JACC VOL. 69, NO. 2, 2017
Letters
JANUARY 17, 2017:244–52
*Molecular Cardiology-IRCCS ICS Maugeri
guidelines do not address adjunctive antiplatelet
Via Maugeri
therapy in resuscitated patients with suspected
10–27100 Pavia
STEMI scheduled to undergo PCI, the initiation of a
Italy
combination of aspirin and clopidogrel or the new
E-mail:
[email protected]
P2Y 12 receptor inhibitors is considered reasonable (2). Unfortunately, a majority of patients are coma-
http://dx.doi.org/10.1016/j.jacc.2016.09.981 Please note: Dr. Priori has served as a scientific advisor for Medtronic and Gilead; has received unrestricted research/educational grants from Gilead and Boston Scientific; and holds equity in Audentes Rx. Dr. Napolitano holds equity in Audentes Rx. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
tose despite the return of spontaneous circulation and remain intubated under mechanical ventilation. Thus, the administration of crushed and dissolved tablets via a nasogastric tube remains the only option. Moreover, combined hypothermia at a target temperature of 32 C to 36 C may have an influence
REFERENCES 1. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 2007;116:1137–44. 2. Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000;343:262–7. 3. Ye D, Medeiros Domingo A, Tester DJ, et al. Role of in-vitro functional studies to guide pharmacotherapy for an infant with a novel channelopathic mutation (I397F) in SCN5A (abstr). Heart Rhythm 2011;8:
on the platelet inhibitory effect of the drugs, considering the related changes in the hepatic cytochrome P450 system (3). Under these circumstances, Bjelland et al. (4) found that the antiplatelet effect of clopidogrel is decreased by delayed absorption and altered pharmacological transformation during TTM. Another study reported that resuscitated patients treated with TTM exhibit a sluggish response to P2Y 12 receptor inhibitors as determined by
S394.
the PRI/VASP-index 24 h after administration of
Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention
loading doses of 1 of the following agents: clopidogrel,
The CRUSH Study
However, I understand the concern regarding the
prasugrel, and ticagrelor. This effect was most marked with the use of clopidogrel (3). With regard to adjunctive antithrombotic therapy in patients with TTM after cardiac arrest with suspected STEMI intending to undergo PCI, the initiation of a combination of aspirin and prasugrel may be reasonable despite insufficient evidence. bleeding risk with prasugrel, including a “black box” warning by the U.S. Food and Drug Administration
I read the CRUSH (Pharmacodynamic and Pharma-
and the provided contraindications for its use in
cokinetic Profiles of Prasugrel in Patients With
patients with prior stroke or intracranial bleeding;
ST-Segment Elevation Myocardial Infarction Under-
hence, it will be important to assess these con-
going Primary Percutaneous Coronary Intervention: A
traindications
Randomized Comparison of Standard Versus Crushed
brain imaging study may be warranted in such
before
antithrombotic
therapy.
A
Formulation) study by Rollini et al. (1) with great
patients before coronary angiography and intense
interest and excitement. The researchers reported
antithrombotic
that in patients with ST-segment elevation myocar-
research will define the specifics of these treatment
dial infarction (STEMI) undergoing percutaneous
strategies.
coronary
intervention
(PCI),
crushed
therapy
is
implemented;
prasugrel
administration is associated with faster drug absorp-
*Won Young Kim, MD, PhD
tion and more prompt and potent antiplatelet effects
*Department of Emergency Medicine
compared with whole-tablet ingestion. Although the
Ulsan University College of Medicine
clinical effect of this result warrants a large-scale
Asan Medical Center
efficacy trial, this finding indicates the potential
88 Olympic-ro 43-gil
benefit of using crushed prasugrel in post–cardiac
Songpa-gu, Seoul 05505
arrest survivors with targeted temperature manage-
Republic of Korea
ment (TTM).
E-mail:
[email protected]
Coronary
angiography
should
be
performed
emergently for out-of-hospital cardiac arrest survivors
with
suspected
STEMI.
further
Although
current
http://dx.doi.org/10.1016/j.jacc.2016.08.082 Please note: Dr. Kim has reported that he has no relationships relevant to the contents of this paper to disclose.
249
250
JACC VOL. 69, NO. 2, 2017
Letters
JANUARY 17, 2017:244–52
antiplatelet agents. However, most evidence derives
REFERENCES 1. Rollini F, Franchi F, Hu J, et al. Crushed prasugrel tablets in patients with
from studies using clopidogrel. Bednar et al. (2)
STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol 2016;67:1994–2004.
showed that, in patients treated with TH, prasugrel
2. Penela D, Magaldi M, Fontanals J, et al. Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J Am Coll Cardiol 2013;61:686–7.
a nasogastric tube) provided more prompt and effec-
3. Ibrahim K, Christoph M, Schmeinck S, et al. High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2014;85:649–56. 4. Bjelland TW, Hjertner O, Klepstad P, Kaisen K, Dale O, Haugen BO. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2010;81:1627–31.
and ticagrelor (administered as crushed tablets via tive platelet inhibition than clopidogrel. Similar observations were reported by Ibrahim et al. (3), who showed that TH markedly impairs the antiplatelet effects of clopidogrel, whereas the platelet inhibitory effects of prasugrel and ticagrelor are affected to a lesser extent but without significant increases in rates of high on-treatment platelet reactivity. These find-
REPLY: Crushed Prasugrel Tablets in
ings may be attributed to the fact that TH is associ-
Patients With STEMI Undergoing Primary
ated with a decrease in cytochrome P450 activity,
Percutaneous Coronary Intervention
which is a key determinant of clopidogrel-induced antiplatelet effects (2,3). Thus, crushed formulations
The CRUSH Study
of prasugrel and ticagrelor may represent better We thank Dr. Kim for his appreciation of our study (1).
treatment options than clopidogrel in TH patients.
Indeed, as indicated by Dr. Kim, crushing of oral an-
In patients who have experienced an ischemic cere-
tiplatelet medications, including prasugrel, repre-
brovascular event, ticagrelor should be preferred
sents an option for patients with out-of-hospital
given that prasugrel would be contraindicated.
cardiac arrest treated with therapeutic hypothermia
Also,
(TH). However, we would like to highlight that
agents (i.e., cangrelor) represent a promising treat-
direct-acting
intravenous
P2Y12-inhibiting
studying these patients was not within the scope of
ment alternative (4). Ultimately, in patients with
the CRUSH (Pharmacodynamic and Pharmacokinetic
intracranial
Profiles of Prasugrel in Patients With ST-Segment
complication prevails over the ischemic benefit of any
Elevation Myocardial Infarction Undergoing Primary
antiplatelet agent.
bleeding,
the
management
of
this
Percutaneous Coronary Intervention: A Randomized
requiring intubation because they would not be
Fabiana Rollini, MD Francesco Franchi, MD *Dominick J. Angiolillo, MD, PhD
amenable to the randomized strategy of standard oral
*University of Florida College of Medicine–Jacksonville
drug intake. Moreover, these patients require a
655 West 8th Street
nasogastric tube, which can lead to different levels of
Jacksonville, Florida 32209
drug bioavailability compared with standard oral
E-mail:
[email protected]fl.edu
Comparison of Standard Versus Crushed Formulation) study, which specifically excluded subjects
administration, thus representing a
study con-
founder. Furthermore, many of these patients are also in cardiogenic shock, who were also excluded; these
patients
have
profiles
of
gastrointestinal
absorption that differ from patients not in cardiogenic shock. Overall, in keeping with the pharmacokinetic/ pharmacodynamic nature of the CRUSH study and its very specific objective of understanding how oral
http://dx.doi.org/10.1016/j.jacc.2016.09.982 Please note: Dr. Angiolillo has received consulting fees or honoraria from Amgen, Bayer, Pfizer, Sanofi, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, and PLx Pharma; has participated in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical; and has received institutional payments for grants from GlaxoSmithKline, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
administration of a crushed formulation of prasugrel compares with whole pills, it was pivotal to have very specific study entry criteria. Indeed, introducing heterogeneity into the study population would have led to confounded results. We agree with Dr. Kim on the importance of defining the optimal antithrombotic treatment for patients
who
experience
out-of-hospital
cardiac
arrest who receive TH and undergo percutaneous coronary intervention. Indeed, low temperatures may decrease the inhibitory effects induced by the oral
REFERENCES 1. Rollini F, Franchi F, Hu J, et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol 2016;67:1994–2004. 2. Bednar F, Kroupa J, Ondrakova M, Osmancik P, Kopa M, Motovska Z. Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction. J Thromb Thrombolysis 2016;41: 549–55. 3. Ibrahim K, Christoph M, Schmeinck S, et al. High rates of prasugrel and ticagrelor non-responder in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2014;85:649–56.
