Ticagrelor or prasugrel versus clopidogrel in

elderly patients with an acute coronary syndrome:

Optimization of antiplatelet treatment in patients
70 years and older—rationale and design of the
POPular AGE study
Khalid Qaderdan, MD, a Maycel Ishak, MD, a Antonius A. C. M. Heestermans, MD, PhD, b Evelyn de Vrey, MD, c
J. Wouter Jukema, MD, PhD, FESC, d Michiel Voskuil, MD, PhD, e Menko-Jan de Boer, MD, PhD, FESC, f
Arnoud W. J. van‘t Hof, MD, PhD, g Björn E. Groenemeijer, MD, PhD, h Gerrit-Jan A. Vos, MD, a Paul W. A. Janssen, MD, a
Thomas O. Bergmeijer, MD, a Johannes C. Kelder, MD, PhD, a Vera H. M. Deneer, PharmD, PhD, i and
Jurriën M. ten Berg, MD, PhD, FESC a Nieuwegein, Alkmaar, Amersfoort, Leiden, Utrecht, Nijmegen, Zwolle,
and Apeldoorn, the Netherlands

Rationale Dual antiplatelet therapy with acetylsalicylic acid in combination with a more potent P2Y12- inhibitor (ticagrelor or
prasugrel) is recommended in patients with acute coronary syndrome without ST-segment elevation (NSTE-ACS) to prevent
atherothrombotic complications. The evidence on which this recommendation is based shows that ticagrelor and prasugrel reduce
atherothrombotic events at the expense of an increase in bleeding events when compared with clopidogrel. However, it remains
unclear whether ticagrelor or prasugrel has a better net clinical benefit in elderly patients with NSTE-ACS when compared with
clopidogrel. The POPular AGE trial is designed to address the optimal antiplatelet strategy in elderly NSTE-ACS patients.
Study design POPular AGE is a multicenter, open-label, randomized controlled trial that aims to include 1000 patients
≥70 years of age with NSTE-ACS. Patients are randomly assigned to receive either clopidogrel or a more potent P2Y12
inhibitor (ticagrelor or prasugrel). The first primary end point is any bleeding event requiring medical intervention. The second
primary end point is the net clinical benefit, a composite of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke,
“PLATelet inhibition and patient Outcomes” major bleeding, or “PLATelet inhibition and patient Outcomes” minor bleeding.
Patients will be followed for 1 year after randomization, and analyses will be performed on the basis of intention to treat.
Conclusion The POPular AGE is the first randomized controlled trial that will assess whether the treatment strategy with
clopidogrel will result in fewer bleeding events without compromising the net clinical benefit in patients ≥70 years of age with
NSTE-ACS when compared with a treatment strategy with ticagrelor or prasugrel. (Am Heart J 2015;170:981-985.e1.)

Dual antiplatelet therapy (DAPT) is crucial to prevent thrombosis (ST) in patients with an acute coronary
major adverse atherothrombotic events, such as cardiovas- syndrome (ACS). According to the 2011 European Society
cular death, myocardial infarction (MI), stroke, and stent of Cardiology (ESC) guideline concerning ACS patients
without ST-segment elevation (NSTE-ACS), the recom-
From the aSt. Antonius Hospital, Department of Cardiology, Nieuwegein, the Netherlands,
b
Medical Center Alkmaar, Department of Cardiology, Alkmaar, the Netherlands,
mended antiplatelet therapy in all age categories consists
c
Meander Medical Center, Department of Cardiology, Amersfoort, the Netherlands, of acetylsalicylic acid in combination with 1 of the 2 more
d

e
Leiden University Medical Center, Department of Cardiology, Leiden, the Netherlands, potent P2Y12 inhibitors, ticagrelor or prasugrel. 1 The
University Medical Center Utrecht, Department of Cardiology, Division Heart & Lungs,
American College of Cardiology/American Heart Associa-
Utrecht, the Netherlands, fRadboud University Medical Center, Department of Cardiology,
Nijmegen, the Netherlands, gIsala, Department of Cardiology, Zwolle, the Netherlands, tion guideline, on the other hand, has no preference for
h
Gelre Hospital, Department of Cardiology, Apeldoorn, the Netherlands, and iSt. Antonius clopidogrel or ticagrelor; however, it remains unclear on
Hospital, Department of Clinical Pharmacy, Nieuwegein, the Netherlands. the choice of P2Y12 inhibitor in treating the elderly. 2
RCT# NCT02317198.
Submitted March 4, 2015; accepted July 20, 2015.
In contrast to clopidogrel, ticagrelor and prasugrel are
Reprint requests: Jurriën M. ten Berg, MD, PhD, FESC, St. Antonius Hospital Nieuwegein, more potent antiplatelet drugs, have a faster onset of
P/O Box 2500, 3432 EM Nieuwegein, the Netherlands. action, and have less interindividual variation in drug effect.
E-mail: jurtenberg@gmail.com
Ticagrelor has another advantage in that it is direct acting
0002-8703
© 2015 Elsevier Inc. All rights reserved. and reversible. 3 Advantages of ticagrelor and prasugrel
http://dx.doi.org/10.1016/j.ahj.2015.07.030 make them more suitable for the treatment of patients with

982 Qaderdan et al
a high thrombotic risk. However, the matter gets
complicated when patients have both a high thrombotic
and a bleeding risk, such as the elderly. In the “TRial to
Assess Improvement in Therapeutic Outcomes by Opti-
mizing Platelet InhibitioN with Prasugrel—Thrombolysis
In Myocardial Infarction (TRITON-TIMI) 38” study, 3
subgroups were identified, that is, patients with history
of stroke who had a net clinical harm and those with a body
weight ≤60 kg and age ≥75 years who had no net clinical
benefit when treated with prausgrel compared with
clopidogrel. 4 Therefore, especially in elderly patients,
evaluation of thrombotic or bleeding events separately
might not be sufficient; and net clinical benefit should be
an essential part of drug evaluation.
The recommendations of both ESC and American
Heart Association/American College of Cardiology are
mainly based on 2 large trials that studied the efficacy
and safety of prasugrel and ticagrelor in comparison
with clopidogrel. 4,5
Although both TRITON-TIMI and “PLATelet inhibition
and patient Outcomes” (PLATO) trials did not show an
age-related harm in net clinical benefit and the PLATO
trial showed even superiority in net clinical benefit, they
failed to include a representative proportion of elderly. 4,5
Large international registries demonstrated that patients
≥75 years of age comprise 30% to 40% of the NSTE-ACS
patients, but the proportion of elderly patients in clinical
trials is only about 18%. 6–9 The underrepresentation of
the elderly is even more pronounced in the TRITON-TIMI
38 and the PLATO trials, where 13% and 15% of the
patients, respectively, were ≥75 years of age. 4,5 Further-
more, an old age is known to be a strong predictor of
thromboembolic as well as of bleeding complications in
patients presenting with NSTE-ACS. 1,4,5 Therefore, it
could be argued that mainly the elderly patients with a
lower risk for bleeding events might be included in
randomized trials that investigated the more potent
P2Y12 inhibitors and that the net clinical benefit might
be different in the real-world population.
Furthermore, patients with NSTE-ACS seem to have a
different prognosis after admission to hospital when
compared with ST-segment elevation MI (STEMI) pa-
tients. The in-hospital mortality risk is lower in patients
with NSTE-ACS when compared with patients with
STEMI. However, long-term cumulative mortality risk
for NSTE-ACS exceeds that of STEMI patients. 1,10–16
Whether the mortality turning point is determined by
ischemic or bleeding events is unknown. However, after
developing a non–coronary artery bypass graft (CAB-
G)-related major bleeding, the mortality risk beyond
30 days in ACS patients remains elevated. 17 Because the
mortality risk due to bleeding remains elevated over time,
the net clinical benefit of a P2Y12 inhibitor might be
determined by the occurrence of bleeding events in
elderly NSTE-ACS patients in the long term; and hence,
one might question whether the recommendation of
American Heart Journal
November 2015
prasugrel or ticagrelor instead of clopidogrel is justified in
the elderly.
Although there is no accepted definition of elderly
based on age, many trials have used an age limit of
≥65 years, whereas others have used an age limit of
≥75 years. We think that, in the modern era, patients
between 65 and 70 years are too young to be considered
elderly. Because bleeding risk is an important issue in
the elderly, we hypothesize that clopidogrel is superior
to ticagrelor or prasugrel in reducing bleeding events and
noninferior in net clinical benefit in elderly patients
≥70 years of age with NSTE-ACS. In light of this hypothesis,
the “Ticagrelor or prasugrel versus clopidogrel in elderly
patients with an acute coronary syndrome: optimization
of antiplatelet treatment in patients aged older than
70 years” (POPular AGE) study will be conducted. The
POPular AGE study is a randomized controlled clinical
trial to assess optimal P2Y12 inhibition in elderly NSTE-ACS
patients in terms of efficacy (secondary prevention of
ischemic endpoints) and safety profile (associated
bleeding risk).
Study objectives
The primary objective is to determine whether
clopidogrel is superior to the more potent P2Y12
inhibitors, that is, ticagrelor and prasugrel, in reducing
bleeding episodes requiring medical intervention at 1 year
in elderly patients presenting with NSTE-ACS on a
background of aspirin or oral anticoagulants. The other
primary objective is to determine whether clopidogrel is
noninferior in terms of net clinical benefit. Net clinical
benefit will be defined as a composite of all-cause mortality,
nonfatal MI, nonfatal stroke, PLATO major bleeding, and
PLATO minor bleeding. The individual end points of net
clinical benefit are chosen in such a manner that there is
a balance between thrombotic and bleeding events, and
also relevant events such as mortality are taken into
consideration. Various relevant secondary objectives con-
cerning safety, net clinical benefit, efficacy, and quality of
life will also be assessed.
Study design and population
POPular AGE is an open-label, multicenter, randomized
controlled trial to be conducted at approximately 10 sites
in the Netherlands and aims to include 1000 patients
≥70 years of age with NSTE-ACS. Diagnosis of NSTE-ACS
(non-STEMI or unstable angina [UA]) will be made by the
treating physician as defined in the ESC guideline. 1
Patients will be randomized within 72 hours after
presentation to 1 of the 2 treatment strategies (clopido-
grel vs ticagrelor or prasugrel) in a parallel 1:1 manner at
the site level. If the patient is randomized to a strategy
with ticagrelor or prasugrel, the investigator is allowed to
give either ticagrelor or prausgrel. In the main analysis,
we will not differentiate between the 2 potent inhibitors.
American Heart Journal
Volume 170, Number 5
However, in the arm with clopidogrel, the investigator is
only allowed to give clopidogrel.
Treatment and follow-up procedures
Before performing any study procedures, eligibility for
inclusion will be determined according to the inclusion and
exclusion criteria as listed in online Appendix A, and written
informed consent will be obtained. Patients are only eligible
for inclusion when the diagnosis of NSTE-ACS (UA or
non-STEMI) made by the clinician is according to the ESC
guideline. In addition to routine diagnostic sampling, an
extra blood sample will be drawn for future analysis and
studies, for example, CYP2C19-genotyping. 18 The initial
loading dose (LD) of the study drug will be administered as
soon as possible after randomization. Because only long-
term treatment with DAPT is an exclusion criterion, those
treated in hospital within 72 hours with DAPT are eligible
for the study. In these patients, in case an LD has already
been given before randomization, a second LD dose will
only be given at the discretion of the treating physician. The
first open-label maintenance dose (MD) of study medication
will be administered at the usual time of the next MD.
Further management of NSTE-ACS, that is, medically or
invasively, will be left at the discretion of the treating
physician. In case the treating physician decides to switch
the P2Y12 inhibitor, this will be considered as a crossover
only if the medication is switched to the drug belonging to
the other randomization arm. If the patient is randomized to
a strategy with ticagrelor or prasugrel, switching between
the potent P2Y12 inhibitors is not considered a crossover. In
the elderly, concerning thrombotic and bleeding complica-
tions, both agents are considered equipotent. Follow-up for
clinical end points, adverse events, and drug reactions will
be assessed within 1 year after randomization or until death
occurs before 1 year. To assess clinical end points, quality of
life, and other relevant data, patients are asked to fill out a
questionnaire at 3 and 12 months after randomization,
supplemented with Short Form 36 19 and EuroQol-5D
questionnaires. 20 All clinical end points will also be
recorded by the investigating group by assessing patient
files at primary care, hospitals, and pharmacy records.
Events will be scored according to predefined definitions,
and source documents will be anonymously gathered and
presented to an independent event committee. The
members of the independent event committee will decide
whether these events fulfill the criteria.
Dosing regimens
Patients who are randomized to the strategy with
clopidogrel will receive an LD of either 300 or 600 mg,
depending on the local standard, and an MD of 75 mg
once daily (OD). If the local standard does not specify an
LD for clopidogrel, an LD of 600 mg will be advised.
Patients who are randomized to the prasugrel or
ticagrelor strategy will receive an LD of either 60 mg
Qaderdan et al 983
prasugrel (MD 5 mg OD in patients ≥75 years and with
weight b60 kg; otherwise, MD 10 mg OD) or 180 mg
ticagrelor (MD 90 mg bidaily) depending on the local
standard. Because prasugrel is contraindicated in patients
with a history of stroke or transient ischemic attack,
ticagrelor will be prescribed to these patients.
Concomitant medication
All patients should receive acetylsalicylic acid 80 to
100 mg OD with an LD of 240 to 500 mg, unless
contraindicated or another antithrombotic regimen is
indicated. Patients already using acetylsalicylic acid
before hospitalization do not require an LD. Additional
medical therapy with, for example, nitrates, angiotensin-
converting enzyme inhibitors, cholesterol-lowering agents,
β-blockers, and antihypertensive drugs is also recom-
mended in accordance with current practice guidelines.
In case an oral anticoagulant is indicated after a patient’s
inclusion in the study, discontinuation of acetylsalicylic
acid (after an assessment of both thrombotic and bleeding
risk) is at the discretion of the treating physician.
Discontinuation of acetylsalicylic is an option according
to the ESC consensus document regarding the management
of antithrombotic therapy in patients with atrial fibrillation
presenting with ACS. 21
Study end points
The primary end points are any bleeding episode
requiring medical intervention and net clinical benefit at
1 year after randomization. The net clinical benefit is a
composite of death from any cause, nonfatal MI, nonfatal
stroke, and PLATO major and minor bleeding. Myocardial
infarction is defined according to the third universal
definition and must be distinct from the index MI. 22Stroke
is defined as a neurological deficit lasting N24 hours or
causing death, which is new, is acute, and has no other
readily identifiable cause such as trauma. The secondary
end points concerning safety, net clinical benefit, and
efficacy are set out in online Appendix B.
Sample size and planned analysis
The estimation of bleeding event rates is based on the 2
large trials, that is, TRITON-TIMI 38 2 and PLATO, 3 and
the relatively smaller trial, the “What is the Optimal
antiplatElet and anticoagulant therapy in patients with
oral anticoagulation and coronary StenTing” (WOEST)
trial. 23 In the PLATO trial, the stronger platelet inhibitor
ticagrelor leads to a 0.4% increase in bleeding event rate
when compared with clopidogrel in a population using a
P2Y12 inhibitor on top of aspirin. 3 However, in the
WOEST trial, extra platelet inhibition with aspirin
augments the combined TIMI major or minor bleeding
event rate with 17.3% in a population using clopidogrel
and oral anticoagulation. 23 Although the population in

984 Qaderdan et al
the WOEST trial is not comparable with that in the PLATO
trial, its population represents older patients at a higher
risk of bleeding as in the real world. Furthermore, the
PLATO trial included only 15% of patients older than
75 years as opposed to 32% to 38% in the registries and
excluded patients with concomitant use of oral antic-
oagulation. 3,6–9 Therefore, the difference in bleeding
event rate in the elderly might be more than 10%,
especially when PLATO major and minor bleeding
criteria are taken into account. Based on expert
consensus, an expected difference of 7% seemed more
than reasonable, with a 10% bleeding event rate in the
clopidogrel group and 17% in the more potent P2Y12
inhibitors group. In a subgroup analysis of patients with a
history of stroke in the PLATO study, another high-risk
population, thrombotic complications in the clopidogrel
and ticagrelor group were observed in 20.8% and 19.0%
of patients, respectively. Assuming the abovementioned
bleeding complications, the net clinical benefit end point
is estimated to occur in 30.8% of patients receiving
clopidogrel versus 36.0% (translating to an odds ratio
[OR] of 1.26) of patients receiving ticagrelor/prasugrel
within 1 year after randomization. Using an α of 0.025
(one sided) and setting the noninferiority threshold at
3.5%, the inclusion of 928 patients (464 per group) is
sufficient to prove noninferiority with a power of 80%
using the χ 2 test.
Using a 2-sided α of 0.05 in a population of N=928 (i.e.
464 patients in each group) and assuming bleeding event
rates (i.e. the combined end point of PLATO major or
minor bleeding after the first year) of 10% in the
clopidogrel group versus 17% in the more potent
antiplatelet drugs group, proves the superiority concept
with a power of 86% when using the χ 2 test.
Statistical and analytical plans
Data analysis will be based on the intention-to-treat
principle. Kaplan-Meier analysis will be used to picture
the event rates, but the formal statistical hypothesis
testing will be performed using the χ 2 test for a 2 × 2
table; the strength of treatment effect will be quantified
using the OR, and the measure of precision will be the
95% confidence interval. The strategy with clopidogrel
will be considered noninferior to the strategy with
prasugrel or ticagrelor in net clinical benefit if the upper
limit of the 1-sided 97.5% confidence interval for the OR
is below the noninferiority margin of 1.26; the formal
hypothesis testing will be performed using the Westlake-
Schuirmann test.
Primary analyses will be carried out on bleeding
events and the net clinical benefit as a composite end
point. This will be performed during the period from
administration of the first dose of the study drug
through 1 week after permanent study drug discontin-
uation. An interim evaluation will be performed by an
independent Data Safety Monitoring Board after the
American Heart Journal
November 2015
inclusion of 500 patients and completion of 30-day
follow-up data.
Funding and trial registration
The POPular AGE trial is registered on ClinicalTrials.gov
(NCT02317198) and is approved by the local ethics
committee. The trial is only funded by ZonMw, a Dutch
governmental organization promoting health care research,
within the context of optimal drug use in daily practice. The
authors are solely responsible for the writing and editing of
the paper and the design, statistical calculation, and conduct
of this study.
Present status
The POPular AGE study started enrollment in July 2013;
and on July 1, 2015, more than 240 patients were included.
Five participating centers are actively enrolling, and others
are still in the startup process. End of the enrollment is
expected in 2017.
Summary
The POPular AGE study is a multicenter, open-label,
randomized controlled trial designed to test the hypoth-
esis that clopidogrel is superior to ticagrelor or prasugrel
in reducing bleeding events and noninferior in net clinical
benefit. The POPular AGE is the first trial that is
exclusively aimed at elderly patients presenting with
NSTE-ACS, and it will provide important information
regarding the benefits and risks of various P2Y12
inhibitors in patients ≥70 years of age with NSTE-ACS.
Furthermore, it is unlikely that clopidogrel, prasugrel, and
ticagrelor will be tested in elderly patients with NSTE-ACS
in separate head-to-head comparisons.
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American Heart Journal
Volume 170, Number 5
Qaderdan et al 985.e1

Appendix A

Inclusion criteria
1. At least 70 y of age
2. Hospitalization for NSTE-ACS less than 72 h

Exclusion criteria
1. Contraindication to P2Y12 inhibitors, that is, clopidogrel, prasugrel,
or ticagrelor
2. Unable to give informed consent or a life expectancy of b1 y
3. Having received thrombolytic therapy within the previous 24 h
4. Severe renal function impairment requiring dialysis
5. Confirmed or persistent severe hypertension (systolic blood pressure
[SBP] N180 mm Hg and/or diastolic blood pressure N110 mm Hg)
at randomization
6. At increased bleeding risk, in the investigator’s opinion, for example,
because of malignancy
7. Cardiogenic shock (SBP ≤80 mm Hg for N30 min) or needing
intraaortic balloon pump at the time of screening
8) History of major surgery, severe trauma, fracture, or organ biopsy
within 90 d before randomization
9. Clinically significant out-of-range values for platelet count or
hemoglobin at screening
10. ACS under DAPT, for example, aspirin with a P2Y12 inhibitor;
clopidogrel, prasugrel, ticagrelor
11. Patients with a known CYP2C19 genotype at the time of randomization

Appendix B

Death Defined as death from any cause at any time during 1 y after randomization. In addition, the following causes of
death will be captured: vascular, cardiovascular, cerebrovascular, bleeding, and any and unknown causes.
Vascular cause will be defined as cardiovascular and cerebrovascular.
Stroke Defined as a neurological deficit lasting N24 h or causing death, which is new, is acute, and has no other readily
identifiable cause such as trauma.
Transient ischemic attack Defined as a neurological deficit lasting b24 h, which is new, is acute, and has no other readily identifiable cause
such as trauma.
MI Defined according to the third universal definition of MI and must be distinct from the index MI.22
UA Defined according to the ESC guideline and must be distinct from the index UA. 1
NSTE-ACS Non-STEMI and UA. Defined according to the ESC guideline. 1
Stent thrombosis Defined according to the ARC-criteria. 24
Urgent revascularization (UR) UR before planned coronary angiography (percutaneous coronary intervention [PCI] or CABG) will be defined
as symptoms of ischemia worsening, in the investigator’s opinion, requiring urgent revascularization before the
planned time of the procedure.
UR after PCI for the index event will be defined as recurrent signs of ischemia leading to a new urgent revascularization
(PCI or CABG surgery) of the vessel(s) either initially invasively treated or not initially invasively treated.
Hospital admission for ACS Defined as any hospital admission for acute coronary syndrome (UA or MI according to ESC guideline) that is distinct
from the index event and lasts N24 h.
Bleeding Defined as any bleeding episode; for comparison, GUSTO, TIMI, PLATO, and BARC bleeding classifications will be used.25
PLATO major bleed Defined according to the criteria of the PLATO trial:
-Life threatening: fatal or intracranial or intrapericardial with cardiac tamponade or hypovolemic shock or severe
hypotension requiring surgery or pressors or transfusion of whole blood or packed red blood cells
(PRBCs)for bleeding N4 U or associated decrease in hemoglobin N50 g/L (3.1 mmol/L)
- Other: significantly disabling or transfusion of whole blood or PRBCs for bleeding 2-3 U or associated decrease
in hemoglobin 30-50 g/L(1.9-3.1 mmol/L). 26
PLATO minor bleed Requires medical intervention to stop or treat bleeding. 26
Other arterial thrombosis Defined as an any event due to arterial thrombosis other than cardiac or cerebral events.
Net clinical benefit A composite of all-cause mortality, nonfatal MI, nonfatal stroke, PLATO major bleeding, and PLATO minor bleeding.