Optimal treatment of patients with NSTE-ACS in the Dutch health care system
Optimal treatment of patients with NSTE-ACS in the Dutch health care system
J. P. van Kuijk 0 1
J. M. ten Berg 0 1
0 Department of Cardiology, St Antonius Hospital , Nieuwegein , The Netherlands
1 J. P. van Kuijk
In the current daily practice of acute coronary syndromes, patients experiencing non-ST-elevation acute coronary syndrome (NSTE-ACS) represent the majority of this population. In these patients it is of utmost importance to estimate both ischaemic and bleeding risk, with subsequent, and preferably tailored pharmacological and, if indicated, invasive treatment. In this paper we describe the several risk scores and evaluate which are most applicable to the Dutch health-care system. Furthermore, we provide an overview of the recommended pharmacological treatment in keeping with the European Society of Cardiology guidelines. An important topic of this paper is how to decide between early or delayed invasive strategies. We describe the recommendations of the European Society of Cardiology and evaluate to which level these should be applied to the Dutch health-care system.
therapeutics; acute coronary syndrome; myocardial infarction
Non-ST-elevation acute coronary syndromes (NSTE-ACS)
comprise a wide clinical spectrum, ranging from patients
free of symptoms at presentation to those with ongoing
ischaemia, haemodynamic or electrical instability or even
cardiac arrest. In patients with unstable angina, there is
myocardial ischaemia without cell loss, however in those with
non-ST-elevation myocardial infarction (NSTEMI), there is
cardiomyocyte necrosis, characterised by elevated troponin
and/or creatine kinase levels.
Patients without an ST-elevation myocardial infarction
(STEMI) and no haemodynamic or electrical instability,
will be presented to cardiac emergency departments where
several diagnostic tools should be available. A 12-lead ECG
is obtained and interpreted <10 min after arrival [
it is mandatory to measure biomarkers of cardiomyocyte
injury, preferably high-sensitive troponin, which have
increased sensitivity and diagnostic accuracy for the detection
of acute myocardial infarction (AMI) [
]. Importantly, the
absolute troponin change (delta) within 1 h can be used as
a surrogate for absolute changes over the previously used
3–6 h [
]. The cut-off levels within the 0/1 h algorithm
depend on the specific assay that is used to measure troponin
]. The specific cut-off values for the most
commonly used assays are presented in the 2015 European
Society of Cardiology (ESC) guidelines for the management
of acute coronary syndromes in patients presenting without
persistent ST-segment elevation, .
In this paper we will describe the recommendations of
the 2015 ESC guidelines on risk stratification and treatment
of NSTE-ACS patients. In addition, we will give advice
on how to apply these recommendations in daily clinical
practice in the Dutch health care system.
Based on the clinical presentation, the initial ECG and
the biomarkers, an ischaemic and bleeding risk assessment
should be performed in every individual patient, as these
assessments provide not only diagnostic but also prognostic
Quantitative assessment of the ischaemic risk in patients
with NSE-ACS, using specific risk scores, is superior to
clinical assessment alone. The Global Registry of Acute
Coronary Events (GRACE) risk score provides the most
Ischaemic and bleeding risk assessment in NSTE-ACS patients is important, however,
data on prospective validation are lacking.
Decision making on pharmacological and invasive therapy should be patient tailored.
accurate risk stratification, whereas the GRACE 2.0 risk
calculator provides a direct estimation of in-hospital
mortality, at 6 months, at 1 year and at 3 years. In addition, the
combined risk of death and myocardial infarction (MI) at
1 year is also provided [
]. Importantly, although the value
of risk scores as prognostic assessment tools is undisputed,
the impact of using risk scores in daily practice on patient
outcomes has not yet been adequately investigated [
NSTE-ACS, the risk is highest at the time of presentation,
and therefore, accurate assessment of acute risk guides
initial evaluation, selection of the site of care, and therapy
]. Therapy includes antithrombotic treatment and
(timing of) coronary angiography, which will be discussed later
in this paper.
In conclusion, the ESC guidelines recommend using
established risk scores for prognosis assessment (Class IB) [
]. For the Dutch health care system, we advise using the
GRACE risk score for general risk estimation at admission
as this is easily accessible and has proven accuracy.
As platelet inhibition/anticoagulation is the cornerstone in
the treatment of suspected NSTE-ACS and major bleeding
events are associated with increased mortality in
NSTEACS, assessing bleeding risk is of utmost importance [
Two bleeding risk scores are mentioned in the 2015
NSTEACS ESC guidelines; CRUSADE (Can Rapid risk
stratification of Unstable angina patients Suppress Adverse
outcomes with Early implementation of the ACC/AHA
guidelines) and ACUITY (Acute Catheterization and Urgent
Intervention Triage strategy) [
]. Overall, in ACS
patients undergoing coronary angiography, the CRUSADE
score was found to be the most discriminatory . In
addition, the predictive value of both scores has not been
established in patients who are treated medically or in those
on oral anticoagulation.
In conclusion, in the ESC guidelines the use of the
CRUSADE score has a Class IIb recommendation to quantify
bleeding risk in patients undergoing coronary angiography
]. In our opinion, the CRUSADE score can be used to
quantify bleeding risk in patients undergoing coronary
angiography, and in patients with an increased risk the use of
platelet inhibitors should be patient tailored.
The primary goals of the pharmacological treatment are
decreasing myocardial oxygen demand and increasing
myocardial oxygen supply. Nitrates are primarily used for
symptom relief and should be used in patients with
ongoing angina. Beta-blockers provide a 13% relative risk
reduction of mortality in the first week after myocardial
infarction in NSTE-ACS [
]. In the acute phase
beta-blockers can be used to lower the heart rate in patients with
ischaemia driven by tachycardia. However, early
administration of beta-blockers should be avoided in patients if the
ventricular function is unknown [
In the pre-PCI era, several randomised trials and
meta-analysis have demonstrated the effectiveness of aspirin in
patients with unstable angina [
]. Several oral, and one
intravenous, P2Y12 inhibitors have been developed
during the last 2 decades, including clopidogrel, prasugrel,
ticagrelor and cangrelor, respectively. The mechanism of
action is inhibition of platelet aggregation that is induced
by adenosine diphosphate. Clopidogrel and prasugrel
irreversibly inactivate the platelet P2Y12 receptors, whereas
ticagrelor is a reversible P2Y12 inhibitor with a plasma
half-life of 6–12 h. Cangrelor is effective in 2 min after
intravenous administration and the duration of effect is 1–2 h,
whereas plasma half-life of the active P2Y12 inhibitor is
The CURE (Clopidogrel in Unstable Angina to Prevent
Recurrent Events) trial was the first study that demonstrated
a beneficial effect of adding clopidogrel to aspirin in
patients with NSTE-ACS (composite of cardiovascular death,
MI or stroke, 9.3% vs. 11.4%; hazard ratio [HR] clopidogrel
vs. aspirin 0.80 95% confidence interval [CI] 0.72–0.90),
but this was associated with an absolute risk increase of
major bleeding of 1% (3.7% vs. 2.7%, relative risk 1.38,
p = 0.001) [
]. In addition, 12,562 ACS patients treated
with this combination of platelet inhibitors, had up to 10%
risk of recurrent ischaemic events in the first year, with up to
2% stent thrombosis [
]. It is also worth noting that in this
study only 2,658 (21%) patients underwent PCI and 2,072
(17%) coronary artery bypass grafting (CABG), therefore,
the majority was treated medically.
The more potent P2Y12 inhibitor prasugrel was tested
against clopidogrel in the TRITON-TIMI 38 (TRial to
Assess Improvement in Therapeutic Outcomes by
Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis in
Myocardial Infarction 38) trial, including 10,074
NSTEACS patients scheduled for PCI [
]. At 15-month
follow-up the composite endpoint was reduced in
prasugreltreated patients (cardiovascular death, non-fatal MI,
nonfatal stroke, 9.9% vs. 12.1%; HR prasugrel vs. clopidogrel
0.81, 95% CI 0.73–0.90), driven by a significant reduction
in myocardial infarction (24% relative risk reduction),
however, this was at the cost of a 40% increase in severe
nonCABG-related bleeding events (2.4% vs. 1.8%, p = 0.02).
Prasugrel is contraindicated in patients with prior stroke/
transient ischaemic attack (TIA) due to net evidence of
harm in this group. Post-hoc analysis demonstrated no net
clinical benefit in patients with a low bodyweight (<60 kg)
or those aged >75 years using prasugrel compared with
clopidogrel. In these patients prasugrel could be reduced to
5 mg daily or replaced by clopidogrel.
The most recent oral P2Y12 inhibitor ticagrelor was tested
against clopidogrel in the PLATO (PLATelet inhibit and
patient Outcomes) trial, including 18,624 patients who had
a moderate to high risk of NSTE-ACS (planned for
either conservative or invasive management) or STEMI [
Ticagrelor demonstrated a 17% relative risk reduction in the
primary composite efficacy endpoint (composite of death
from cardiovascular causes, MI or stroke, 9.8% vs. 11.7%;
HR ticagrelor vs. clopidogrel 0.84 95% CI 0.77–0.92).
Ticagrelor was associated with an 28% increased risk of
non-CABG-related PLATO-defined major bleeding events
(4.5% vs. 3.8%, p = 0.03), but no difference in
life-threatening or fatal bleeding events. Important contraindications
include active pathological bleeding, history of intracranial
haemorrhage and severe hepatic impairment. In addition,
dyspnoea is relatively often reported with ticagrelor use
and caution should be taken in patients at risk for
bradycardia events. Finally, ticagrelor has an increased risk of
interaction with other CYP3A4 inhibitors.
The intravenous adenosine triphosphate (ATP) analogue
cangrelor has a high affinity for the P2Y12 receptor but
binds reversibly and has a short plasma half-life (<10 min).
The CHAMPION trials have tested cangrelor, and a
metaanalysis of these trials observed a 19% relative risk
reduction in periprocedural death, MI, ischaemia-driven
revascularisation and stent thrombosis, compared with clopidogrel
]. Thrombolysis in myocardial infarction (TIMI) major
and minor bleeding rates were increased, but no increase
in the transfusion rate. In 2015, the European Commission
issued marketing authorisation for this compound.
Important contra-indications include active or increased risk of
bleeding and any history of stroke/TIA.
The ESC Task Force for the management of ACS in
patients presenting with NSTE-ACS recommended
initiating P2Y12 inhibitors soon after the diagnosis is
]. In daily practice, this implies pre-treatment
with P2Y12 inhibitors in patients who are scheduled for
an invasive approach. Currently, the only randomised trial
investigating pre-treatment with P2Y12 inhibitors was the
ACCOAST trial (Comparison of Prasugrel at the Time of
Percutaneous Coronary Intervention or as Pretreatment at
the Time of Diagnosis in Patients with Non-ST
Elevation Myocardial Infarction trial) [
]. TIMI major
bleeding rates were significantly increased in the pre-treatment
group at 7 days. Since then, there has been an extensive
discussion and the topic remains controversial. In the
PCICURE trial, clopidogrel pre-treatment compared to placebo,
showed a reduction in cardiovascular death or MI. In
addition, a subgroup analysis of the PLATO trial demonstrated
equal benefit of DAPT with ticagrelor in patients intended
for non-invasive treatment with NSTE-ACS. Currently, no
guideline recommendations on pre-treatment are provided.
Based on current available literature it can only be
concluded that pre-treatment with prasugrel is contraindicated
and for clopidogrel and ticagrelor only data from
(underpowered) subgroup analysis are available. In NSTE-ACS
patients with a conservative management, preferably
ticagrelor, is recommended as soon as the diagnosis has been
confirmed, of course only when there are no
A specific, and increasing, subgroup of patients are the
elderly. In the ACCOAST trial the increased bleeding risk
with prasugrel was also present in the subgroup of patients
aged >75 years. In the PCI-CURE trial subgroup of 1,042
patients aged ≥65 years, no significant benefit of
clopidogrel pre-treatment compared with placebo was observed
]. In the PLATO trial, patients ≥65 years demonstrated
a superiority of ticagrelor compared with clopidogrel.
However, in patients ≥75 years this superiority was no longer
statistically significant [
]. On the other hand, ticagrelor
was not associated with an increased bleeding risk
compared with clopidogrel in this specific population. In
conclusion, in elderly patients with a high bleeding risk it seems
more reasonable to postpone the administration of a P2Y12
inhibitor until after angiography.
PRECISE-DAPT demonstrated improved integrated
discrimination and reclassification performance as compared
with other bleedings scores [
]. The PRECISE-DAPT can
be used as an algorithm at the moment of hospital discharge
to identify patients with an increased bleeding risk in whom
duration of DAPT should be shortened. In addition, a DAPT
score was developed to identify patients who might
benefit of prolonged DAPT after 1 year of event-free treatment
26, 32, 33
]. The duration of DAPT in patients with
NSTEACS is extensively discussed elsewhere in this issue of the
Netherlands Heart Journal [DOI].
The combination of anticoagulation and platelet inhibitors
is proven to be more effective than either treatment alone
in reducing ischaemic events in NSTE-ACS patients [
Unfractionated heparin (UFH)
In patients with NSTE-ACS the use of UFH as an
anticoagulant is still daily practice in a number of countries,
however, there is evidence for an increased bleeding risk
compared with other anticoagulants [
]. If UFH is used
during PCI, it can be given under activated clotting time
(ACT) guidance (250–350 s) or in a weight-adjusted
manner (70–100 IU/kg). No dose adjustment to renal function
Low-molecular-weight heparin (LMWH)
The most widely used LMWH in NSTE-ACS is enoxaparin
at a dose of 1 mg/kg twice daily in patients with normal
renal function. It has a more predictable dose-effect
relationship than UFH. However, the treatment regimen in the
period before, during and after the PCI can be confusing, as
this depends on the last time of administration.
Meta-analysis testing enoxaparin versus UFH in ACS demonstrated
favourable safety and efficacy profiles of enoxaparin during,
mainly primary, PCI [
]. Prior studies in NSTE-ACS
patients treated conservatively demonstrated that enoxaparin
was also superior to UFH [
ACS, except for patients who are scheduled for immediate
coronary angiography. Once-daily dosing is sufficient, but
due to its renal elimination, it is contraindicated if eGFR
<20 mL/min/1.73 m2. The OASIS-5 (Organization to Assess
Strategies in Acute Ischaemic Syndromes 5) study tested
enoxaparin versus fondaparinux and observed an equal
efficacy, but a more favourable safety profile of fondaparinux
]. We should point out that fondaparinux is associated
with an increased risk of catheter thrombosis which can be
prevented by an additional weight-adjusted bolus of UFH
at the time of PCI.
The direct thrombin inhibitor bivalirudin has a more
predictable anticoagulant effect than UFH. Bivalirudin has
been tested against UFH in several trials with several
different treatment regimens, including the ACUITY and
ISAR-REACT 3 and 4 (Intracoronary Stenting and
Antithrombotic Regimen—Rapid Early Action for Coronary
Treatment) trials. In NSTE-ACS patients undergoing PCI
bivalirudin has a comparable efficacy but is safer than UFH.
It has a Class IA recommendation in the ESC NSTE
guidelines, but still fondaparinux has the advantage of parenteral
Specific comments on the Dutch health care system
In the Dutch health care system, the majority of patients
admitted with NSTE-ACS are pre-treated with dual
antiplatelet inhibition. The most important reason for this
regimen is the fact that due to the current health care system
the choice for conservative or invasive management in a
significant part of the NSTE-ACS population is made during
the first 48 h of admission and not directly at presentation.
Therefore, treatment with a single platelet inhibitor during
this period, could result in “undertreatment” of a significant
part of this population. The Dutch ACS working group has
therefore suggested pre-treatment of NSTE-ACS patients
with low to moderate bleeding risk and high probability of
PCI. In contrast, in patients with known coronary anatomy
or clinical evidence of 3-vessel disease/left main
involvement (high likelihood of CABG), a choice for single
antiplatelet therapy can be made.
Invasive coronary angiography
Routine versus selective invasive approach
The selective factor Xa inhibitor fondaparinux is
considered to have the most favourable efficacy and safety profiles
and is recommend as first-choice anticoagulation in
NSTEIn current Dutch practice, most patients with NSTE-ECS
undergo invasive coronary angiography. The obtained
information on coronary anatomy and disease is used for further
decision making on the treatment regimen
(pharmacological, PCI or CABG). Multiple studies and several
metaanalyses have demonstrated that, compared with a
selective invasive strategy, a routine invasive strategy in
NSTEACS patients improves clinical outcomes and reduce
recurrent ACS episodes, rehospitalisation and revascularisation
Timing of invasive strategy
In the ESC guidelines on management of NSTE-ACS, risk
criteria are provided to support the clinical decision
making on the timing of the invasive strategy. The
very-highrisk criteria are: 1) haemodynamic instability or cardiogenic
shock, 2) recurrent or ongoing chest pain refractory to
medical treatment, 3) life-threatening arrhythmias or cardiac
arrest, 4) mechanical complications of MI, 5) acute heart
failure, and 6) recurrent dynamic ST-T wave changes,
particularly with intermittent ST elevation. The three
highrisk criteria are: 1) rise or fall in cardiac troponin
compatible with MI, 2) dynamic ST-wave or T-wave changes
(symptomatic or silent), and 3) GRACE score >140. The
seven intermediate-risk criteria are: diabetes mellitus, renal
insufficiency (eGFR <60 mL/min/1.73 m2), LVEF <40% or
congestive heart failure, early post-infarction angina, prior
PCI, prior CABG, and GRACE risk score >109 or <140.
Finally, the presence of any characteristics not mentioned
in the prior criteria is mentioned as low-risk criteria [
Immediate invasive strategy
Performing a coronary angiography within 2 h is
recommended in NSTE-ACS patients with at least one
very-highrisk criterium as mentioned above. As most randomised
trials have excluded these patients, it is recommended to treat
this category of patients according to STEMI patients.
Early invasive or delayed invasive strategy
The ESC guidelines for NSTE-ACS recommend an early
invasive approach (<24 h) in patients with at least one
highrisk criterion [
]. This recommendation also includes timely
transfer of patients admitted to hospitals without on-site
catheterisation facilities. Importantly, this is announced as
a ‘performance measure in NSTE-ACS’. These
recommendations are based on 2 meta-analyses including in total
seven RCTs in 5,370 NSTE-ACS patients and four
observational studies including 77,499 patients, comparing early
and delayed invasive strategy [
]. Remarkably, the only
difference in favour of an early invasive strategy was a
significant lower risk of refractory ischaemia, but not in in
death or major bleeding event. Sub-analysis of two trials
has provided some evidence in favour of an early
invasive strategy only in patients with a high-risk profile. The
TIMACS (Timing of Intervention in Acute Coronary
Syndromes) trial demonstrated no difference between early and
delayed invasive strategy in the complete study population.
Only in a pre-specified sub-analysis of high-risk patients
(one third of patients with a GRACE risk score >140) did
an early invasive strategy lower the risk of death, MI or
stroke at six months. However, the study was not
powered for this subgroup analysis [
]. Of note, sub-analysis
from a negative trial can at best be generating hypothesis
but cannot really contribute to the implementation of new
guidelines. In addition, in a post hoc analysis of the
ACUITY trial, delayed invasive strategy in NSTE-ACS patients
with high-risk criteria was an independent predictor of
30day and 1-year mortality, however, again the trial was not
powered for this sub-analysis [
Specific comments on the Dutch health care system
In the Dutch health care system, the recommendations on
invasive strategies in NSTE-ACS patients are not
completely adopted, as earlier described in the consensus
document of the ‘working group on ACS’ of the Dutch society
of cardiology (NVVC) [
]. The most important reason is
the lack of scientific evidence on a benefit of an early
invasive versus a delayed invasive strategy. As described above,
only sub-analysis of 2 RCTs demonstrated a possible
benefit, however, as these are not adequately powered, these
results can only be interpreted as hypothesis-generating
results. In addition, in the Dutch health care system, there are
many non-PCI hospitals with the presence of a cardiac care
unit and the capability of performing coronary angiography
during daytime only. Patients admitted to these hospitals
with a NSTE-ACS are pharmacologically treated
according the current ESC guidelines, and, if admitted during the
weekend, coronary angiography is performed on the first
day after the weekend. With this current practice, there are
only rarely examples of calamities. Two important factors
are the fundament for the adequate function of the current
Dutch system; first, in unstable patients or patients with
very-high-risk criteria the ambulance staff already decides
to present the patient to a PCI centre, and second, if a prior
stable NSTE-ACS patient who has been admitted to a
nonPCI centre develops very-high-risk criteria, an immediate
transfer to a PCI centre is always possible with very short
time delays. The latter is due to the short travel distances
between the hospitals and the adequately functioning
In the current NSTE-ACS guidelines the rise and fall of
troponin is considered a high-risk criterium, and therefore
should lead to same day transfer to a hospital with on-site
catheterisation facilities. We would like to point out that
this group of patients represents the majority of the
NSTEACS population which is why, in our opinion, this criterium
should not be applied directly to the Dutch system. Instead
a rise in troponin levels should be assessed in relation to the
patient’s clinical presentation as the current high-sensitive
troponin assays very often detect a rise in troponin levels in
cases with a non-coronary aetiology, i. e. pericarditis,
myocarditis, pulmonary pathology, aortic pathology, and type 2
myocardial infarction. Most of these patients can be treated
locally in a non-PCI centre. Importantly, the current
standard of care in these patients has turned out to be safe and
effective in daily care, therefore, in our opinion, same day
transfer is not mandatory in most of these patients.
In NSTE-ACS patients admitted to a non-PCI centre,
coronary angiography is performed locally and thereafter
data are discussed in dedicated heart teams in centres with
on-site cardiac surgery. Based on the decided treatment
regimen, patients are transferred to the treating hospitals if
necessary. Medical treatment is prescribed in keeping with
existing guidelines during the waiting period for coronary
angiography and DAPT is initiated based on the arguments
In the current NSTE-ACS ESC guidelines the importance
of risk assessment is emphasised. Regarding ischaemic risk
assessment, the GRACE 2.0 risk score seems most
applicable. Importantly the ischaemic and bleeding risk scores have
the major limitation of not being prospectively validated,
and therefore there is a clear need for prospective testing of
these risk scores in randomised clinical trials in NSTE-ACS
patients. Depending on adequately validated risk scores,
decision making regarding antithrombotic and anticoagulation
therapy could be more tailored to the patient. Furthermore,
especially in the Dutch health care system, the decision for
early or delayed invasive strategies should be patient
tailored, and not solely be based on a short list of high-risk
criteria provided by non-prospective validation cohorts.
Conflict of interest J.P. van Kuijk and J.M. ten Berg declare that they
have no competing interests.
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