European Heart Journal - Cardiovascular Pharmacotherapy
doi:10.1093/ehjcvp/pvz077
Prasugrel vs. ticagrelor after acute coronary
syndrome: a critical appraisal of the
ISAR-REACT 5 trial
Patrick Sulzgruber and Alexander Niessner*
Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria
..
In the era of invasive coronary angiography and stent implantation in ..
patients presenting with acute coronary syndrome, antiplatelet treat- ..
..
ment strategies occupy a central position in the pharmacotherapeutic ..
approach to prevent recurrent myocardial ischaemia.1,2 In addition ..
..
to standard acetylsalicylic acid therapy, the faster acting and more ..
potent antiplatelet agents ticagrelor and prasugrel were recently ..
..
investigated in direct comparison with clopidogrel in terms of efficacy ..
and safety. Within the Trial to Assess Improvement in Therapeutic ..
..
Outcomes by Optimizing Platelet Inhibition with Prasugrel– ..
Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), prasugrel ..
..
was found to be superior to clopidogrel in patients presenting with ..
acute coronary syndrome via reducing the primary composite car- ..
..
diovascular endpoint defined by death from cardiovascular causes, ..
non-fatal myocardial infarction. and non-fatal stroke.3 Notably this ..
..
effect was mainly driven by a reduction of recurrent myocardial is-
chaemic events. Similarly, in the Platelet Inhibition and Patient
Outcomes (PLATO) trial, ticagrelor proved to be superior to clopi-
dogrel via reducing the frequency of the composite cardiovascular
outcome defined as death from cardiovascular causes, any myocardial
infarction, or stroke.4 While patients in the prasugrel arm showed an
elevated risk of major bleeding events during TRITON-TIMI 38,
PLATO showed no increase in the safety endpoint for any major
bleeding event for ticagrelor, but an increased rate of non-
procedure-related bleeding events.
However, valid data on the relative merits of treatment for
prasugrel as compared with ticagrelor in individuals that underwent
coronary angiography are scarce. To fill this gap of knowledge,
Schüpke et al. compared the efficacy and safety of prasugrel and tica-
grelor, both in addition to standard acetylsalicylic acid, in patients
with acute coronary syndrome within the Intracoronary Stenting and
Antithrombotic Regimen: Rapid Early Action for Coronary
The opinions expressed in this article are not necessarily those of the
Editors of the European Heart Journal – Cardiovascular Pharmacotherapy
or of the European Society of Cardiology.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of
Cardiology.
* Corresponding author. Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria. Tel: þ43 1
4040046140, Fax: þ43 1 4040042160, Email: alexander.niessner@meduniwien.ac.at
C The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
EDITORIAL
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Treatment (ISAR-REACT 5) trial.5 The authors of this multicentre
randomized controlled trial enrolled 4018 patients with acute coron-
ary syndrome that underwent coronary angiography, covering a
representative fraction of individuals presenting with ST-segment
elevation myocardial infarction (STEMI; 41.1%). The data of ISAR-
REACT 5 highlighted that prasugrel-based dual antithrombotic treat-
ment was superior to the ticagrelor-based strategy in reducing the in-
cidence of the composite endpoint of death, myocardial infarction, or
ischaemic stroke (prasugrel, 6.9% vs. ticagrelor, 9.3%; P = 0.006; num-
ber needed to treat = 42) which was mainly attributed to a strong re-
duction in the incidence of recurrent myocardial ischaemia.
Notably, the observed superiority of prasugrel needs to be empha-
sized when considering the lower than expected rate of observed
endpoints, a relevant number of individuals receiving conservative
.. treatment (14.2%), and the delay of prasugrel loading in individuals
.. presenting with non-ST-segment elevation myocardial infarction
..
.. (NSTEMI). Moreover, the authors observed no difference in the
.. safety endpoint for any major bleeding event for both treatment
..
.. arms. The detected treatment benefits were evident for almost all
.. relevant subgroups and on-treatment analyses.
..
.. The lack of a double-dummy design may have introduced a report-
..
.. ing bias. However, since the provided results are conflicting with the
.. primary hypothesis of the study, i.e. that ticagrelor holds a more
..
.. potent antithrombotic potential, this bias appears to be unlikely.
.. The fact that endpoint events were predominantly ascertained via
..
.. telephone follow-up contacts and not personal patient visits confers
.. an increased risk for accompanying detection bias. Further, it needs
..
.. to be considered that ISAR-REACT 5 excluded patients that
.. presented with a history of cerebrovascular events. This subgroup
..
.. mirrors a subset of participants that showed a net clinical harm for
.. prasugrel within the TRITON-TIMI 38 trial, but not for ticagrelor in
..
.. PLATO, which might alter the overall picture of the results in ISAR-
.. REACT 5 via introducing a selection bias in terms of efficacy and
..
. safety in the prasugrel arm.
2 Editorial

..
It is noteworthy that the authors reported that 19% of patients did
not receive any trial drug at the time of discharge. Unfortunately,
there is no clear explanation provided for this particularly high rate of
study drop-outs during the index stay, but the majority of early drop-
outs might be deductible via patients receiving a loading of trial drug
without confirmation of acute coronary syndrome during coronary
angiography, or a contraindication for prasugrel and ticagrelor due to
.. within the subgroup analysis for patients that were treated conserva-
.. tively after acute coronary syndrome.
..
.. In conclusion, ISAR-REACT 5 clearly shows a beneficial effect of
.. prasugrel over ticagrelor in terms of efficacy and comparable safety
..
.. characteristics in the general acute coronary syndrome population.
.. Therefore, a dual antiplatelet therapy of prasugrel in addition to stand-
..
.. ard acetylsalicylic acid seems the treatment approach of choice in
.. patients presenting with acute coronary syndrome undergoing percu-

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the need for triple antithrombotic therapy. ..
Of note, patients in the ticagrelor arm discontinued the trial drug .. taneous coronary intervention (PCI). However, the clinical implemen-
more frequently and sooner after discharge, as compared with indi-
.. tation needs to be undertaken with caution in selected patients—
..
viduals receiving prasugrel (prasugrel, 12.5% vs. ticagrelor, 15.2%; P = .. especially considering individuals presenting with type 2 diabetes melli-
0.03). The most likely reasons for non-adherence to ticagrelor were
.. tus, those who received conservative therapy, or patients with prior
..
the typical side effect of dyspnoea as well as its twice-daily administra- .. cerebrovascular events. Similarly, the effects of prasugrel compared
tion. Consequently, the presented data give the overall impression of
.. with ticagrelor from a long-term perspective beyond 1 year of follow-
..
a more favourable side effect profile of prasugrel in this head to head .. up deserve further attention as do subgroup analyses for bleeding.
..
comparison with ticagrelor. .. Conflict of interest: P.S. reports grants from Daiichi Sankyo and
Of utmost importance, the fraction of participants that were ..
.. Boehringer-Ingelheim outside the submitted work. A.N. reports per-
excluded for investigation of the primary safety endpoint in the prasu- .. sonal fees from Bayer, BMS, and Pfizer; and grants and personal fees
grel treatment arm was 10 times higher as compared with patients ..
.. from Boehringer Ingelheim and Daiichi Sankyo outside the submitted
receiving ticagrelor, which is mainly attributed to the fact that patients .. work.
that underwent coronary angiography during NSTEMI received a ..
..
loading dose for prasugrel not before coronary angiography. As a ..
consequence, within the safety analysis—only assessing patients who .. References
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