Circulation

EDITORIAL

Cangrelor for ST-Segment–Elevation

Myocardial Infarction
Pharmocodynamic Evidence Is In

Article, see p 1661 David Erlinge, MD, PhD

C
angrelor is an intravenous P2Y12-receptor antagonist indicated for use in pa-
tients undergoing percutaneous coronary intervention (PCI), in conjunction
with acetylsalicylic acid, to reduce thrombotic adverse events, in patients who
have not received oral P2Y12 inhibitors before PCI or where oral P2Y12 inhibition
is not feasible or desirable. In comparison with oral P2Y12 inhibition, cangrelor has
the pharmacokinetic advantages of adequate platelet inhibition within minutes of
administration and a half-life of 3 to 6 minutes with a return of complete platelet
function within 60 minutes of discontinuation.1
The pivotal 3 randomized clinical trials of the CHAMPION trial program (Can-
grelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibi-
tion)2–4 were pooled in an analysis showing that cangrelor treatment in comparison
Downloaded from http://ahajournals.org by on April 2, 2019

with clopidogrel reduced periprocedural ischemic complications but increased the

risk of mild bleeding.5
Patients with ST-segment–elevation myocardial infarction (STEMI) only consti-
tuted ≈12% of the study population in CHAMPION, but with a consistent 19%
relative reduction of the primary end point. From a clinical perspective, the STEMI
population is ideal for cangrelor because there is little time for pretreatment with
oral P2Y12 inhibitors and increased thrombotic risk. Furthermore, pretreatment is
questionable before angiographic diagnosis if the patient needs acute surgery. In
a large registry study we did not find any benefit from pretreatment with ticagre-
lor before arriving at the PCI laboratory.6 In contrast to the study populations in
CHAMPION, current real-world use of cangrelor in Sweden was recently reported
to be almost exclusively in patients with STEMI (>98%).7
Furthermore, in CHAMPION, cangrelor was combined with clopidogrel, which is
now replaced in the guidelines by the more potent P2Y12 inhibitors ticagrelor and
prasugrel for acute coronary syndromes. Thus, there is an urgent need for clinical
information on the use of cangrelor in combination with ticagrelor for patients
who have STEMI treated with primary PCI (P-PCI).
The CANTIC study (Platelet Inhibition with Cangrelor and Crushed TICagrelor
The opinions expressed in this article are
in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention) is a not necessarily those of the editors or
prospective, randomized, double-blind, placebo-controlled, parallel design inves- of the American Heart Association.
tigation of the pharmacodynamic effects of cangrelor versus placebo in patients Key Words: Editorials ◼ percutaneous
undergoing P-PCI treated with crushed ticagrelor presented in this issue of Circu- coronary intervention ◼ pharmacology
lation.8 After diagnostic angiography, patients were randomly assigned to a blind- ◼ purinergic P2Y receptor antagonists
◼ ST elevation myocardial infarction ◼
ed 2-hour infusion of either cangrelor or placebo. At the same time, 180 mg of stents ◼ thrombosis
crushed ticagrelor was administered to both groups. Planned use of glycoprotein
© 2019 American Heart Association, Inc.
IIb/IIIa inhibitors (GPI) was not allowed. Platelet reactivity was measured with Veri-
fyNow P2Y12 point-of-care testing and vasodilator-stimulated phosphoprotein. https://www.ahajournals.org/journal/circ

Circulation. 2019;139:1671–1673. DOI: 10.1161/CIRCULATIONAHA.119.039253 April 2, 2019 1671

 Erlinge
Pharmacodynamics were registered for 22 patients in
each group.
Cangrelor was associated with marked reduced
EDITORIAL
platelet reactivity as early as 5 minutes after the start
of infusion, which persisted during the entire duration
of drug infusion, fulfilling the primary end point. High
on-treatment platelet reactivity (HPR) was significantly
lower with cangrelor, with no patients with HPR dur-
ing cangrelor infusion, whereas more than half of the
patients had HPR at the end of PCI and one-third at
the end of the 2-hour placebo infusion. There was no
difference in platelet reactivity 1 hour after discontinu-
ation of the infusions, indicating a lack of drug–drug
interaction between cangrelor and ticagrelor. The
study was not powered for clinical end points but bail-
out GPI was more common in the placebo group, and
1 patient in the placebo group experienced an acute
definitive stent thrombosis. Bleeding complications
were similar.
Dr Angiolillio and his coworkers should be con-
gratulated for filling an important knowledge gap
regarding cangrelor in combination with ticagrelor in
patients undergoing P-PCI. This treatment combina-
tion is already widely used worldwide for patients with
STEMI without sufficient data from randomized clini-
cal trials. The results are reassuring, demonstrating re-
duced platelet reactivity and no HPR during PCI during
the 2-hour infusion. The findings are consistent with
a nonrandomized pharmacodynamic study of combin-
Downloaded from http://ahajournals.org by on April 2, 2019
ing cangrelor and ticagrelor for P-PCI that also demon-
strated superior inhibition of platelet reactivity during
infusion and found a continuous potent P2Y12 inhibi-
tion in patients transitioned from cangrelor to ticagre-
lor9 and with a smaller open-label randomized trial.10
Thus, with these 3 studies where the CANTIC study
is state-of-the art, the pharmacodynamic evidence for
the combination of cangrelor and ticagrelor in P-PCI is
now well established.
Converting from cangrelor to the thienopyridines
clopidogrel and prasugrel after PCI is complicated by a
pharmacodynamic competitive effect between cangre-
lor and their active metabolite.11 Therefore, oral load-
ing with clopidogrel should take place only at the end,
and prasugrel 30 minutes before the end of cangre-
lor infusion, leaving a time window for clot formation
and stent thrombosis. It is therefore reassuring that the
current CANTIC study did not find any signs of drug–
drug interaction between cangrelor and ticagrelor. This
combination seems ideal in patients undergoing P-PCI,
because ticagrelor can be given immediately after di-
agnostic angiography, resulting in consistent platelet
inhibition with no HPR even after the end of infusion.
The study has several limitations. It is a small study
that started out screening 99 patients, but, in the end,
only 22 patients in each group fulfilled criteria and had
complete pharmacodynamic data. It is adequately pow-
1672 April 2, 2019
Cangrelor for ST-Segment–Elevation MI
ered for pharmacodynamics, but, to evaluate clinical
outcomes, a study of several thousand patients would
be needed. It does not answer the question of whether
GPI or cangrelor is to be preferred. There is no doubt
that GPI would also have resulted in rapid and marked
inhibition of platelet aggregation. However, from a
pharmacodynamic perspective, GPI only inhibits the
final aggregation step with no effect on the platelets
with regard to shape change, surface thrombin activa-
tion or vesicular release of procoagulants, inflamma-
tion, and growth factors. By inhibiting P2Y12 receptors,
cangrelor blocks the early activation of the platelets and
all subsequent activation steps. In a pooled analysis of
CHAMPION, cangrelor without GPI was associated with
similar antithrombotic benefit and lower risk-adjusted
bleeding in comparison with clopidogrel and concomi-
tant GPI.12 The same conclusion was drawn in an ex-
ploratory analysis from the CHAMPION trials.13 Can-
grelor could be an equal antithrombotic as GPI with
reduced bleeding risk.
In conclusion, the CANTIC study provides solid phar-
macodynamic evidence for the use of cangrelor in com-
bination with ticagrelor for patients undergoing P-PCI.
If this translates into reduced clinical end points, such as
reduced stent thrombosis, the questions of myocardial
infarctions and mortality can only be answered by large
randomized clinical trials.
ARTICLE INFORMATION
Correspondence
David Erlinge, MD, PhD, Department of Cardiology, Clinical Sciences, Lund Uni-
versity, Skåne University Hospital Lund, Sweden. Email David.erlinge@med.lu.se
Affiliation
Department of Cardiology, Clinical Sciences, Lund University, Skåne University
Hospital Lund, Sweden.
Disclosures
None.
REFERENCES
1. Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Steinhubl SR.
Pharmacokinetics and pharmacodynamics of a bolus and infusion of can-
grelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol.
2010;50:27–35. doi: 10.1177/0091270009344986
2. Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson
CM, Pollack CV Jr, Montalescot G, Mahaffey KW, Kleiman NS, Goodman
SG, Amine M, Angiolillo DJ, Becker RC, Chew DP, French WJ, Leisch F,
Parikh KH, Skerjanec S, Bhatt DL. Platelet inhibition with cangrelor in
patients undergoing PCI. N Engl J Med. 2009;361:2318–2329. doi:
10.1056/NEJMoa0908628
3. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot
G, 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, Skerjanec S, Harrington RA; CHAMPION PLATFORM Investi-
gators. Intravenous platelet blockade with cangrelor during PCI. N Engl J
Med. 2009;361:2330–2341. doi: 10.1056/NEJMoa0908629
4. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW,
Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P,
Circulation. 2019;139:1671–1673. DOI: 10.1161/CIRCULATIONAHA.119.039253
 Erlinge
Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu
T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; CHAMPION
PHOENIX Investigators. Effect of platelet inhibition with cangrelor dur-
ing PCI on ischemic events. N Engl J Med. 2013;368:1303–1313. doi:
10.1056/NEJMoa1300815
5. Steg PG, Bhatt DL, Hamm CW, Stone GW, Gibson CM, Mahaffey KW,
Leonardi S, Liu T, Skerjanec S, Day JR, Iwaoka RS, Stuckey TD, Gogia HS,
Gruberg L, French WJ, White HD, Harrington RA; CHAMPION Investiga-
tors. Effect of cangrelor on periprocedural outcomes in percutaneous
coronary interventions: a pooled analysis of patient-level data. Lancet.
2013;382:1981–1992. doi: 10.1016/S0140-6736(13)61615-3
6. Koul S, Smith JG, Götberg M, Omerovic E, Alfredsson J, Venetsanos
D, Persson J, Jensen J, Lagerqvist B, Redfors B, James S, Erlinge D.
No benefit of ticagrelor pretreatment compared with treatment dur-
ing percutaneous coronary intervention in patients with ST-segment-
elevation myocardial infarction undergoing primary percutaneous
coronary intervention. Circ Cardiovasc Interv. 2018;11:e005528. doi:
10.1161/CIRCINTERVENTIONS.117.005528
7. Grimfjard P, Lagerqvist B, Erlinge D, Varenhorst C, James S. Clinical use
of cangrelor: nationwide experience from the Swedish Coronary Angi-
ography and Angioplasty Registry (SCAAR) [published online January 28,
2019]. Eur Heart J Cardiovasc Pharmacother. doi: 10.1093/ehjcvp/pvz002
https://academic.oup.com/ehjcvp/advance-article-abstract/doi/10.1093/
ehjcvp/pvz002/5292475?redirectedFrom=fulltext
8. Franchi F, Rollini F, Rivas A, Wali M, Briceno M, Agarwal M, Shaikh Z, Nawaz
A, Silva G, Been L, Smairat R, Kaufman M, Pineda A, Suryadevara S, Soffer
D, Zenni MM, Bass TA, Angiolillo DJ. Platelet inhibition with cangrelor
and crushed ticagrelor in patients with ST-segment–elevation myocardial
infarction undergoing primary percutaneous coronary intervention: results
Downloaded from http://ahajournals.org by on April 2, 2019
Circulation. 2019;139:1671–1673. DOI: 10.1161/CIRCULATIONAHA.119.039253
Cangrelor for ST-Segment–Elevation MI
of the CANTIC Study. Circulation. 2019;139:1661–1670. doi: 10.1161/
CIRCULATIONAHA.118.038317
9. Mohammad MA, Andell P, Koul S, James S, Scherstén F, Götberg M,
Erlinge D. Cangrelor in combination with ticagrelor provides consis-
EDITORIAL
tent and potent P2Y12-inhibition during and after primary percuta-
neous coronary intervention in real-world patients with ST-segment-
elevation myocardial infarction. Platelets. 2017;28:414–416. doi:
10.1080/09537104.2016.1246714
10. Alexopoulos D, Pappas C, Sfantou D, Xanthopoulou I, Didagelos M,
Kikas P, Ziakas A, Tziakas D, Karvounis H, Iliodromitis E. Cangrelor in
ticagrelor-loaded STEMI patients  undergoing primary percutaneous
coronary intervention. J Am Coll Cardiol. 2018;72:1750–1751. doi:
10.1016/j.jacc.2018.07.041
11. Schneider DJ, Agarwal Z, Seecheran N, Gogo P. Pharmacodynamic effects
when clopidogrel is given before cangrelor discontinuation. J Interv Car-
diol. 2015;28:415–419. doi: 10.1111/joic.12229
12. Vaduganathan M, Harrington RA, Stone GW, Deliargyris EN, Steg PG,
Gibson CM, Hamm CW, Price MJ, Menozzi A, Prats J, Elkin S, Mahaffey
KW, White HD, Bhatt DL; CHAMPION Investigators. Cangrelor with and
without glycoprotein  IIb/IIIa inhibitors in  patients  undergoing percuta-
neous  coronary intervention. J Am Coll Cardiol. 2017;69:176–185. doi:
10.1016/j.jacc.2016.10.055
13. Vaduganathan M, Harrington RA, Stone GW, Deliargyris EN, Steg
PG, Gibson CM, Hamm CW, Price MJ, Menozzi A, Prats J, Elkin S, Ma-
haffey KW, White HD, Bhatt DL. Evaluation of ischemic and bleeding
risks associated with 2 parenteral antiplatelet strategies comparing
cangrelor with glycoprotein IIb/IIIa inhibitors: an exploratory analy-
sis from the CHAMPION Trials. JAMA Cardiol. 2017;2:127–135. doi:
10.1001/jamacardio.2016.4556
April 2, 2019 1673