Review Article

Journal of Cardiovascular
Pharmacology and Therapeutics
What Are Optimal P2Y12 Inhibitor 1-10
ª The Author(s) 2019
Article reuse guidelines:
and Schedule of Administration in Patients sagepub.com/journals-permissions
DOI: 10.1177/1074248419882923
With Acute Coronary Syndrome? journals.sagepub.com/home/cpt

Michael V. Cohen, MD1,2 , and James M. Downey, PhD1

Abstract
Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective
or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified.
The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary
artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that
occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve
with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment
elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for
upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However,
optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI
transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are
confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary
artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It
is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish post-
infarction heart failure.

Keywords
cangrelor, clopidogrel, myocardial infarction, P2Y12 inhibitor, prasugrel, ticagrelor

Acute myocardial infarction (AMI) and postinfarction heart
failure continue to be the leading causes of disability and death.
It was recognized decades ago that the loss of contractile myo-
cardium was a major contributor to postinfarction heart failure.
Salvage of ischemic myocardium at risk of infarction by urgent
reperfusion therapy was proven in the Thrombolysis In Myo-
cardial Infarction (TIMI) trials to greatly improve outcomes in
these patients. Today percutaneous coronary intervention (PCI)
and coronary artery stenting are routine procedures for the
treatment of both AMI and chronic stable angina pectoris.
Because there is an increased risk of occlusive thrombus for-
mation caused by coronary artery plaque rupture in diseased
coronary arteries or in deployed coronary stents, it has become
routine to treat these patients with agents that interfere with
thrombogenesis both during and following PCI. Anticoagulants
such as heparin are routinely employed for acute care. Recog-
nizing the contribution of platelets to clot formation, long-term
prevention of intracoronary thrombi is now commonly accom-
plished with drugs that prevent platelet aggregation. Glycopro-
tein IIb/IIIa inhibitors (GPIs) are potent antiplatelet agents, but
their short half-lives make them suitable for only acute care.
Antagonists of the platelet’s P2Y12 adenosine diphosphate
(ADP) receptor have proven to be effective blockers of platelet
aggregation for both acute and chronic care. These include
ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor.
The less potent COXII blocker acetylsalicylic acid (ASA), that
is, aspirin also directly inhibits aggregation. Whereas the GPIs
and cangrelor are intravenous preparations, ASA and the other
4 P2Y12 antagonists are oral medications. It is now universally
accepted that both anticoagulants and antiplatelet agents are to
be used in patients with AMI treated with and without stents.
The timing of administration of the antiplatelet agents has
yet to be firmly established. Current guidelines recommend
1
Department of Physiology and Cell Biology, University of South Alabama
College of Medicine, Mobile, AL, USA
2
Department of Medicine, University of South Alabama College of Medicine,
Mobile, AL, USA
Manuscript submitted: August 20, 2019; accepted: September 26, 2019.
Corresponding Author:
Michael V. Cohen, Department of Physiology and Cell Biology, University of
South Alabama College of Medicine, MSB 3050, Mobile, AL 36688, USA.
Email: mcohen@southalabama.edu
2 Journal of Cardiovascular Pharmacology and Therapeutics XX(X)
oral P2Y12 treatment should be upstream of PCI, but how far
upstream is not specified. Because performing PCI on an anti-
coagulated patient treated with upstream antiplatelet agents can
increase the risk of bleeding, it has been asked whether the
benefit outweighs the potential bleeding risk? Anticoagulation
with heparin alone may suffice for stent deployment, while
P2Y12 inhibition that is needed for chronic treatment can be
started only after successful recanalization has been confirmed.
A recent analysis by Allencharril et al1 concluded that, “If
indeed the full anti-platelet effect is needed only a few hours
after restoration of macrovascular coronary flow and not imme-
diately after reperfusion, oral agents administered at the time of
PCI likely suffice.” There are, however, several theoretical and
practical considerations that influence the decision of when to
administer these drugs.
Advantages of Intravenous Inhibitors of
Platelet Aggregation
In a patient with AMI, the coronary artery is occluded by
thrombus. To prevent clot propagation and occlusion of
branches, anticoagulation is initiated with an agent such as
heparin when the patient is first seen by medical personnel.
There is no controversy at this point. But then there is the
presumed need for prophylactic administration of agents which
will prevent clots from forming in diseased arteries and the
stents typically implanted in patients with AMI. This role has
been assigned to agents that prevent platelet aggregation. They
are useful for chronic treatment as they are orally administered,
and the bleeding risk has been accepted. Because infarct size is
proportional to the duration of the ischemic period, most cen-
ters have reduced their door-to-balloon time to *60 minutes,
but this interval is not likely to be shortened much further.
Ideally, inhibition of thrombus formation should occur as early
as possible to prevent progression of thrombosis. Indeed
heparin and aspirin are given upon diagnosis. But the potent
platelet inhibitors are critical adjuvants to heparin because
heparin does not prevent platelet aggregation on ruptured pla-
ques or stents which can act as seeds for thrombi. Attenuation
of this thrombosis can easily be accomplished with intravenous
agents, GPI and cangrelor, which cause immediate inhibition of
platelet function. Both have short plasma half-lives and are
administered as infusions. Either can be introduced just before
PCI and the infusion continued for several hours which would
permit an orderly transition to an oral agent after the PCI for
long-term treatment.
Limitations of Oral Platelet Inhibitors
Clopidogrel and Prasugrel
Many interventionalists still choose to use the more convenient
oral P2Y12 antagonists in lieu of the intravenous preparations
which indeed may not be available in all cardiac treatment
facilities. And this is where the controversy begins. First, there
is the issue of absorption, a consideration for all oral drugs.
Gastrointestinal motility may be diminished in critically ill
patients with AMI2,3 and morphine may further decrease motil-
ity and increase the time needed for drug absorption.3 As a
result, absorption may take hours, and this process will vary
among patients.
The need for metabolic activation can further delay the pro-
duction of a therapeutic plasma concentration. Clopidogrel and
prasugrel are thienopyridines, irreversible inhibitors of platelet
aggregation and pro-drugs which require in vivo metabolic
activation. Clopidogrel requires 2 metabolic steps before the
active metabolite is formed. Activation of clopidogrel is caused
by the CYP450 system, but, unfortunately, genetic polymorph-
isms are present in some individuals that cause them to be
incapable of making this conversion.4-6 Percutaneous coronary
intervention patients with low or no response to clopidogrel, as
expected, have increased risk of ischemic events following
PCI7-10 and more stent thromboses.11 Prasugrel is activated
after only 1 metabolic conversion, and there are no enzyme-
deficient individuals. These metabolic conversions require
time and further delay the onset of effect.
So when should either clopidogrel or prasugrel be adminis-
tered? If given to the patient just before PCI in the catheteriza-
tion suite, it will be certain that the antiplatelet effect will not
be optimal during the stent deployment which typically takes
only about 30 minutes. The anti-platelet agent would ideally
have to be administered 2 or more hours before a planned PCI
to ensure that platelet aggregation will be fully blocked at the
time of PCI. Of course, 2-hour upstream treatment would sel-
dom be possible in the patient being treated with primary PCI
for ST-segment elevation MI (STEMI). But if it were possible,
the subsequent invasive procedure and postprocedure recovery
would be done with anticoagulation and significant blockade of
platelet aggregation leading to a greater chance of procedural
or other bleeding with no way to restore platelet reactivity. This
latter fear is the major reason for hesitating to recommend
upstream administration of these anti-platelet aggregation
drugs even when the PCI is elective. The onset of inhibition
of aggregation can be accelerated by greatly increasing the
loading dose as is routinely done with the irreversible inhibitor
clopidogrel (600 mg),12 but then the bleeding risk is further
increased as the eventual dose becomes overly effective at
blocking platelet aggregation.12,13
Ticagrelor and Cangrelor
Ticagrelor is not a thienopyridine but rather a member of the
cyclopentyltriazolopyrimidine class. It does not require meta-
bolic conversion, and, unlike clopidogrel and prasugrel, is a
reversible inhibitor of the P2Y12 platelet receptor. Cangrelor,
the intravenous platelet receptor inhibitor, is also a member of
this class. Because metabolic conversion to an active metabo-
lite is not necessary, ticagrelor’s effect on platelets is seen more
quickly after administration than that of clopidogrel or prasu-
grel.2,3 However, ticagrelor is still an oral drug, and, therefore,
subject to the same delayed absorption as the other oral
preparations.3
Cohen and Downey
Uncertainty About Timing of Drug
Administration Related to Paucity of Data
So when should these oral preparations be administered to
maximize therapeutic effects and minimize undesirable side
effects? Appropriate randomized, blinded studies are not avail-
able to definitively address this issue. Ideally, there would be a
trial comparing blinded upstream administration of the agent to
administration shortly before or even after PCI. Importantly,
platelet activity would be monitored before, during, and after
PCI to determine the state of platelet inhibition at these crucial
times. The appearance of postischemic events could be corre-
lated with the measured platelet activity. Although no such trial
has been conducted, there have been a few attempts to compare
upstream to provisional (peri-PCI) administration of antiplate-
let drugs without consistent documentation of platelet func-
tional effects. Some of the more revealing studies will be
summarized.
Intravenous GPI and Cangrelor Shortly
Before PCI Optimize Benefits in all ACS
Several investigations of the intravenous GPIs, tirofiban, epti-
fibatide, and abciximab, are informative. In the earlier studies,
GPI infusions begun shortly before PCI in patients with STEMI
significantly decreased post-ischemic complications (death,
recurrent MI, need for surgical revascularization, and possible
stroke) at 30 days and 6 months and even out to 1 year.14-16
This advantage of GPI was also seen if the coronary artery
lesion was stented rather than just ballooned.17 Because benefit
was also seen in patients without stenting, it would appear that
the benefit was not just related to the prevention of stent throm-
bosis. The efficacy of GPI was further validated when upstream
administration of GPI was contrasted with an infusion begun
before or shortly after intracoronary balloon inflation. Patients
with moderate- and high-risk acute coronary syndromes in the
Acute Catheterization and Urgent Intervention Triage strategY
(ACUITY) timing trial by Stone et al.18 received a bolus and
then prolonged infusion of eptifibatide or tirofiban 12 to 18
hours before PCI or eptifibatide or abciximab 5 to 10 minutes
before balloon inflation. There was an equal number of
ischemic events (death, recurrent MI, and need for surgical
revascularization) with upstream and delayed GPI administra-
tion. These results suggest that there was no added benefit from
extended treatment prior to balloon inflation.
Giugliano et al19 also evaluated possible differential effects of
upstream eptifibatide (more than 12 hours) before PCI and
delayed eptifibatide started after angiography but prior to PCI
in patients being revascularized for both unstable angina pectoris
and non-STEMI (NSTEMI). Seventy percent of patients were
also treated with a loading dose of clopidogrel, usually, 300
mg. Fifty-seven percent of the study population underwent PCI
(2666 in the early group and 2723 in the delayed group). Although
patients who underwent PCI in the early-eptifibatide group had
fewer primary and secondary end points than those in the delayed-
eptifibatide group (Kaplan–Meier rates 8.0% vs 10.5%), the
3
difference was not significant. Any possible benefit of upstream
use of GPI was negated by nearly 50% more major bleeding than
in the delayed group and 100% more when only bleeding not
related to coronary artery bypass grafting (CABG) is considered.
Recanalization in STEMI With or Without
Platelet Inhibition
Heestermans et al20 compared administration of tirofiban a
mean of 94 minutes before balloon inflation with infusion a
mean of 37 minutes after balloon inflation in patients with
STEMI. There were more than 800 patients in each group.
Infarct size was significantly smaller, death or recurrent MI
at 30 days significantly less, and death significantly less in the
upfront group suggesting a benefit for upstream loading com-
pared to treatment after PCI. Bleeding rates were comparable.
The beneficial clinical effect of pre-PCI GPI is not unique to
this class of drugs. The intravenous P2Y12 inhibitor cangrelor is
similarly protective when infused shortly before PCI,21,22 and
addition of a GPI has no additive effect.22 This would indicate
that platelet inhibition at the time of PCI in STEMI patients
does reduce postischemic complications. Some of this benefit
may be related to direct cardioprotection from reduced platelet
reactivity in the first minutes of reperfusion which may reduce
the reperfusion injury and thus infarct size. That benefit might
be unique to STEMI patients who have abrupt reperfusion of
deeply ischemic myocardium. Cardioprotective effects of pla-
telet inhibitors will be discussed below.
Oral Agent: Upstream Clopidogrel for
Maximal Effect in NSTEMI
The use of oral antiplatelet agents in acute coronary syndrome
has been extensively explored. Although intravenous agents
have been noted to be quite efficacious, a transition from intra-
venous to oral medication is needed for long-term treatment of
patients following PCI and stenting. Therefore, one wonders if
treatment could be initiated and maintained with a single oral
agent. Historically, the most widely used platelet P2Y12 recep-
tor inhibitor has been clopidogrel, although recently published
guidelines23 now label it as a second-tier treatment option
behind prasugrel and ticagrelor because of its less effective
blockade of platelet function and its troubling incidence of
disabling genetic polymorphisms. Multiple studies have
demonstrated clopidogrel’s efficacy in PCI patients.24-28 But,
as expected, patients with either low or no response to clopido-
grel have increased risk of ischemic events when compared to
normal responders.7-11 As discussed above, Heestermans et al20
provided convincing evidence that there is a long-term benefit
to having platelets blocked prior to PCI as opposed to after-
ward. Therefore, if upstream administration is needed, the
question becomes, “How far upstream?”
In the Intracoronary Stenting and Antithrombotic Regimen:
Rapid Early Action for Coronary Treatment (ISAR-REACT) 4
trial, Sibbing et al29 treated all NSTEMI patients with ASA and
600 mg of clopidogrel. The time interval between
4 Journal of Cardiovascular Pharmacology and Therapeutics XX(X)
administration of these drugs and the PCI is not indicated, but
platelet aggregation studies were performed just before PCI.
Patients treated with clopidogrel were noted to have either high
platelet reactivity (HPR) or no HPR. Thus, patients with per-
sistent HPR had not responded to clopidogrel, possibly because
of inadequate time for absorption from the gut or presence of a
genetic polymorphism. Patients in each group were then ran-
domized to either co-treatment with abciximab or bivalirudin
before PCI. There were between 100 and 200 patients in each
of the 4 groups. Following abciximab treatment which also
inhibits platelet aggregation, ischemic complications were not
different in HPR and no HPR subgroups. However, all adverse
clinical end points were significantly more frequent in biva-
lirudin patients with HPR than those with no HPR (22.0% vs
5.0%, P < .0001). Thus, the presence of inhibited platelet
reactivity at the time of recanalization was beneficial during
PCI whether it was related to either clopidogrel or abciximab.
But in HPR patients treated with bivalirudin which has no
platelet antiaggregatory effect, the protection was negligible.
The need for timely upstream administration of a P2Y12
antagonist is obvious. But can we extrapolate these findings
to the setting of urgent primary PCI in patients with STEMI
who have a high ischemic burden and little time for upstream
loading?
Oral Agent: Upstream Prasugrel in NSTEMI
Insures Adequate Platelet Blockade but
Bleeding Risk Increases
Prasugrel is more potent than clopidogrel30,31 and its efficacy is
not affected by CYP450 polymorphisms.30 Therefore, it has
several advantages over clopidogrel. And it was shown to be
better than clopidogrel at preventing ischemic complications of
cardiovascular death, nonfatal MI, and nonfatal stroke at 15
mos (10.0% vs 12.4%, P ¼ .02) in the large Triton-TIMI 38
study.32 In A Comparison of prasugrel at the time oif percuta-
neous Coronary intervention Or as pre-treatment At the time of
diagnosis in patients with non-ST-segment elevation myocar-
dial infarction (ACCOAST) trial of prasugrel treatment of
NSTEMI patients, the timing of drug administration was either
early before diagnostic coronary angiography or delayed until
after diagnostic angiography but before PCI.33 In the early
group in which diagnostic coronary angiography was under-
taken 2 to 48 hours following randomization, either 30 mg of
prasugrel or placebo was administered. If PCI was needed after
the angiogram, those patients previously treated with prasugrel
received an additional 30 mg, whereas patients in the untreated
control group were given 60 mg. The interval between the
second loading dose and PCI is unknown. Ischemic complica-
tions and the frequency of stent thrombosis at 7 and 30 days
were similar in both early and delayed groups. Major bleeding
was significantly more frequent in the pretreatment group,
although one-half of all episodes were related to urgent CABG
and one-half of non-CABG-related TIMI major bleeding
events were caused by vascular access-site bleeding. What is
missing in this large cohort is the determination of adequacy of
platelet receptor blockade, especially in those patients fully
treated between diagnostic coronary angiography and PCI. But
in a very small subgroup, platelet reactivity was measured
before the treatment, at the time of arterial access (median of
4.8 h after the first loading dose), and again at the time of PCI
and 1 hour later. Not surprisingly at 4.8 hours after the first
loading dose patients who had received 30 mg of prasugrel had
a substantial blockade of platelet aggregation, whereas platelet
aggregation was normal in placebo-treated patients. Thirty
minutes after the second loading dose and the PCI, there was
a minimal effect on platelet aggregation in the delayed treat-
ment group. But after an additional 30 minutes, platelet aggre-
gation was substantially blocked in this group, and there was no
longer any difference between early and delayed treatment
groups. Thus, oral prasugrel acted in less than 1 hour to block
platelet aggregation. This very rapid effect undoubtedly
accounted for the absence of increased ischemic complications
in the delayed group when compared to individuals treated
upstream. This similarity of clinical outcome was observed
despite lack of an effective antiplatelet effect at reperfusion
in the delayed group. In NSTEMI where there is much less
myocardium at risk of infarction, platelet inhibition at the
moment of reperfusion does not appear to be as critical.
In the ISAR-REACT 5 trial,34 the effect of prasugrel was
again evaluated in patients with acute coronary syndromes. In
all patients, 46.2% had NSTEMI, 41.1% had STEMI, and 12.7%
had unstable angina. Patients were randomized to be treated with
loading doses of either prasugrel or ticagrelor. The complicated
treatment algorithm resulted in administration of the antiplatelet
agent immediately after randomization in all STEMI patients. In
patients without ST-segment elevation, ticagrelor was likewise
administered immediately after randomization, whereas prasu-
grel administration was delayed until after diagnostic angiogra-
phy. In none of the groups is the interval between ingestion of
the P2Y12 antagonist and coronary recanalization known.
Furthermore, GPI agents were used in 12.3% of patients under-
going PCI. When clinical outcomes (death, MI, and stroke) after
1 year of follow-up of all patients were combined, prasugrel was
significantly better than ticagrelor. But when patients were seg-
regated according to presenting syndrome, prasugrel was
favored over ticagrelor, but the differences were not significant.
Oral Agent: Upstream Ticagrelor in STEMI
Patients Has Few Benefits, but Is
“Upstream” Really Upstream?
Ticagrelor is not a pro-drug, and, therefore, the only impedi-
ment to initiation of its platelet antiaggregatory effect is
absorption from the gut. In the landmark PLATelet inhibition
and patient Outcomes (PLATO) trial,35 in more than 18 000
patients with acute coronary syndrome followed for 1 year,
ticagrelor treatment at presentation resulted in fewer vascular
deaths, MIs, or strokes than clopidogrel (9.8% vs 11.7%,
P < .001). Two trials to compare upstream and delayed
Cohen and Downey
administration have been reported. In the Administration of
Ticagrelor in the cath Lab or in the Ambulance for New ST
elevation myocardial Infarction to open Coronary artery
(ATLANTIC) trial, STEMI patients were treated with either
ticagrelor or placebo upstream in the ambulance, and then in
the cardiac catheterization suite before PCI. Patients previously
treated with ticagrelor received a placebo, whereas those pre-
viously given a placebo were treated with a loading dose of
ticagrelor.36 In a small subset of upstream and delayed treat-
ment patients, platelet reactivity was measured. There were no
differences between the groups in the proportion of patients
with resolution of ST-segment elevation before PCI, the pro-
portion of patients with resumption of TIMI 3 flow in the
infarct-related artery at the time of initial coronary angiogram
or postischemic complications at 30 days. However, the inci-
dence of stent thrombosis was significantly lower in the
upstream group. In two-thirds of patients radial artery access
was used, and there was no difference in major bleeding epi-
sodes. Notably, the median difference in timing of ticagrelor’s
administration between upstream and delayed groups was only
31 minutes and the median interval between administration of
the second loading dose and PCI was 28 minutes. In light of
these small differences in timing of ticagrelor administration in
the 2 groups, it is not surprising that there was no effect on
platelet reactivity at PCI in either group. Changes in platelet
reactivity only began to appear 1 hour after PCI, first mainly in
the upstream group. Certainly prevention of reperfusion injury
due to platelet inhibition at the time of reperfusion would not
have occurred in either group. Thus, upstream ticagrelor was
safe but resulted in few benefits. The short time between tica-
grelor administration in upstream and delayed groups
diminishes the impact of these observations.
Koul et al37 performed a similar investigation with ticagre-
lor administered upstream or in the cardiac catheterization suite
in STEMI patients. Thirty-eight percent of those not treated
with ticagrelor received clopidogrel. There were no differences
in ischemic complications or frequency of stent thrombosis in
the groups. Also, bleeding rates were not different. It is uncer-
tain what was the interval between ticagrelor administration in
the pretreatment and pre-PCI groups. It was estimated that in
nearly one-half of the patients the interval was more than 1
hour. Nor is the interval between ticagrelor administration and
PCI known. These studies of timing of administration of anti-
platelet therapies do not permit a definitive recommendation.
GPI and cangrelor are effective when administered shortly
before PCI. But oral prasugrel and ticagrelor appear to be mini-
mally more effective when administered upstream of PCI in
STEMI patients, although it is uncertain whether “upstream”
can really be achieved in these patients. Upstream treatment is
more promising in NSTEMI when oral agents can be given far
enough upstream to provide platelet inhibition at the time of
balloon inflation. Procedure-associated bleeding appears to be
less of a problem with radial artery access. But the appropriate
randomized trial with monitoring of platelet reactivity has not
been done, and probably cannot be done in STEMI patients in
whom every effort is being made to do PCI with little delay.
5
P2Y12 Antagonists Are Cardioprotective:
A New Wrinkle
The oral antiplatelet agents clopidogrel and ticagrelor and the
intravenous agent cangrelor are extremely cardioprotective in
animal models and dramatically reduce myocardial infarct size
after the release of a coronary occlusion of 30 to 60 minutes.38
This cardioprotective effect is quite robust and has been docu-
mented in mice,39 rats,40 rabbits,41 pigs,42-44 and non-human
primates.45 The protection is thought to use a mechanism sim-
ilar to that in ischemic preconditioning which was the first
intervention that unambiguously made the heart resistant to
ischemia-induced infarction in animal experiments.
Most of the clinical investigations of platelet inhibitors
have centered on rethrombosis and bleeding. These are com-
mon complications following PCI and are directly related to
the adequacy of the anti-thrombotic effect that platelet inhi-
bitors were designed to provide. However, vascular compli-
cations of coronary occlusion and stent thrombosis which
result in MI would not be expected to be affected by a cardi-
oprotective intervention, and, therefore, are not robust end
points for outcome studies of cardioprotection. Postinfarction
heart failure is related to infarct size and should be directly
affected by a cardioprotective intervention. Documentation of
both out-patient and in-patient heart failure should be the
most sensitive clinical end point for a cardioprotection trial.
But, unfortunately, this was seldom addressed in the past
clinical trials of platelet inhibitors following primary PCI.
As a result, the possible contribution of cardioprotection to
the clinical success of platelet inhibitors in AMI until recently
has not been considered.
Much is known about the mechanism of conditioning’s car-
dioprotection and has been previously summarized.46 Briefly,
there are 2 phases: a triggering phase before a lethal ischemic
insult and a mediator phase at reperfusion. In the triggering
phase, brief periods of myocardial ischemia cause the release
of adenosine, opioids, and bradykinin which initiate complex
signaling cascades involving mitochondrial KATP channels,
reactive oxygen species (ROS), and activation of protein kinase
C. At reperfusion increased affinity of adenosine A2B receptors
allow them to be populated which in turn inhibit glycogen
synthase kinase-3b via Akt and extracellular regulated kinase.
Glycogen synthase kinase-3b inhibition blocks the formation
of lethal mitochondrial permeability transition pores (mPTP),
the putative end-effectors of cardioprotection. Mitochondrial
permeability transition pore is a high conductance pore that
dissipates the transmembrane proton/electrochemical gradient
that drives adenosine triphosphate (ATP) generation when
open. Pore formation would lead to ATP depletion, enhanced
ROS production, failure of membrane ion pumps, solute entry,
organelle swelling, and ultimate mitochondrial rupture and car-
diomyocyte necrosis. It is now known that the mediator path-
way can actually still be instituted at the time of reperfusion if
conditions are just right. Low pH during myocardial ischemia
blocks mPTP formation. Reperfusion does not wash out acidic
6 Journal of Cardiovascular Pharmacology and Therapeutics XX(X)
metabolites immediately, so it is still possible to trigger cardi-
oprotective signaling if it is done before tissue pH rises.47
Although appropriate clinical trials have never been done,
there is suggestive evidence that this phenomenon of cardio-
protection is also seen in man.38 But there is an important
caveat. Intravenous cangrelor or intraperitoneal ticagrelor is
extremely protective in animals only when administered prior
to reperfusion. If the P2Y12 antagonist is introduced 10 minutes
after reperfusion, then all cardioprotection is lost41 presumably
because the mPTP will have already formed. Therefore, infarct
size reduction is dependent on the P2Y12 antagonist being
present in the first few minutes of reperfusion.
Although platelet P2Y12 receptor blockers were initially
used clinically for their anticoagulant properties, the serendip-
itous discovery of their off-target cardioprotective properties
significantly enhances the value of these agents. Infarct size is a
primary determinant of the postischemic course of primary PCI
patients. Thus, this cardioprotective benefit of antiplatelet
treatment would be the most apparent in the setting of primary
PCI in which infarction has been terminated by abrupt reperfu-
sion. The amount of contractile mass lost is a primary determi-
nant of postischemic recovery and the appearance of
postinfarction heart failure.48,49 This is not a trivial problem.
In the 2015 CIRCUS trial, nearly 30% of patients presenting
with an anterior STEMI either died or developed new or wor-
sening heart failure in the year following their PCI.50 Hence,
clinical trials in anterior STEMI patients would likely be the
most revealing about the possible benefit of platelet inhibition
at the time of reperfusion. In the Cyclosporine to ImpRove
Clinical oUtcome in ST-elevation myocardial infarction (CIR-
CUS) trial, one-half of the patients by design were treated with
cyclosporine, but virtually all of them had received a loading
dose of a P2Y12 inhibitor prior to recanalization. There was no
benefit from cyclosporine despite its having been shown to
reduce infarct size in many animal models.51-54 It is possible
that the P2Y12 inhibitor had already conditioned these patients
rendering cyclosporine treatment redundant.
It is instructive to evaluate the status of another cardiopro-
tective intervention which already has been applied clinically.
Remote ischemic conditioning (RIC) is achieved by repeated
inflation and deflation of a blood pressure cuff on an arm or
thigh to create several cycles of local ischemia and reperfu-
sion prior to recanalization of an occluded coronary artery.
This remote conditioning has been reported to reduce infarct
size in preclinical animal models55,56 as well as man.57-60
Cardioprotection in patients treated with RIC has been
demonstrated by documenting either smaller rises in cardiac
enzymes after STEMI58-60 or smaller infarcts and greater
myocardial salvage indices as measured by cardiac magnetic
resonance several days after PCI.57,59,60 A small study sug-
gests that RIC can significantly diminish cardiac mortality
and the appearance of heart failure.61 However, a recent larger
clinical study in 5115 patients with STEMI failed to document
any advantage of RIC on clinical outcomes 1 year after PCI.62
Slightly more hospitalizations for heart failure actually
occurred in the RIC group (192 vs 182) indicating no benefit.
However, because out-patient heart failure events were not
documented, the true effect on heart failure may have been
somewhat obscured.
Animal studies reveal a similar anti-infarct effect with the
P2Y12 inhibitors clopidogrel,41 ticagrelor,40 and cangrelor40,41
suggesting a class effect. Surprisingly, the effect of prasugrel
on infarct size has not been studied. We found only 1 report in
which prasugrel reportedly decreased infarct size, but a rat
model with permanent occlusion of a coronary artery was
used.63 There are several reports suggesting ticagrelor confers
added cardioprotection because of its ability to raise tissue
adenosine levels.42-44 Roubille et al64 reported in a relatively
small study (30 STEMI patients) that either clopidogrel loading
or ischemic postconditioning reduced infarct size and that they
had an additive effect when combined. Those patients were
actually studied prior to 2005 when door-to-balloon times were
much longer than today’s so it is likely that many of those
receiving oral clopidogrel did have some platelet inhibition at
the time of balloon inflation. Such a study could not be con-
ducted today because it would be unethical to withhold an
antiplatelet drug in the control group.
The GPI inhibitors have received little attention in this
regard, but there is some evidence that they may be simi-
larly protective. Some early studies suggest an anti-infarct
effect in patients14,29 and Heestermans et al20 saw reduced
infarct size in patients that were given tirofiban prior to
reperfusion compared to those receiving it after reperfusion.
Evidence indicates that the cardioprotective targets for the
P2Y 12 antagonist are the receptors on platelets since a
thrombocytopenic rat’s heart can no longer be protected
against infarction by ticagrelor.65 If the important preclini-
cal observations noted above are extrapolated to the clinical
theater, then adequate blockade of the platelet P2Y12 ADP
receptor must be evident in the first minutes of reperfusion
to get the anti-infarct effect.
If we assume that the human heart can also be similarly
protected against infarction by a P2Y12 inhibitor, then platelets
would have to be inhibited prior to balloon inflation. It is
unlikely that this could be accomplished with an oral agent
with today’s short door-to-balloon time. The delay before these
oral agents take effect can be shortened by greatly increasing
the dose. The recommended loading dose for clopidogrel is 600
mg which is 8 times the maintenance dose. Increasing the dose
from 300 to 600 mg did improve clopidogrel’s clinical benefit
after PCI in STEMI patients.12,13 But was the protection opti-
mal? All patients will not absorb the drug at the same rate, and
we know there are many patients that are unresponsive to clo-
pidogrel. Because of shortened door-to-balloon times, the ben-
efit of any oral upstream P2Y12 treatment may have diminished
because of inadequate absorption, but this potential loss of
efficacy may be offset by the shortened ischemia time and the
latter’s effect on infarction. Here we suggest an alternative
approach in which platelet inhibition at the time of balloon
inflation could be assured and would provide maximum safety
for the patient as well.
Cohen and Downey
Cooperative Action of Intravenous Cangrelor
and Oral Ticagrelor
In a small group of patients with STEMI Franchi et al66 treated
all with a loading dose of crushed ticagrelor pills after comple-
tion of diagnostic coronary angiography and the decision to
proceed with PCI. At the same time, patients were randomized
to receive an infusion of either cangrelor or placebo. Platelet
reactivity was assessed 5 and 30 minutes after beginning the
infusion, immediately after PCI, and at various times following
the procedure. After only 5 minutes of cangrelor infusion plate-
let aggregation was significantly blocked, but there was no
change in the ticagrelor-only group. After 30 minutes and at
the end of the PCI (mean of 41 minutes [21-54 minutes]) plate-
let reactivity was still at baseline in the ticagrelor-only group
but was in the therapeutic range in those receiving cangrelor.
At 1 hour after treatment with ticagrelor, a small effect on
platelet aggregation in the ticagrelor-only group could be mea-
sured; significant blockade of aggregation was documented
only after an additional 1 hour. The cangrelor and placebo
infusions were suspended after 2 hours. During the next hour
platelet aggregation in the ticagrelor-only group was blocked
further, while the antiaggregatory effect in those previously
treated with cangrelor partially reversed so that platelet aggre-
gation was equally blocked in both groups.
Alexopoulos et al67 did a similar randomized study in a
cohort of STEMI patients and made similar observations.
Notably, neither Franchi 66 nor Alexopoulos 67 observed
any major bleeding. Although Mohammad et al68 did not
randomize STEMI patients to either a cangrelor or placebo
group, they observed continued blockade of platelet aggre-
gation after the 2-hour cangrelor infusion was suspended
as a result of ticagrelor administration 41 to 50 minutes
before PCI. Clinical outcomes were not examined in any
of these studies.
Recommendation for Intravenous Cangrelor
Before PCI and Oral Ticagrelor Several
Hours Later
These latter 3 studies demonstrated that a smooth transition
from the effect of an intravenous to an oral P2Y12 inhibitor is
possible. This protocol leads to effective blockade of platelet
aggregation in the minutes to hours after PCI and also har-
nesses the cardioprotective potential of P2Y12 blockade. A
small modification of the protocol would make it even more
appealing to clinicians. Cardiovascular surgeons have been
very vocal about the major bleeds resulting from administration
of P2Y12 antagonists to patients that require CABG. They usu-
ally opt to wait a few days for the platelet effects of these drugs
to dissipate. But a delay is not feasible in the patient with
STEMI who requires urgent surgical coronary revasculariza-
tion. Cangrelor has a plasma elimination half-time of only 3 to
5 minutes following discontinuation, and there is near-full
recovery of platelet function in 60 to 90 minutes after infusion
termination.69 Any anticoagulation from administered heparin
7
could be reversed with protamine, so these patients could
quickly be made ready for a surgical intervention. Therefore,
it is suggested that a cangrelor infusion be started shortly before
PCI, but ticagrelor administration be delayed until after the PCI
when it has been determined that CABG is not needed. Then a
loading dose of ticagrelor can be given and the cangrelor infu-
sion continued for 2 to 4 hours. This would be a fairly easy
protocol to test against a currently employed loading dose of
ticagrelor in STEMI patients. The primary end points would
have to include infarct size and the incidence of postinfarction
heart failure.
Caution Against Use of Cangrelor With
Either Clopidogrel or Prasugrel
The transition noted above from intravenous to oral P2Y12
inhibitors works well when the agents are cangrelor and
ticagrelor. There is no competition between these 2 rever-
sible inhibitors.70 However, this is not the case for the irre-
versible inhibitors clopidogrel 71 and prasugrel. 70 By
blocking the receptor cangrelor inhibits the receptor binding
necessary for irreversible inhibition of both. Clopidogrel
must not be administered until after the cangrelor infusion
is stopped,71 while prasugrel can be administered up to 30
minutes before the end of the cangrelor infusion,70 thus
leading to several unavoidable hours when P2Y12 blockade
would be absent or inadequate.
Conclusion
Hence, there is a reasonable and justifiable strategy for the
administration of P2Y12 antagonists to patients before primary
PCI and coronary artery stenting. In general, the objective is to
block platelet aggregation to minimize the risk of thrombosis in
the coronary artery and stent in the early moments after stent
deployment and to marshal the powerful effects of the drugs’
cardioprotective property in the required few minutes after
reperfusion. For elective procedures, upstream administration
of the P2Y12 antagonist is sufficient, for example, 90 to 120
minutes for ticagrelor, with the interval before PCI needed for
adequate absorption of the oral preparation and metabolism, if
required, of the pro-drug to its active metabolite. In addition,
the use of the radial artery for arterial access will greatly mini-
mize peri-procedural hemorrhage when upstream oral P2Y12
blockers are used. For the patient with either unstable angina or
an NSTEMI, it is likely that the coronary artery will not have
been completely occluded thus minimizing deleterious reperfu-
sion injury. Therefore, the efficacy of P2Y12 inhibitor therapy
will mainly reflect its anticoagulant properties rather than its
cardioprotective qualities.
In urgent situations in which the patient presents with an
STEMI early platelet inhibition becomes more important, but
logistical considerations make upstream administration pro-
blematic because of the limited door-to-balloon time. In this
case, it may be prudent to use an intravenous preparation such
as cangrelor and then administer oral ticagrelor only after
8 Journal of Cardiovascular Pharmacology and Therapeutics XX(X)
adequate recanalization has been achieved and emergent sur-
gical revascularization has been deemed not to be necessary.
There is little doubt that recanalization of STEMI patients
after total coronary artery occlusion exposes the heart to
reperfusion injury. With a proper dosing schedule, P2Y 12
antagonists should provide important cardioprotection to
these patients as well as anticoagulation. Increased myocar-
dial salvage should lead to better cardiac function and less
post-infarction heart failure. We believe this hypothesis war-
rants clinical testing.
Author Contributions
M.V.C. and J.M.D. contributed equally to conception, analysis, and
composition.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Michael V. Cohen https://orcid.org/0000-0003-4543-6708
References
1. Allencherril J, Alam M, Levine G, et al. Do we need potent
intravenous antiplatelet inhibition at the time of reperfusion dur-
ing ST-segment elevation myocardial infarction? J Cardiovasc
Pharmacol Ther. 2019;24(3):215-224.
2. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind
assessment of the ONSET and OFFSET of the antiplatelet effects
of ticagrelor versus clopidogrel in patients with stable coronary
artery disease: the ONSET/OFFSET study. Circulation. 2009;
120(25):2577-2585.
3. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel
and ticagrelor loading doses in ST-segment elevation myocardial
infarction patients: RAPID (Rapid Activity of Platelet Inhibitor
Drugs) primary PCI study. J Am Coll Cardiol. 2013;61(15):
1601-1606.
4. Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450
2C19 681G>A polymorphism and high on-clopidogrel platelet
reactivity associated with adverse 1-year clinical outcome of elec-
tive percutaneous coronary intervention with drug-eluting or
bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925-1934.
5. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determi-
nants of response to clopidogrel and cardiovascular events.
N Engl J Med. 2009;360(4):363-375.
6. Carlquist JF, Knight S, Horne BD, et al. Cardiovascular risk
among patients on clopidogrel anti-platelet therapy after place-
ment of drug-eluting stents is modified by genetic variants in both
the CYP2C19 and ABCB1 genes. Thromb Haemost. 2013;109(4):
744-754.
7. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in
patients and recurrent events post-stenting: results of the
PREPARE POST-STENTING study. J Am Coll Cardiol. 2005;
46(10):1820-1826.
8. Price MJ, Angiolillo DJ, Teirstein PS, et al. Platelet reactivity and
cardiovascular outcomes after percutaneous coronary interven-
tion: a time-dependent analysis of the gauging responsiveness
with a verifynow P2Y12 assay: impact on thrombosis and safety
(GRAVITAS) trial. Circulation. 2011;124(10):1132-1137.
9. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity
and clinical outcomes after coronary artery implantation of drug-
eluting stents (ADAPT-DES): a prospective multicentre registry
study. Lancet. 2013;382(9892):614-623.
10. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the
definition of on-treatment platelet reactivity to adenosine diphos-
phate associated with ischemia and bleeding. J Am Coll Cardiol.
2013;62(24):2261-2273.
11. Sibbing D, Steinhubl SR, Schulz S, Schömig A, Kastrati A. Plate-
let aggregation and its association with stent thrombosis and
bleeding in clopidogrel-treated patients: initial evidence of a ther-
apeutic window. J Am Coll Cardiol. 2010;56(4):317-318.
12. Montalescot G, Sideris G, Meuleman C, et al. A randomized
comparison of high clopidogrel loading doses in patients with
non-ST-segment elevation acute coronary syndromes: the
ALBION (Assessment of the best Loading dose of clopidogrel
to Blunt platelet activation, Inflammation and Ongoing Necrosis)
trial. J Am Coll Cardiol. 2006;48(5):931-938.
13. Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading
dose of clopidogrel on platelet function in patients undergoing
coronary stent placement. Heart. 2001;85(1):92-93.
14. Neumann F-J, Kastrati A, Schmitt C, et al. Effect of glycoprotein
IIb/IIIa receptor blockade with abciximab on clinical and angio-
graphic restenosis rate after the placement of coronary stents
following acute myocardial infarction. J Am Coll Cardiol.
2000;35(4):915-921.
15. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glyco-
protein IIb/IIIa inhibition with coronary stenting for acute myo-
cardial infarction. N Engl J Med. 2001;344(25):1895-1903.
16. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial
comparing primary infarct artery stenting with or without abcix-
imab in acute myocardial infarction. J Am Coll Cardiol. 2003;
42(11):1879-1885.
17. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty
with stenting, with or without abciximab, in acute myocardial
infarction. N Engl J Med. 2002;346(13):957-966.
18. Stone GW, Bertrand ME, Moses JW, et al. Routine upstream
initiation vs deferred selective use of glycoprotein IIb/IIIa inhibi-
tors in acute coronary syndromes: the ACUITY timing trial.
JAMA. 2007;297(6):591-602.
19. Giugliano RP, White JA, Bode C, et al. Early versus delayed,
provisional eptifibatide in acute coronary syndromes. N Engl J
Med. 2009;360(21):2176-2190.
20. Heestermans AACM, Hermanides RS, Gosselink ATM, et al. A
comparison between upfront high-dose tirofiban versus provi-
sional use in the real-world of non-selected STEMI patients
undergoing primary PCI: insights from the Zwolle acute myocar-
dial infarction registry. Neth Heart J. 2010;18(12):592-597.
Cohen and Downey
21. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet
inhibition with cangrelor during PCI on ischemic events. N Engl
J Med. 2013;368(14):1303-1313.
22. Vaduganathan M, Harrington RA, Stone GW, et al. Cangrelor
with and without glycoprotein IIb/IIIa inhibitors in patients under-
going percutaneous coronary Intervention. J Am Coll Cardiol.
2017;69(2):176-185.
23. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline
focused update on duration of dual antiplatelet therapy in patients
with coronary artery disease: a report of the American college of
cardiology/American heart association task force on clinical prac-
tice guidelines: an update of the 2011 ACCF/AHA/SCAI guide-
line for percutaneous coronary intervention, 2011 ACCF/AHA
guideline for coronary artery bypass graft surgery, 2012 ACC/
AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis
and management of patients with stable ischemic heart disease,
2013 ACCF/AHA guideline for the management of ST-elevation
myocardial infarction, 2014 AHA/ACC guideline for the manage-
ment of patients with non-ST-elevation acute coronary syn-
dromes, and 2014 ACC/AHA guideline on perioperative
cardiovascular evaluation and management of patients under-
going noncardiac surgery. Circulation. 2016;134(10):e123-e155.
24. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio
G. Randomized trial of high loading dose of clopidogrel for
reduction of periprocedural myocardial infarction in patients
undergoing coronary intervention: results from the ARMYDA-2
(Antiplatelet therapy for Reduction of MYocardial Damage dur-
ing Angioplasty) study. Circulation. 2005;111(16):2099-2106.
25. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading
dose of clopidogrel on platelet reactivity and clinical outcomes in
patients with non-ST-segment elevation acute coronary syndrome
undergoing coronary stenting. J Am Coll Cardiol. 2006;48(7):
1339-1345.
26. Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel
loading dose in patients with ST-segment elevation myocardial
infarction undergoing primary angioplasty: results from the
HORIZONS-AMI (Harmonizing Outcomes with RevascularIZa-
tiON and Stents in Acute Myocardial Infarction) trial. J Am Coll
Cardiol. 2009;54(15):1438-1446.
27. Mehta SR, Tanguay J-F, Eikelboom JW, et al. Double-dose versus
standard-dose clopidogrel and high-dose versus low-dose aspirin
in individuals undergoing percutaneous coronary intervention for
acute coronary syndromes (CURRENT-OASIS 7): a randomised
factorial trial. Lancet. 2010;376(9748):1233-1243.
28. Song YB, Hahn J-Y, Gwon H-C, et al. A high loading dose of
clopidogrel reduces myocardial infarct size in patients undergoing
primary percutaneous coronary intervention: a magnetic reso-
nance imaging study. Am Heart J. 2012;163(3):500-507.
29. Sibbing D, Bernlochner I, Schulz S, et al. Prognostic value of a high
on-clopidogrel treatment platelet reactivity in bivalirudin versus
abciximab treated non-ST-segment elevation myocardial infarction
patients: ISAR-REACT-4 (Intracoronary Stenting and Antithrom-
botic Regimen: Rapid Early Action for Coronary Treatment-4)
platelet substudy. J Am Coll Cardiol. 2012;60(5):369-377.
30. Alexopoulos D, Dimitropoulos G, Davlouros P, et al. Prasugrel
overcomes high on-clopidogrel platelet reactivity post-stenting
9
more effectively than high-dose (150-mg) clopidogrel: the impor-
tance of CYP2C19*2 genotyping. JACC Cardiovasc Interv. 2011;
4(4):403-410.
31. Ichikawa S, Tsukahara K, Minamimoto Y, et al. Pharmacody-
namic assessment of platelet reactivity after a loading dose of
prasugrel or clopidogrel in patients with ST-segment elevation
myocardial infarction. Circ J. 2016;80(12):2520-2527.
32. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel com-
pared with clopidogrel in patients undergoing percutaneous cor-
onary intervention for ST-elevation myocardial infarction
(TRITON-TIMI 38): double-blind, randomised controlled trial.
Lancet. 2009;373(9665):723-731.
33. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with
prasugrel in non-ST-segment elevation acute coronary syn-
dromes. New Engl J Med. 2013;369(11):999-1010.
34. Schüpke S, Neumann F-J, Menichelli M, et al. Ticagrelor or pra-
sugrel in patients with acute coronary syndromes (IN PRESS).
N Engl J Med. 2019.
35. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus
clopidogrel in patients with acute coronary syndromes. N Engl
J Med. 2009;361:1045-1057.
36. Montalescot G, van ‘t Hof AW, Lapostolle F, et al. Prehospital
ticagrelor in ST-segment elevation myocardial infarction. N Engl
J Med. 2014;371(11):1016-1027.
37. Koul S, Smith JG, Götberg M, et al. No benefit of ticagrelor
pretreatment compared with treatment during percutaneous
coronary intervention in patients with ST-segment-elevation
myocardial infarction undergoing primary percutaneous cor-
onary intervention. Circ Cardiovasc Interv. 2018;11(3):
e005528.
38. Cohen MV, Downey JM. The impact of irreproducibility and
competing protection from P2Y12 antagonists on the discovery
of cardioprotective interventions. Basic Res Cardiol. 2017;
112(6):64.
39. Bell RM, Sivaraman V, Kunuthur SP, Cohen MV, Downey JM,
Yellon DM. Cardioprotective properties of the platelet P2Y12
receptor inhibitor, cangrelor: protective in diabetics and reliant
upon the presence of blood. Cardiovasc Drugs Ther. 2015;29(5):
415-418.
40. Yang X-M, Cui L, Alhammouri A, Downey JM, Cohen MV.
Triple therapy greatly increases myocardial salvage during ische-
mia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther.
2013;27(5):403-412.
41. Yang X-M, Liu Y, Cui L, et al. Platelet P2Y12 blockers confer
direct postconditioning-like protection in reperfused rabbit hearts.
J Cardiovasc Pharmacol Ther. 2013;18(3):251-262.
42. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S,
Birnbaum Y. Ticagrelor protects the heart against reperfusion
injury and improves remodeling after myocardial infarction.
Arterioscler Thromb Vasc Biol. 2015;35(8):1805-1814.
43. Vilahur G, Gutiérrez M, Casani L, et al. Protective effects of
ticagrelor on myocardial injury after infarction. Circulation.
2016;134(22):1708-1719.
44. Birnbaum Y, Birnbaum GD, Birnbaum I, Nylander S, Ye Y.
Ticagrelor and rosuvastatin have additive cardioprotective effects
via adenosine. Cardiovasc Drugs Ther. 2016;30(6):539-550.
10
45. Yang X-M, Liu Y, Cui L, et al. Two classes of anti-platelet drugs
reduce anatomical infarct size in monkey hearts. Cardiovasc
Drugs Ther. 2013;27(2):109-115.
46. Cohen MV, Downey JM. Signalling pathways and mechanisms of
protection in pre- and postconditioning: historical perspective and
lessons for the future. Br J Pharmacol. 2015;172(8):1913-1932.
47. Yang X-M, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV.
Multiple, brief coronary occlusions during early reperfusion pro-
tect rabbit hearts by targeting cell signaling pathways. J Am Coll
Cardiol. 2004;44(5):1103-1110.
48. Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh
BJ, Gibbons RJ. Infarct size after acute myocardial infarction
measured by quantitative tomographic 99mTc sestamibi imaging
predicts subsequent mortality. Circulation. 1995;92(3):334-341.
49. Miura T, Miki T. Limitation of myocardial infarct size in the
clinical setting: current status and challenges in translating animal
experiments into clinical therapy. Basic Res Cardiol. 2008;
103(6):501-513.
50. Cung T-T, Morel O, Cayla G, et al. Cyclosporine before PCI in
patients with acute myocardial infarction. N Engl J Med. 2015;
373(11):1021-1031.
51. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting
mitochondrial permeability transition pore opening: a new para-
digm for myocardial preconditioning? Cardiovasc Res. 2002;
55(3):534-543.
52. Argaud L, Gateau-Roesch O, Muntean D, et al. Specific inhibition
of the mitochondrial permeability transition prevents lethal reper-
fusion injury. J Mol Cell Cardiol. 2005;38(2):367-374.
53. Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Precondition-
ing and postconditioning: the essential role of the mitochondrial
permeability transition pore. Cardiovasc Res. 2007;75(3):
530-535.
54. Zalewski J, Claus P, Bogaert J, et al. Cyclosporine a reduces
microvascular obstruction and preserves left ventricular function
deterioration following myocardial ischemia and reperfusion.
Basic Res Cardiol. 2015;110(2):18.
55. Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a
distance: reduction of myocardial infarct size by partial reduction
of blood supply combined with rapid stimulation of the gastro-
cnemius muscle in the rabbit. Circulation. 1997;96(5):1641-1646.
56. Rossello X, He Z, Yellon DM. Myocardial infarct size reduction
provided by local and remote ischaemic preconditioning: refer-
ences values from the hatter cardiovascular institute. Cardiovasc
Drugs Ther. 2018;32(2):127-133.
57. Bøtker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic
conditioning before hospital admission, as a complement to
angioplasty, and effect on myocardial salvage in patients with
acute myocardial infarction: a randomised trial. Lancet. 2010;
375(9716):727-734.
58. Crimi G, Pica S, Raineri C, et al. Remote ischemic post-
conditioning of the lower limb during primary percutaneous
coronary intervention safely reduces enzymatic infarct size in
anterior myocardial infarction: a randomized controlled trial.
JACC Cardiovasc Interv. 2013;6(10):1055-1063.
Journal of Cardiovascular Pharmacology and Therapeutics XX(X)
59. White SK, Frohlich GM, Sado DM, et al. Remote ischemic con-
ditioning reduces myocardial infarct size and edema in patients
with ST-segment elevation myocardial infarction. JACC Cardio-
vasc Interv. 2015;8(1 Pt B):178-188.
60. Eitel I, Stiermaier T, Rommel KP, et al. Cardioprotection by
combined intrahospital remote ischaemic perconditioning and
postconditioning in ST-elevation myocardial infarction: the ran-
domized LIPSIA CONDITIONING trial. Eur Heart J. 2015;
36(44):3049-3057.
61. Gaspar A, Lourenço AP, Pereira MA, et al. Randomized con-
trolled trial of remote ischaemic conditioning in ST-elevation
myocardial infarction as adjuvant to primary angioplasty (RIC-
STEMI). Basic Res Cardiol. 2018;113(3):14.
62. Hausenloy DJ, Kharbanda RK, Møller UK, et al. Effect of
remote ischaemic conditioning on clinical outcomes in patients
with acute myocardial infarction (CONDI-2/ERIC-PPCI): a
single-blind randomised controlled trial (IN PRESS). Lancet.
2019.
63. Sugidachi A, Yamaguchi S, Jakubowski JA, et al. Selective block-
ade of P2Y12 receptors by prasugrel inhibits myocardial infarction
induced by thrombotic coronary artery occlusion in rats. J Car-
diovasc Pharmacol. 2011;58(3):329-334.
64. Roubille F, Lairez O, Mewton N, et al. Cardioprotection by clo-
pidogrel in acute ST-elevated myocardial infarction patients: a
retrospective analysis. Basic Res Cardiol. 2012;107(4):275.
65. Cohen MV, Yang X-M, White J, Yellon DM, Bell RM, Downey
JM. Cangrelor-mediated cardioprotection requires platelets and
sphingosine phosphorylation. Cardiovasc Drugs Ther. 2016;
30(2):229-232.
66. Franchi F, Rollini F, Rivas A, et al. Platelet inhibition with can-
grelor and crushed ticagrelor in patients with ST-segment-
elevation myocardial infarction undergoing primary percutaneous
coronary intervention: results of the CANTIC study. Circulation.
2019;139(14):1661-1670.
67. Alexopoulos D, Pappas C, Sfantou D, et al. Cangrelor in
ticagrelor-loaded STEMI patients undergoing primary percuta-
neous coronary intervention. J Am Coll Cardiol. 2018;72(14):
1750-1751.
68. Mohammad MA, Andell P, Koul S, et al. Cangrelor in combina-
tion with ticagrelor provides consistent and potent P2Y12-
inhibition during and after primary percutaneous coronary
intervention in real-world patients with ST-segment-elevation
myocardial infarction. Platelets. 2017;28(4):414-416.
69. Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Stein-
hubl SR. Pharmacokinetics and pharmacodynamics of a bolus and
infusion of cangrelor: a direct, parenteral P2Y12 receptor antago-
nist. J Clin Pharmacol. 2010;50(1):27-35.
70. Schneider DJ. Transition strategies from cangrelor to oral platelet
P2Y12 receptor antagonists. Coron Artery Dis. 2016;27(1):65-69.
71. Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers
WS. Transitioning patients from cangrelor to clopidogrel: phar-
macodynamic evidence of a competitive effect. Thromb Res.
2008;121(4):527-534.