Management of elderly patients with a non-ST-segment-elevation acute coronary syndrome
Management of elderly patients with a non-ST-segment-elevation acute coronary syndrome
M. E. Gimbel 0
J. M. ten Berg 0
0 Department of Cardiology, St. Antonius Hospital , Nieuwegein , The Netherlands
Elderly patients with an acute coronary syndrome are underrepresented in randomised controlled trials. Neither the European Society of Cardiology nor the American Heart Association/American College of Cardiology acute coronary syndrome guidelines provide specific recommendations for elderly patients. However, elderly patients are at higher thrombotic and bleeding risk compared with younger patients leading to difficulties in choosing the optimal treatment. In this review, we discuss the uncertainties we encounter in treating elderly patients with non-STelevation acute coronary syndrome and suggest treatment options based on the existing literature.
Acute coronary syndrome; Aged; Percutaneous coronary intervention; Platelet aggregation inhibitors; Coronary angiography; Elderly
Elderly patients portray a heterogeneous group due to their
comorbidities and differences in cognition and functional
status. They comprise a rapidly increasing subgroup of
patients with an acute coronary syndrome (ACS) of which
non-ST-segment-elevation ACS (NSTE-ACS) is the most
common form . Compared with younger patients, elderly
patients with ACS are at higher risk of both
atherothrombotic events and bleeding, due to frailty and
comorbidities such as renal failure [2–4]. These higher risks require
a different treatment. However, neither the European
Society of Cardiology (ESC)  nor American Heart
Association/American College of Cardiology (AHA/ACC) 
ACS guidelines provide specific recommendations
regarding the treatment of elderly patients. In addition, most
evidence is expert consensus or based on subgroup analyses
of randomised controlled trials (RCTs) in which the elderly
were underrepresented. This complicates every day clinical
decision-making regarding the optimal treatment of these
In this article, we discuss the uncertainties we encounter
in treating elderly patients with NSTE-ACS and suggest
treatment options based on the existing literature. Our
search is shown in the Appendix.
Step one: Risk assessment
The first step in treating ACS patients is assessing ischaemic
and bleeding risk for which the guidelines recommend the
use of the GRACE and CRUSADE risk scores [2, 3].
Following the guidelines, an ACS patient with a higher
ischaemic risk would require strong-acting antiplatelet
inhibitors and an invasive strategy, while in patients with
a higher bleeding risk one would be cautious with an
invasive strategy and preference could be given to less
potent antiplatelet inhibitors. However, there is much
overlap between risk factors indicating ischaemic and bleeding
complications (Tables 1 and 2). Consequently, a
considerable number of elderly patients have both a high predicted
ischaemic and bleeding risk. Thus, these risk scores are
not very helpful in determining the optimal antithrombotic
treatment. In addition, it is questionable whether the risk
scores are as predictive in the elderly as in younger patients.
Research on the applicability of the GRACE score in 544
Table 1 GRACE risk score
Risk factor at admission
Bpm beats per minute
aRisk factors indicating ischaemic and bleeding complications
Bpm beats per minute, GFR glomerular filtration rate
aRisk factors indicating ischaemic and bleeding complications
elderly (≥80 years) NSTE-ACS patients showed good
diagnostic accuracy for the prediction of in-hospital mortality
with an area under the curve (AUC) of 0.75 , while the
CRUSADE bleeding score was not predictive in 369 elderly
patients ≥75 years as compared with 1667 younger patients
<75 years (AUC 0.52 vs. AUC 0.74) . Other bleeding
scores (ACTION and Mehran) were not predictive in
elderly patients either .
Based on these data, we advise to use the GRACE score
in elderly patients, whereby a high score is an indication
for strong-acting platelet inhibitors and an invasive
strategy. To address modifiable bleeding risk factors we advise
using the CRUSADE score. Only in those patients with the
highest risk of bleeding (i. e. prior history of bleeding,
cerebrovascular accident, oral anticoagulant usage, frailty and
malignancy) do we advise to use less potent antiplatelet
agents. In addition, caution with an invasive therapy is
advised in the frail elderly.
Step two: Measures to reduce bleeding risk
Bleeding risk can be reduced by taking some treatment
options into account. First, to reduce gastrointestinal bleeding
risk, the guidelines advise to prescribe a proton-pomp
inhibitor (PPI) in patients with prior gastrointestinal ulcer or
haemorrhage, oral anticoagulant therapy, chronic NSAID/
corticosteroid use or two or more of the following: age
≥65 years, dyspepsia, gastroesophageal reflux,
Helicobacter pylori infection and chronic alcohol use. The
prevention of gastrointestinal ulcer or haemorrhage with a PPI
has been proven in a randomised trial with 991 patients
aged ≥60 years receiving aspirin without gastric or
duodenal ulcer at baseline endoscopy who were treated with
esomeprazole or placebo. Esomeprazole reduced the risk of
gastroduodenal ulcers in comparison with placebo (4.4% vs
18.3%, p < 0.0001) after 6 months . Thus, more liberal
to what is advised in the guidelines, it may be beneficial to
treat all patients ≥60 years using aspirin with a PPI.
Second, use the transradial access when performing
coronary angiography. A meta-analysis consisting of 24
randomised trials and 22,843 participants compared radial
versus femoral access for catheterisation and found a
reduction in major bleeding (OR 0.71 [95%CI 0.48–1.04])
and major vascular complications (OR 0.26 [95% CI
0.17–0.41]) when a radial approach was used . One of
the included trials was The RadIal Versus femorAL access
for coronary intervention (RIVAL) trial which randomised
7021 ACS patients, including 1035 (15%) over the age of
75 years, to radial or femoral access. The elderly subgroup
analysis demonstrated a superior effect of transradial access
driven by a reduction in major access site complications
of 3.6% vs 6.6% p = 0.03 . However, when the radial
approach fails, the femoral approach with bivalirudin has
proven to yield similar bleeding rates compared with
radial access and using heparin in a meta-analysis of eight
randomised trials including 27,491 ACS patients .
Third, in patients undergoing percutaneous coronary
intervention (PCI), fondaparinux with a bolus of
unfractionated heparin (UFH) is advised rather than enoxaparin by
both the ESC guidelines for ACS and the expert position
paper on antithrombotic therapy in the elderly [5, 13]. This
is based on the Organization to Assess Strategies in Acute
Ischemic Syndromes (OASIS)-5 trial which revealed a net
clinical benefit (death, myocardial infarction (MI),
refractory ischaemia or major bleeding) in favour of fondaparinux
(7.3% vs 9.0%, HR 0.81, p < 0.001) compared with
enoxaparin which was consistent in the subgroup of 12,261 (61%)
patients ≥65 years . Caution is advised with the use of
enoxaparin in the elderly as the Superior Yield of the New
Strategy of Enoxaparin, Revascularization, and
GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial, comparing
enoxaparin versus UFH, observed a higher, although
nonsignificant (p = 0.085) bleeding risk with enoxaparin compared
with UFH in 2540 (25%) elderly patients (≥75 years) .
Therefore UFH might be the anticoagulant of choice in
elderly patients who cannot receive fondaparinux. However,
also bivalirudin could be second choice as beneficial results
were observed in the Randomized Evaluation in PCI
Linking Angiomax to reduced Clinical Events
(REPLACE)2 trial, determining the efficacy of bivalirudin with bailout
glycoprotein IIb/IIIa inhibition compared with heparin with
planned glycoprotein IIb/IIIa inhibition. Bivalirudin
significantly reduced the rates of in-hospital major bleeding by
2.4% vs 4.1%, p < 0.001. A subgroup analysis of 806
(13.4%) elderly patients (>75 years)  showed the same
Step three: Antiplatelet therapy
According to the guidelines, treatment of NSTE-ACS
patients consists of lifelong aspirin and a P2Y12 inhibitor for
one year. What evidence is there to treat elderly patients
Aspirin reduced death or MI by 48% after 12 months in
a placebo-controlled randomised trial including 796 ACS
patients . This effect was confirmed by a
meta-analysis of 96,316 patients performed by the Antiplatelet
Trialists’ Collaboration. Moreover, the benefit of aspirin seems
even greater in older compared with younger patients .
Therefore aspirin is advised in all elderly ACS patients
except for those with severe renal and liver insufficiency,
severe uncontrolled heart failure or an active peptic ulcer.
The preferred P2Y12 inhibitor is ticagrelor, or prasugrel
in those patients in whom the coronary anatomy is known
and who are going to proceed to PCI. Do these
recommendations also apply to the elderly?
The PLATelet inhibition and patient Outcomes (PLATO)
trial randomised 18,624 ACS patients to ticagrelor or
clopidogrel on top of aspirin and found a significant clinical
benefit and overall safety for ticagrelor (death from vascular
causes, MI or stroke 9.8% vs 11.7%; TIMI major
bleeding 7.9% vs 7.7%). This beneficial effect also seems true
for the elderly (≥75 years) as the advantages of ticagrelor
compared with clopidogrel were similar in the elderly
subgroup analysis (cardiovascular death, MI or stroke 17.2%
vs 18.3%; overall PLATO major bleeding 14.2% vs 13.5%)
The Trial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Inhibition with Prasugrel –
Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38
randomly assigned 13,608 patients to prasugrel or
clopidogrel. Prasugrel reduced the risk of death from cardiovascular
causes, MI or stroke by 2.2% (9.9% vs 12.1%); however,
non-CABG related TIMI major bleeding was significantly
higher (2.4% vs 1.8%). A post-hoc analysis identified
elderly patients aged ≥75 years as deriving no net-clinical
benefit for prasugrel compared with clopidogrel 0.99 (95%
CI 0.81–1.21; p = 0.92)  driven by higher rates of
bleeding in the elderly, where fatal bleeding occurred in 1% of the
patients treated with prasugrel versus 0.1% in those treated
with clopidogrel . Consequently, prasugrel 10 mg is not
recommended for elderly patients ≥75 years.
However, a pharmacokinetic modelling substudy from
TRITON-TIMI 38 predicted that a 5 mg prasugrel
exposure in a subgroup of 891 elderly (≥75 years) patients
would reduce bleeding risk and maintain efficacy .
This was further evaluated in The Comparison of
Prasugrel and Clopidogrel in Very Elderly and Non-Elderly
Patients With Stable Coronary Artery Disease
(GENERATIONS) trial which examined the pharmacokinetic and
pharmacodynamic response of prasugrel 5 mg in elderly
patients (≥75 years) and found non-inferiority of the
reduced dose in the elderly compared with the 10 mg dose
in non-elderly. Moreover, prasugrel 5 mg compared with
clopidogrel 75 mg in elderly patients was associated with
a significantly greater antiplatelet effect . In the
Targeted Platelet Inhibition to Clarify the Optimal Strategy
to Medically Manage Acute Coronary Syndromes
(TRILOGY-ACS) trial medically managed ACS patients were
randomised to prasugrel or clopidogrel . Of the 9326
included patients, 2083 were ≥75 years and were treated
with prasugrel 5 mg. This reduced dose of prasugrel in
elderly patients was non-inferior to clopidogrel in preventing
ischaemic complications and no differences in bleeding
rates were observed . Consequently, if prasugrel is
used in the treatment of elderly ACS patients, the reduced
dosage of 5 mg is recommended.
Clopidogrel is advised in patients who cannot receive
ticagrelor or prasugrel or require oral anticoagulation.
The Clopidogrel in Unstable Angina to Prevent Recurrent
Events (CURE) trial investigated the effect of clopidogrel
versus placebo in addition to aspirin in 12,652 patients with
NSTE-ACS. CURE showed a significant 20% reduction in
the composite outcome of cardiovascular death, nonfatal MI
or stroke in patients receiving clopidogrel . An equal
benefit of clopidogrel was observed in young and elderly
patients ( 65 vs >65 years). Recently, an observational
study including 190 patients aged ≥75 years admitted
for MI identified frailty as an independent predictor of
major bleeding . Therefore, in addition to patients who
cannot receive ticagrelor or prasugrel, we advise to also
treat the frail elderly patients with clopidogrel. Currently,
the Ticagrelor or prasugrel versus clopidogrel in elderly
patients with an acute coronary syndrome and a high
bleeding risk: optimization of antiplatelet treatment in high-risk
elderly (POPular AGE) trial is investigating whether
elderly (≥70 years) NSTE-ACS patients should be treated
with ticagrelor/prasugrel or clopidogrel using a randomised
controlled design .
Furthermore, PRAGUE-18 performed a head-to-head
comparison between ticagrelor and prasugrel. A total of
121 (9.8%) elderly patients (≥75 years) were included .
There were no differences in safety and efficacy between
ticagrelor and prasugrel; this was consistent in the elderly.
However, an interim analysis after 1130 included patients
led to the decision to terminate the study early because of
The guidelines advise not to administer prasugrel before
coronary angiography based on the Comparison of
Prasugrel at the Time of PCI or as Pretreatment at the Time
of Diagnosis in Patients with Non-ST Elevation
Myocardial Infarction (ACCOAST) which showed no reduction in
major ischaemic events in NSTE-ACS patients scheduled
for catheterisation and pretreated with prasugrel compared
with placebo . TIMI major bleeding was significantly
more frequent in the prasugrel group. These findings were
consistent in 715 (18%) elderly patients aged ≥75 years.
Pretreatment with ticagrelor or clopidogrel has not been
adequately investigated and therefore no recommendations
are formulated in the guidelines. The PCI-CURE showed
a reduction in cardiovascular death or MI by about a third
with pretreatment with clopidogrel compared with placebo,
with little difference in bleeding rate . There is no
specific research regarding pretreatment with ticagrelor in
NSTE-ACS patients. However, a subgroup analysis from
PLATO showed equal benefit of dual antiplatelet therapy
(DAPT) with ticagrelor in patients intended for
non-invasive management . Therefore we consider pretreatment
with clopidogrel and ticagrelor safe when other diagnoses
such as aortic dissection are unlikely or ruled out. Yet, in
elderly patients at a high risk of bleeding we advise to
postpone the administration of the P2Y12 inhibitor until after
Step five: Invasive management
The guidelines recommend an invasive strategy in addition
to the antithrombotic treatment in most ACS patients. Does
this also apply to the elderly?
Compared with younger ACS patients, the elderly are
less likely to undergo coronary angiography and subsequent
revascularisation [32, 33]. However, real-world data from
registries showed benefit from an invasive strategy,
particularly in the elderly. Indeed, this effect seems to increase
with increasing age [33, 34]. A meta-analysis comparing
the routine invasive strategy with selective invasive strategy
in NSTE-ACS patients reported a lower hazard of
cardiovascular death or MI in patients ≥65 years undergoing
invasive therapy (26.1% vs 34.9%, p = 0.007) . Also, the
Treat Angina with Aggrastat and Determine Cost of
Therapy with an Invasive or Conservative Strategy –
Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial
found a substantial reduction in death or MI at 6 months
in the elderly patient (≥75 years) undergoing invasive
strategy compared with conservative strategy, mainly driven by
a reduction in non-fatal MI (21.6% vs 10.8%). However,
the invasive strategy led to significantly higher rates of
major bleeding in older patients (16.6% vs 6.5%) compared
with the conservative strategy . This was consistent in
the Global Registry of Acute Coronary Events (GRACE)
registry where the rates of major bleeding according to age
were <70 years: 2.2%; 70–80 years: 3.3%; >80 years: 7.0%
. The Italian Elderly ACS trial found no significant
differences in death, MI or severe bleeding between invasive
versus initially conservative treatment in 313 elderly
patients (≥75 years) with NSTE-ACS. Although, a subgroup
analysis showed significant benefit from invasive treatment
in patients with elevated troponin levels . Also the
coMOrbilidades en el Síndrome Coronario Agudo (MOSCA)
study found no significant differences between invasive
versus conservative treatment in comorbid elderly patients
(≥70 years) with non-ST-segment-elevation MI . Both
trials were ended prematurely. The After Eighty study
provides the best evidence in favour of a routine invasive
strategy in 457 clinically stable elderly patients (≥80 years) with
NSTE-ACS and low bleeding rates (1.7% vs 1.8%) .
The low bleeding rates could be due to the predominant use
of the radial artery and selection of clinically stable elderly
patients. Attenuation of the efficacy of an invasive strategy
was observed with increasing age. Furthermore,
generalisability to all elderly patients is debatable as only 457 of the
4187 octogenarians with NSTE-ACS were included.
The ESC guideline recommends timing of invasive
strategy based on risk criteria for ischaemic complications.
The immediate invasive strategy is restricted to
haemodynamically unstable patients and patients with angina
while on maximal medical treatment. Patients with a
significant rise or fall in cardiac troponin, dynamic ECG or
GRACE score >140 should undergo angiography within
24 h. Patients with diabetes mellitus, renal insufficiency,
decreased left ventricular ejection fraction or congestive
heart failure, early post-infarction angina, prior PCI or
CABG and GRACE risk score >109 to <140 should
undergo angiography within 72 h. Reviewing the literature,
advantage of early versus delayed invasive strategy was
driven by a reduction in episodes of refractory ischaemia
and shorter hospital stay; these results were consistent in
elderly subgroup analyses [41–43].
We advise, in accordance with the guidelines, to treat the
elderly high-risk NSTE-ACS patients with a routine
invasive strategy. However, as frailty is associated with higher
rates of adverse long-term outcomes after PCI , clinical
assessment of frailty and expected benefit of the procedure
Step six: Duration of dual antiplatelet therapy
Controversy exists about the optimal duration of DAPT
after NSTE-ACS. The guidelines recommend DAPT for
one year, but based on individual ischaemic and bleeding
risk, duration of DAPT may be shortened (3–6 months) or
extended (up to 30 months).
The Prevention of Cardiovascular Events in Patients with
Prior Heart Attack using Ticagrelor Compared with Placebo
on a Background of Aspirin – Thrombolysis in Myocardial
Infarction (PEGASUS-TIMI) 54 trial investigated the
effect of prolonged DAPT with ticagrelor in patients with
prior MI . Ticagrelor 60 mg was superior in reducing
cardiovascular death, MI or stroke over placebo in 3083
(15%) patients aged ≥75 years (11.0% vs 13.9% vs 13.5%
respectively). However, elderly patients derived more harm
from ticagrelor 60 mg compared with placebo (TIMI major
bleeding: 4.11% vs 1.68%). Furthermore, patients at high
bleeding risk (i. e. prior history of stroke, known bleeding
disorder or recent bleeding history) were excluded from the
A meta-analysis, comparing extended DAPT versus
aspirin alone in patients with prior MI found an overall
relative risk (RR) of major adverse cardiovascular events of
0.78 in favour of prolonged DAPT; this was consistent in the
elderly (≥75 years). However, bleeding risk was increased
(RR 1.92) although the rate of fatal bleeding and
intracerebral haemorrhage was not significantly different.
Furthermore, there was a trend towards reduced all-cause mortality
. Another meta-analysis comparing short-term DAPT
(3–6 months) with 12-months of DAPT in low-risk patients
with mainly stable coronary artery disease and
drug-eluting-stents showed a significant reduction in major bleeding
(OR 0.58) with short-term DAPT with no significant
differences in ischaemic events. This was consistent in patients
aged ≥65 years .
Recent trials (Zotarolimus-Eluting versus Bare-Metal
Stents in uncertain Drug-Eluting Stent Candidates (ZEUS))
 and Prospective Randomized Comparison of the
BioFreedom Biolimus A9 Drug-Coated Stent versus the
Gazelle Bare-Metal Stent in Patients at High Bleeding
Risk (LEADERS-FREE)  supported a DAPT duration
of one month after second generation drug-eluting stent
implantation in patients at high bleeding risk or unable to
use DAPT for a longer time period. A consistent treatment
effect was observed in the elderly (≥75 years) .
Taking the above into consideration, we would advise to
treat elderly NSTE-ACS patients with DAPT for 12 months.
In non-frail, elderly patients without any bleeding during
the first year of DAPT and at high ischaemic risk one could
consider extended DAPT duration. In elderly patients at
high bleeding risk, we recommend a shorter DAPT duration
(3–6 months), although, scientific evidence is scarce.
This article provides an overview on the optimal
management of elderly patients with NSTE-ACS based on the
existing literature. For most elderly NSTE-ACS patients,
treatment should consist of DAPT with aspirin and ticagrelor
given at the time of diagnosis together with fondaparinux.
A routine invasive approach is preferred using transradial
access and a bolus of UFH. Probably all elderly patients
treated for NSTE-ACS should start with a PPI. DAPT for
12 months seems to be the most optimal duration in most
elderly patients. Furthermore, it is important to assess frailty
rather than age when considering the optimal treatment.
However, there is still much debate about the optimal
treatment in these elderly patients as most evidence is based on
subgroup analysis and trials with an unrepresentative
participation of elderly patients. Further research is needed to
increase certainty about treatment strategies in elderly ACS
Conflict of interest M.E. Gimbel and J.M. ten Berg declare that they
have no competing interests.
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We used references from the ESC and AHA/ACC
guidelines and the expert position paper of Andreotti et al. on
anti-thrombotic therapy. Furthermore, we hand searched
PubMed using synonyms for elderly (aged [Mesh] OR
elder*[tiab] OR octogenarian*[tiab] OR nonagenarian*[tiab]
OR centenarian*[tiab]) and non-ST-elevation myocardial
infarction (non-ST elevated myocardial infarction[Mesh]
OR angina, unstable [Mesh] OR unstable angina[tiab] OR
non-ST-elevat*[tiab] OR non-ST-segment elevat*[tiab] OR
without ST-segment elevat*[tiab] OR non-STEMI[tiab] OR
NSTEMI[tiab]) and coronary angiography (percutaneous
coronary intervention [Mesh] OR coronary angiography
[Mesh] OR percutaneous coronary intervention*[tiab] OR
angiograph*[tiab] OR cardiac catheter*[tiab]) and
antiplatelet therapy (ticagrelor[tiab] OR clopidogrel[tiab] OR
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