EDITORIAL

To Pretreat or Not to Pretreat (With Oral P2Y12 Antagonists)? That is

the Question
Angela Lowenstern, MD; L. Kristin Newby, MD, MHS

T he treatment of patients presenting with non-ST-

segment elevation myocardial infarction (NSTEMI) con-
tinues to evolve. As advancing technical capabilities in the
among stented patients.2,3 Given hematological side effects
associated with ticlodipine, clopidogrel, another member of
the thienopyridine family, became an attractive alternative.
cardiac catheterization lab have expanded percutaneous The CURE (Clopidogrel in Unstable Angina to Prevent
revascularization options, medical treatments have also Recurrent Events) trial showed a 30% reduction in major
continued to progress, offering ongoing improvements in adverse cardiovascular events when clopidogrel was added
outcomes. The 2014 American Heart Association/American to aspirin for treatment of patients presenting with non-ST-
College of Cardiology guidelines reflect the importance of segment elevation acute coronary syndrome.4 Additionally,
medical management, including platelet inhibition, and rec- within a subset of patients in the CURE trial who were
ommend treatment with both aspirin and a P2Y12 receptor randomized to pretreatment with clopidogrel, results showed
inhibitor, either clopidogrel or ticagrelor, before coronary the benefits of clopidogrel within 24 hours of randomization
angiography and possible percutaneous coronary intervention and extending long term, without increased bleeding risk.5,6
(PCI).1 However, because of the increased risk of bleeding, the Prasugrel, a third-generation thienopyridine with increased
guidelines also recommend subsequent discontinuation of the potency compared with clopidogrel, was subsequently
P2Y12 inhibitor 5 to 7 days before coronary artery bypass developed. The TRITON-TIMI (Trial to Assess Improvement
grafting (CABG) if surgical revascularization therapy is in Therapeutic Outcomes by Optimizing Platelet Inhibition
pursued. The management of antiplatelet therapy in patients with Prasugrel–Thrombolysis in Myocardial Infarction) 38
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with NSTEMI continues to change as further data are obtained trial showed improved outcomes among patients treated
regarding the optimal management of these patients. with PCI who received prasugrel compared with clopidogrel.7
As reflected in guidelines recommendations, treatment However, the TRILOGY ACS (Targeted Platelet Inhibition to
with P2Y12 inhibitors is a foundational element of therapy Clarify the Optimal Strategy to Medically Manage Acute
for patients presenting with NSTEMI. Before the mid-1990s, Coronary Syndromes) trial showed that among medically
the benefit of treatment of coronary artery disease with managed patients, there was no significant difference
percutaneous intervention was limited by stent thrombosis between the 2 P2Y12 inhibitors.8 Ticagrelor addressed some
in the setting of aspirin alone or by bleeding among patients of the challenges with the thienopyridines, including incon-
treated with intensive anticoagulation. In the mid-1990s, sistent metabolism and irreversible binding. The PLATO
ticlodipine, a member of the thienopyridine family, became (Platelet Inhibition and Patient Outcomes) trial showed a
the first commercially available P2Y12 receptor inhibitor and 1.9% absolute reduction in death from cardiovascular
data soon began to show benefit of dual antiplatelet therapy causes, myocardial infarction, or stroke among patients
treated with ticagrelor compared with clopidogrel.9 Can-
grelor, the only intravenously administered P2Y12 inhibitor,
The opinions expressed in this article are not necessarily those of the editors
or of the American Heart Association.
is characterized by rapid onset and offset, with platelets
From the Division of Cardiology, Department of Medicine and the Duke Clinical regaining normal reactivity within 30 to 60 minutes of
Research Institute, Duke University Medical Center, Durham, NC. cessation,3 making it an attractive treatment for patients
Correspondence to: L. Kristin Newby, MD, MHS, Division of Cardiology, undergoing procedures. Trials examining its routine use
Department of Medicine and the Duke Clinical Research Institute, Duke compared with clopidogrel showed that cangrelor improved
University Medical Center, P.O. Box 17969, Durham, NC 27715-7969. E-mail:
kristin.newby@duke.edu outcomes when used during PCI, and reduced the risk of
J Am Heart Assoc. 2017;6:e007288. DOI: 10.1161/JAHA.117.007288. stent thrombosis and death among patients who received it
ª 2017 The Authors. Published on behalf of the American Heart Association, periprocedurally.10,11
Inc., by Wiley. This is an open access article under the terms of the Creative Large bodies of data all show the benefit of treatment with
Commons Attribution-NonCommercial License, which permits use, distribu-
dual antiplatelet therapy including aspirin and a P2Y12
tion and reproduction in any medium, provided the original work is properly
cited and is not used for commercial purposes. receptor inhibitor. Although the landscape of treatment with

DOI: 10.1161/JAHA.117.007288 Journal of the American Heart Association 1

 To Pretreat or Not to Pretreat Lowenstern and Newby

EDITORIAL
P2Y12 medications has evolved, the processes of care in the ischemic and bleeding risks associated with the timing of
diagnosis and treatment of patients with NSTEMI have also P2Y12 administration in the setting of NSTEMI.
progressed. At the time that the CURE trial was completed, As explored by Badri et al, when surgical revascularization
patients underwent PCI at a median of 10 days following is the intended strategy, pretreatment with a P2Y12 receptor
presentation and frequently did not have PCI until a second inhibitor may lead to increased postoperative bleeding
hospital stay, when the acute event was resolved. This is in complications. Unfortunately, patient presenting features
stark contrast to current management and more-recent offer little insight into which patients will ultimately require
studies in which patients underwent coronary angiography surgical revascularization during their hospitalization. Thus,
largely within 48 hours. These changes in clinical practice the early medical management of an NSTEMI requires careful
may underlie discordance in results among studies examining consideration of the benefits and risks of these medications,
outcomes among patients treated with P2Y12 therapy before timing of their use, and potential consequences of these
coronary angiography. Whereas a substudy of the CURE trial decisions. As may be expected, the increasing potency of the
showed benefit among patients pretreated with clopidogrel P2Y12 inhibitors has been accompanied by a higher risk of
before coronary angiography, the small, randomized ARMYDA- bleeding, including procedure-related bleeding. Even when
5 (Antiplatelet Therapy for Reduction of Myocardial Damage clopidogrel, the least potent of the P2Y12 inhibitors, was
During Angioplasty-5) PRELOAD and PRAGUE-8 (PRimary added to aspirin in the CURE study, the bleeding risk was
Angioplasty in patients transferred from General community significantly higher than with aspirin alone.4 Similarly, with the
hospitals to specialized PTCA Units with or without Emer- progressive increase in potency of P2Y12 inhibitors, bleeding
gency thrombolysis-8) trials showed no benefit.5,12,13 The risk has increased—compared with clopidogrel, prasugrel
ACCOAST (Comparison of Prasugrel at the Time of Percuta- caused increased risk of bleeding, including life-threatening
neous Coronary Intervention or as Pretreatment at the Time of bleeding, and ticagrelor increased the risk of non-CABG-
Diagnosis in Patients with Non-ST Elevation Myocardial related major bleeding.7,9 Guidelines currently recommend
Infarction) trial similarly showed no benefit in pretreatment that P2Y12 inhibitor therapy should be held for at least 5 days
with prasugrel. for clopidogrel or ticagrelor and 7 days for prasugrel before
In the context of this changing landscape of diagnosis, surgery (Class I, Levels of Evidence B and C, respectively).
medical management, and interventional treatment for However, the guidelines also provide the recommendation
NSTEMI, Badri et al examined the association of precatheter- that it is reasonable to perform surgery before these time
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ization use of P2Y12 therapy and timing of administration of points, and perhaps as early as 3 days from discontinua-
these medications with outcomes among patients undergoing tion.1,15 These guidelines stem from the inherent properties of
surgical revascularization therapy in this issue of JAHA.14 The each medication, including their metabolism and clearance.
investigators used Acute Coronary Treatment and Intervention For example, platelet inhibition with clopidogrel is irreversible
Outcomes Network (ACTION) Registry data collected between and platelet reactivity is only regained with regeneration of
2009 and 2014 to identify patients diagnosed with NSTEMI new platelets, which occurs at a rate of 10% to 15% per
who underwent left heart catheterization during the first day.16 Conversely, given its very short half-life, cangrelor can
24 hours from admission and subsequently had CABG during safely be administered up to 1 to 6 hours pre-CABG without
the same hospitalization. In their analysis, nearly two thirds of an increase in bleeding, compared with placebo therapy,17
patients were treated with a P2Y12 inhibitor before catheter- and offers an alternative P2Y12 treatment strategy that
ization. Compared with patients who did not receive P2Y12 avoids the issues of pretreatment with an oral agent.
before catheterization, those who did had longer wait times to As new developments in P2Y12 inhibitors have led to
CABG, although still less than the labeled recommendations increased potency, reversible platelet binding, and even the
for 5 to 7 days following cessation of P2Y12 treatment, and ability to administer a P2Y12 medication intravenously with
longer total hospital stays. Additionally, they experienced rapid onset, in-hospital care of patients undergoing early
higher rates of post-CABG bleeding and increased rates of coronary angiography and revascularization has also contin-
transfusion. Despite the varying potencies across P2Y12 ued to evolve. Patients now frequently undergo coronary
inhibitors, there was no difference in post-CABG bleeding angiography within the first 24 to 48 hours of hospitalization;
among patients treated with clopidogrel, ticagrelor, or data from the ACTION Registry suggest that 60% of patients
prasugrel. In the era of early catheterization for NSTEMI, the undergo coronary angiography within 48 hours.18 In this
investigators bring into question the current practice of setting, the benefit of pretreatment with P2Y12 therapy
P2Y12 therapy preceding evaluation of coronary anatomy. before coronary angiography that was observed in the CURE
However, ischemic end points were not evaluated in this trial, where coronary angiography occurred a median of
study, and given its retrospective and observational nature, 10 days from presentation,4 may no longer be directly
further data are needed in order to fully assess the balance of applicable. A subanalysis of the CURE trial, however, argues

DOI: 10.1161/JAHA.117.007288 Journal of the American Heart Association 2

 To Pretreat or Not to Pretreat Lowenstern and Newby

EDITORIAL
against this. It showed that the benefits of clopidogrel began summary: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. 2014;130:2354–
within hours of randomization with a statistically significant 2394.
benefit between groups in the first 24 hours, which was 2. Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, Vrolix
M, Missault L, Chierchia S, Casaccia M, Niccoli L, Oto A, White C, Webb-Peploe
largely driven by reduction of in-hospital refractory ischemia.6 M, Van Belle E, McFadden EP. Randomized multicenter comparison of
Nonetheless, the benefit of pretreatment must be balanced conventional anticoagulation versus antiplatelet therapy in unplanned and
elective coronary stenting. The full anticoagulation versus aspirin and
with the possible delays and increased bleeding risks ticlopidine (FANTASTIC) study. Circulation. 1998;98:1597–1603.
associated with a surgical revascularization. 3. Laine M, Paganelli F, Bonello L. P2Y12-ADP receptor antagonists: days of
future and past. World J Cardiol. 2016;8:327–332.
A number of other important points must also be
4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in
considered. Many patients do not undergo early coronary Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of
clopidogrel in addition to aspirin in patients with acute coronary syndromes
angiography and would miss the early benefit of P2Y12 without ST-segment elevation. N Engl J Med. 2001;345:494–502.
inhibitor observed in CURE. Furthermore, only 11% to 13% of 5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg
patients admitted with NSTEMI will ultimately be found to K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in
Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of
have anatomy that necessitates CABG.19 With a low rate of pretreatment with clopidogrel and aspirin followed by long-term therapy in
patients undergoing percutaneous coronary intervention: the PCI-CURE study.
CABG and the benefits observed with P2Y12 pretreatment, Lancet. 2001;358:527–533.
perhaps it is better to tolerate the inherent surgical delays and 6. Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford PJ, Blumenthal M, Budaj A,
bleeding risks associated with P2Y12 pretreatment in the Wittlinger T, Fox KA; Clopidogrel in Unstable Angina to Prevent Recurrent
Events Trial Investigators. Early and late effects of clopidogrel in patients with
small subset of patients who ultimately undergo CABG, rather acute coronary syndromes. Circulation. 2003;107:966–972.
than to miss the benefits of P2Y12 pretreatment for all 7. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S,
Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G,
patients. Finally, management of additional factors that are Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus
more strongly associated with CABG-related bleeding than the clopidogrel in patients with acute coronary syndromes. N Engl J Med.
2007;357:2001–2015.
use and timing of P2Y12 inhibitors may also afford a better 8. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel
balance of benefit and risk for early use of P2Y12 inhibitors JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE,
Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A,
among patients requiring CABG. Whereas medications Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD,
Merkely B, Gasparovic V, Corbalan R, Cinteza M, McLendon RC, Winters KJ,
presurgery are an important factor to consider when evalu- Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; Trilogy
ating bleeding risk, it is essential to also recognize that ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes
without revascularization. N Engl J Med. 2012;367:1297–1309.
numerous other variables contribute to bleeding, including
9. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J,
patient age, sex, renal function, the surgeon who performs the Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG,
Storey RF, Harrington RA; PLATO Investigators, Freij A, Thorsen M. Ticagrelor
Downloaded from http://ahajournals.org by on May 22, 2023

procedure, and the definition of bleeding that is used.20 versus clopidogrel in patients with acute coronary syndromes. N Engl J Med.
The treatment of patients with NSTEMI is a field that 2009;361:1045–1057.
continues to evolve. Although we know patients benefit from 10. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM,
Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS, Goodman SG, Amine
treatment with dual antiplatelet therapy, the timing of M, Angiolillo DJ, Becker RC, Chew DP, French WJ, Leisch F, Parikh KH,
Skerjanec S, Bhatt DL. Platelet inhibition with cangrelor in patients undergoing
initiation of P2Y12 therapy remains unclear. Potency of PCI. N Engl J Med. 2009;361:2318–2329.
platelet inhibition is offset by bleeding risk, particularly among 11. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G,
patients undergoing CABG therapy, and precatheterization Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV Jr, Manoukian
SV, Widimsky P, Chew DP, Cura F, Manukov I, Tousek F, Jafar MZ, Arneja J,
treatment with a P2Y12 inhibitor may to lead to increased Skerjanec S, Harrington RA; CHAMPION PLATFORM Investigators. Intravenous
platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361:2330–
time to CABG, increased length of stay, and increased 2341.
bleeding risk with CABG. Large, randomized trials are needed 12. Widimsky P, Motovska Z, Simek S, Kala P, Pudil R, Holm F, Petr R, Bilkova D,
Skalicka H, Kuchynka P, Poloczek M, Miklik R, Maly M, Aschermann M;
to fully understand the optimal timing of P2Y12 inhibitor PRAGUE-8 Trial Investigators. Clopidogrel pre-treatment in stable angina: for
therapy and how timing affects outcomes related to surgical all patients > 6 h before elective coronary angiography or only for
angiographically selected patients a few minutes before PCI? A randomized
revascularization. multicentre trial PRAGUE-8. Eur Heart J. 2008;29:1495–1503.
13. Di Sciascio G, Patti G, Pasceri V, Gatto L, Colonna G, Montinaro A; ARMYDA-5
PRELOAD Investigators. Effectiveness of in-laboratory high-dose clopidogrel
Disclosures loading versus routine pre-load in patients undergoing percutaneous coronary
intervention: results of the ARMYDA-5 PRELOAD (Antiplatelet therapy for
Reduction of MYocardial Damage during Angioplasty) randomized trial. J Am
Newby reports modest research grant support from Amlyin/ Coll Cardiol. 2010;56:550–557.
BMS, GlaxoSmithKline, Boehringer Ingelheim, and Sanofi. 14. Badri M, Abdelbaky A, Li S, Chiswell K, Wang TY. Precatheterization Use of
P2Y12 Inhibitors in Non-ST-Elevation Myocardial Infarction Patients Under-
going Early Cardiac Catheterization and In-Hospital Coronary Artery Bypass
Grafting: Insights From the National Cardiovascular Data Registry. J Am Heart
References Assoc. 2017;6:e006508. doi: 10.1161/JAHA.117.006508.
1. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DRJr, 15. Society of Thoracic Surgeons Blood Conservation Guideline Task Force,
Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK,
Peterson ED, Sabatine MS, Smalling RW, Zieman SJ; ACC/AHA Task Force Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on
Members; Society for Cardiovascular Angiography and Interventions and the Blood Transfusion, Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A,
Society of Thoracic Surgeons. 2014 AHA/ACC guideline for the management Stafford-Smith M, Waters J; International Consortium for Evidence Based
of patients with non-ST-elevation acute coronary syndromes: executive Perfusion, Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011

DOI: 10.1161/JAHA.117.007288 Journal of the American Heart Association 3

 To Pretreat or Not to Pretreat Lowenstern and Newby

EDITORIAL
update to the Society of Thoracic Surgeons and the Society of Cardiovascular 19. Parikh SV, de Lemos JA, Jessen ME, Brilakis ES, Ohman EM, Chen AY, Wang TY,
Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Peterson ED, Roe MT, Holper EM; CRUSADE and ACTION Registry-GWTG
Surg. 2011;91:944–982. Participants. Timing of in-hospital coronary artery bypass graft surgery for non-
16. Weber AA, Braun M, Hohlfeld T, Schwippert B, Tschope D, Schror K. Recovery ST-segment elevation myocardial infarction patients results from the National
of platelet function after discontinuation of clopidogrel treatment in healthy Cardiovascular Data Registry ACTION Registry-GWTG (Acute Coronary Treat-
volunteers. Br J Clin Pharmacol. 2001;52:333–336. ment and Intervention Outcomes Network Registry-Get With The Guidelines).
JACC Cardiovasc Interv. 2010;3:419–427.
17. Angiolillo DJ, Firstenberg MS, Price MJ, Tummala PE, Hutyra M, Welsby IJ,
Voeltz MD, Chandna H, Ramaiah C, Brtko M, Cannon L, Dyke C, Liu T, 20. Kim JH, Newby LK, Clare RM, Shaw LK, Lodge AJ, Smith PK, Jolicoeur EM, Rao
Montalescot G, Manoukian SV, Prats J, Topol EJ; BRIDGE Investigators. SV, Becker RC, Mark DB, Granger CB. Clopidogrel use and bleeding after
Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac coronary artery bypass graft surgery. Am Heart J. 2008;156:886–892.
surgery: a randomized controlled trial. JAMA. 2012;307:265–274.
18. Roe MT, Messenger JC, Weintraub WS, Cannon CP, Fonarow GC, Dai D, Chen
AY, Klein LW, Masoudi FA, McKay C, Hewitt K, Brindis RG, Peterson ED,
Rumsfeld JS. Treatments, trends, and outcomes of acute myocardial infarction
Key Words: Editorials • acute coronary syndrome
and percutaneous coronary intervention. J Am Coll Cardiol. 2010;56:254–263. • antiplatelet therapy • coronary artery bypass graft surgery
Downloaded from http://ahajournals.org by on May 22, 2023

DOI: 10.1161/JAHA.117.007288 Journal of the American Heart Association 4