EDITORIAL

Newer P2Y12 Inhibitors: How Does the Interventional Cardiologist

Choose?
David M. Shavelle, MD, FACC, FSCAI

D ual antiplatelet therapy remains the cornerstone of the

medical management of patients with acute coronary
syndrome (ACS). In ACS patients receiving a coronary stent,
tended to be younger, less likely female, and more likely to
have private insurance than clopidogrel-treated patients.
Factors associated with prasugrel use were cardiogenic
the combination of aspirin and a P2Y12 inhibitor reduces shock, drug-eluting stent implantation, and presentation with
rates of stent thrombosis and major adverse cardiovascular an ST-segment elevation MI. To explore the relative impor-
events. Given the well-known limitations of clopidogrel with tance of ischemia or mortality and bleeding when selecting a
variable antiplatelet effects and delayed onset of action, P2Y12 inhibitor, patients were classified as having high or low
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newer P2Y12 inhibitors have been developed (Table). In Acute Coronary Treatment and Intervention Outcomes
randomized controlled clinical trials, prasugrel and ticagrelor (ACTION) mortality and bleeding risk scores. The highest
reduce rates of major adverse cardiovascular events com- use of prasugrel was seen in patients with both a low bleeding
pared with clopidogrel, although both agents are associated score and a low mortality score. These findings suggest that
with increased bleeding complications.1,2 Despite the clear physicians may perceive bleeding risk as a more important
benefits of these agents in randomized controlled clinical factor compared with ischemia or mortality risk when
trials and meta-analyses, contemporary use in clinical selecting a P2Y12 inhibitor. The current study and others
practice appears to be low.3 Factors associated with the clearly show the difficulty that physicians face when weighing
decision to select a particular P2Y12 inhibitor for the the benefits and risks of antiplatelet therapy. The benefits of
management of patients with ACS are complex, multifacto- enhanced antiplatelet therapy with a reduction in ischemic
rial, and poorly described. risk occur at the cost of increased bleeding events. The
In this issue of the Journal, Vora et al studied 11 969 results of the current analysis apply only to patients with
patients enrolled in the Treatment With ADP Receptor acute MI undergoing PCI. The selection of a specific P2Y12
Inhibitors: Longitudinal Assessment of Treatment Patterns inhibitor in ACS patients receiving medical therapy alone
and Events After Acute Coronary Syndrome (TRANSLATE-ACS) without PCI is likely to be even more complex. The authors
study to explore how antiplatelet therapy is selected for clearly outlined the limitations of the current analysis
patients with acute myocardial infarction (MI) undergoing including the inability to account for unmeasured cofounders
percutaneous coronary intervention (PCI).4 TRANSLATE-ACS in this registry cohort, the lack of provider-reported rationales
is a well-described contemporary registry of ACS patients for P2Y12 inhibitor selection, and the limited ability of the
treated at >200 hospitals throughout the United States.5 applied risk models to accurately assess mortality and
Prasugrel was used in 26% of patients, and those patients bleeding risk. In addition, several other factors may be
difficult and/or impossible to study and may also affect the
selection of a particular P2Y12 inhibitor. Participation in
The opinions expressed in this article are not necessarily those of the editors clinical trials evaluating new drugs often enhances a physi-
or of the American Heart Association. cian’s ability to adopt newer agents into routine clinical
From the Division of Cardiovascular Medicine, University of Southern California, practice following US Food and Drug Administration (FDA)
Los Angeles, CA.
approval. Although all hospitals participating in the TRANS-
Correspondence to: David M. Shavelle, MD, FACC, FSCAI, Division of
Cardiovascular Medicine, Keck School of Medicine, 1510 San Pablo Street,
LATE-ACS study were approved for inpatient prasugrel use,
Suite 322, Los Angeles, CA 90033. E-mail: shavelle@usc.edu significant barriers often exist for long-term outpatient
J Am Heart Assoc. 2016;5:e004460 doi: 10.1161/JAHA.116.004460. approval and receipt of prasugrel; physician knowledge of
ª 2016 The Authors. Published on behalf of the American Heart Association, this difficulty could potentially discourage initial selection of
Inc., by Wiley Blackwell. This is an open access article under the terms of the this agent. Although a small number of patients initiated on
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is >1 P2Y12 inhibitor were excluded, and no information was
properly cited and is not used for commercial purposes. provided for patients who switched between different P2Y12

DOI: 10.1161/JAHA.116.004460 Journal of the American Heart Association 1

 Newer P2Y12 Inhibitors Shavelle

EDITORIAL
Table. Comparison of P2Y12 Inhibitors Currently Approved for Clinical Use

P2Y12 Receptor Time to Peak Maintenance Dose,

Inhibitor Mechanism of Action Activity Loading Dose Route Indications*

Clopidogrel Thienopyridine that irreversibly 2–6 hours 300–600 mg† 75 mg daily, ACS patients managed medically
inhibits the P2Y12 receptor oral and those undergoing PCI;
patients with STEMI; patients
with recent MI, recent stroke,
or established peripheral
vascular disease
Prasugrel Thienopyridine that irreversibly 30 minutes 60 mg 10 mg daily,‡ ACS patients undergoing PCI
o
inhibits the P2Y12 receptor to 4 hours ral
Ticagrelor Nonthienopyridine reversible 30 minutes 180 mg 90 mg twice ACS patients managed medically
direct-acting inhibitor of the to 2 hours daily, oral and those undergoing PCI
ATP receptor P2Y12
Cangrelor Nonthenopyridine ATP analogue 2–30 minutes None 4 lg/kg/min, Adjunct to PCI in patients who
that reversibly inhibitors intravenous have not been treated with
the P2Y12 receptor infusion a P2Y12 inhibitor and who
have not been given a
glycoprotein IIB/IIIA inhibitor
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ACS indicates acute coronary syndrome; ATP, adenosine triphosphate; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial
infarction.
*Indications based on the current U.S. Food and Drug Administration approval.
†
Loading doses up to 1200 mg have been used in clinical trials.
‡
Maintenance dose of 5 mg daily can be used in patients with body weight <60 kg.

inhibitors, which may happen frequently in clinical practice.6,7 study period. Although the main indication for prasugrel use
Although these results are contemporary, patients were was unstable angina or non–ST-segment elevation MI, 33%
enrolled until October 2012; ticagrelor received FDA approval of patients received prasugrel for indications other than ACS.
in 2011 and thus was not widely adopted during the study Perhaps the most important finding of this study was that
period. An intravenous P2Y12 inhibitor (cangrelor) has also prasugrel was used in 34% of ACS patients with a docu-
recently received FDA approval. The role of these 2 additional mented contraindication (history of stroke or transient
agents in contemporary practice remains unclear. ischemic accident, age >75 years, and body weight
Several other investigators have explored similar issues <60 kg). The selection of newer P2Y12 inhibitors may be
regarding the contemporary selection of antiplatelet ther- even more complex in European countries.10,11 Indirectly
apy.8,9 Using a national prospective registry within the related to the current discussion for coronary indications is
country of Israel, Beigel et al studied 1093 patients with that the use of P2Y12 inhibitors in patients undergoing
acute MI undergoing PCI at 25 hospitals who were discharged endovascular intervention appears to be even more variable,
on a P2Y12 inhibitor during March and April 2013.8 Impor- with less data from contemporary clinical practice.12 A recent
tantly, from 2012 to the present in Israel, all 3 P2Y12 publication using data from the Centers for Medicare and
inhibitors (clopidogrel, ticagrelor, and prasugrel) were uni- Medicaid Services found that a P2Y12 inhibitor was used in
formly available with a similar cost for acute MI patients only 81% of patients undergoing an endovascular proce-
undergoing PCI. The authors found that 35% received dure.13 Physician specialty and the clinical setting in which
clopidogrel, 43% received prasugrel, and 22% received the procedure was performed (inpatient, outpatient, or office)
ticagrelor. Predictors of clopidogrel use were older age, were strongly associated with P2Y12 inhibitor use. In this
chronic renal failure and stroke, and presentation with non– particular study, all current P2Y12 inhibitors were included as
ST-segment elevation MI. Notably, patients discharged on a single category, such that relative use of a particular agent
ticagrelor had the highest rate of crossover to another P2Y12 could not be evaluated.
inhibitor. Sandhu et al evaluated 44 hospitals throughout the Additional studies should continue to explore reasons for
state of Michigan that were participating in a prospective selection of specific P2Y12 inhibitors in both coronary and
multicenter registry that included >55 000 patients undergo- endovascular intervention. Targeting patients at the highest
ing PCI from 2010 to 2011.9 Overall, 17% of the patients were risk for ischemic events, with an acceptable bleeding risk,
prescribed prasugrel at hospital discharge, and the rates of should allow the most effective and safest use of the newer
prasugrel use increased from 8.4% to 22.5% throughout the P2Y12 inhibitors.

DOI: 10.1161/JAHA.116.004460 Journal of the American Heart Association 2

 Newer P2Y12 Inhibitors Shavelle

EDITORIAL
percutaneous coronary intervention: review of the literature and practical
Disclosures considerations. Am Heart J. 2016;176:44–52.
Dr Shavelle receives research support from St. Jude Medical 7. Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in
patients with coronary artery disease. Nat Rev Cardiol. 2016;13:11–27.
Inc., Abbott Vascular Inc., Abiomed Inc. and The National 8. Beigel R, Iakobishvili Z, Shlomo N, Segev A, Witberg G, Zahger D, Atar S, Alcalai
Institutes of Health; Dr Shavelle has served as a paid R, Kapeliovich M, Gottlieb S, Goldenberg I, Asher E, Matetzky S. Real-world use
of novel P2Y12 inhibitors in patients with acute myocardial infarction: a
consultant for St Jude Medical Inc. treatment paradox. Cardiology. 2016;136:21–28.
9. Sandhu A, Seth M, Dixon S, Share D, Wohns D, Lalonde T, Moscucci M, Riba
AL, Grossman M, Gurm HS. Contemporary use of prasugrel in clinical practice:
insights from the Blue Cross Blue Shield of Michigan Cardiovascular
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Key Words: Editorials • acute coronary syndrome • antipla-
6. De Luca L, Capranzano P, Patti G, Parodi G. Switching of platelet P2Y12 telet agents • antiplatelet drug • percutaneous coronary
receptor inhibitors in patients with acute coronary syndromes undergoing intervention

DOI: 10.1161/JAHA.116.004460 Journal of the American Heart Association 3

 Newer P2Y12 Inhibitors: How Does the Interventional Cardiologist Choose?
David M. Shavelle

J Am Heart Assoc. 2016;5:e004460; originally published September 23, 2016;

doi: 10.1161/JAHA.116.004460
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