) as compared with standard
DAPT in patients with ACS, including STEMI. Although
a discussion of the implications of dropping aspirin is
beyond the scope of this Review, this strategy has the
potential to reduce bleeding associated with the use of
more potent antithrombotic therapy without affecting
ischaemic protection, and is currently being investigated
in several ongoing studies.
Rivaroxaban is currently approved by the EMA at
the dose of 2.5 mg twice daily in patients stabilized after
an ACS, co‑administered with either aspirin or DAPT,
and has received a class IIb recommendation in the
ESC guidelines for selected patients with STEMI at low
risk of bleeding who are treated with aspirin and clopi‑
dogrel3,4,117. Rivaroxaban is not approved by the FDA for
this indication because of missing data in the pivotal
trial. Rivaroxaban can also be considered as a therapeu‑
tic option in patients requiring chronic oral anticoagu‑
lant therapy in addition to antiplatelet therapy, such as
those with atrial fibrillation undergoing PCI118. However,
a detailed discussion of this topic goes beyond the scope
of this Review, and is described elsewhere119.
Limitations and optimization strategies
Given the clinical benefit shown in clinical trials in
patients with ACS, prasugrel and ticagrelor are now
the recommended first-line P2Y12-receptor inhibitors
in the setting of PPCI1–4,9. However, subgroup analyses
of the STEMI populations in the TRITON-TIMI 38 and
PLATO trials97,103 showed a nonsignificant reduction in
the primary end points for prasugrel or ticagrelor versus
clopidogrel in the specific group of patients receiving
PPCI. Arguably, the results in PPCI were consistent with
the overall study findings, and the reason for the absence
of significant benefit for prasugrel and ticagrelor in PPCI
could be the insufficient numbers of patients in the sub‑
groups to yield adequate statistical power97,103. However,
these findings could also be caused by limitations of oral
antiplatelet therapy. Indeed, several pharmacodynamic
studies conducted in patients with STEMI undergoing
PPCI have consistently demonstrated delayed antiplate‑
let effects of oral P2Y12 inhibitors, including prasugrel
and ticagrelor, which require >2 h to exert full antiplate‑
let effects120–123. This finding might explain why the use
of prasugrel or ticagrelor in clinical trials did not reduce
the incidence of acute stent thrombosis associated with
bivalirudin administration29,33–36. The delayed onset and

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a CRUSH study127 (prasugrel) tablets was associated with faster drug absorption and
300 more prompt and potent antiplatelet effects compared
P = 0.053 Crushed
P <0.001 with whole-­tablet ingestion, with an effect observed as
Integral early as 30 min after loading-dose administration127,128
250
(FIG. 4). Although the clinical benefit of these findings
P = 0.022 should be tested in larger trials powered for efficacy and
P2Y12 reaction units (PRU)

200
safety, the use of a crushed loading dose of prasugrel or
ticagrelor seems a reasonable option in PPCI, given the
ANOVA P = 0.008
150 known association between peri-PCI platelet reactivity,
P = 0.023
­thrombotic events, and long-term outcomes56,93,129.
Pretreatment, defined as administration of the load‑
100 P = 0.102
ing dose before assessment of coronary anatomy, seems
P = 0.178 another appealing strategy to provide stronger platelet
50 inhibition at the time of PPCI, even if supporting data
are not strong130. In the STEMI subgroup of a large
meta-analysis on patients undergoing PCI, pretreatment
0
0 0.5 1 2 4 6 24 with clopidogrel was associated with an approximately
Time (h) 50% reduction in mortality131. In the TRITON-TIMI 38
b MOJITO study128 (ticagrelor) trial, only 32% of patients with STEMI received the
350 loading dose before PPCI and, therefore, the value of
pretreatment with prasugrel in STEMI is unknown.
300 In the PLATO trial, all patients were pretreated, so the
P2Y12 reaction units (PRU)

role of ticagrelor pretreatment in STEMI was tested in

250
200
150
100
*P = 0.006 *
50
0 cant reduction in the rate of definite acute (≤24 h) stent
Baseline 1 2 4 8
Time (h)
Figure 4 | Pharmacodynamic comparison of crushed versus integral tablets
Nature Reviews | Cardiology
of P2Y12-receptor inhibitors in ST‑segment elevation myocardial infarction.
a | Comparison in P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 between
crushed and whole tablets of 60 mg prasugrel loading dose. b | Comparison in PRU
between crushed and whole tablets of 180 mg ticagrelor loading dose. ANOVA P values
are for the comparison between groups over time. Reprinted from Sardella, G.,
Calcagno, S. & Mancone, M. Different prasugrel administration in STEMI patients:
go faster and no fear to crush! J. Am. Coll. Cardiol. 67 (17), 2005–2007 © (2016),
with permission from Elsevier.
attenuated antiplatelet effects of P2Y12-receptor inhib­
itors have been attributed to impaired drug absorption
resulting in reduced drug bioavailability in the early
hours after the loading dose120,123. Given the higher
prothrombotic milieu of the STEMI setting, strategies
to increase bioavailability of orally administered P2Y12-
receptor inhibitors have been advocated for patients
undergoing PPCI120. Because the pharmacokinetic and
pharmacodynamic profiles of P2Y12-receptor inhibitors
are dose-dependent, the use of higher loading-dose
regimens seems an intuitive option and has been tested
in pharmacodynamic studies. However, this strategy
was associated with no or marginal enhancement of
platelet inhibition123–126. The administration of crushed
prasugrel and ticagrelor in patients undergoing PPCI
has been tested in the CRUSH127 and MOJITO128 stud‑
ies, respectively. These studies showed that crushing
the ATLANTIC trial132, in which patients (n = 1,862)
undergoing emergency angiography were randomly
assigned to receive either prehospital (in the ambulance)
or in‑hospital (in the cardiac catheterization lab­oratory)
treatment with a 180 mg loading dose of ticagrelor,
in addition to aspirin. Prehospital ticagrelor did not
improve pre-PCI markers of coronary reperfusion and
was not associated with significant differences in platelet
reactivity132,133. Although this strategy showed a signifi‑
thrombosis with no difference in major bleeding, the
trial was not powered for clinical end points, and results
should be considered as exploratory only132,134. The
ACC/AHA guidelines recommend the administration of
an oral P2Y12-receptor inhibitor as soon as possible after
first medical contact or at the time of PPCI, whereas the
ESC guidelines recommend initiating therapy as early as
possible before angiography1–4.
Inability to achieve adequate platelet inhibition with
oral P2Y12-receptor inhibitors in PPCI is further exacer‑
bated by other clinical conditions commonly associated
with STEMI, such as inability to swallow (in patients who
are sedated, intubated, in shock, or those with ­nausea
or vomiting), therapeutic hypothermia, or morphine
administration120,132,133,135. Use of intravenous agents,
such as GPIs or cangrelor, in the catheterization lab­
ora­tory has the potential to provide immediate platelet
inhib­ition until the full antiplatelet effect of oral P2Y12-
receptor inhibitors is achieved48,55. In the FABOLUS PRO
study48, the addition of a bolus only of tirofiban led to
near-complete platelet inhibition, without the need for
an infusion, in patients undergoing PPCI who received a
60 mg loading dose of prasugrel. However, the safety and
efficacy of this strategy is unknown. Although cangre‑
lor has been shown to enhance platelet inhibition when
administered in addition to prasugrel or ticagrelor ther‑
apy, the clinical benefit of its use in addition to these
agents in PPCI is yet to be tested55.

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Practical recommendations of the agent should, therefore, be based on the throm‑

With the availability of several anticoagulant and
antiplatelet agents with different safety and efficacy
profiles, finding the best antithrombotic cocktail to
help reperfusion during PPCI is a challenge for clin­
icians. The ultimate goal of antithrombotic therapy is
to provide a rapid onset of potent pharmacodynamic
effect to prevent stent thrombosis and periprocedural
MI, without increasing serious bleeding. The choice
STEMI intended for PPCI
At clinical presentation
Aspirin LD (325 mg oral or 80–150 mg intravenous)
Consider UFH bolus (4,000–5,000 IU)
Consider pretreatment
Ticagrelor or prasugrel (clopidogrel if tricagrelor
and prasugrel contraindicated)
Intravenous anticoagulant Intravenous anticoagulant
Low risk of bleeding High risk of bleeding*
Heparin Bivalirudin (consider prolonged
(UFH if previous UFH bolus) infusion at PCI dose)
Consider cangrelor in P2Y12-naive patients
Consider GPI for bail-out use
P2Y12 inhibitor LD at time of PPCI
Consider crushed tablets
Preferred agents Alternative agent
Prasugrel or ticagrelor Clopidogrel
Choice between agents is based on If both ticagrelor and prasugrel
contraindications and precautions contraindicated or not available
Continue DAPT for 12 months‡
Consider adding vorapaxar or low-dose rivaroxaban§
In selected patients at low risk of bleeding if receiving
background therapy of aspirin and clopidogrel
Figure 5 | Proposed algorithm for the choice of antithrombotic Naturetherapy in| patients
Reviews Cardiology
with ST‑segment elevation myocardial infarction (STEMI) undergoing primary
percutaneous coronary intervention (PPCI). *Clinical factors known to be associated
with increased risk of bleeding are: history of bleeding, oral anticoagulant therapy,
female sex, advanced age, low body weight, chronic kidney disease, diabetes mellitus,
anaemia, chronic steroid or nonsteroidal anti-inflammatory drug therapy151. ‡Shorter
dual antiplatelet therapy (DAPT; 6 months) can be considered in patients with overt
bleeding or who are at high risk of bleeding, whereas prolonging DAPT beyond
12 months is a reasonable option in selected patients at low risk of bleeding or
without overt bleeding while receiving DAPT. §Vorapaxar and low-dose rivaroxaban
have not been tested as adjunctive therapy to prasugrel or ticagrelor. GPI,
glycoprotein IIb/IIIa inhibitor; LD, loading dose; PCI, percutaneous coronary
intervention; UFH, unfractionated heparin.
botic and bleeding risk of the individual patient, and
in some centres might also be dictated by economic
considerations (FIG. 5).
For patients at low risk of bleeding events, the use
of heparin as an anticoagulant, in particular UFH,
seems to be the most cost-effective option. In many sys‑
tems, a fixed bolus of UFH (generally 4,000–5,000 IU)
is ­routinely administered upstream, at the time of clin­
ical presentation, as this strategy has been associated
with better clinical outcomes, particularly for those
patients who then are treated with bivalirudin in the
catheteriza­tion laboratory. Importantly, such a strategy
is ­simple and not associated with potential time delays
that might occur with bolus and infusion administration
of other antithrombotic strategies. For patients who con‑
tinue receiving UFH during PPCI, an additional bolus
should be administered based on activated clotting time
levels. For patients not receiving upstream UFH, enoxa‑
parin can be considered as an alternative anticoagulant,
as endorsed by the ESC guidelines, although its use is
not recommended in the ACC/AHA guidelines1–4,136.
Conversely, bivalirudin should be considered in those
with a high risk of bleeding, such as elderly patients or
patients with anaemia, thrombocytopenia, or chronic
kidney disease. If bivalirudin is used, strategies to
reduce the risk of acute stent thrombosis should be
employed, such as an initial bolus of UFH or prolonging
the infusion at PCI-dose for up to 4 h after reperfusion.
Cangrelor seems to be an attractive strategy to achieve
immediate and potent platelet inhibition. Cangrelor can
be considered for all patients undergoing PPCI not pre‑
treated with oral P2Y12-receptor antagonists, especially
for those with clinical or angiographic factors of high
thrombotic risk. This strategy would also allow bridging
of the gap associated with the delayed onset of action of
oral P2Y12-receptor inhibitors, including prasugrel and
ticagrelor, which require several hours before they reach
their full platelet inhibitory effects. Although GPIs are
also an option to obtain immediate platelet inhibition,
their routine use has fallen out of favour, and they are
mostly reserved for bail-out use. Compared with GPIs,
cangrelor seems to be associated with fewer major
bleeding events and has lower incidence of thrombo‑
cytopenia, a well-known and potentially lethal adverse
effect of GPIs54,58. However, a direct comparison between
cangrelor and GPIs has not been tested in large-scale,
adequately powered clinical trials. Whereas overdosing
of GPIs is not uncommon and has been associated with
an increased risk of bleeding complications137, cangre‑
lor overdosing is rare and was not associated with an
increase in rates of bleeding or other adverse events138.
Moreover, in patients with planned use of GPIs, the
UFH dose should be adjusted, whereas with cangre‑
lor, the full dose of UFH should be used. Although the
use of cangrelor in addition to bivalirudin seems to be
the antithrombotic cocktail associated with the ideal
safety and efficacy profile, the clinical outcomes associ­
ated with this drug combination and how it compares
with other strategies has not been tested in adequately
­powered studies.

NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 15

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REVIEWS

Among oral antiplatelet agents, aspirin at a loading-­
dose regimen (325 mg) should be administered immedi‑
ately at time of clinical presentation, unless available in an
intravenous formulation which can also be considered as
a route of administration. The P2Y12-receptor inhibitors
prasugrel and ticagrelor should be the preferred choice,
with clopidogrel use reserved for patients in whom both
these more potent agents are contraindicated. On the
basis of the results of pharmaco­kinetic and pharmaco‑
dynamic studies, the use of crushed tablets should be
considered to enhance bioavailability in the early hours
after the loading dose. Data from pharmaco­dynamic
studies comparing prasu­grel and ticagrelor do not sug‑
gest superiority of one agent over the other121,122,139–142.
In the randomized PRAGUE‑18 study143, the efficacy
and safety of prasugrel and ticagrelor were compared in
patients with acute MI (n = 1,230) treated with primary
or immediate PCI. Although no differ­ence between the
two agents in the 30‑day incidence of MACE (~4% in
both groups) was shown, the study was terminated early
for futility and was underpowered to detect differences in
clinical events and, therefore, the results should be con‑
sidered as hypothesis-­generating. Indeed, in the absence
of adequately powered clinical ­trials, the choice between
prasugrel and ticagrelor should be based on clinical
grounds, taking into consideration patient characteris‑
tics, presence of contraindications, and ease of access to
a specific med­ication. Ongoing clinical investigations,
such as the ISAR-REACT 5 trial144, might provide further
insights into this topic. The use of tailored antiplatelet
therapy on the basis of results of platelet-function and
genetic testing has also been investi­gated to optimize
outcomes in patients with coro­nary artery disease,
including those with STEMI. Data available so far from
randomized clinical trials do not support the routine use
of platelet-­function monitoring145,146, whereas the role of
genetic testing specifically in STEMI is being tested in an
­ongoing clinical trial147.
Despite the absence of strong evidence supporting
the ischaemic benefit of pretreatment, no data exist
suggesting harm. However, pretreatment might expose
patients to unnecessary platelet inhibition and related
bleeding risk when PPCI is not performed, such as in
patients found not to have coronary artery disease pre‑
senting with other causes of chest pain (such as a­ ortic
dissection) or patients requiring CABG surgery130.
Indeed, the ability of a given health-care system or
STEMI network to make an accurate diagnosis of STEMI
might also define whether patients should be pretreated
with an oral P2Y12-receptor inhibitor. Indeed, this con‑
sideration is particularly relevant in the USA, where
almost one-third of STEMI activations to date have
been false activations148,149. Details on DAPT duration go
beyond the scope of this manuscript and are described
elsewhere150. In brief, regardless of the choice of P2Y12-
receptor inhibitor, current guidelines recommend that
DAPT should be continued for at least 12 months in
patients with STEMI. Discontinuation can be considered
after 6 months in patients with overt bleeding or who
are at high risk of bleeding, whereas prolonging DAPT
beyond 12 months is a reasonable option in selected
patients without overt bleeding or who are at low risk of
bleeding while receiving DAPT150,151.
Conclusions
Antithrombotic therapy has a pivotal role in the treat‑
ment of patients with STEMI undergoing PPCI. Several
anticoagulant and antiplatelet agents are currently avail‑
able, and finding the optimal cocktail is a clinical chal‑
lenge that needs to be tailored for each patient. The use
of intravenous anticoagulant agents is mandatory during
PPCI, and the choice between a heparin and bivaliru‑
din should be on the basis of the patient’s haemorrhagic
risk and, for some centres, financial resources given the
higher costs of bivalirudin. DAPT with a combination
of aspirin and either prasugrel or ticagrelor is the anti‑
platelet treatment of choice, as these agents achieve more
prompt and potent platelet inhibition compared with
clopidogrel, and improve clinical outcomes. Nonetheless,
patients continue to experience ischaemic events despite
COX1 and P2Y12-receptor blockade, which has raised
interest in alternative or adjunctive antithrombotic strat‑
egies. The use of intravenous cangrelor is an attractive
strategy to achieve immediate and potent platelet inhib­
ition during PPCI, whereas the use of agents target­
ing thrombin-mediated effects on platelet activation,
namely vorapaxar and low-dose rivaroxaban, might be
useful in selected patients in the secondary prevention
of long-term adverse events. However, further studies
are warranted to explore the efficacy and safety profiles
of these strategies when used in addition to prasugrel
or ticagrelor.

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Author contributions
F.F. and D.J.A. researched data for the article, discussed its
content, and wrote the manuscript. F.R. discussed the content
of the manuscript and reviewed/edited it before submission.
Competing interests statement
D.J.A. has received payment as an individual for consulting
fees or honoraria from Abbott Vascular, Amgen, AstraZeneca,
Bayer, Daiichi-Sankyo, Eli Lilly, Merck, Pfizer, PLx Pharma,
Sanofi, and The Medicines Company; and for participation in
review activities from CeloNova, Johnson & Johnson, and
St. Jude Medical. Institutional payments for grants have been
received from AstraZeneca, CSL Behring, Daiichi-Sankyo, Eli
Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Gilead,
Novartis, Osprey Medical, and The Medicines Company.
The other authors declare no competing interests.

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