Received: 6 May 2022 | Accepted: 20 July 2022

DOI: 10.1002/jhm.12931

CHOOSING WISELY®: THINGS WE DO FOR

NO REASON™

Things We Do for No Reason™: Routine pretreatment with a

P2Y12 receptor inhibitor before invasive coronary
angiography for patients with a non‐ST elevation acute
coronary syndrome

Kevin O'Malley MD1 | Yoseob Joseph Hwang MD, MSc1,2 | Jeffrey Trost MD1 |
Leonard Feldman MD1,3
1
Department of Medicine, Division of Hospital Medicine at Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
2
Center for Drug Safety and Effectiveness, Johns Hopkins University, Baltimore, Maryland, USA
3
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Correspondence: Kevin O'Malley, MD, Department of Medicine, Division of Hospital Medicine at Johns Hopkins Hospital, Johns Hopkins University, 600 N. Wolfe
Street, Meyer 8‐4141, Baltimore, MD 21287, USA.
Email: komalle5@jhmi.edu; Twitter: @doctorkevinmd

Inspired by the ABIM Foundation's Choosing Wisely® campaign, the
“Things We Do for No Reason™” (TWDFNR) series reviews practices that
have become common parts of hospital care but may provide little value
to our patients. Practices reviewed in the TWDFNR series do not
represent clear‐cut conclusions or clinical practice standards, but are
meant as a starting place for research and active discussions among
hospitalists and patients. We invite you to be part of that discussion.
CLINICAL SCENARIO
A 55‐year‐old man with hypertension and diabetes mellitus presents
to the emergency department (ED) with substernal chest pain. His
electrocardiogram reveals lateral ST depressions and his cardiac
biomarkers are elevated. After diagnosing the patient with a non‐ST
elevation acute coronary syndrome (NSTE‐ACS), the ED physician
orders 325 mg of aspirin, a heparin infusion, and signs out to the
hospitalist. Cardiology has not seen the patient, leaving the
hospitalist to wonder whether to administer a loading dose of an
oral P2Y12 receptor inhibitor.
B A C K GR O U N D
In the United States, more than 500,000 persons will experience an
NSTE‐ACS each year.1 Risk stratification with a validated score (such
as GRACE or TIMI) can guide the appropriateness and timing of
invasive coronary angiography (ICA).2 Guidelines recommend that
high‐risk, stabilized patients receive an early invasive management
strategy (defined as ICA within 24 h of admission).2 If ICA leads to a
percutaneous coronary intervention (PCI) with stent placement, then
dual‐antiplatelet therapy (DAPT) is indicated, typically with aspirin
and an oral P2Y12 inhibitor, such as clopidogrel, ticagrelor, or
prasugrel.1,2 For patients with an NSTE‐ACS, providers typically start
oral P2Y12 inhibitor with a loading dose in one of two time periods:
(1) a “pretreatment” or “upstream” strategy in which the P2Y12
inhibitor is administered before ICA3 or (2) a “downstream” strategy in
which the P2Y12 inhibitor is administered after ICA is complete and a
PCI is planned or completed.3
W H Y Y O U M I G H T TH I N K I T I S H E L P F U L
TO ROUTINELY A DMINISTER P 2Y12
IN H IBIT OR P RETRE ATME NT FOR PAT I EN TS
W IT H A N N S T E‐A CS
Pretreatment seeks to prevent periprocedural ischemic events such as
periprocedural myocardial infarction (MI), stent thrombosis, and infarct‐
related artery occlusion. To overcome a delayed onset of action the
pretreatment strategy administers the P2Y12 inhibitor before ICA.3,4
The PCI‐CURE study, a postrandomization subgroup analysis
of the 21% of patients in CURE who received a PCI, suggested a
potential benefit to pretreatment (Table 1).5 The CURE trial
randomized 12,562 adults with an NSTE‐ACS who presented within

J. Hosp. Med. 2022;1–4. wileyonlinelibrary.com/journal/jhm © 2022 Society of Hospital Medicine. | 1

2 | PRETREATMENT FOR PATIENTS WITH A NON‐ST ELEVATION ACUTE CORONARY SYNDROME

TABLE 1 Select studies evaluating P2Y12 inhibitor pretreatment in patients with NSTE‐ACS
Enrollment (n)
Study NSTE‐ACS (%) Median time
(published) Design PCI (%) to PCI Pretreatment No pretreatment Key findings

PCI‐CURE5 Subgroup 2658 6 daysb Clopidogrel, 300 mg After PCI, 28 days of Pretreatment reduced the
(2001) analysis of 2658 (100%) then 75 mg daily clopidogrel or composite outcome of
an RCTa 2658 (100%) ticlopidine CV death, MI, or UTVR

CREDO6 RCT 2116 9.8 hb Clopidogrel, 300 mg After PCI, 28 days of Pretreatment reduced a
(2003) 1407 (66%) then 75 mg daily clopidogrel composite outcome of
1815 (86%) death, MI, or UTVR
when given
6–24 h before PCI

ACCOAST7 RCT 4033 4.3 hb Prasugrel 30 mg. Prasugrel 60 mg at the Pretreatment increased
(2013) 4033 (100%) If after ICA plan for PCI, time of PCI bleeding but did not
2770 (68%) an additional reduce ischemic
prasugrel 30 mg events or mortality

ISAR‐REACT 5 Randomized, 4018 Not provided Pretreatment with Postcoronary Pretreatment increased
(2014)8 open label 2365 (59%) ticagrelor 180 mg angiography the risk of the primary
3377 (84%) followed by 90 mg treatment with composite endpoint of
twice daily prasugrel 60 mg death, MI, or stroke at
followed by 10 mg one year
dailyd

DUBIUS9 RCT 1449 23.3 hc Ticagrelor 180 mg then Ticagrelor 180 mg or No difference in either
(2020) 1305 (90%) 90 mg twice daily prasugrel 60 at the ischemic or bleeding
1334 (92%) time of PCI outcomes

Dworeck Cohort 64,857 Not provided 59,894 overall 4963 overall Pretreatment increased
et al.10 64,857 (100%) – Clopidogrel (45.3%) – Clopidogrel (18.9%) the risk of in‐hospital
(2020) 64,857 (100%) – Ticagrelor (52.9%) – Ticagrelor (78.8%) bleeding and did not
– Prasugrel (1.8%) – Prasugrel (2.3%) improve survival or
reduce stent
thrombosis

Abbreviations: CAD, coronary artery disease; CV, cardiovascular; ICA, invasive coronary angiography; MACE, major adverse cardiovascular events;
MI, myocardial infarction; NSTE‐ACS, non‐ST elevation acute coronary syndrome; PCI, percutaneous intervention; RCT, randomized controlled trial;
UTVR, urgent‐target vessel revascularization.
a
Prespecified analysis of the CURE trial.
b
From study on drug administration.
c
From randomization.
d
Administered after ICA, except for STEMI patients who received a loading dose as soon as possible after randomization.

24 h of symptom onset to either clopidogrel (300 mg immediately
11
followed by 75 mg daily) or placebo (all received aspirin). Of the
2658 patients studied in PCI‐CURE, PCI was performed at a median
of 6 days after receiving the study drug. The primary composite
outcome of 30‐day cardiovascular death, MI, or urgent target vessel
revascularization at 30 days of PCI occurred in 59 patients who
received clopidogrel pretreatment and 86 patients who received the
placebo (relative risk [RR]: 0.70; 95% confidence interval [CI]:
0.50–0.97; p = .03).
The CREDO trial, which enrolled 2116 patients referred for elective
PCI or deemed at high risk of requiring PCI, suggested that P2Y12
inhibitor pretreatment, if given early enough, could reduce adverse
6
cardiac events (Table 1). Importantly, approximately two‐thirds of the
study population in CREDO had either unstable angina or a recent MI.
Researchers randomized participants to either clopidogrel or placebo
given 3–24 h before PCI (all received aspirin). While the main analysis did
not find a significant difference between the two groups, the subgroup,
which received clopidogrel 6–24 h before PCI rather than 3–6 h before
PCI, had a borderline statistically significant relative risk reduction (RRR) in
the primary composite outcome of death, MI, or urgent revascularization
at 28 days (RRR: 38.5%; 95% CI: −1.6 to 62.9; p = .051).
A systematic review and meta‐analysis of seven studies
(n = 32,383) by Bellemain‐Appaix et al.12 evaluated the use of
pretreatment in patients with an NSTE‐ACS. For the review,
researchers defined major adverse cardiovascular events (MACE) as
a composite of death, cardiovascular death, stroke, MI, urgent target
vessel revascularization, or glycoprotein IIb/IIIa inhibitor bailout
therapy. They found a significant reduction in MACE with
pretreatment (odds ratio [OR]: 0.84; 95% CI: 0.72–0.98; p = .02).
Given the data from these trials, practice guidelines issued in
2011 and 2012 by several professional societies advocated for a
pretreatment strategy.13,14
O'MALLEY ET AL.
WHY A ROUTINE PRACTICE OF P2Y12
INH I BITOR P RETRE ATME NT I N N ST E‐A C S
M I G H T NO T B E H E L PF U L WH E N AN EA R L Y
INV ASIVE APPROACH IS PLANNED
Pretreatment increases bleeding risk in patients with NSTE‐ACS and
may cause harm for patients who do not need PCI without reducing
the risk of periprocedural ischemic events or mortality.
Pretreatment with a P2Y12 receptor inhibitor
increases the bleeding risk for patients with
NSTE‐ACS
Antiplatelet therapy increases bleeding risk, and the risk increases
with each additional agent.15 The systematic review and meta‐
analysis by Bellemain‐Appaix et al.12 found a statistically significant
risk for major bleeding events with pretreatment (OR: 1.32; 95% CI:
1.16–1.49; p < .0001).
The ACCOAST trial found a higher risk for bleeding with
pretreatment (Table 1).7 In this trial, researchers randomized 4033 adults
with an NSTE‐ACS and ICA planned within 2–48 h to either pretreatment
with prasugrel or placebo. Researchers terminated the study early due to
excess bleeding events in the pretreatment arm (TIMI major bleeding:
7
2.6% vs. 1.4%; hazard ratio [HR]: 1.90; 95% CI: 1.19–3.02; p = .006).
A large registry‐based cohort study of 64,857 adults undergoing PCI
for NSTE‐ACS from the Swedish Coronary Angiography and Angioplasty
Registry (SCAAR) compared the impact of pretreatment to no pretreat-
ment (Table 1).10 This study used propensity score‐based matching to
address confounding and observed an increased risk for in‐hospital
bleeding with pretreatment (OR: 1.49; 95% CI: 1.06–2.12; p = .02).10
When no PCI is indicated, a routine practice of P2Y12
inhibitor pretreatment may cause harm
Pretreatment exposes patients with a presumed NSTE‐ACS to DAPT
before confirming an indication for PCI. Routinely using a pretreatment
strategy for suspected NSTE‐ACS may significantly disadvantage certain
patients. Patients who need surgical revascularization may suffer a delay
in care while awaiting P2Y12 inhibition to “wash out.” Patients diagnosed
with other entities, such as an aortic dissection, may experience
unnecessary and potentially serious bleeding complications.
When an early invasive strategy is used, P2Y12
inhibitor pretreatment provides no mortality benefit
and uncertain protection against nonfatal ischemic
events
The current evidence has not shown that pretreatment improves
survival for patients with an NSTE‐ACS, and the evidence for
protection against nonfatal ischemic events is mixed.5–12,16 Further,
| 3
evidence supporting pretreatment relies on subgroup analyses of
relatively older clinical trials,5,6,11,12 while more recent randomized
trials fail to show a benefit from pretreatment.7–10
While the analysis by Bellemain‐Appaix et al.12 found a
significant reduction in MACE with pretreatment overall, when
analyzing data just from patients who received a PCI (n = 17,545), the
observed reduction in MACE did not reach statistical significance
(OR: 0.83; 95% CI: 0.69–1.01; p = .06).
More recent data has not shown a survival benefit or a reduction in
ischemic events with pretreatment for patients with an NSTE‐ACS and
one trial suggests a risk for harm.7–10,16 Despite early termination, the
ACCOAST trial enrolled 4033 of 4100 planned patients and reached 398
of 400 intended endpoints (Table 1).7 From this data set, researchers did
not find a significant between‐group difference in the primary composite
outcome of cardiovascular death, MI, stroke, urgent revascularization, or
glycoprotein IIb/IIIa inhibitor rescue therapy through Day 7 (HR: 1.02;
95% CI: 0.84–1.25; p = .81). The DUBIUS trial randomized 1449 patients
with an NSTE‐ACS to either ticagrelor pretreatment or no pretreatment
and found no significant difference in cardiac event rates.9 A post hoc
analysis of the ISAR‐REACT 5 trial compared ticagrelor pretreatment to
prasugrel downstream treatment following ICA among patients with
NSTE‐ACS. In the analysis, the risk for the composite outcome of death,
MI, or stroke at 1 year was higher with pretreatment (HR: 1.41; 95% CI:
1.04–1.90).8,16 A cohort study from the SCAAR found that pretreatment
failed to reduce stent thrombosis (OR: 0.81; 95% CI: 0.42–1.55; p = .52)
or improve survival at 30 days (OR: 1.17; 95% CI: 0.66–2.11; p = .58) or 1
year (OR: 1.34; 95% CI: 0.77–2.34; p = .30).10
International guideline organization recommendations
The 2020 European Society of Cardiology (ESC) guidelines recommend
against pretreatment in patients with an NSTE‐ACS and unknown
coronary anatomy when an early invasive strategy is planned.17 The 2021
American College of Cardiology and American Heart Association guide-
lines for coronary artery revascularization acknowledge the existence of
conflicting pretreatment data and state that a strategy of administering a
P2Y12 inhibitor after exploring the coronary anatomy for most patients
undergoing ICA offers a similar benefit to pretreatment.2
WHEN PRETREATMENT MAY BE
APPROPRIATE
Consider pretreatment in NSTE‐ACS patients who cannot undergo
early ICA with attention to individual bleeding risk.
WHAT YOU SHOULD D O I NSTEAD
Do not routinely administer an oral P2Y12 inhibitor to patients with an
NSTE‐ACS when early ICA is planned. For most patients with an NSTE‐
ACS, the decision to start a P2Y12 inhibitor can be safely made in the
4 | PRETREATMENT FOR PATIENTS WITH A NON‐ST ELEVATION ACUTE CORONARY SYNDROME
cardiac catheterization laboratory after exploration of the coronary
anatomy. For patients who cannot undergo early ICA, it may be
advisable to consult with a cardiologist regarding P2Y12 inhibitor use.
R E C O MM E N D A T IO N S
• Do not routinely administer an oral P2Y12 inhibitor in patients
with an NSTE‐ACS prior to early‐invasive ICA.
CONCL US I ON
Returning to our case, the hospitalist chose not to start an oral P2Y12
receptor inhibitor. The following day, ICA revealed severe multivessel
coronary artery disease. The hospitalist consulted cardiac surgeons
who performed a coronary artery bypass graft a few days later,
illustrating why hospitalists should not use a pretreatment strategy
for patients with an NSTE‐ACS who will receive an early ICA.
CO NFL I CT OF INTERES T
The authors declare no conflict of interest.
ORCID
Kevin O'Malley http://orcid.org/0000-0002-4868-8137
Leonard Feldman http://orcid.org/0000-0002-4444-6624
TWITTER
Kevin O'Malley @doctorkevinmd
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How to cite this article: O'Malley K, Hwang YJ, Trost J,
Feldman L. Things We Do for No Reason™: Routine
pretreatment with a P2Y12 receptor inhibitor before invasive
coronary angiography for patients with a non‐ST elevation
acute coronary syndrome. J Hosp Med. 2022;1‐4.
doi:10.1002/jhm.12931