Pharmacotherapy of

non-ST-elevation
acute coronary syndrome
a review of international guidelines

Prepared by : Adel Khalil

Supervision by : Dr. Khaled Alakhali PhD
A review of international perspectives on the management of non-ST-
elevation acute coronary syndrome.

Abstract

Non-ST-elevation acute coronary syndrome (NSTE-ACS) encompasses

NSTE-myocardial infarction (NSTEMI) and unstable angina (UA). In the UK,
the annual incidence of hospital admissions relating to NSTE-ACS is around
50,000. However, owing to the difficulty in diagnosing NSTE-ACS, it is hard
to establish its true prevalence. There is emerging evidence that the long-
term mortality of NSTEMI is equivalent to, or potentially higher than, that
of STEMI.

The intensity of treatment and intervention in patients with NSTE-ACS is

ultimately guided by risk of future adverse cardiovascular events. This
article provides an overview of the pharmacotherapy of NSTE-ACS, with
reference to recommendations from clinical guidelines from the United
States, UK, Europe and Australia and New Zealand.

Keywords: guidelines; non-ST-elevation acute coronary syndrome; NSTEMI.

Original submitted: 18 July 2019; Revised submitted: 8 July 2021; Accepted

for publication: 21 July 2021.

Key points
• The use of validated risk scoring systems to establish the future risk of
adverse cardiovascular and bleeding events is recommended to inform
risk/benefit decisions regarding treatment/intervention for NSTE-ACS
patients;
• Coronary angiography and subsequent revascularisation is dependent
on the ischaemic risks of the patient;
• Pharmacotherapy is guided by phase of treatment in relation to
management strategy (i.e. pre-treatment, peri-procedural and post-
treatment phase);
 • All patients with NSTE-ACS should be offered treatment with dual
antiplatelets. The duration of dual antiplatelet therapy is dependent on
the relative thrombotic and bleeding risks of the patient;
• Other drugs used in the management of NSTE-ACS are statins,
angiotensin-converting enzyme inhibitors inhibitors, beta-blockers,
aldosterone antagonists and anticoagulants;
• Variations exist between the guidelines in relation to the following
areas:
o Timing of administration of P2Y12 inhibitors in relation to coronary
angiography;
o Choice of anticoagulants and P2Y12 inhibitors during the acute
phase of NSTE-ACS;
o Duration of dual antiplatelet therapy;
o Duration of beta-blocker therapy.
• The main reason for the variation between guidelines is owing to the
availability of more recent evidence, which affects the more recent
guidelines (National Institute for Health and Care Excellence and
European Society of Cardiology).

Introduction

The clinical presentations of unstable angina (UA) and non-ST-elevation

myocardial infarction (NSTEMI) can be identical and they have recently been
grouped together by the term non-ST-elevation acute coronary syndrome
(NSTE-ACS)[1]. Patients presenting with NSTE-ACS on electrocardiogram (ECG)
are classified as having UA or NSTEMI depending on the absence or presence of
biochemical markers of myocardial necrosis, respectively[2].
UA is defined as myocardial ischaemia at rest or minimal exertion in the
absence of cardiomyocyte necrosis[1]. NSTEMI is where cardiomyocyte
necrosis exists[1]. Compared with patients with NSTEMI, individuals with UA
have a substantially lower risk of death and appear to derive less benefit from
intensified antiplatelet therapy as well as early invasive treatment[3].
Symptomatically, UA is differentiated from stable angina by specific clinical
findings of prolonged angina at rest (>20 minutes); new onset of severe angina;
angina that is increasing in frequency, longer in duration or lower in threshold;
or angina that occurs after a recent episode of myocardial infarction (MI)[3].
NSTE-ACS is caused by a partially occluded coronary artery, as opposed to the
complete occlusion found in STEMI, usually as the result of the formation of a
non-occlusive thrombus, which often develop within a disrupted atherosclerotic
plaque[4]. Other possible causes of NSTE-ACS are Prinzmetal’s angina, re-
stenosis following percutaneous coronary intervention, recreational drug use or
focal coronary artery spasm[1].
The clinical presentations of NSTE-ACS vary widely: some patients are
asymptomatic at presentation, while others may experience ongoing ischaemia,
haemodynamic instability or cardiac arrest[2].
This article discusses the pharmacotherapy of NSTE-ACS, from symptom
onset to secondary prevention. The recommendations from four important
clinical guidelines will be referred to and summarised:

1. The American College of Cardiology (ACC)/American Heart Association

(AHA) guideline[1];
2. The National Institute for Health and Care Excellence (NICE) guideline[5];
3. The National Heart Foundation of Australia & Cardiac Society of Australia
and New Zealand (ANZ) guideline[6];
4. European Society of Cardiology (ESC) guideline[3];
This article aims to provide readers with an international perspective on the
management of NSTE-ACS, however the focus will be on UK-based management.
An international perspective can provide an objective assessment of the key
similarities and differences in the management of NSTE-ACS and highlight any
gaps in evidence which may need to be addressed.

Epidemiology

The diagnosis of NSTEMI is more difficult to establish than STEMI and therefore
its prevalence is harder to estimate. The difference between STEMI and NSTE-
ACS is highlighted with an ECG, with STEMI having persistent (>20 minutes) ST-
segment elevation; while NSTE-ACS may still present with ECG changes, but not
in the form of persistent ST-segment elevation[3]. These changes may include
transient ST-segment elevation, ST-segment depression and T-wave inversions
[3].
The annual incidence of hospital admissions for ACS in the UK is more than
80,000, of which NSTE-ACS accounts for two-thirds[7]. The introduction of
highly sensitive cardiac troponin (hs-cTn) measurements in place of standard
troponin assays have resulted in an increase in the detection of NSTEMI, among
those presenting with suspected NSTE-ACS, and a reciprocal decrease in the
diagnosis of UA[8]. Epidemiological data show that the incidence for NSTEMI is
rising compared with STEMI[9]. Data for 2017/2018 from the Myocardial
Ischaemia National Audit Project (MINAP) show that there were 92,233
admissions to NHS hospitals in the UK with an acute MI; 39% were STEMI, and
61% were NSTEMI[10]. The rise in incidence of NSTEMI was largely owing to
the refinement in operational diagnosis and the changes in patient
characteristics, including the increased prevalence of diabetes, hypertension
and obesity[11].

Prognosis

Patients who experience a MI will most likely experience other cardiovascular-

related events in the future[12]. Prognosis depends on the timing and nature of
intervention[13]. NSTEMI patients appear to have lower 30-day mortality rate
compared with STEMI patients, while at one- or two-years follow-up the
mortality rates become comparable[14,15].
Early revascularisation, as well as the use of antithrombotic agents and beta-
blockers, have markedly reduced the incidence of life-threatening arrhythmias
in the acute phase of NSTE-ACS to <3%[3,16]. The acute phase of NSTE-ACS
includes the time from diagnosis to angiography to stent insertion. The acute
phase is also referred to as pre- and peri-procedural periods in this article. Most
arrhythmic events occur within 12 hours of NSTE-ACS symptom onset[16].
Patients with life-threatening arrhythmias are more likely to have prior heart
failure, have left ventricular ejection fraction (LVEF) at <30%, and have multi-
vessel coronary artery disease (CAD)[16]. Patients with a high ischaemic risk
are at greater risk of a major adverse cardiac event than patients with a lower
ischaemic risk[3]. Risk is highest at the time of presentation but remains
elevated past the acute phase[3]. By six months, NSTE-ACS mortality rates may
equal or exceed those of STEMI[17]. By 12 months, rates of death, MI and
recurrent instability in large-scale patient registries are >10%[3]. While early
events are related to ruptured coronary plaques and associated thrombosis, the
majority of later events may be the result of coronary and systemic
atherosclerosis progression[18].
In contrast to the treatment pathway for STEMI, which is based largely around
evidence-based emergency provision of reperfusion therapy, the treatment
pathway for NSTE-ACS is more diverse and dependent on local resource
availability, such as staff and access to cardiac catheter laboratories[5,19]. In
addition, NSTE-ACS patients tend to be older in age and have more co-
morbidities (e.g. hypertension, diabetes, heart failure), therefore having a wider
range of clinical risks, making them more challenging to diagnose and treat
[19,20]. The intensity of treatment is ultimately guided by risk and therefore
directly relates to the prognosis of the individual.

Risk stratification

All guidelines recommend that as soon as a diagnosis of NSTE-ACS is suspected

and/or confirmed, patients should be formally assessed to establish their future
risk of adverse cardiovascular and bleeding events using validated risk scoring
systems[1,3,5,6]. Risk scores can inform risk/benefit decisions regarding
treatment[1,3,5,6]. In NSTE-ACS, quantitative assessment of ischaemic risk by
means of scores is superior to clinical assessment alone[3]. Examples of risk
scoring systems that are validated in large populations and used internationally
are:

• Thrombolysis in myocardial infarction (TIMI) risk score[21];

• Global registry of acute coronary events (GRACE) score[22];
• Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression
using integrilin (eptifibatide) therapy (PURSUIT) score[23].
NICE, ESC and ANZ guidelines all advocate for the use of the GRACE tool to
identify patients who will benefit from an invasive treatment strategy, however
the US guideline is less prescriptive, with either TIMI or GRACE being
recommended[1,3,5,6].
The GRACE scoring system was derived from a large registry of ACS patients
(n=11,389) to predict in-hospital mortality at six months, one year and three
years[22]. Prediction risk scores are based on variables such as age, heart rate,
systolic blood pressure, creatinine levels, Killip classification of heart failure, ST-
segment deviation, elevated cTn and the occurrence of cardiac arrest on
admission[22].
Bleeding risk assessment

Major bleeding events are associated with increased mortality in people with
NSTE-ACS[24]. Bleeding risk scores used in clinical practice include:

• Can rapid risk stratification of unstable angina patients suppress adverse

outcomes with early implementation of the ACC/AHA guidelines
(CRUSADE) bleeding risk score[25];
• Acute catheterisation and urgent intervention triage strategy (ACUITY)
bleeding risk score[24].
Overall, both the CRUSADE and ACUITY scores have reasonable and comparable
predictive value for major bleeding in ACS patients undergoing coronary
angiography[26–28]. The predictive values of both scores have not been
established in patients who are not undergoing coronary angiography or in
those who are taking oral anticoagulants.

Acute pharmacotherapy management in suspected NSTE-

ACS

General supportive measures, such as the initiation of nitrates and beta-

blockers, should be provided when emergency services arrive (and before ACS
is confirmed), with the goal to decrease myocardial oxygen demand or increase
myocardial oxygen supply[1,3,6]. Oxygen should only be administrated in
patients with NSTE-ACS if oxygen saturation is <90% or if the patient is in
respiratory distress, as some evidence suggests that routine use of
supplemental oxygen in cardiac patients may have untoward effects, such as
increased coronary vascular resistance and increased mortality risk[1,29].
For patients who are unresponsive to nitrates and beta-blockers or where
contraindications are present, opiate administration is reasonable, with the
caveat that morphine may slow intestinal absorption of oral antiplatelets (i.e.
P2Y12 inhibitors)[30]. Non-steroidal anti-inflammatory drugs (NSAIDs, except
aspirin) should not be initiated for analgesia during the acute phase, and any
ongoing treatment with NSAIDs should be discontinued during hospitalisation
owing to the increased risk of major adverse cardiovascular events (MACE)
associated with their use[31].
Once general supportive measures are provided, platelet inhibition should be
initiated. A single loading dose of aspirin is normally recommended as soon as
possible to all patients upon presentation of NSTE-ACS (unless
contraindications exist)[1,3,5,6]. Following this, a maintenance dose of aspirin
should be continued indefinitely. Four randomised controlled trials have
demonstrated the benefit of aspirin in patients with UA by reducing the
incidence of MI or death[32]. Loading and maintenance dose recommendations
differ between guidelines, as outlined in Table 1 below.

Table 1: Recommended loading and maintenance doses for aspirin across

four international guidelines for people with NSTE-ACS[1,3,5,6]

Pharmacotherapy management of confirmed NSTE-ACS in

the pre-treatment and peri-procedural phase

While percutaneous coronary intervention (PCI) is the mainstream intervention

in patients with STEMI, the mainstream intervention/procedure for patients
with NSTE-ACS is invasive coronary angiography with coronary
revascularisation (PCI or coronary artery bypass graft [CABG]), as appropriate
[1,3,5,6]. Invasive coronary angiography allows clinicians to:

• Confirm the diagnosis of ACS related to obstructive epicardial CAD (or to

rule out a coronary origin of chest pain) and, as a consequence, to guide
antithrombotic treatment and avoid unnecessary exposure to
antithrombotic agents;
• Identify culprit lesion(s);
• Establish the indication for coronary revascularisation and assess the
suitability of coronary anatomy for PCI and CABG;
 • Stratify the patient’s short- and long-term risk[3].
In patients considered at low risk of ischaemic events, a conservative
management strategy is recommended, which consists of a non-invasive stress
test (e.g. exercise tolerance test) before deciding on an invasive strategy[3,5].
The pharmacological management of patients in the acute phase is divided into
treatment during the pre-treatment phase and the peri-procedural phase.

Antiplatelet use during pre-treatment

The use of P2Y12 inhibitors (e.g. clopidogrel, prasugrel or ticagrelor) soon after
the diagnosis of NSTE-ACS, irrespective of management strategy, is referred to
as pre-treatment, defined as P2Y12 inhibitor administration before coronary
angiography, and when coronary anatomy is unknown[33]. To date, this
practice is not yet supported by large-scale randomised controlled trials[3,5].
Fortunately, the recommended standard treatment with potent P2Y12 receptor
inhibitors (e.g. ticagrelor or prasugrel) exhibits a fast onset of action, thereby
allowing a loading dose to be administered after diagnostic coronary
angiography and directly before PCI[3]. The use of P2Y12 inhibitors is discussed
in subsequent sections of this article.

Anticoagulants

Anticoagulation therapy should be offered in addition to antiplatelet therapy in

the peri-interventional phase[1,3,5,6]. There is evidence that anticoagulation is
effective in reducing ischaemic events in NSTE-ACS and, when combined with
antiplatelets, it has been shown to be more effective than either treatment alone
[34].
The preferred anticoagulant differs between the guidelines. Fondaparinux is
recommended by NICE in the pre-treatment phase (i.e. before coronary
angiography) for NSTE-ACS patients who do not have a high bleeding risk and
who are not undergoing immediate angiography[5].
The recommendation made by NICE for fondaparinux as a pre-treatment
anticoagulant was based largely on evidence from the OASIS-5 trial[5,35]. The
OASIS-5 trial treated patients with fondaparinux during the conservative
treatment phase, who may subsequently undergo cardiac catheterisation[35].
The trial showed reduced major bleeding and mortality, and non-inferiority in
the reduction of ischaemic events compared with enoxaparin/unfractionated
heparin (UFH)[35].
For patients undergoing PCI, the peri-interventional anticoagulant
recommendations are: enoxaparin by the US guideline, or UFH by the European
and NICE guidelines[1,3,5]. The ANZ guideline does not favour either UFH or
enoxaparin over the other[6]. ESC recommends that fondaparinux is given with
a single bolus of UFH for cases of medical treatment or logistical constraints for
transferring the patient to PCI within the required time frame[3]. Bivalirudin is
recommended as a second-line treatment, as an alternative to either UFH or
enoxaparin for individuals at increased risk of bleeding events[1,3,6].
A meta-analysis of trials investigating enoxaparin versus UFH in ACS showed a
marginally significant reduction in the combined endpoint of death or MI at 30
days in favour of enoxaparin, but no significant differences in major bleeds at 7
days. However, this meta-analysis did not include a dedicated large-scale
randomised study in NSTE-ACS[36].

The recommendation to use UFH over bivalirudin was based largely on the
VALIDATE-SWEDEHEART trial, conducted in a contemporary setting of
preferred radial access and selective use of GP IIb/IIIa inhibitors[37]. The trial
confirmed that bivalirudin compared with heparin was associated with a similar
incidence of all-cause death and ischaemic events after PCI[37]. The ACUITY
trial, which compared bivalirudin with UFH or low molecular weight heparin
(LMWH), found no significant differences for the composite ischaemia endpoint
at 30 days or for major bleeds[38]. However, bivalirudin was shown in a meta-
analysis to be associated with a significant increased risk of stent thrombosis
and MI[39]. For this reason, the use of bivalirudin is reserved as an alternative
to UFH plus glycoprotein (GP) IIb/IIIa inhibitors during PCI[1,3,6].
GP IIb/IIIa inhibitors such as tirofiban, eptifibatide or abciximab are limited to
peri-procedural use during PCI for NSTE-ACS patients[3,6]. Administered
intravenously, GP IIb/IIIa inhibitors have an immediate effect, thereby
providing an immediate reduction in the risk of ischemic events during PCI[40].
However, concerns over high bleeding risk and cost have led to a steady decline
in their use[40]. European, UK and US guidelines recommend that GP IIb/IIIa
inhibitors be limited to bailout use (i.e. for thrombotic procedural complications
such as slow flow, no reflow, or angiographic evidence of a large thrombus)
[1,3,5]. The majority of trials evaluating GP IIb/IIIa inhibitors in PCI-treated ACS
patients predate the era of routine DAPT[41]. Therefore, in the current
landscape of use of potent platelet inhibition with ticagrelor or prasugrel, where
randomised data on GP IIb/IIIa use are limited, routine use of these agents
cannot be recommended. Parenteral anticoagulation should be discontinued
after PCI, unless otherwise indicated (e.g. the confirmed presence of LV
aneurysm with thrombus formation)[1,3,5,6]. Anticoagulation can be continued
in patients not undergoing angiography, for a maximum of eight days or until
hospital discharge, whichever occurs first[42].

Beta-blockers

Beta-blocker treatment should be initiated in the acute phase of NSTE-ACS with

help with ongoing ischaemic symptoms, unless contraindicated[1,3,5,6]. The
evidence for the beneficial effects of beta-blockers in NSTE-ACS is derived from
a meta-analysis of 27 studies showing that treatment was associated with a
13% relative risk reduction of mortality in the first week following MI[43].
The continuation of beta-blockers after discharge from hospital as part of a
secondary prevention regime is discussed in the next section.

Secondary prevention in non-ST-elevation acute coronary

syndrome

Long-term pharmacotherapy in NSTE-ACS patients, also known as secondary

prevention treatment, is aimed at modifying risks of further CV events. These
pharmacotherapies, coupled with important lifestyle changes, are of paramount
importance because of the high risk for recurrent ischaemic events after an
NSTE-ACS episode. The pharmacotherapy for secondary prevention in both
STEMI and NSTE-ACS are similar; detail relating to this can be found in
‘Pharmacotherapy of STEMI: a review of international guidelines‘.

P2Y12 inhibitors

Patients with NSTE-ACS should be treated with dual antiplatelet therapy

(DAPT)[1,3,5,6]. A P2Y12 inhibitor is recommended, in addition to aspirin, for 12
months unless there are contraindications, such as excessive bleed risk[1,3,5,6].
Available P2Y12 inhibitors include clopidogrel, prasugrel, ticagrelor and
cangrelor.
The choice of P2Y12 inhibitor in NSTE-ACS patients is dependent on the risk of
future adverse cardiovascular events and the corresponding reperfusion
strategy chosen. The European guideline specifies the preference for prasugrel
in patients who are undergoing PCI[3]. This recommendation was based on the
ISAR-REACT 5 trial, which showed that a prasugrel-based strategy was superior
to a ticagrelor-based strategy in the reduction of composite rate of death, MI or
stroke (6.9 vs. 9.3%, P=0.006) without any increase in bleeding complications
(4.8 vs. 5.4%, P=0.46)[44].
NICE also considered the evidence provided by the ISAR-REACT 5 trial[5].
Prasugrel should not be used before knowing the coronary anatomy in NSTE-
ACS patients owing to the higher bleeding risk[45]. As the time to coronary
angiograph in the UK is up to 72 hours, this may preclude the use of prasugrel
owing to the unknown coronary anatomy. Thus, NICE does not favour prasugrel
and recommends ticagrelor and prasugrel equally for this group of patients[5].
The American and ANZ guidelines were released before the ISAR REACT 5 trial
and are not as specific, but instead recommended the use of ticagrelor or
prasugrel over clopidogrel[1,6]. Ticagrelor and clopidogrel are indicated for all
reperfusion strategies (i.e. PCI or angiography-guided revascularisation)[46].
Ticagrelor has a faster and more consistent onset of action compared with
clopidogrel, in addition to a quicker offset of action with more rapid recovery of
platelet function[47]. Ticagrelor was found to be more effective than clopidogrel
in patients with moderate to high-risk NSTE-ACS in the PLATO trial[46].
Prasugrel is a prodrug, and acts by irreversibly binding its active metabolite
onto platelet P2Y12 receptors and inhibiting their action. It has a faster onset and
a more potent antiplatelet effect than clopidogrel[48]. The TRITON-TIMI 38 trial
demonstrated that patients receiving prasugrel had fewer recurrent CV events
and less stent thrombosis, but more bleeding complications, compared with
clopidogrel[49]. Therefore, prasugrel should be considered in patients who
present with stent thrombosis, despite compliance with clopidogrel therapy[50]
. Prasugrel is contraindicated in patients with prior stroke/transient ischaemic
attack; the TRITON-TIMI 38 trial showed there was an increased risk of major
and fatal bleeding in this group[49]. Moreover, the study showed no apparent
benefit for the use of prasugrel over clopidogrel in patients aged above 75 years
or with low bodyweight (<60kg)[49].
Clopidogrel is used in combination with aspirin at a maintenance dose of 75mg
daily in patients with NSTE-ACS. Generally, clopidogrel is used when ticagrelor
or prasugrel are not suitable; for example, in those with an indication for oral
anticoagulation and in those with prior intracranial bleeding[1,3,5,6].
Clopidogrel is an inactive prodrug that requires oxidation by the hepatic
enzyme CYP450 to generate an active metabolite[51]. Around 85% of the
prodrug is hydrolysed by esterase enzymes into an inactive form, leaving only
15% of clopidogrel available for transformation to the active metabolite, which
inactivates platelet P2Y12 receptors and thus inhibits platelet aggregation[51].
For this reason, pharmacodynamic and pharmacokinetic studies have described
substantial inter-individual variability in the antiplatelet response to
clopidogrel, resulting in an increased risk of ischaemic and bleeding events in
clopidogrel hypo- and hyper-responders, respectively[52,53]. DAPT comprising
aspirin and clopidogrel has been shown to reduce recurrent ischaemic events in
the NSTE-ACS setting compared with aspirin alone[54].
Prasugrel and ticagrelor are more potent antiplatelets in comparison with
clopidogrel and have shown increased risk of major bleeding compared with
clopidogrel[48,55]. Therefore, for patients with a high risk of bleeding,
clopidogrel may be a more appropriate option. In addition, clopidogrel may be
useful for those who require long-term oral anticoagulation as most trials
involving the use of dual antiplatelet in conjunction with anticoagulant (i.e.
triple therapy) were based on the use of clopidogrel[56,57]. ESC, NICE and ANZ
guidelines state that the use of prasugrel or ticagrelor as part of triple therapy
should be avoided[3,5,6]. The use of triple therapy in patients requiring long-
term oral anticoagulants will not be covered within this article, as it was not
featured equally in all four guidelines and the evidence around the optimal
duration of triple therapy is still evolving[3,5,6].

Duration of dual antiplatelet therapy

Consisting of a P2Y12 inhibitor and aspirin, DAPT is generally recommended for

12 months in patients with NSTE-ACS[1,3,5,6]. However, in specific clinical
scenarios, DAPT duration can be shortened (<12 months) or extended (>12
months), depending on the presenting ischaemic and bleeding risk, the
occurrence of adverse events and comorbidities[3,6]. Patients identified as
having a higher risk of bleeding (e.g. those with previous bleeding
complications, low platelet count, or concurrent use of anticoagulants) should
be assessed and considered for a shorter duration of dual antiplatelet therapy
(i.e. <12 months). The US guideline outlined a shortened duration of <12
months but does not mention an exact duration[1]. Shortened DAPT duration is
not covered in the NICE guideline[5]. ESC and ANZ guidelines recommend that
DAPT duration may be shortened to 3–6 months, balancing the ischaemic and
bleeding risks[3,6,58–60].
Extended dual antiplatelet therapy

The extended use of DAPT (beyond 12 months) may be considered in patients

with moderate-high ischaemic risk without increased risk of major bleeds[3,6].
The definitions of high ischaemic risks and low bleeding risks are outlined in the
ESC guidance[3]. The US guideline recommends DAPT therapy for at least 12
months for patients who received PCI, depending on stent type[1]. Extended
DAPT is recommended with either clopidogrel, ticagrelor or prasugrel[3,6]. The
European guideline has a separate DAPT-focused update, which recommends
the use of ticagrelor over clopidogrel/prasugrel for extended DAPT therapy[61].
This recommendation is based on a meta-analysis on the effect of extended
DAPT in patients with previous MI, which evaluated all three P2Y12 inhibitors
[62]. While the results of the meta-analysis may suggest a consistent class effect
among clopidogrel, ticagrelor or prasugrel in the decreased risk of MACE,
cardiovascular death and stroke, the PEGASUS study — which only evaluated
ticagrelor — contributed ≥60% to pooled endpoint estimates within this meta-
analysis and was the only trial included in its totality (and as such the only
properly powered study for post-MI patients); ESC therefore recommends the
use of ticagrelor as first-line treatment[3,63]. This showed that ticagrelor at
doses of 60mg twice daily (in conjunction with aspirin 75–150mg once daily
and compared with aspirin monotherapy) reduces the risk of ischaemic events
in patients who have already reached the first anniversary of their heart attack.
The recommendation for treatment duration for the use of ticagrelor (in
addition to aspirin), ranges from a period of up to three years to no upper limit
[3,6]. However, ESC does suggest the use of extended DAPT with clopidogrel
and prasugrel as well, where patients are not eligible for ticagrelor use.
The authors of the PEGASUS-TIMI 54 trial found that for 1,000 patients initiated
on ticagrelor 60mg twice daily for 3 years, 13 primary end-point events would
be prevented, including 5 ischemic strokes[63]. This benefit would come at a
cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds[63].
The benefits and risks of extended DAPT must therefore be considered carefully
on a case-by-case basis.
Another treatment strategy for extended therapy is the use of dual
antithrombotic therapy (DAT), consisting of factor-Xa inhibition with a very low
dose of rivaroxaban (2.5mg twice daily) plus aspirin. This regimen was
recommended as an option for maintenance treatment beyond 12 months post
ACS PCI by ESC[3]. More details can be found under ‘Secondary prevention‘.
A proton-pump inhibitor (PPI) is recommended to be taken in combination with
DAPT in patients with higher risk of gastrointestinal bleeds. It is important to
note the interaction between certain PPIs (e.g. omeprazole and esomeprazole)
which undergo CYP450 metabolism and hence reduce plasma levels of
clopidogrel[64]. The FDA, MHRA and EMA currently advise avoiding
omeprazole and esomeprazole in patients taking clopidogrel[65–67].

Lipid modification therapy

Statins inhibit the rate-limiting step in cholesterol synthesis and may also
reduce vascular inflammation, improve endothelial function and decrease
thrombus formation, in addition to lowering LDL[68]. All four guidelines
recommend initiation of high-intensity statin therapy as early as possible
following admission in all NSTE-ACS patients (in the absence of
contraindications)[1,3,5,6]. The evidence for the use of a high-intensity statin
was supported by a meta-analysis of eight studies involving 13,208 patients
with ACS, which found that the initiation of statin therapy before or after PCI led
to 35 fewer MACE at 12 months per 1,000 treated[69]. High-dose statins versus
no- or low-dose statins reduced the combined endpoint of death, recurrent MI
and stroke (OR 0.52, 95% CI 0.37-0.73). There was non-significant reduction in
MI (OR 0.81, 95% CI 0.65-1.01; P=0.06).
The preferred statin is atorvastatin at 80mg daily, unless patient preference,
interacting drugs or high risk of adverse effects warrant a dose reduction[1,5].
This was based on the PROVE IT-TIMI 22 and MIRACL trials, which showed a
lowering of low-density lipoprotein cholesterol (LDL-C) levels by ≥50%[70,71].
ESC and ANZ guidelines do not specify the preferred high-intensity statin but do
have a ‘treat to target’ approach[3,6]. The treatment target are as follows:

• To lower LDL-C to <1.4 mmol/L and to reduce it by at least 50% if the

baseline LDL-C level is 1.8–3.5 mmol/L[3];
• A target LDL-C of 1.8 mmol/L[6].
The addition of ezetimibe is recommended if the LDL-C is not sufficiently
lowered on statin therapy alone[3,5,6]. The IMPROVE-IT trial demonstrated a
modest benefit for ezetimibe used in combination with a statin[72].
Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors (e.g. evolocumab
and alirocumab) are recommended by NICE and ESC in patient cohorts where
cholesterol is insufficiently managed on statin and ezetimibe therapy[3,5].
PCSK9 inhibitors have been shown to be effective at reducing cholesterol and
LDL-C to <1.3mmol/L[73].

Beta-blockers

The current recommendation from ESC, NICE, ANZ and ACC guidelines is that
beta-blockers should be used, in the absence of contraindications, in patients
with reduced left ventricular systolic dysfunction (LVSD) (i.e. LVEF ≤40%) or
heart failure (HF)[1,3,5,6]. The US guideline recommends using a beta-blocker
with evidence of mortality reduction in patients with HF, such as sustained-
release metoprolol succinate, carvedilol or bisoprolol[2]. Sustained-release
metoprolol succinate is not licensed in the UK market. Beta-blockers have been
associated with a significant reduction in mortality and/or cardiovascular
events in this cohort of patients[74,75].
The evidence for the use of beta-blockers in patients without reduced LVSD or
HF is limited[76]. The benefit of long-term (>1 year) beta-blocker therapy in
patients with prior MI is also a subject of debate in recent years[76,77].
Recommendations regarding beta-blocker use in this group of patients
therefore differs between guidelines. The US guideline recommends that it is
‘reasonable’ to continue beta-blocker therapy in patients with normal LV
function with NSTE-ACS; while ANZ and NICE recommends discontinuation of
beta-blockers after 12 months’ therapy in this group of patients[1,5,6]. ESC does
not provide specific recommendations around this topic[3].
The need for, and duration of, beta-blocker therapy following MI to maintain a
protective effect on cardiac events in the absence of LVSD are unknown and are
currently being investigated in several randomised controlled trials[78].

Angiotensin-converting enzyme inhibitors

Angiotensin-converting enzyme (ACE) inhibitors are recommended by all

guidelines in patients with reduced ventricular systolic dysfunction, heart
failure, hypertension or diabetes[1,3,5,6]. Agents with proven efficacy should be
used, such as enalapril and ramipril[79].
In patients without impaired LV function, the use of ACE inhibitors was not
shown to reduce all-cause mortality, cardiovascular mortality, non-fatal MI,
stroke and heart failure by some trials[80]. A meta-analysis, including 24 trials
and 61,961 patients, documented that, in patients with coronary syndrome
without heart failure, ACE inhibitors reduced cardiovascular events and death
when compared with placebo but not when compared with active controls[81].
Therefore, the use of ACE inhibitors in patients with coronary syndromes
without heart failure or high cardiovascular risk is not generally recommended
by ESC, unless required to meet blood pressure targets[3]. ANZ, ACC and NICE
recommend that ACE inhibitors should be initiated and continued indefinitely in
all patients presenting with MI[1,5,6]. ACE inhibitors are thought to have a role
in the prevention of cardiac remodelling, which refers to changes in size, shape,
structure and function of the heart, often occurring after injury to the heart
muscles[82].
In patients who cannot tolerate ACE inhibitors, an angiotensin receptor blocker
(e.g. losartan) should be used[1,3,5,6].

Aldosterone antagonist

In patients displaying signs and/or symptoms of heart failure and reduced left
ventricular ejection fraction post NSTE-ACS, an aldosterone antagonist should
be initiated 3–14 days post-MI in patients with no existing contraindications
[1,3,5]. The preferred aldosterone antagonist is eplerenone and is
recommended in patients with LV dysfunction (LVEF ≤40%), congestive heart
failure or diabetes[83]. Eplerenone therapy has been shown to reduce
morbidity and mortality in these patients after ACS[83].

Anticoagulants

Dual antithrombotic therapy consisting of aspirin and a low-dose anticoagulant

is recommended as a treatment option for maintenance treatment beyond 12
months post ACS PCI[3,5,84]. The only low-dose anticoagulant currently
approved for use for this indication is rivaroxaban 2.5mg twice daily[85]. In a
secondary prevention setting, the COMPASS trial found that rivaroxaban 2.5mg
twice a day plus aspirin 100mg daily reduced the risk of the combined
ischaemic endpoint, overall mortality and cardiovascular mortality alone; while
it increased risks of major bleeding complications without a significant increase
in the risk of fatal, intracranial or critical organ bleeding event[85]. Greater
absolute risk reductions were seen in high-risk patients and, therefore, this
treatment most benefits those with high thrombotic risk[3,84].
Conclusion

The management of NSTE-ACS is a rapidly evolving field of practice and this

review has highlighted several differences across the four guidelines in relation
to a number of pharmacotherapy areas. This is largely because of the variation
in the publication year of the guidelines: from 2014 for the US guideline, to 2016
for the ANZ guideline, and 2020 for the UK and European guidelines[1,3,5,6].
The developments in the management of NSTE-ACS in recent years have
resulted in the variations in recommendations across the different guidelines.
Evidence remains lacking regarding the use of P2Y12 inhibitor before coronary
angiography (i.e. in the pre-treatment phase)[33]. The evidence in this area of
practice remains limited, and has been identified by the European guideline as
an area for future research[3].
The next key difference between the guidelines was related to the choice of
anticoagulant during the peri-interventional phase of NSTE-ACS.
Lastly, key differences exist in the guidelines involving the recommendations
around pharmacotherapy for secondary prevention in two therapy areas: long-
term antiplatelet therapy, and beta-blocker therapy. The evidence around the
optimal duration of DAPT in this cohort of patients is still limited and has been
identified as a gap in practice by ESC[3]. The benefits of the long-term use of
beta-blockers in patients with normal LV function and no other indications for
beta-blockers remain unknown. NICE and ANZ recommend limiting the use of
beta-blockers in this cohort of patients to 12 months[5,6]. While beneficial
effects of beta-blockers beyond 12 months are limited, discontinuation may be
associated with some risks[5]. Further research is therefore recommended to
establish the outcome of patients with NSTE-ACS who are using long-term beta-
blockers, compared with those who have discontinued beta-blockers[3,5].
References

1. 1

Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the
Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: Executive
Summary. Circulation 2014;130:2354–94. doi:10.1161/cir.0000000000000133

2. 2

Sheridan PJ. Critical review of unstable angina and non-ST elevation myocardial
infarction. Postgraduate Medical Journal 2002;78:717–26. doi:10.1136/pmj.78.926.717

3. 3

Collet J-P, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute
coronary syndromes in patients presenting without persistent ST-segment
elevation. European Heart Journal 2020;42:1289–367. doi:10.1093/eurheartj/ehaa575

4. 4

Rott D, Leibowitz D. STEMI and NSTEMI are two distinct pathophysiological

entities. European Heart Journal 2007;28:2685–2685. doi:10.1093/eurheartj/ehm368

5. 5

NG185: Acute Coronary Syndromes. National Institute of Health and Care Excellence.
2020.https://www.nice.org.uk/guidance/ng185 (accessed Aug 2021).

6. 6

Chew DP, Scott IA, Cullen L, et al. National Heart Foundation of Australia and Cardiac
Society of Australia and New Zealand: Australian clinical guidelines for the
management of acute coronary syndromes 2016. Medical Journal of
Australia 2016;205:128–33. doi:10.5694/mja16.00368

7. 7

Kotecha T, Rakhit RD. Acute coronary syndromes. Clin Med 2016;16:s43–8.

doi:10.7861/clinmedicine.16-6-s43

8. 8

Shah ASV, Anand A, Strachan FE, et al. High-sensitivity troponin in the evaluation of
patients with suspected acute coronary syndrome: a stepped-wedge, cluster-
 randomised controlled trial. The Lancet 2018;392:919–28. doi:10.1016/s0140-
6736(18)31923-8

9. 9

McManus DD, Gore J, Yarzebski J, et al. Recent Trends in the Incidence, Treatment, and
Outcomes of Patients with STEMI and NSTEMI. The American Journal of
Medicine 2011;124:40–7. doi:10.1016/j.amjmed.2010.07.023

10. 10

Myocardial Ischaemia National Audit Project: 2019 summary report (2017/18 data).
NICOR. 2019.https://www.nicor.org.uk/wp-content/uploads/2019/09/MINAP-2019-
Summary-Report-final.pdf (accessed Aug 2021).

11. 11

Puymirat E, Simon T, Cayla G, et al. Acute Myocardial

Infarction. Circulation 2017;136:1908–19. doi:10.1161/circulationaha.117.030798

12. 12

Park H-W, Yoon C-H, Kang S-H, et al. Early- and late-term clinical outcome and their
predictors in patients with ST-segment elevation myocardial infarction and non-ST-
segment elevation myocardial infarction. International Journal of
Cardiology 2013;169:254–61. doi:10.1016/j.ijcard.2013.08.132

13. 13

Myerson M, Coady S, Taylor H, et al. Declining Severity of Myocardial Infarction From

1987 to 2002. Circulation 2009;119:503–14. doi:10.1161/circulationaha.107.693879

14. 14

Terkelsen CJ, Lassen JF, Nørgaard BL, et al. Mortality rates in patients with ST-elevation
vs. non-ST-elevation acute myocardial infarction: observations from an unselected
cohort. European Heart Journal 2004;26:18–26. doi:10.1093/eurheartj/ehi002

15. 15

Marceau A, Samson J-M, Laflamme N, et al. SHORT AND LONG-TERM MORTALITY

AFTER STEMI VERSUS NON-STEMI: A SYSTEMATIC REVIEW AND META-
ANALYSIS. Journal of the American College of Cardiology 2013;61:E96.
doi:10.1016/s0735-1097(13)60097-2
16. 16

Piccini JP, White JA, Mehta RH, et al. Sustained Ventricular Tachycardia and Ventricular
Fibrillation Complicating Non–ST-Segment–Elevation Acute Coronary
Syndromes. Circulation 2012;126:41–9. doi:10.1161/circulationaha.111.071860

17. 17

Savonitto S. Prognostic Value of the Admission Electrocardiogram in Acute Coronary

Syndromes. JAMA 1999;281:707. doi:10.1001/jama.281.8.707

18. 18

Fox KA, Anderson Jr FA, et al. Time course of events in acute coronary syndromes:
implications for clinical practice from the GRACE registry. Nat Rev Cardiol 2008;5:580–
9. doi:10.1038/ncpcardio1302

19. 19

Corcoran D, Grant P, Berry C. Risk stratification in non-ST elevation acute coronary

syndromes: Risk scores, biomarkers and clinical judgment. IJC Heart &
Vasculature 2015;8:131–7. doi:10.1016/j.ijcha.2015.06.009

20. 20

Veerasamy M, Edwards R, Ford G, et al. Acute Coronary Syndrome Among Older

Patients. Cardiology in Review 2015;23:26–32. doi:10.1097/crd.0000000000000016

21. 21

Antman EM, Cohen M, Bernink PJLM, et al. The TIMI Risk Score for Unstable
Angina/Non–ST Elevation MI. JAMA 2000;284:835. doi:10.1001/jama.284.7.835

22. 22

Granger CB. Predictors of Hospital Mortality in the Global Registry of Acute Coronary
Events. Arch Intern Med 2003;163:2345. doi:10.1001/archinte.163.19.2345

23. 23

Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of Outcome in Patients With
Acute Coronary Syndromes Without Persistent ST-Segment
Elevation. Circulation 2000;101:2557–67. doi:10.1161/01.cir.101.22.2557

24. 24
 Mehran R, Pocock SJ, Nikolsky E, et al. A Risk Score to Predict Bleeding in Patients With
Acute Coronary Syndromes. Journal of the American College of
Cardiology 2010;55:2556–66. doi:10.1016/j.jacc.2009.09.076

25. 25

Subherwal S, Bach RG, Chen AY, et al. Baseline Risk of Major Bleeding in Non–ST-
Segment–Elevation Myocardial Infarction. Circulation 2009;119:1873–82.
doi:10.1161/circulationaha.108.828541

26. 26

Abu-Assi E, Raposeiras-Roubin S, Lear P, et al. Comparing the predictive validity of

three contemporary bleeding risk scores in acute coronary syndrome. European Heart
Journal: Acute Cardiovascular Care 2012;1:222–31. doi:10.1177/2048872612453924

27. 27

Liu R, Lyu S, Zhao G, et al. Comparison of the performance of the CRUSADE, ACUITY-
HORIZONS, and ACTION bleeding scores in ACS patients undergoing PCI: insights
from a cohort of 4939 patients in China. J Geriatr Cardiol 2017;14:93–9.
doi:10.11909/j.issn.1671-5411.2017.02.011

28. 28

Costa F, Tijssen JG, Ariotti S, et al. Incremental Value of the CRUSADE, ACUITY, and
HAS‐BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent
Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet
Therapy. JAHA 2015;4. doi:10.1161/jaha.115.002524

29. 29

Cabello JB, Burls A, Emparanza JI, et al. Oxygen therapy for acute myocardial
infarction. Cochrane Database of Systematic Reviews Published Online First: 19
December 2016. doi:10.1002/14651858.cd007160.pub4

30. 30

Kubica J, Kubica A, Jilma B, et al. Impact of morphine on antiplatelet effects of oral

P2Y12 receptor inhibitors. International Journal of Cardiology 2016;215:201–8.
doi:10.1016/j.ijcard.2016.04.077

31. 31
 Schjerning Olsen A-M, Fosbøl EL, Lindhardsen J, et al. Duration of Treatment With
Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent
Myocardial Infarction in Patients With Prior Myocardial
Infarction. Circulation 2011;123:2226–35. doi:10.1161/circulationaha.110.004671

32. 32

Théroux P, Ouimet H, McCans J, et al. Aspirin, Heparin, or Both to Treat Acute Unstable
Angina. N Engl J Med 1988;319:1105–11. doi:10.1056/nejm198810273191701

33. 33

Sibbing D, Kastrati A, Berger PB. Pre-treatment with P2Y12inhibitors in ACS patients:

who, when, why, and which agent? Eur Heart J 2015;37:1284–95.
doi:10.1093/eurheartj/ehv717

34. 34

Eikelboom JW, Anand SS, Malmberg K, et al. Unfractionated heparin and low-
molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-
analysis. The Lancet 2000;355:1936–42. doi:10.1016/s0140-6736(00)02324-2

35. 35

Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and Safety of Fondaparinux Versus
Enoxaparin in Patients With Acute Coronary Syndromes Undergoing Percutaneous
Coronary Intervention. Journal of the American College of Cardiology 2007;50:1742–51.
doi:10.1016/j.jacc.2007.07.042

36. 36

Silvain J, Beygui F, Barthelemy O, et al. Efficacy and safety of enoxaparin versus

unfractionated heparin during percutaneous coronary intervention: systematic review
and meta-analysis. BMJ 2012;344:e553–e553. doi:10.1136/bmj.e553

37. 37

Nührenberg TG, Hochholzer W, Mashayekhi K, et al. Efficacy and safety of bivalirudin

for percutaneous coronary intervention in acute coronary syndromes: a meta-analysis
of randomized-controlled trials. Clin Res Cardiol 2018;107:807–15. doi:10.1007/s00392-
018-1251-1

38. 38
 Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for Patients with Acute Coronary
Syndromes. N Engl J Med 2006;355:2203–16. doi:10.1056/nejmoa062437

39. 39

Zhang S, Gao W, Li H, et al. Efficacy and safety of bivalirudin versus heparin in patients
undergoing percutaneous coronary intervention: A meta-analysis of randomized
controlled trials. International Journal of Cardiology 2016;209:87–95.
doi:10.1016/j.ijcard.2016.01.206

40. 40

Abtan J, Ducrocq G, Steg PhG, et al. Characteristics and outcomes of patients requiring
bailout use of glycoprotein IIb/IIIa inhibitors for thrombotic complications of
percutaneous coronary intervention: An analysis from the CHAMPION PHOENIX
trial. International Journal of Cardiology 2019;278:217–22.
doi:10.1016/j.ijcard.2018.11.114

41. 41

Neumann F-J, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on

myocardial revascularization. European Heart Journal 2018;40:87–165.
doi:10.1093/eurheartj/ehy394

42. 42

Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes. N Engl J

Med 2006;354:1464–76. doi:10.1056/nejmoa055443

43. 43

Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart

disease. I. Treatments following myocardial infarction. JAMA 1988;260:2088–
93.https://www.ncbi.nlm.nih.gov/pubmed/2901501

44. 44

Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or Prasugrel in Patients with

Acute Coronary Syndromes. N Engl J Med 2019;381:1524–34.
doi:10.1056/nejmoa1908973

45. 45
 Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with Prasugrel in Non–ST-
Segment Elevation Acute Coronary Syndromes. N Engl J Med 2013;369:999–1010.
doi:10.1056/nejmoa1308075

46. 46

Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide
polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute
coronary syndromes: a genetic substudy of the PLATO trial. The Lancet 2010;376:1320–
8. doi:10.1016/s0140-6736(10)61274-3

47. 47

Gurbel PA, Bliden KP, Butler K, et al. Randomized Double-Blind Assessment of the
ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in
Patients With Stable Coronary Artery Disease. Circulation 2009;120:2577–85.
doi:10.1161/circulationaha.109.912550

48. 48

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus Clopidogrel in Patients
with Acute Coronary Syndromes. N Engl J Med 2007;357:2001–15.
doi:10.1056/nejmoa0706482

49. 49

De Servi S, Goedicke J, Schirmer A, et al. Clinical outcomes for prasugrel versus

clopidogrel in patients with unstable angina or non-ST-elevation myocardial infarction:
an analysis from the TRITON-TIMI 38 trial. European Heart Journal: Acute
Cardiovascular Care 2014;3:363–72. doi:10.1177/2048872614534078

50. 50

Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for
reduction of ischaemic events including stent thrombosis in patients with acute
coronary syndromes treated with percutaneous coronary intervention and stenting in
the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. The
Lancet 2008;371:1353–63. doi:10.1016/s0140-6736(08)60422-5

51. 51

Savi P, Labouret C, Delesque N, et al. P2Y12, a New Platelet ADP Receptor, Target of
Clopidogrel. Biochemical and Biophysical Research Communications 2001;283:379–83.
doi:10.1006/bbrc.2001.4816
52. 52

Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel Resistance Is Associated With

Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute
Myocardial Infarction. Circulation 2004;109:3171–5.
doi:10.1161/01.cir.0000130846.46168.03

53. 53

Simon T, Verstuyft C, Mary-Krause M, et al. Genetic Determinants of Response to

Clopidogrel and Cardiovascular Events. N Engl J Med 2009;360:363–75.
doi:10.1056/nejmoa0808227

54. 54

Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary

Syndromes without ST-Segment Elevation. N Engl J Med 2001;345:494–502.
doi:10.1056/nejmoa010746

55. 55

James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with
acute coronary syndromes intended for non-invasive management: substudy from
prospective randomised PLATelet inhibition and patient Outcomes (PLATO)
trial. BMJ 2011;342:d3527–d3527. doi:10.1136/bmj.d3527

56. 56

Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in
patients taking oral anticoagulant therapy and undergoing percutaneous coronary
intervention: an open-label, randomised, controlled trial. The Lancet 2013;381:1107–15.
doi:10.1016/s0140-6736(12)62177-1

57. 57

Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial
Fibrillation Undergoing PCI. N Engl J Med 2016;375:2423–34.
doi:10.1056/nejmoa1611594

58. 58

Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy
after percutaneous coronary intervention with drug eluting stents: meta-analysis of
randomised controlled trials. BMJ 2015;350:h1618–h1618. doi:10.1136/bmj.h1618
59. 59

Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting
bleeding complications in patients undergoing stent implantation and subsequent
dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient
datasets from clinical trials. The Lancet 2017;389:1025–34. doi:10.1016/s0140-
6736(17)30397-5

60. 60

Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual
antiplatelet therapy after DES implantation in patients with or without acute coronary
syndromes: an individual patient data pairwise and network meta-analysis of six
randomized trials and 11 473 patients. Eur Heart J 2017;:ehw627.
doi:10.1093/eurheartj/ehw627

61. 61

Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet
therapy in coronary artery disease developed in collaboration with EACTS. European
Heart Journal 2017;39:213–60. doi:10.1093/eurheartj/ehx419

62. 62

Udell JA, Bonaca MP, Collet J-P, et al. Long-term dual antiplatelet therapy for
secondary prevention of cardiovascular events in the subgroup of patients with
previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur
Heart J 2015;:ehv443. doi:10.1093/eurheartj/ehv443

63. 63

Bonaca MP, Bhatt DL, Steg PG, et al. Ischaemic risk and efficacy of ticagrelor in relation
to time from P2Y12inhibitor withdrawal in patients with prior myocardial infarction:
insights from PEGASUS-TIMI 54. Eur Heart J 2015;37:1133–42.
doi:10.1093/eurheartj/ehv531

64. 64

Yasuda H, Yamada M, Sawada S, et al. Upper Gastrointestinal Bleeding in Patients

Receiving Dual Antiplatelet Therapy after Coronary Stenting. Intern Med 2009;48:1725–
30. doi:10.2169/internalmedicine.48.2031

65. 65
 FDA reminder to avoid concomitant use of Plavix (clopidogrel) and omeprazole. Food
and Drugs Administration.
2010.https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s055lbl.pdf (
accessed Jul 2021).

66. 66

Clopidogrel and proton pump inhibitors: interaction-updated advice. Drug Safety

Update 2010; 3:4. Medicines and Healthcare products Regulatory Agency.
2010.https://www.gov.uk/drug-safety-update/clopidogrel-and-proton-pump-
inhibitors-interaction-updated-advice (accessed Jul 2021).

67. 67

Public statement: Interaction between clopidogrel and proton pump inhibitors.

European Medicines Agency. 2009.https://www.ema.europa.eu/en/news/public-
statement-possible-interaction-between-clopidogrel-proton-pump-
inhibitors#:~:text=The%20European%20Medicines%20Agency%20is,myocardial%20inf
arction%20(heart%20attack) (accessed Jul 2021).

68. 68

Sposito AC, Chapman MJ. Statin Therapy in Acute Coronary

Syndromes. ATVB 2002;22:1524–34. doi:10.1161/01.atv.0000032033.39301.6a

69. 69

Navarese EP, Kowalewski M, Andreotti F, et al. Meta-Analysis of Time-Related Benefits

of Statin Therapy in Patients With Acute Coronary Syndrome Undergoing
Percutaneous Coronary Intervention. The American Journal of
Cardiology 2014;113:1753–64. doi:10.1016/j.amjcard.2014.02.034

70. 70

Schwartz GG. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute

Coronary Syndromes<SUBTITLE>The MIRACL Study: A Randomized Controlled
Trial</SUBTITLE>. JAMA 2001;285:1711. doi:10.1001/jama.285.13.1711

71. 71

Ray KK, Cannon CP, McCabe CH, et al. Early and Late Benefits of High-Dose
Atorvastatin in Patients With Acute Coronary Syndromes. Journal of the American
College of Cardiology 2005;46:1405–10. doi:10.1016/j.jacc.2005.03.077

72. 72
 Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after
Acute Coronary Syndromes. N Engl J Med 2015;372:2387–97.
doi:10.1056/nejmoa1410489

73. 73

Ray KK, Colhoun HM, Szarek M, et al. Effects of alirocumab on cardiovascular and
metabolic outcomes after acute coronary syndrome in patients with or without
diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled
trial. The Lancet Diabetes & Endocrinology 2019;7:618–28. doi:10.1016/s2213-
8587(19)30158-5

74. 74

Andersson C, Shilane D, Go AS, et al. Beta-Blocker Therapy and Cardiac Events Among
Patients With Newly Diagnosed Coronary Heart Disease. Journal of the American
College of Cardiology 2014;64:247–52. doi:10.1016/j.jacc.2014.04.042

75. 75

Hwang D, Lee JM, Kim HK, et al. Prognostic Impact of β-Blocker Dose After Acute
Myocardial Infarction. Circ J 2019;83:410–7. doi:10.1253/circj.cj-18-0662

76. 76

Dahl Aarvik M, Sandven I, Dondo TB, et al. Effect of oral β-blocker treatment on
mortality in contemporary post-myocardial infarction patients: a systematic review and
meta-analysis. European Heart Journal – Cardiovascular Pharmacotherapy 2018;5:12–
20. doi:10.1093/ehjcvp/pvy034

77. 77

Hong J, Barry AR. Long-Term Beta-Blocker Therapy after Myocardial Infarction in the
Reperfusion Era: A Systematic Review. Pharmacotherapy 2018;38:546–54.
doi:10.1002/phar.2110

78. 78

Zeitouni M, Kerneis M, Lattuca B, et al. Do Patients need Lifelong β-Blockers after an

Uncomplicated Myocardial Infarction? Am J Cardiovasc Drugs 2019;19:431–8.
doi:10.1007/s40256-019-00338-4

79. 79
 Baker W, Coleman C, Kluger J, et al. Systematic review: comparative effectiveness of
angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for
ischemic heart disease. Ann Intern Med 2009;151:861–71. doi:10.7326/0003-4819-151-
12-200912150-00162

80. 80

Effects of an Angiotensin-Converting–Enzyme Inhibitor, Ramipril, on Cardiovascular

Events in High-Risk Patients. N Engl J Med 2000;342:145–53.
doi:10.1056/nejm200001203420301

81. 81

Bangalore S, Fakheri R, Wandel S, et al. Renin angiotensin system inhibitors for patients
with stable coronary artery disease without heart failure: systematic review and meta-
analysis of randomized trials. BMJ 2017;:j4. doi:10.1136/bmj.j4

82. 82

Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction.

Experimental observations and clinical implications. Circulation 1990;81:1161–72.
doi:10.1161/01.cir.81.4.1161

83. 83

Zannad F, McMurray JJV, Krum H, et al. Eplerenone in Patients with Systolic Heart
Failure and Mild Symptoms. N Engl J Med 2011;364:11–21.
doi:10.1056/nejmoa1009492

84. 84

NICE TA607: Rivaroxaban for preventing atherothrombotic events in people with

coronary or peripheral artery disease. National Institute for Health and Care Excellence.
2019.https://www.nice.org.uk/guidance/ta607 (accessed Jul 2021).

85. 85

Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in
patients with stable coronary artery disease: an international, randomised, double-
blind, placebo-controlled trial. The Lancet 2018;391:205–18. doi:10.1016/s0140-
6736(17)32458-3