Optimal pharmacological therapy in ST-elevation myocardial infarction—a review
Optimal pharmacological therapy in ST-elevation myocardial infarction-a review
R. S. Hermanides 0 1 2 3
S. Kilic 0 1 2 3
A. W. J. van 't Hof 0 1 2 3
0 Department of Cardiology, Maastricht UMC , Maastricht , The Netherlands
1 Isala Heart Centre , Zwolle , The Netherlands
2 A. W. J. van 't Hof
3 Department of Cardiology, Zuyderland Medical Centre (Heerlen location) , Heerlen , The Netherlands
Antithrombotic therapy is an essential component in the optimisation of clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. There are currently several intravenous anticoagulant drugs available for primary percutaneous coronary intervention. Dual antiplatelet therapy comprising aspirin and P2Y12 inhibitor represents the cornerstone treatment for STEMI. However, these effective treatment strategies may be associated with bleeding complications. Compared with clopidogrel, prasugrel and ticagrelor are more potent and predictable, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in primary percutaneous coronary intervention. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. In this review, we provide a critical and updated review of currently available antithrombotic therapies used in patients with STEMI undergoing primary PCI. Finding a balance that minimises both thrombotic and bleeding risk is difficult, but crucial. Further randomised trials for this optimal balance are needed.
STEMI; Antithrombotic therapy
Acute ST-elevation myocardial infarction (STEMI) is a
major cause of mortality worldwide. The rapid restoration
of blood flow in the occluded culprit coronary artery with
primary percutaneous coronary intervention (PCI) will
prevent heart failure, preserves ventricular function and
reduces mortality [
]. The cause of STEMI is erosion or
rupture of an atherosclerotic plaque with subsequent platelet
adherence, activation, aggregation, and activation of the
clotting cascade and downstream myocardial ischaemia and
necrosis after complete coronary artery occlusion . The
main elements involved in this process are platelet and
Antiplatelet and anticoagulant medications for STEMI
Classification of anticoagulants (Tab. 1)
1. Unfractionated heparin
2. Low-molecular-weight heparin
4. Thrombin receptor antagonist protease-activated receptor
5. Factor Xa inhibitor
• Selecting the right antiplatelet and antithrombotic agent is of paramount importance in the
treatment of STEMI patients undergoing primary PCI.
Adjunctive pharmacotherapy should be tailored to the individual patient, based on assessment
of ischaemic and bleeding risk.
With regard to antiplatelet therapy in STEMI, the recommend first-line P2Y12 inhibitors in the
setting of primary PCI are ticagrelor and prasugrel.
In patients with a low bleeding risk the use of heparin, with or without GPI, as an anticoagulant
seems to be cost-effective and has been associated with better clinical outcome when
compared to bivalirudin.
Fig. 1 Mechanism of thrombus
formation during STEMI, and
targets of available
antithrombotic agents. After plaque
rupture, a complex mechanism
of thrombus formation is
mediated. COX cyclooxygenase,
TP thromboxane prostanoid,
STEMI ST-elevation myocardial
Classification of antiplatelet agents
2. P2Y12 receptor inhibitors
– clopidogrel, prasugrel (irreversible inhibitors)
– cangrelor and ticagrelor (reversible inhibitors)
3. Glycoprotein IIb/IIIa inhibitors
– tirofiban, abciximab, eptifibatide
Anticoagulant therapy before and during primary
Based on several small randomised trials, anticoagulation
with unfractionated heparin became an accepted and
important therapy for STEMI, especially before and during
the PCI procedure [
]. The major anticoagulant effect of
STEMI ST-elevation myocardial infarction, HITT heparin induced thrombocytopenia and thrombosis, PPCI primary percutaneous coronary
intervention, GPIs glycoprotein IIb/IIIa inhibitors, PK pharmacokinetic, PD pharmacodynamics UFH unfractionated heparin
unfractionated heparin is based on inactivation of
thrombin and activated factor X (factor Xa) reacts by binding
to antithrombin III, an endogenous inhibitor of factor Xa
and thrombin IIa. This binding induces a conformational
change in antithrombin 3, which markedly accelerates its
ability to inactivate these factors. The recommended
periprocedural dosing in patients who also receive a
glycoprotein IIb/IIIa inhibitor is 50 to 70 U/kg (target activated
clotting time [ACT] > 200 s); in patients not receiving a GP IIb/
IIIa inhibitor, the recommended peri-procedural dosing is
60 to 100 U/kg (target ACT, 250 to 350 s) [
unfractionated heparin has a Class I indication (level of
evidence (LOE):C) for anticoagulation during primary PCI
in the new European Society of Cardiology (ESC)
guideline . A major limitation of unfractionated heparin is the
increased risk of heparin-induced thrombocytopenia, a
serious, potentially lethal, and immunologically mediated
Low-molecular-weight heparins seem to offer a better
clinical efficacy in STEMI when administered intravenously as
compared with unfractionated heparin. In the ATOLL study
], 900 STEMI patients were randomly assigned to receive
an intravenous bolus of 0.5 mg/kg enoxaparin or
unfractionated heparin before primary PCI. Comparison of enoxaparin
versus unfractionated heparin in the ATOLL study showed
that enoxaparin was associated with a significant reduction
in the secondary endpoint (a composite of death, recurrent
acute coronary syndrome or urgent revascularisation) and
a significant reduction in individual endpoints, including
mortality, major bleeding, and urgent revascularisation. It
is recommended to use enoxaparin, preferentially via
intravenous route, 0.5 mg/kg. Based on a potential benefit in the
secondary endpoint, the new ESC guidelines give a Class
IIa (LOE: A) indication for enoxaparin in this setting [
The OASIS-6 trial, which evaluated fondaparinux
(factor X inhibitor) use in STEMI patients, received a lot of
criticism because of the heterogeneity in the medical and
invasive treatment of the enrolled patients and showed a high
rate of catheter thrombosis and coronary complications [
Fondaparinux is not recommended in the ESC guidelines
as background anticoagulant for primary PCI (Class III;
Bivalirudin is a direct inhibitor of soluble and
clotbound thrombin [
]. It has a rapid onset of action and
a half-life of 25 min and is therefore given as an intravenous
infusion. The results of several bivalirudin studies
(HEATPPCI, MATRIX, BRAVE-4, EUROMAX, BRIGHT) have
led to discussions about its added value (Tab. 2). Recent
meta-analyses have demonstrated no mortality benefit but
fewer bleeding complications in bivalirudin users [
The EUROMAX trial is a randomised clinical trial
comparing bivalirudin versus heparin plus optional glycoprotein
IIb/IIIa inhibitors in patients undergoing primary PCI for
STEMI. The 1-year mortality outcomes showed that the
total number of deaths was identical in both study arms
(59 events in each) with no appreciable differences in the
two treatment arms between 30 days and 1 year [
despite a bivalirudin-associated reduction in the
occurrence of the study’s primary endpoint which was death
or major bleeding at 30 days. The most recent
publication, the VALIDATE-SWEDEHEART, a registry-based,
randomised, controlled trial that compared bivalirudin with
heparin monotherapy in patients with STEMI or
70–100 U/kg without
GPI or 50–70 U/kg
Routine or bailout
(25.9% of patients)
Bailout (4.6% of
1:1 to receive or not
infusion (full dose for
up to 4 h or reduced
dose of 0.25 mg/kg/h
for ≥6 h)
prasugrel (31%), or
1:1 to radial versus
MACE (death, MI,
or stroke) at 30 days;
NACE (MACE or
major bleeding) at
5.9% vs. UFH 6.5%
(P = 0.43); NACE:
bivalirudin 7.0% vs.
UFH 8.2% (P = 0.13)
See primary end
BARC type 3–5
BARC type 3 or 5
Bivalirudin 6.0% vs.
UFH 5.5% (P = 0.64)
See primary end
Table 2 (Continued)
STEMI ST-elevation myocardial infarction, UFH unfractionated heparin, CABG coronary artery bypass grafting, GPI glycoprotein IIb/
IIIa inhibitors, PPCI primary percutaneous coronary intervention, MACE major adverse cardiac events, NACE net adverse clinical events,
MI myocardial infarction, BARC bleeding academic research consortium, NA not available, TVR target vessel revascularisation, TLR target lesion
elevation myocardial infarction (NSTEMI) who underwent
PCI (predominantly radial PCI) and received treatment with
high-intensity platelet inhibitors, did not find a difference
with respect to the rate of death, repeat myocardial
infarction, or major bleeding events during 180 days of
]. Bivalirudin, with or without previous heparin
therapy, has a Class IIa (LOE: A) indication in the new 2017
ESC STEMI guidelines, that also specify that at PCI the
recommended dosing is an initial bolus of 0.75 mg/kg and
an infusion of 1.75 mg/kg/hr during PCI. Following PCI,
an infusion of 0.25 mg/kg/hr can be continued if clinically
Antiplatelet therapy before and during primary PCI
Aspirin irreversibly blocks both cyclo-oxygenase 1
(COX1) and COX-2 and inhibits the production of thromboxane
]. Thromboxane A2 stimulates further platelet
activation and aggregation, which is produced by activated
platelets. The large ISIS-2 trial showed that use of aspirin
was associated with decreased rates of re-infarctions and
non-fatal strokes at mid-term follow-up, with the highest
benefit seen in patients undergoing PCI [
Given its established benefits in secondary prevention
], aspirin should be used indefinitely in all patients
with STEMI. The dosage of aspirin is topic of
discussion. In respect of the first few days of treatment, the
CURRENT-OASIS 7 trial [
] failed to demonstrate
a difference in hard clinical outcomes when comparing
low doses (75–100 mg/day) or relatively high doses of
300–325 mg/day. There were, however, fewer
gastro-intestinal bleeds with the lower doses. The ESC recommends
administering an initial loading dose of 150–500 mg of oral
or intravenous acetylsalicylic acid, unless contraindicated,
followed by a life-long maintenance dose of 75–100 mg
daily (Class I; LOE: B) (Tab. 3; [
]). Patients who are
truly intolerant to aspirin may instead receive clopidogrel
(75 mg/day) as long-term secondary prevention [
P2Y12 receptor inhibitors
Clopidogrel The second-generation thienopyridine
clopidogrel is the most widely used P2Y12 receptor inhibitor
]. The clinical use of clopidogrel in acute coronary
syndrome has been investigated in the large CURE trial, which
evidenced a significant reduction in a composite of
cardiovascular death, recurrent acute myocardial infarction or
stroke when a 300 mg loading dose followed by a 75 mg
daily dose of the drug was added to aspirin versus
aspirin alone (9.3% versus 11.4%; p < 0.001). Furthermore,
the CURRENT-OASIS 7 trial showed benefit of a 600 mg
loading dose instead of a 300 mg loading dose [
However, there is growing concern about response variability
in patients with clopidogrel use [
]. Genetic testing
before starting clopidogrel therapy, in high-risk STEMI
patients, and platelet function testing, in those who suffer
adverse events, may facilitate the monitoring of
clopidogrel treatment, and is currently being investigated [
current recommendations by the ESC state a loading dose
of 600 mg of clopidogrel followed by a maintenance dose
of 75 mg daily (or 150 mg until day 8) only when
prasugrel or ticagrelor are either not available or contraindicated
(Class I; LOE: A) (Tab. 3; [
Prasugrel Prasugrel is an oral, third-generation
thienopyridine. Like clopidogrel, it is a prodrug, and thus needs to be
metabolised via cytochrome P450 in the liver to produce
an active metabolite. The PRINCIPLE-TIMI trial showed
that a 60 mg loading dose and 10 mg maintenance dose of
prasugrel achieved superior results in terms of platelet
inhibition compared with a 600 mg loading dose and 150 mg
maintenance dose of clopidogrel [
]. The TRITON-TIMI
38 study compared a 60 mg loading dose followed by 10 mg
daily maintenance dose of prasugrel with a 300 mg loading
stabilisation (>24 h after
treatment with other
STEMI ST-elevation myocardial infarction, COX1 cyclo-oxygenase-1, PAR-1 protease-activated receptor-1, LD loading dose, MD maintenance
dose, NSAIDs non-steroidal anti-inflammatory drugs, PCI percutaneous coronary intervention, CVA cerebrovascular accident, ICH intracerebral
haemorrhage, CrCl creatinine clearance
dose and 75 mg daily maintenance dose of clopidogrel, with
the loading dose administered after coronary angiography
]. The trial demonstrated a significant reduction of the
composite endpoint of cardiovascular death, non-fatal acute
myocardial infarction and non-fatal stroke in the prasugrel
group (9.9% versus 12.1%; p < 0.001), with early survival
advantages after only 3 days persisting at a mean
followup of 14.5 months. The ESC recommends a 60 mg loading
dose and 10 mg daily maintenance dose of prasugrel in
patients undergoing PCI (Class I; LOE: A) after visualisation
of the coronary arteries (Tab. 3; [
]). Of note, prasugrel
is contraindicated in patients with prior stroke/transient
ischaemic attack and its use is generally not recommended
in patients aged ≥75 years or in patients with lower body
weight (<60 kg).
Ticagrelor Ticagrelor is a class of adenosine diphosphate
(ADP) blockers, triazolopyrimidines, which act as ADP
analogues directly binding to P2Y12 causing allosteric
reversible blockage of the receptor. The PLATO trial [
comparing a standard 300–600 mg loading dose and 75 mg
daily maintenance dose of clopidogrel with a 180 mg
loading dose and 90 mg twice daily maintenance dose of
ticagrelor, showed a significant reduction in the composite
primary endpoint of cardiovascular deaths, acute
myocardial infarction and non-fatal strokes (9.8% ticagrelor group
versus 11.7% clopidogrel group; p < 0.001), mainly driven
by a reduction of deaths (4.0% versus 5.1%) and acute
myocardial infarction (5.8% versus 6.9%). Treatment with
ticagrelor was associated with significantly higher rates of
bleeding not related to coronary artery bypass graft (4.5%
versus 3.8%; p = 0.03) or spontaneous bleeding (3.1%
versus 2.3%; p = 0.01). As expected, dyspnoea was more
frequent in patients treated with ticagrelor (13.8% versus
7.8%; p < 0.001), even if this was not a significant cause
of treatment discontinuation. These PLATO findings were
confirmed in the real-world SWEDEHEART registry,
however, in SWEDEHEART, ticagrelor was preferentially used
in patients with a low bleeding risk and death, and patients
on ticagrelor were significantly more often assessed with
coronary angiography and treated with PCI [
Pre-hospital treatment with P2Y12 receptor inhibitors in
STEMI was tested in the ATLANTIC trial [
], defined as
administration of loading dose before coronary angiogram,
to provide stronger platelet inhibition. This trial showed
a significant reduction in the rate of acute stent
thrombosis with no difference in major bleeding. Pre-PCI markers
of coronary reperfusion did not improve with pre-hospital
use of ticagrelor, whereas post-PCI reperfusion did [
Of note, the ESC recommends that patients undergoing
primary PCI receive a combination of dual antiplatelet therapy
as early as possible before angiography.
The new ESC guidelines recommend a ticagrelor 180 mg
loading dose followed by 90 mg twice daily in all
intermediate to high-risk acute coronary syndrome patients (Class I;
LOE: A) (Tab. 3 and 4; [
Switching to clopidogrel after ticagrelor pre-treatment
Based on PLATO data, the more potent P2Y12 inhibitor
ticagrelor is preferred over clopidogrel in the STEMI
setting (Fig. 2). However, a recently published Dutch
observational study (40% STEMI patients) demonstrated (based
on a propensity score-adjusted multivariate analysis) that
in the era of current second-generation drug-eluting stents
treatment with ticagrelor compared with clopidogrel was an
independent predictor of net adverse clinical and cerebral
events (NACCE) and major bleeding [
]. Furthermore, in
the TOPIC study patients with acute coronary syndrome
treated with PCI were randomised after one month of dual
antiplatelet therapy with ticagrelor, to continued treatment
with ticagrelor until 12 months, or to switching to
clopidogrel. The main outcome consisted of a net clinical
benefit for the switched group, primarily driven by a
significantly higher bleeding risk in patients on a continued potent
P2Y12 inhibitor [
There are no studies in which the impact of ticagrelor versus
prasugrel on outcome in patients with STEMI was tested
directly. An adjusted indirect comparison meta-analysis [
of prasugrel versus ticagrelor in patients with acute
coronary syndrome has shown that both drugs are superior to
clopidogrel. Head-to-head comparison suggests similar
efficacy and safety of prasugrel and ticagrelor, but prasugrel
appears more protective against stent thrombosis, especially
in the early phase of post-stent implantation.
Cangrelor is an intravenous direct-acting P2Y12 blocker
with an almost immediate antiplatelet effect, a plasmatic
half-life of 3–5 min and rapid restoration of platelet
function just 1 h after infusion cessation. The large CHAMPION
series, including STEMI patients in CHAMPION PCI and
CHAMPION PHOENIX, showed by pooled analysis [
a significant reduction in stent thrombosis at 30 days (0.9%
versus 1.3%, p = 0.0027). We certainly need future large
trials to evaluate the safety and benefits of cangrelor in
primary therapy, especially as upstream therapy with the
aim of abortion of infarction. The Food and Drug
Administration (FDA) and the European Medical Agency (EMA)
have approved the use of cangrelor (30 μg/kg bolus plus
4 μg/kg/min infusion initiated before PCI and continued for
≥2 h or for the duration of PCI, whichever is longer) for
clinical use by as adjunct therapy to PCI for reducing the
risk of peri-procedural myocardial infarction, repeat
coronary revascularisation, and stent thrombosis in patients who
have not been treated with an oral P2Y12 receptor
antagoNON-CABG-related TIMI major bleedings (%)
Stent Thrombosis (Absolute %)
nist and are not being given a glycoprotein IIb/IIIa inhibitor.
Cangrelor may be considered in patients who have not
received P2Y12 receptor inhibitors according to current ESC
guidelines (Class IIb; LOE: A) [
Glycoprotein IIb/IIIa inhibitors (GPIs)
GPIs can be classified into two groups: small (eptifibatide,
tirofiban) and non-small (abciximab) molecules, which
are characterised by different pharmacological properties
(Tab. 4). They target the final pathway of platelet
aggregation, competing with von Willebrand factor and fibrinogen
for glycoprotein IIb/IIIa receptor binding and provide fast
and potent antiplatelet effects. There are several randomised
trials examining abciximab versus placebo without
potent P2Y12 inhibitors in STEMI (RAPPORT, ADMIRAL,
ISAR-2, CADILLAC, and ACE trial). In a meta-analysis
of these trials, abciximab was associated with significant
reductions in mortality at 30 days and 6 to 12 months and
in re-infarction at 30 days [
]. In addition, there was no
increase in bleeding. In the past few years several other
GPI trials (ON-TIME 2 trial, HORIZONS-AMI trial,
FINESSE) were conducted, with conflicting results. The last
two GPI trials, EUROMAX and MATRIX, investigated
GPI and heparin versus bivalirudin and were discussed in
the bivalirudin section.
Use of GPI has waned by the introduction of new
P2Y12 inhibitors. However, recent data have clearly shown
a delayed onset of action of both prasugrel and ticagrelor
In our opinion GPI can be recommended as early as
possible (upstream strategy) among high-risk STEMI
patients, such as those with advanced Killip class or anterior
myocardial infarction, and those presenting within the first
three hours after symptom onset [
This was also shown in several pre-specified
sub-analyses in the ON-TIME 2 trial.
The ON-TIME 2 randomised trial showed that when
tirofiban is administered in the pre-hospital setting as
double bolus in association with 600 mg clopidogrel, aspirin,
and heparin this results in beneficial effects in terms of an
average reduction of the ST-segment 1 h after primary PCI
and better clinical outcome at 1 year compared with placebo
Moreover, pre-hospital administration of tirofiban
reduces initial thrombus burden, improves initial patency
of the infarct-related vessel before primary PCI, and
suggests that pre-hospital use is superior to provisional use as
a bailout strategy [
Based on the INFUSE-AMI trial [
] (reduction in
infarct size at day 30 on magnetic resonance imaging) and
AIDA-4 trial [
] (borderline reduction in heart failure), the
Fig. 3 Proposed algorithms
for the choice of
antithrombotic therapy in STEMI
patients undergoing primary PCI.
myocardial infarction, PPCI primary
intervention, UFH unfractionated
heparin, PCI percutaneous
coronary intervention, LD low dose,
DAPT dual antiplatelet
therapy, GPI glycoprotein IIb/IIIa
STEMI intended for PPCI
At clinical presentation:
Aspirin LD (325mg oral or 80-150mg intravenous)
Consider UFH bolus (4000-5000IE)
Ticagrelor or prasugrel (clopidogrel if ticagrelor and
prasugrel are contraindicated)
Low risk of bleeding
Heparin (UFH if previous UFH bolus)
High risk of bleeding
Bivalirudin (consider prolonged infusion at PCI
Consider cangrelor in P2Y12-naive patients
Consider GPI for bailout use
intra-coronary route may be considered, but the intravenous
route should remain the standard of care for administration
In the end, as determined by the ESC guidelines [
routine use or upstream use of GPI is not included in the
guidelines anymore. Using GPI as bailout therapy in the
event of angiographic evidence of a large thrombus, slow
flow/no-reflow phenomenon or other thrombotic
complications is recommendable, although this strategy has not been
tested in randomised trials.
Antithrombotic therapy after STEMI
Vorapaxar Protease-activated receptors (PARs) are a
family of guanine nucleotide-binding proteins- (G proteins-)
coupled receptors, and PAR1 and PAR4 are expressed on
human platelets. The only PAR1 antagonist that has
completed phase III clinical investigations and is available for
clinical use is vorapaxar. Vorapaxar is a synthetic tricyclic
3-phenylpyridine that is an analogue of himbacine, and
after oral administration, vorapaxar is rapidly absorbed with
high bioavailability and a long half-life [
The TRACER trial was conducted in patients with
NSTEMI and did not show a favourable balance between
efficacy and bleeding with vorapaxar in acute management
The TRA 2°P-TIMI 50 trial [
] was a secondary
prevention trial designed to investigate the efficacy and safety
of vorapaxar in the reduction of atherothrombotic events in
patients with established atherosclerosis receiving aspirin
and/or clopidogrel. Patients (n = 26,449) were randomly
assigned to vorapaxar 2.5 mg daily or placebo. After a median
follow-up of 30 months, vorapaxar significantly reduced
the primary endpoint (death from cardiovascular causes,
myocardial infarction, or stroke) by 13% compared with
placebo, driven by a 17% reduction in the rate of myocardial
infarction, at the expense of a significant increase in
moderate or severe bleeding and a twofold increase in
intracranial bleeding. Particularly in patients with previous STEMI
(n = 9,248), vorapaxar led to a significant 27% reduction in
the risk of cardiovascular death, myocardial infarction or
stroke. The efficacy and safety of vorapaxar in combination
with prasugrel and ticagrelor has not been tested. Future
studies with different antiplatelet combinations, duration
and doses are needed to clarify if vorapaxar has a role in the
treatment of patients with STEMI. Vorapaxar (2.08 mg once
daily maintenance dose) is currently approved by the FDA
and EMA for the reduction of thrombotic events in patients
with a history of myocardial infarction or peripheral arterial
disease (Tab. 3).
Rivaroxaban Rivaroxaban is a factor Xa inhibitor which
does not require an antithrombin cofactor for its activity.
In the setting after acute coronary syndrome (the ATLAS
ACS-2 trial) 2.5/5 mg rivaroxaban twice daily combined
with acetylsalicylic acid or acetylsalicylic acid plus
clopidogrel demonstrated a statistically significant reduction of
death from cardiovascular causes, myocardial infarction or
stroke compared with placebo in patients after acute
coronary syndrome [
]. However, there was also a reduction
in all-cause and cardiovascular mortality, with an increased
risk of major bleeding and intracranial bleeding but not
of fatal bleeding. More recently, the GEMINI-ACS 1 trial,
a phase 2 trial, [
] showed that a dual pathway
antithrombotic therapy approach combining low-dose rivaroxaban
(2.5 mg twice daily) with a P2Y12 inhibitor in the treatment
of patients with acute coronary syndrome had a similar risk
of clinically significant bleeding as aspirin and a P2Y12
In patients with atrial fibrillation undergoing PCI,
rivaroxaban may be considered as a therapeutic option as
recently published in the PIONEER-AF trial [
Furthermore, in patients with stable angina, those assigned to
rivaroxaban (2.5 mg twice daily) plus aspirin had better
cardiovascular outcomes and more major bleeding events than
those assigned to aspirin alone [
]. In patients with a low
bleeding risk who receive aspirin and clopidogrel,
lowdose rivaroxaban (2.5 mg twice daily) may be considered
(Class 2b; LOE: B for both) as determined by the ESC
guidelines (Tab. 3; [
The rationale for use of oral antithrombotic agents in the
therapy of STEMI patients is modulating the effects of
thrombin on both coagulation cascade and platelet
aggregation, as well as lowering thrombotic complications, without
increasing serious bleeding (Fig. 3). In patients with a low
bleeding risk, the use of heparin, with or without GPI, as
an anticoagulant seems to be cost-effective and has been
associated with better clinical outcome. For patients not
receiving upstream unfractionated heparin, enoxaparin can be
considered as an alternative anticoagulant. In patients with
a high bleeding risk bivalirudin should be considered. We
need a strategy to reduce the risk of acute stent thrombosis
if bivalirudin is used, such as an initial bolus of
unfractionated heparin or prolonged infusion at PCI for up to 4 h after
With regard to antiplatelet therapy in STEMI, the
recommend first-line P2Y12 inhibitors in the setting of
primary PCI are prasugrel and ticagrelor [
with P2Y12 inhibitors in STEMI has been tested in the
ATLANTIC trial  and showed a significant reduction
in the rate of acute stent thrombosis with no difference
in major bleeding. However, pre-PCI markers of coronary
reperfusion did not improve with pre-hospital use of
ticagrelor. Nevertheless, in our opinion a loading dose of
aspirin and potent P2Y12 inhibitors (ticagrelor or prasugrel)
should be given as early as possible (upstream strategy)
in STEMI patients. Maybe it is better to give the potent
P2Y12 inhibitors crushed [
] as it is effective and
safe; pre-hospital feasibility will be tested in the
Netherlands in the near future (ONTIME-3 trial, clinicaltrials.gov
nr NCT03400267). Clopidogrel use is reserved for patients
when prasugrel or ticagrelor is contraindicated. However,
there are several clinical conditions commonly associated
with an inability to achieve adequate platelet inhibition with
oral use of P2Y12 receptor inhibition, for example inability
to swallow, nausea, shock and intubation.
For patients with these clinical conditions cangrelor is
an option. It showed an enhanced platelet inhibition when
administered in addition to prasugrel or ticagrelor therapy,
but the clinical benefit of its use in addition to these agents
should be tested in a pre-hospital STEMI trial.
Especially in high-risk STEMI patients, early GPI use
may be considered as upstream therapy. However, there is
no definitive answer regarding the current role of routine
upstream use of GPI in primary PCI in the era of potent
dual antiplatelet therapy, particularly when ticagrelor or
prasugrel is used. The peri-procedural administration of GPI
may be based on thrombus burden or in case with impaired
Selecting the right antiplatelet and antithrombotic agents
is of paramount importance in the treatment of STEMI
patients undergoing primary PCI. New agents allow a
reduction in rates of clinical events, including mortality, but
this benefit may be reduced by the higher bleeding risk
in some patients. Therefore, adjunctive pharmacotherapy
should be tailored to the individual patient, based on
assessment of ischaemic and bleeding risk. In this approach
we decide on the optimal agent but also on the timing
(prehospital, in catheterisation laboratory before angiography,
or in catheterisation laboratory after angiography) and the
means of administration (intravenous, intracoronary
Conflict of interest R.S. Hermanides, S. Kilic and A.W.J. van’t Hof
declare that they have no competing interests.
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