The Arranged Marriage of Cangrelor and Bivalirudin∗

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 8, NO. 3, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

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http://dx.doi.org/10.1016/j.jcin.2015.01.004

EDITORIAL COMMENT

The Arranged Marriage of Cangrelor and Bivalirudin* Gilles Montalescot, MD, PHD, Gérard Helft, MD, PHD

B

ivalirudin and cangrelor are 2 intravenous

IIb/IIIa inhibitors are mostly used provisionally. A

drugs, 1 for anticoagulation and the other for

bivalirudin-based regimen compared with a heparin-

antiplatelet therapy, with a rapid onset of

based regimen for PCI increases ischemic events and

action, thus in theory perfectly adapted to percuta-

stent thrombosis (1). Any strategy that could reduce

neous coronary intervention (PCI) that requires

major thrombotic events after PCI would be welcome

simultaneous thrombin and platelet inhibition. These

in bivalirudin-oriented catheterization laboratories.

effects are especially needed for mechanical coronary

The use of the more potent P2Y12 receptor antagonists

reperfusion of acute patients such as those presenting

prasugrel and ticagrelor in patients receiving bivalir-

with ST-segment elevation myocardial infarction

udin is an option but was not confirmed in the EURO-

(STEMI). The short half-lives and good tolerance of

MAX trial (European Ambulance Acute Coronary

these 2 drugs add to the attractiveness of their profile

Syndrome [ACS] Angiography) (61% use of prasugrel or

in the contemporary era of expeditious and safety-

ticagrelor) and HEAT-PPCI study (How Effective Are

oriented care.

Antithrombotic Therapies in Primary Percutaneous

Bivalirudin anticoagulation has been associated

Coronary Intervention) (89% use of prasugrel or tica-

with a reduction of major bleeding complications,

grelor) studies, both of which showed a persistent

the magnitude of which varies based on whether

excess of stent thrombosis (2,3). Cangrelor, more

glycoprotein IIb/IIIa inhibitors are used in the con-

potent and more rapidly active than prasugrel and

trol arm with unfractionated heparin (1). There is

ticagrelor, is another option, considering the demon-

no significant reduction of major bleeding when

strated reduction of ischemic events (
20%) and stent

glycoprotein IIb/IIIa inhibitors are used provision-

thrombosis (
40%) compared with clopidogrel in the

ally with both anticoagulant strategies of unfractio-

CHAMPION-PHOENIX trial (A Clinical Trial Comparing

nated heparin and bivalirudin. Currently, glycoprotein

Cangrelor to Clopidogrel Standard Therapy in Subjects Who Required Percutaneous Coronary Intervention) and a meta-analysis (4,5). These attractive results were

*Editorials published in JACC: Cardiovascular Interventions reflect the

associated with no excess bleeding but also no reduc-

views of the authors and do not necessarily represent the views of JACC:

tion in mortality. The study reported in this issue of

Cardiovascular Interventions or the American College of Cardiology.

JACC: Cardiovascular Interventions examines this

From the ACTION Study Group, Institut de Cardiologie (AP-HP), Hôpital

marriage

Pitié-Salpêtrière, University Paris 6, INSERM UMRS 1166, Paris, France.

CHAMPION-PHOENIX trial (6).

Dr. Montalescot has received consulting fees from Bayer, Boehringer Ingelheim, Cardiovascular Research Foundation, Europa Organisation, the Gerson Lehrman Group, Iroko Cardio International, Lead-Up, Lumi-

of

bivalirudin

and

cangrelor

in

the

SEE PAGE 424

nex, McKinsey & Company, Inc., Remedica, Servier, TIMI Study Group, WebMD, Wolters Kluwer Health, Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Menarini Group, Roche,

In this subset analysis of patients receiving bivalir-

Sanofi, Pfizer, Daiichi Sankyo, and Medtronic; and grant support from

udin (19% of the CHAMPION-PHOENIX population),

Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines

cangrelor compared with clopidogrel significantly

Company, Menarini Group, Sanofi, Pfizer, Roche, Accumetrics, Med-

reduced ischemic events as well as stent thrombosis

tronic, Abbott Laboratories, Daiichi Sankyo, Nanosphere Inc., and

to the same magnitude as in the main trial. This

Stentys. Dr. Helft has received funding from Boston Scientific, Medtronic, Biotronik, and Terumo; and honoraria from Abbott, Bayer, Servier,

finding does not mean that cangrelor can eliminate

Inspire MD, AstraZeneca, and Boehringer Ingelheim.

the excess of stent thrombosis related to bivalirudin

Montalescot and Helft

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 8, NO. 3, 2015 MARCH 2015:434–5

Cangrelor and Bivalirudin

use. Indeed, a similar effect of cangrelor was reported

too expensive in places where glycoprotein IIb/IIIa

with unfractionated heparin in the initial publication

inhibitors were not as popular. In addition to the

(p value for interaction ¼ 0.51). Are these findings

stent thrombosis and cost issues, practicality was also

relevant? It is noteworthy that this subset analysis

seen as a limiting factor for bivalirudin (1 bolus,

applies almost exclusively to patients from the United

2 infusion doses, prolonged infusion after PCI). The

States (93%) when the global study recruited the

recent European Guidelines on Myocardial Revascu-

majority of patients outside the United States (63%)

larization give the same Class IIa recommendation to

where anticoagulants other than bivalirudin were

bivalirudin and enoxaparin, the latter being another

generally used. So the findings are relevant to these

alternative to unfractionated heparin, without the

catheterization laboratories using bivalirudin. The

stent thrombosis, cost, and practicality concerns of

cangrelor effect is preserved but does not eliminate

bivalirudin (8–10).

the excess risk of stent thrombosis related to bivalir-

In conclusion, the arranged marriage of bivalirudin

udin itself. In the rest of the world where other an-

and cangrelor presupposes that they are comple-

ticoagulants are used, the cangrelor effect is similarly

mentary and that the 2 are perfectly matched, but, as

present. The survival curves show clearly the timing

we indicate, nothing suggests such complementarity

of the cangrelor effect, preventing stent thrombosis

here. The same company selling both drugs may want

in the first 3 h after PCI, exactly as in the ATLANTIC

to arrange this marriage but is fully aware that the

study (A 30 Day Study to Evaluate Efficacy and Safety

physicians can always refuse this marriage and sim-

of Pre-hospital vs. In-hospital Initiation of Ticagrelor

ply look for another choice. This arranged marriage

Therapy in STEMI Patients Planned for Percutaneous

may not be forced, especially when the cost is taken

Coronary

pre-

into account, knowing that effectiveness is not

hospital (rather than in-hospital) ticagrelor in pri-

guaranteed. Finally, 1 reason for marrying bivalirudin

mary PCI (7). The timing of P2Y 12 inhibition appears

and cangrelor may well be a cultural trademark in labs

to be a key modulator of stent thrombosis and is

where the economic pressure is not too important

best obtained with an early oral load of ticagrelor

and where bivalirudin adoption is so pervasive, there

or later intravenous administration of cangrelor.

is reluctance to change. Elsewhere, tolerance of a

Neither strategy is associated with increased bleed-

different type of marriage will be necessary, accept-

ing. Late administration of clopidogrel, particu-

ing a selection of patients for cangrelor and routine

larly in STEMI, would be the least effective strategy

anticoagulant strategies other than bivalirudin.

Intervention

[PCI])

when

using

for the prevention of post-procedural thrombotic REPRINT REQUESTS AND CORRESPONDENCE: Dr.

events. There are obvious regional differences in the use of

Gilles Montalescot, ACTION Study Group, Institut de

bivalirudin, which has replaced unfractionated hep-

Cardiologie, Pitié-Salpêtrière University Hospital, 47

arin in places where glycoprotein IIb/IIIa inhibitors

Boulevard de l’Hôpital, 75013 Paris, France. E-mail:

were commonly used, but was seen as less useful and

[email protected].

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percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013;382: 1981–92. 6. White HD, Bhatt DL, Gibson CM, et al. Outcomes with Cangrelor versus Clopidogrel on a Background of Bivalirudin: insights from the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]).

9. Montalescot G, Zeymer U, Silvain J, et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011;378:693–703. 10. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revas-

et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371: 1016–27.

cularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619.

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KEY WORDS anticoagulation, antiplatelet therapy, P2Y12 antagonists, percutaneous coronary intervention, stent thrombosis

J Am Coll Cardiol Intv 2015;8:424–33. 7. Montalescot G, van’t Hof AW, Lapostolle F,

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