Current Cardiology Reports

, 16:493

Cangrelor: Review of the Drug and the CHAMPION Programme (Including PHOENIX)

Authors

  • Marcello Marino
    • University of Pavia
  • Diego Rizzotti
    • Fondazione IRCCS Policlinico San Matteo
    • Fondazione IRCCS Policlinico San Matteo
New Therapies for Cardiovascular Disease (KW Mahaffey, Section Editor)

DOI: 10.1007/s11886-014-0493-4

Cite this article as:
Marino, M., Rizzotti, D. & Leonardi, S. Curr Cardiol Rep (2014) 16: 493. doi:10.1007/s11886-014-0493-4
Part of the following topical collections:
  1. Topical Collection on New Therapies for Cardiovascular Disease

Abstract

Platelet inhibition is the main goal of ancillary pharmacologic therapy during percutaneous coronary interventions (PCI). Thienopyridines and ticagrelor are oral drugs developed for this purpose. Cangrelor is an intravenous, non-thienopyridine antagonist of the P2Y12 receptor with a rapid, potent, predictable, and quickly reversible effect. Cangrelor has been studied in a broad population intended to receive PCI in the CHAMPION program, where it was compared with different clopidogrel regimens. The first two trials, CHAMPION PCI and PLATFORM, failed their primary objective, likely for challenges in the adjudication of PCI-related myocardial infarction. In a third trial that implemented the universal definition of MI, CHAMPION PHOENIX, a reduction of thrombotic events, including stent thrombosis, was observed. In the BRIDGE trial cangrelor has been studied in patients who had to prematurely interrupt antiplatelet therapy for surgery. Cangrelor appears a promising agent in patients who require PCI or when a rapid reversal is needed.

Keywords

CangrelorPercutaneous coronary interventionsPlatelet inhibitionAcute coronary syndromeCHAMPION Programme

Clinical Trial Acronyms

CHAMPION PCI

Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition PCI

CHAMPION PLATFORM

Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition PLATFORM

CHAMPION PHOENIX

Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition PHOENIX

BRIDGE

Maintenance of Platelet inihiBition With cangRelor After dIscontinuation of ThienopyriDines in Patients Undergoing surGEry

GUSTO

Global Utilization of Streptokinase and Tissue plasminogen activator in Occluded arteries

ACUITY

Acute Catheterization and Urgent Intervention Triage StrategY

TIMI

Thrombolysis in Myocardial Infarction

Introduction

Percutaneous coronary intervention (PCI) is central in the management of patients with both stable and unstable coronary artery disease. To maintain the immediate results of PCI and prevent complications and recurrence of thrombotic events [1], ancillary pharmacologic therapy targeted to inhibit platelet activity is essential. Over the last decades, the inhibition of the platelet adenosine diphosphate (ADP) receptor – P2Y12 has become integral to preventing procedural complications, including stent thrombosis, especially in the setting of acute coronary syndromes (ACS) [2]. Thienopyridines, a class of oral pro-drugs that irreversibly block the P2Y12 receptor, such as ticlopidine [3, 4], subsequently replaced by clopidogrel [57] have been established for these indications. However, clopidogrel produces only a moderate inhibition of ADP-induced platelet aggregation and its efficacy is limited by interpatient variability in drug response [8]. To improve the pharmacological inhibition of the platelet P2Y12 receptor, prasugrel and ticagrelor were developed.

Prasugrel is a third-generation thienopyridine that allow a consistent, more efficient conversion to the active metabolite than clopidogrel [9]. It also demonstrated superior anti-ischemic efficacy compared with clopidogrel in clopidogrel-naïve patients with ACS and known coronary anatomy undergoing PCI, while at the cost of increased major and minor bleeding [10]. Prasugrel was not superior to clopidogrel in medically managed patients or when administered before diagnostic coronary angiography [11, 12].

Ticagrelor is a reversible, direct-acting P2Y12 inhibitor (not a thienopyridine) with a more rapid onset and offset of action compared with clopidogrel and is also more potent [13]. In patients presenting with ACS, including medically-managed patients and patients pretreated with clopidogrel, ticagrelor reduced ischemic events, including a nominally significant effect on mortality, compared with clopidogrel with a similar rate of major bleeding, although with an increase in non coronary-artery-bypass-graft (CABG) related bleedings [14].

However, the usefulness of oral P2Y12 can be impaired in patients who cannot swallow or absorb medications, such as those who are vomiting, in shock, or intubated. In patients with acute myocardial infarction nausea was reported in almost 2/3 of all patients, and vomiting in nearly 1/3 [15]. Furthermore, all the available P2Y12 inhibitors require at least 5 days of discontinuation to reverse their effect, a relevant limitation when a rapid reversal is required (e.g., need for urgent surgery, which could be potentially delayed).

Cangrelor is an intravenous P2Y12 inhibitor. Its peculiar pharmacological profile makes this molecule attractive. Due to its rapid onset and offset of action, cangrelor provides flexibility during PCI, especially in the acute and emergency settings, like primary PCI for ST elevation myocardial infarction (STEMI) or non-ST elevation acute coronary syndrome, a setting in which time to cardiac catheterization has decreased substantially [16, 17]. In this setting, neither ticagrelor, nor prasugrel provided pharmacodynamic evidence of a rapid effect and at 2 hours from the administration of the loading dose, one third to half of patients with STEMI had high platelet reactivity as assessed with the VerifyNow assay [18, 19] with both oral agents. Finally, glycoprotein IIb/IIIa inhibitors (GPI) are effective antiplatelet agents but they do increase TIMI and GUSTO bleeding [2022] so that they are used only in selected cases, such as a bail-out or in very high ischemic risk patient [23].

Cangrelor has the potential to overcome these limitations. In this review, we will briefly summarize the rationale for cangrelor development, focusing on its phase III programme.

Cangrelor: A Potent, Rapid, Intravenous P2Y12 Inhibitor

Pharmacology Overview

Chemically known as N-2-methylthio-ethyl-2-(3,3,3-trilflouroprpylthiol)-5’-adenyl acid, cangrelor is an analogue of adenosine triphosphate (ATP), the natural antagonist of the P2Y12 receptor (Fig. 1). It is dephosphorylated to the nucleoside and its primary metabolite is essentially inactive. It is characterized by a potent, predictable inhibition of ADP-induced inhibition of platelet aggregation that is virtually immediate (when administered as a bolus) and rapidly reversible (Fig. 2) [24, 25]. Cangrelor achieves almost complete and immediate inhibition of ADP-induced platelet aggregation when administered as a bolus of 30 μg/kg, and continuous infusion sustains the high degree of inhibition. The plasma half-life is approximately 3 to 5 minutes and platelet function is restored within 1 hour after cessation of infusion [24]. Importantly, cangrelor does not have a significant renal or hepatic metabolism [26], a relevant difference as compared with oral P2Y12 inhibitors that can be particularly attractive in the acute setting.
https://static-content.springer.com/image/art%3A10.1007%2Fs11886-014-0493-4/MediaObjects/11886_2014_493_Fig1_HTML.gif
Fig. 1

Cangrelor and ATP. Chemical structure of cangrelor and ATP. Cangrelor is a true analog of ATP

https://static-content.springer.com/image/art%3A10.1007%2Fs11886-014-0493-4/MediaObjects/11886_2014_493_Fig2_HTML.gif
Fig. 2

Cangrelor: Phase I human pharmacokinetics and pharmacodynamics. Cangrelor administrated intravenously reaches rapidly an elevated concentration and achieves an almost complete platelet inhibition. After the stop of infusion its plasmatic concentration rapidly decreases and platelet activity returns to its basal level in about 60 minutes. (Adapted from: Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Steinhubl SR. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol. 2010 Jan;50(1):27–35) [25]

Transition from Intravenous Cangrelor to Oral P2Y12 Receptor Antagonists

Since cangrelor is administered intravenously, transition to an oral P2Y12 antagonist is needed. The block of the P2Y12 receptor during cangrelor infusion makes the receptor unavailable to the active metabolite of clopidogrel, which is short lived (≈20 minutes). For this reason, simultaneous administration of clopidogrel with a loading dose of 600 mg and cangrelor prevents platelet inhibition by clopidogrel active moiety. This implies that, for clopidogrel to be effective, cangrelor infusion has to be terminated [27]. This problem can be potentially avoided with ticagrelor [28]. The optimal transition of cangrelor to and from novel P2Y12 antagonists is being studied. Two randomized controlled trial are ongoing, TRANSITION I (NCT01766466) and TRANSITION II (NCT01852019), and are testing the transition to and from ticagrelor and prasugrel, respectively.

From Bench to Bedside: Phase II Development and CHAMPION PCI and PLATFORM

Cangrelor was tested in phase II studies in different clinical situations, mostly in patients with ACS and in patients undergoing PCI. Given as an infusion, up to 4 μg/kg/minute, cangrelor demonstrated a linear PK with a dose-dependent effect that required approximately 2.5 hours to be evident at a dosage of 0.05 μg/kg/minute and 1.5 hour at a dosage of 1 μg/kg/minute [24]. Dosages of 2 and 4 μg/kg/min provided a complete (>80 %) inhibition of ADP-induced platelet aggregation in all patients [29, 30], the latter dosage having a faster onset with no evidence of excessive rate of bleeding compared to placebo or to other agents, including clopidogrel, abciximab and alteplase [2932]. Of note, a trend to less bleeding with cangrelor compared to abciximab was reported, although not statistical significant [29].

This promising results have laid the foundation for cangrelor phase III programme, CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON).

This program originally consisted of two randomized 1:1, double-blind, double-dummy trials, CHAMPION PCI and CHAMPION PLATFORM. These trials tested the hypothesis that cangrelor, given during PCI, could reduce thrombotic events compared to clopidogrel administered at the beginning or at the end of PCI respectively (Table 1), with an acceptable safety profile [33, 34].
Table 1

Design and characteristics of the CHAMPION trials

 

CHAMPION PLATFORM

CHAMPION PCI

CHAMPION PHOENIX

Study Patients

70 % troponin elevated at baseline

P2Y12 inhibitor naive

Placebo or clopidogrel control (all patients received 600 mg) loaded at the end of PCI

70 % troponin elevated at baseline

Previous chronic clopidogrel allowed

Placebo or clopidogrel control (all patients received 600 mg) loaded at the start of PCI

35 % troponin elevated at baseline

P2Y12 inhibitor naive

Placebo or clopidogrel (300 mg or 600 mg) loaded at the start (96.5 % and 50.5 %) or at the end of PCI (3.5 % and 49.5 %)

Clinical setting

NSTEMI: troponin elevated

STEMI: ECG changes including persistent (>20 min) ST-segment elevation in ≥2 contiguous leads

PCI required (stable angina, NSTE-ACS, STEMI)

UA: ECG changes and pain and age/diabetes

NSTEMI: troponin elevated

Stable angina: capped (15 %)

UA: ECG changes and pain and age/diabetes

Stable angina: capped (15 %)

Number of patients (mITT)

5,301

8,667

10,942

Comparator

600 mg clopidogrel

Loaded at the end of PCI

600 mg clopidogrel

Loaded at the end of PCI

300 or 600 mg (per hospital standard of care), loaded at the start or at the end of PCI per physician

Primary Endpoint

Death/MI/IDR at 48 h

Death/MI/IDR at 48 h

Death/MI/IDR/ST at 48 h

MI definition

Not UDMI: reliance on cardiac markers alone to define PCI MI

Not UDMI: reliance on cardiac markers alone to define PCI MI

UDMI implemented: reliance on cardiac markers and other evidence of ischaemia to define PCI MI

1 baseline sample

1 baseline sample

2 baseline samples ≥6 h apart required in NSTE-ACS patients to confirm resolving MI at baseline

Biomarker normal at baseline: MI defined as CK-MB ≥3 × ULN post-PCI

Biomarker normal at baseline: MI defined as CK-MB ≥3 × ULN post PCI

Baseline normal patients: MI defined as CK-MB ≥3 × ULN post PCI

Biomarker elevated at baseline: elevation in CK-MB ≥3 × ULN and 50 % increase from baseline sample or ECG changes

Biomarker elevated at baseline: elevation in CK-MB ≥3 × ULN and 50 % increase from baseline sample or ECG changes

Baseline abnormal patients were classified into MI increasing or decreasing at baseline:

Increasing: re-elevation in CK-MB post PCI (≥3 × ULN and 50 % increase from baseline) + additional evidence of ischaemia (2 of 2): ECG changes AND angiographic evidence

Decreasing: re-elevation in CK-MB post PCI (≥3 × ULN and 50 % increase from baseline) + additional evidence of ischaemia (at least 1 of 3): ischemic symptoms, ECG changes, or angiographic evidence

Stent thrombosis definition

Non-standard definition

Angiographic stent thrombosis associated with IDR

Confirmed by clinical events committee using angiographic source data

Non-standard definition

Angiographic stent thrombosis associated with IDR

Confirmed by clinical events committee using angiographic source data

Either definite stent thrombosis as per ARC definition, for post PCI events

or

intraprocedural stent thrombosis for events occurring within PCI = (any procedural new or worsened thrombus related to the stent, based on angiographic evidence)

Legend: ACS = acute coronary syndrome. ARC = Academic Research Consortium. CK-MB = creatine phosphokinase myocardial band. ECG = electrocardiogram. IDR = ischaemia-driven revascularization. MI = myocardial infarction. mITT = modified intention-to-treat. NSTE-ACS = non-ST-elevation acute coronary syndromes. NSTEMI = non-ST-segment elevation myocardial infarction. PCI = percutaneous coronary intervention. ST = stent thrombosis. STEMI = ST-segment elevation myocardial infarction. UA = unstable angina. UDMI = universal definition of myocardial infarction. ULN = upper limit of normal.

(Adapted from: 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 Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet. 2013 Dec 14;382(9909):1981–92. Steg PG 2013) [41]

The two studies were launched almost concurrently in 2007. The primary endpoint, identical for the 2 studies and adjudicated by the same clinical event committee, was the combined composite of death, MI, or ischemia-driven revascularization (IDR) at 48 hours in a broad population of patients requiring PCI. Cangrelor (or matching placebo) was administered as a bolus (30 μg/kg) followed by an infusion of 4 μg/kg/minute in patients with STEMI but only after confirmation of coronary anatomy suitable for PCI in patients with stable angina or non-ST elevation ACS. The infusion was continued for at least 2 hours (or until the conclusion of the PCI if longer). At the end of the infusion, patients in the cangrelor arm received 600 mg of clopidogrel. The comparator arm differed in the two studies. It was clopidogrel 600 mg in CHAMPION PCI and initial placebo in CHAMPION PLATFORM, where clopidogrel 600 mg was administered only at the end of PCI. Only clopidogrel naïve patients were eligible in PLATFORM while patients already on clopidogrel were included in CHAMPION PCI. Patients with STEMI were eligible in CHAMPION PCI but not in CHAMPION PLATFORM [33, 34].

Unexpectedly, in 2009 both studies were prematurely interrupted following a recommendation of the Data and Safety Monitoring Committee for futility. At that time, CHAMPION PCI enrolled 8877 of the expected 9000 patients (98,6 %) and CHAMPION PLATFORM 5362 of the expected 6400 subjects (83.8 %). The primary end-point rate was similar between cangrelor and control in CHAMPION PCI and PLATFORM (7.5 % for cangrelor, 7.1 % for clopidogrel, odds ratio (OR) 1.05, 95 % confidence interval (CI), 0.88 to 1.24; P = 0.59; and 7.0 % vs 8.0 %, OR 0.87; 95 % CI, 0.71 to 1.07; P = 0.17 respectively).

Rethinking Procedural-Related Myocardial Infarction: The CHAMPION PHOENIX Trial

Despite the premature interruption of both studies, some observations have suggested the possibility of a benefit for cangrelor. First, a significant effect has been observed across the two trials on secondary but relevant endpoints, such as death, stent thrombosis, or Q-wave myocardial infarction (MI) not dependent upon biomarkers. Also, time from hospital admission to angiography was shorter than expected (6.3 hours in CHAMPION PCI and 7.9 in PLATFORM) [35], so many patients only had one or none cardiac marker value prior to PCI or had cardiac markers that were increasing at the time of PCI, making the adjudication of PCI-related MI extremely challenging or in some instances virtually impossible. Reinforcing this hypothesis, subgroup analyses indicated efficacy of cangrelor in patients with stable angina, probably because in these cases procedural MI is more easily adjudicated since pre-PCI markers are normal. Taken together, these observations have indicated the possibility that a suboptimal definition of procedural-related MI may have reduced the ability to detect an effect for cangrelor.

The MI definition used in CHAMPION PCI and PLATFORM did require biomarkers elevation but clinical judgement was applied to interpreting the relationship to the PCI or to the index event; that definition preceded the Universal definition of MI [36]. According to the original CEC definition the presence of stable or falling biomarkers at the time of PCI was not required to define PCI-related MI endpoint. Two independent analyses of the CHAMPION dataset retrospectively applied the Universal MI definition and consistently indicated a reduced number of PCI-related MI events and more favorable treatment effects for cangrelor [35, 37].

Based in part on these analyses, the CHAMPION PHOENIX trial was designed [38]. CHAMPION PHOENIX had many similarities with CHAMPION PCI and PLATFORM, including the regimen of cangrelor administration, and some important differences. First and foremost, the definition of MI as endpoint. Second, unlike CHAMPION PCI and PLATFORM, in PHOENIX the comparator arm was clopidogrel 300 or 600 mg, at the investigator discretion. Third, the primary end-point was the composite of death, MI, IDR, or stent thrombosis (including intraprocedural) at 48 hours. Finally the population of interest was restricted to clopidogrel naïve patients.

The definition of MI used in PHOENIX was based on the second Universal definition of MI [36] for all types of MI but PCI-related (type 4a) MI, where this definition was expanded to include some elements (like angiographic complications) that were later included in the Third Universal MI definition [39]. In PHOENIX PCI-related MI could be assessed using cardiac biomarkers only if troponin pre-PCI was normal or elevated but stable or falling according to at least two samples over 6 hours. As learned from CHAMPION PCI and PLATFORM, a great emphasis was placed on an accurate assessment of baseline status: in PHOENIX, 98 % of the enrolled patients had at least two troponin values before PCI. Patients with NSTE-ACS, with one or none biomarker assessment available or increasing biomarkers before PCI required additional evidence of MI. By definition, PCI-related MI was not adjudicated in patients with STEMI as entry diagnosis.

PHOENIX enrolled 11,145 patients. Cangrelor significantly reduced the primary endpoint compared to clopidogrel (4.7 % vs 5.9 %; OR, 0.78; 95 % CI, 0.66 to 0.93; P = 0.005) [40•] with no significant excess in the key safety endpoint of GUSTO severe bleeding (0.16 % vs 0.11 %; OR, 1.5; 95 % CI, 0.53 to 4.22; p = 0.44) or blood transfusions (0.5 % vs 0.3 %; OR 1.56; 95 % CI 0.83 to 2.93; P = 0.16); however, less severe bleedings like ACUITY major bleeding (4.3 vs 2.5; OR, 1.72; 95 % CI, 1.39 to 2.13; p < 0.001) were increased with cangrelor. Efficacy results were maintained at 30 days. Cangrelor effect was mostly evident on MI (3.8 % vs 4.7 %; OR, 0.80; 95 % CI, 0.67 to 0.97; P = 0.02) with no mortality difference. Also, stent thrombosis, the key secondary endpoint, was significantly reduced with cangrelor by 38 % (OR 0.62, 95 % CI: 0.43-0.90; P = 0.01) (Tables 2 and 3).
Table 2

Efficacy end-points in CHAMPION trials

 

CHAMPION PCI

CHAMPION PLATFORM

CHAMPION PHOENIX

Cangrelor

Clopidogrel

OR (95 % CI)

Cangrelor

Placebo

OR (95 % CI)

Cangrelor

Clopidogrel

OR (95 % CI)

Primary end point*

7.5 %

7.1 %

1.05 (0.88–1.24)

7.0 %

8.0 %

0.87 (0.71–1.07)

4.7 %

5.9 %

0.78 § (0.66–0.93)

MI

7.1 %

6.6 %

1.09 (0.91–1.29)

6.7 %

7.2 %

0.92 (0.74–1.13)

3.8 %

4.7 %

0.8 § (0.67–0.97)

Q wave MI

0.1 %

0.3 %

0.4 (0.12–1.27)

0.2 %

0.3 %

0.5 (0.15–1.65)

0.2 %

0.3 %

0.61 (0.29–1.29)

ST

0.2 %

0.3 %

0.63 (0.25–1.63)

0.2 %

0.6 %

0.31 § (0.11–0.85)

0.8 %

1.4 %

0.62 § (0.43–0.90)

IDR

0.3 %

0.6 %

0.56 (0.28–1.11)

0.7 %

0.9 %

0.79 (0.43-1.44)

0.5 %

0.7 %

0.74 (0.45–1.20)

Death

0.2 %

0.1 %

1.59 (0.52–4.87)

0.2 %

0.7 %

0.33 § (0.13-0.83)

0.3 %

0.3 %

1.0 (0.52–1.92)

Death, Q wave MI, or IDR

0.6 %

0.9 %

0.67 (0.39–1.14)

0.9 %

1.6 %

0.55 § (0.33–0.93)

0.9 %

1.2 %

0.76 (0.53–1.11)

Legend: Data refers to modified intention-to-treat population. OR = odds ratio. CI = confidence interval. MI = myocardial infarction. ST = stent thrombosis. IDR = ischemia driven revascularization. * In CHAMPION PHOENIX primary end-point includes ST (in adjunct to death, MI and IDR). § statistical significant difference

Table 3

Safety end-points in CHAMPION trials

 

CHAMPION PCI

CHAMPION PLATFORM

CHAMPION PHOENIX

Cangrelor

Clopidogrel

OR (95 % CI)

Cangrelor

Placebo

OR (95 % CI)

Cangrelor

Clopidogrel

OR (95 % CI)

GUSTO

Mild

19.6 %

16.9 %

1.2 § (1.07–1.34)

16.0 %

11.7 %

1.44 (1.23–1.69)

NA

NA

NA

Moderate

0.9 %

0.8 %

1.21 (0.76–1.90)

0.8 %

0.5 %

1.54 (0.76–3.09)

0.4 %

0.2 %

1.69 (0.85–3.37)

Severe

0.2 %

0.3 %

0.91 (0.39–2.14)

0.3 %

0.2 %

1.5 (0.53–4.21)

0.2 %

0.1 %

1.5 (0.53–4.22)

TIMI

Minor

0.8 %

0.6 %

1.39 (0.84–2.30)

0.8 %

0.6 %

1.37 (0.72–2.62)

0.2 %

0.1 %

3.0 (0.81–11.10)

Major

0.4 %

0.3 %

1.36 (0.68–2.71)

0.2 %

0.3 %

0.44 (0.14–1.44)

0.1 %

0.1 %

1.0 (0.29–3.45)

ACUITY

Minor

17.6 %

15.2 %

1.19 § (1.06–1.33)

12.0 %

9.3 %

1.34 § (1.12–1.59)

11.8 %

8.6 %

1.42 § (1.26–1.61)

Major

3.6 %

2.9 %

1.26 (0.99–1.60)

5.5 %

3.5 %

1.61 § (1.23–2.10)

4.3 %

2.5 %

1.72 § (1.39–2.13)

Any blood transfusion

1.1 %

1 %

1.09 (0.72–1.67)

1 %

0.6 %

1.62 (0.87–3.03)

0.5 %

0.3 %

1.56 (0.83–2.93)

Legend: OR = odds ratio. CI = confidence interval. NA = not available. § statistical significant difference

CHAMPIONs Meta-Analyses

A patient-level meta-analysis of the three CHAMPION trials (≈25,000 patients) using Universal MI definition to define MI in PLATFORM and PCI [41] and the original CEC-definition in PHOENIX showed a reduction in the composite of death, MI, IDR, or stent thrombosis at 48 hour with cangrelor by 19 % (3.8 % for cangrelor vs 4.7 % for control; OR 0.81, 95 % CI 0.71–0.91, p = 0.0007), and of stent thrombosis by 41 % (0.5 % vs 0.8 %, OR 0.59, 95 % CI 0.43–0.80, p = 0.0008) [42]. Cangrelor also reduced the triple composite of all-cause death, MI, or IDR at 48 hours by 19 % (3.6 % vs 4.4 %, OR 0.81, 95 % CI 0.71–0.92, p = 0.0014). These benefits were maintained at 30 days and there was no difference in the primary safety outcome (GUSTO severe bleeding unrelated to CABG, 0.2 % in both groups), in GUSTO moderate bleeding (0.6 % vs 0.4 %), or in transfusion (0.7 % vs 0.6 %), but cangrelor increased GUSTO mild bleeding (16.8 % vs 13.0 %, p < 0.0001). There was no difference in TIMI major bleeding (0.3 % vs 0.2 % P = NS), while cangrelor increased TIMI minor (0.6 % vs 0.4 %, P = 0.0218) and ACUITY bleedings, both major (4.2 % vs 2.8 %, P <0.0001) and minor (13.8 % vs 11 %, P <0.0001). The benefit of cangrelor on the primary end-point was consistent across all of the pre-specified subgroups, including admission diagnosis (STEMI, NSTE-ACS or stable angina).

In a non-patient level meta-analysis of the same studies, results were mainly consistent. In this analysis, the definition of MI as end-point was the original, CEC definition used for the primary analysis for each of the three studies [43]. Cangrelor did not differ from clopidogrel with respect to all cause death (0.26 % vs 0.36 %, RR 0.72, 95 % CI 0.36–1.43) and MI (5.3 % vs. 5.7 %; RR 0.94, 95 % CI 0.78–1.13). On the other hand, it was superior to clopidogrel in terms of Q wave MI (0.15 % vs. 0.28 %, RR 0.53, 95 % CI 0.30–0.92, p = 0.03; Number Need to Treat [NNT] = 728), IDR (0.52 % vs. 0.74 %, RR 0.72, 95 % CI 0.52–0.98, p = 0.04; NNT = 474) and stent thrombosis (0.49 % vs. 0.84 %, RR 0.60, 95 % CI 0.44–0.82, p = 0.001; NNT = 287). GUSTO severe bleeding and TIMI major bleeding were not different between cangrelor and control. The main limitation of this analysis is that it is not patient-level, and it also shows mild to moderate heterogeneity. Similar results were observed in another study-level meta-analyses [44].

A BRIDGE for Surgery

Another small phase II study, the BRIDGE trial, randomized 210 patients already receiving thienopyridine as chronic therapy and awaiting CABG surgery to cangrelor without a bolus and with an infusion of 0.75 μg/kg per minute or placebo. Cangrelor (or matching placebo), which was administered after thienopyridines had been stopped (2–7 days before surgery), was to be given for at least 48 hours and to be discontinued 1 to 6 hours before CABG. The primary efficacy end point, platelet reactivity (assessed with the VerifyNow system as a P2Y12 reaction unit (PRU)), was reduced (intended as PRUs < 240) in cangrelor arm (98.8 % vs 19.0 %, risk ratio [RR] 5.2 [95 % CI, 3.3-8.1] p < .001). Excessive CABG surgery-related bleeding occurred in 11.8 % vs 10.4 % in the cangrelor and placebo groups, respectively (RR 1.1 [95 % CI, 0.5-2.5] p = 0.763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor [45].

Future Directions

While cangrelor has proved to be superior compared with clopidogrel, this latter is increasingly less used in patients with ACS, where prasugrel and ticagrelor are emerging options. Cangrelor has not been directly compared versus prasugrel or ticagrelor. Future trials are needed to assess cangrelor efficacy in the context of modern antithrombotic therapy.

Cangrelor may have a peculiar indication in the very early phase of patients with STEMI intended for primary PCI, as a “facilitated” regimen, where the oral route is suboptimal due to nausea, vomiting, intubation but data in this context are lacking.

Data from the BRIDGE trial in patients who need to interrupt oral agents are promising but not sufficient to provide final recommendations in this context due to small number of patients enrolled. Last but not least, data on cost-effectiveness are needed to comprehensively assess cangrelor effectiveness.

Conclusions

Cangrelor – an intravenous, potent, quickly reversibly P2Y12 inhibitor – has a superior anti-thrombotic efficacy compared to clopidogrel in patients undergoing PCI with a reassuring safety profile and can overcome some of the limitations of currently available oral P2Y12 inhibitors. Its peculiar and unique pharmacological profile provides flexibility during PCI and makes this drug attractive in addition (rather than in substitution) to oral P2Y12 inhibitor. To definitively assess its effectiveness, it will be important to study cangrelor in patients treated with modern agents (including ticagrelor and prasugrel), in emergency settings (where it may be the preferred medication), and to examine its cost-effectiveness.

Compliance with Ethics Guidelines

Conflict of Interest

Marcello Marino, Diego Rizzotti, and Sergio Leonardi declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Copyright information

© Springer Science+Business Media New York 2014