What is the evidence for cangrelor use in STEMI shock patients, emergency stent procedures, and bridge therapy for patients with ACS that need CABG? How does the bleeding risk and efficacy of cangrelor compare to glycoprotein IIb/IIIa inhibitors?

Comment by InpharmD Researcher

Cangrelor offers a fast onset of action and short half-life, resulting in decreased bleeding risk compared to glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa) inhibitors. Tables 1 to 7 provide data regarding the efficacy of cangrelor in specific circumstances. The European Society of Cardiology (ESC) supports the use of intravenous antiplatelets as a bridging strategy if aspirin and P2Y12 inhibitors must be discontinued perioperatively, but U.S. guidelines do not provide specific recommendations due to lack of sufficient evidence.
Background

A 2021 article discusses the current data for the use of cangrelor as an intravenous (IV) P2Y12 receptor inhibitor. In general, the real-world clinical use of cangrelor is primarily observed in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Lesser data exists for complicated patients, such as those with ST-segment-elevation myocardial infarction (STEMI) presenting with cardiogenic shock. But one descriptive experience from a single-center found cangrelor is associated with lower bleeding events in patients with cardiogenic shock. For stents, data largely focuses upon cangrelor as a bridging agent in already stented patients undergoing coronary surgery. For example, one referenced study of patients with ACS or a stent undergoing coronary artery bypass graft (CABG) surgery (BRIDGE trial) suggests that cangrelor maintains better inhibition of platelet reactivity versus placebo (98.8% versus 19.0%; p<0.001) but had numerically higher rates of bleeding (11.8% versus 10.4%; p= 0.76). Cangrelor is currently not approved by the Food and Drug Administration (FDA) as a bridge therapy before CABG surgery. The MONET BRIDGE study will focus on stented patients bridged with cangrelor prior to surgery. [1]

A 2020 review article discusses the use of cangrelor in the surgical setting. In comparison with glycoprotein IIb/IIIa inhibitors (GPIs) inhibitors, the platelet inhibition effect of cangrelor is immediate but has a short half-life of 3 to 5 minutes. Platelet function typically is restored within 30 to 60 minutes after stopping infusion. Cangrelor has been investigated as a bridging agent in the BRIDGE and ongoing MONET BRIDGE studies for patients undergoing CABG. The European Society of Cardiology (ESC) supports the use of intravenous antiplatelets as a bridging strategy if aspirin and P2Y12 inhibitors must be discontinued perioperatively, but U.S. guidelines do not provide specific recommendations due to lack of evidence. [2-3]

Finally, a 2019 article provided a general overview regarding the use of intravenous antiplatelet therapies, including GPIIb/IIIa inhibitors and cangrelor in PCI. Intravenous use of GPIs is reported to be sporadic in current practice due to bleeding concerns associated with routine use as well as the availability of more potent alternatives for ACS. Specific situations that may call for use of GPIs include the presence of a large intraprocedural thrombus burden, slow flow or ‘no reflow’ complications of PCI, and bridging the full onset of action of oral P2Y12 inhibitors. For use of GPIs in patients with acute STEMI undergoing PCI, a 2005 meta-analysis (N= 27,115 patients from 11 RCTs) found a significant reduction in frequency of myocardial infarction and mortality at 30 days with the use of GPIs. Another 2007 meta-analysis arrived at a similar conclusion. Cangrelor, having a short half-life and rapid offset of action, is advantageous over GPIs due to the lack of increased bleeding risk in the event of overdose. Additionally, the dose does not need to be adjusted based on renal function. Studies have shown no association between cangrelor and increased risk for major or minor bleeding (according to thrombolysis in myocardial infarction [TIMI] classification) or with acquired thrombocytopenia, unlike GPIs. In three landmark CHAMPION randomized trials, GPIs were not shown to reduce ischemic complications, while also resulting in increased bleeding rates. For patients with ACS undergoing PCI, the use of cangrelor in catheterization laboratories may prevent surgical delays for patients with mechanical complications of STEMI. Ultimately, it was concluded that cangrelor may provide faster onset of action with reduced complications as well as more desirable pharmacologic characteristics compared to GPIs. [4]

References:

[1] De Luca L, Steg PG, Bhatt DL, Capodanno D, Angiolillo DJ. Cangrelor: Clinical Data, Contemporary Use, and Future Perspectives. J Am Heart Assoc. 2021;10(13):e022125. doi:10.1161/JAHA.121.022125
[2] Cao D, Chandiramani R, Capodanno D, Berger JS, Levin MA, Hawn MT, Angiolillo DJ, Mehran R. Non-cardiac surgery in patients with coronary artery disease: risk evaluation and periprocedural management. Nat Rev Cardiol. 2021;18(1):37-57. doi: 10.1038/s41569-020-0410-z.
[3] Knuuti, J. et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur. Heart. J. 2020; 41:407–477 .
[4] Capodanno D, Milluzzo RP, Angiolillo DJ. Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use. Ther Adv Cardiovasc Dis. 2019;13:1753944719893274. doi:10.1177/1753944719893274
glycoprotein IIb/IIIa receptor inhibitors vs. cangrelor

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the evidence for cangrelor use in STEMI shock patients, emergency stent procedures, and bridge therapy for patients with ACS that need CABG? How does the bleeding risk and efficacy of cangrelor compare to glycoprotein IIb/IIIa inhibitors?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-7 for your response.


 

Cangrelor Use in Routine Practice: A Two-Center Experience

Design

Descriptive, retrospective study

N= 146

Objective

To describe:

1) patient and procedural characteristics

2) clinical outcomes

3) the transition to oral P2Y12-inhibitors of cangrelor-treated patients undergoing coronary angiography or percutaneous coronary intervention (PCI) in two Dutch tertiary PCI centers during the first years of routine cangrelor use

Study Groups

Cangrelor-treated patients (N= 146)

Inclusion Criteria

Patients treated with cangrelor, undergoing coronary angiography with the intent of PCI

Exclusion Criteria

Age < 18 years, treated with cangrelor before march 23, 2015

Methods

The use of cangrelor was indicated if pretreatment with an oral P2Y12-inhibitor was not feasible or desirable and PCI could not be postponed. Patients with ST-segment elevation myocardial infarction (STEMI) were routinely pretreated with aspirin 160 mg, ticagrelor 180 mg or prasugrel 60 mg, and unfractionated heparin 5,000 IU soon after diagnosis was established.

Patients received cangrelor as a bolus of 30 µg/kg followed by an infusion of 4 µg/kg/min for at least 2 h or the duration of the procedure, whichever lasted longer. Patients would receive a loading dose of an oral P2Y12-inhibitor directly after completion of cangrelor infusion.

Duration

March 2015 to April 2021

Outcome Measures

Primary: all-cause death, myocardial infarction, definite stent thrombosis, major bleeding at 48 hours and 30 days

Baseline Characteristics

 

Cangrelor-treated patients (N= 146)

Age, years

63.7 ± 11.7

Male

110 (75.3%)

Body mass index, kg/m2

26.8 ± 3.7

Concomitant diseases

Hypertension

Dyslipidemia

Current smoker

Diabetes mellitus

 

35.7%

33.7%

39.0%

16.3%

Medical history

Prior myocardial infarction

Prior PCI

Prior coronary artery bypass graft (CABG)

Prior stroke or transient ischemic attack (TIA)

 

12.6%

13.3%

4.2%

6.3%

Clinical presentation of STEMI

123 (84.2%)

Results

Endpoint

Cangrelor-treated patients (N= 146)

All-cause mortality

48 hours

30 days

 

16 (11.0%)

37 (25.3%)

Myocardial infarction

48 hours

30 days

 

0

2 (1.7%)

Definite stent thrombosis

48 hours

30 days

 

0

2 (1.7%)

Major bleeding

48 hours

30 days

 

8 (5.6%)

17 (12.5%)

Major or minor bleeding

48 hours

30 days

 

20 (13.8%)

31 (22.0%)

Study Author Conclusions

Conclusively, cangrelor was used almost exclusively in STEMI patients undergoing PCI. Even though cangrelor was used in high-risk patients, its use was associated with a low rate of stent thrombosis.

InpharmD Researcher Critique

As a descriptive study, no formal analysis was performed to determine the appropriate sample size. Therefore, whether the true magnitude of effect can accurately represent the general population remains uncertain. 



References:

van der Sangen NMR, Cheung HY, Verouden NJW, et al. Cangrelor Use in Routine Practice: A Two-Center Experience. J Clin Med. 2021;10(13):2829. Published 2021 Jun 26. doi:10.3390/jcm10132829

 

Cangrelor in cardiogenic shock and after cardiopulmonary resuscitation: A global, multicenter, matched pair analysis with oral P2Y12 inhibition from the IABP-SHOCK II trial

Design

Global, multicenter, observational study

N= 136

Objective

To evaluate the clinical course of patients in cardiogenic shock (CS) undergoing percutaneous coronary intervention (PCI) treated with cangrelor or oral P2Y12-receptor inhibitors

Study Groups

Cangrelor-treated patients (n= 88)

Oral P2Y12 inhibitor-treated patients (n= 88)

Inclusion Criteria

Acute coronary syndrome (ACS) complicated by CS, undergoing PCI, and treated with cangrelor

Exclusion Criteria

Age ≥ 90 years, prolonged pre-procedural resuscitation 

Methods

Cangrelor was administered during PCI via bolus of 30 mcg/kg followed by an infusion of 4 mcg/kg/min (or 0.75 mcg/kg/min without a bolus in case of bridging) for at least 2 hours. Patients were given oral P2Y12 receptor inhibitors (clopidogrel, prasugrel, or ticagrelor). Patients were matched to a control cohort from a large randomized Intra-aortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK) II trial that was treated with oral P2Y12 receptor inhibitors. Matching was based on age, sex, cardiac arrest, type of myocardial infarction, culprit lesion localization, glycoprotein IIb/IIIa inhibitor (GPI) use, and oral antiplatelet therapy (clopidogrel vs. prasugrel/ticagrelor either as initial therapy or after switching from cangrelor to oral P2Y12 inhibition). After 1:1 matching, 88 pairs were identified and included in the analysis. 

Duration

November 2015 to August 2017

Outcome Measures

30-day mortality, 12-month mortality, in-hospital moderate and severe bleeding (according to Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] criteria), definite acute stent thrombosis, thrombolysis in myocardial infarction (TIMI) flow improvement

Baseline Characteristics

 

IABP-SHOCK II matched cohort (n= 88)

Multi-center cangrelor-treated patients (n= 88)

p-value

Age, years

70.5  68.5 NS

Female

28.4% 28.4% NS 

NSTE-ACS

29.5%  29.5% NS 

STEMI

70.5% 70.5% NS 

Concomitant medications

Glycoprotein IIb/IIIa inhibitor

Aspirin

P2Y12-receptor blocker

Ticagrelor/prasugrel

Clopidogrel

Cangrelor full dose

Cangrelor bridging dose

Unfractionated heparin

Bivalirudin

 

12/88 (13.6%)

81/88 (92.0%)

-

60/88 (56.8%)

38/88 (43.2%)

-

-

74/88 (84.1%)

15/88 (17.0%)

 

12/88 (13.6%)

40/41 (97.6%)

60/88 (56.8%)

38/88 (43.2%)

79/88 (89.9%)

15/88 (17.0%)

84/88 (95.5%)

6/88 (6.8%)

NS 

PCI

85/88 (96.6%)

77/86 (89.5%)

NS 

Type of stent 

DES 

BMS

 

44/79 (55.7 %)

36/79 (45.6 %)

 

71/77 (92.2 %)

 

3/77 (3.9 %)

 

< 0.001

< 0.001

BMS, bare metal stent; DES, drug-eluting stent; NS, not significant; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

Results

Endpoint

IABP-SHOCK II matched cohort (n= 88)

Multi-center cangrelor-treated patients (n= 88)

p-value

30-day mortality

32 (36.4%) 26 (29.5%) 0.34

12-month mortality

41 (47.1%) 30 (34.1%) 0.079

In-hospital moderate/severe bleeding

17 (19.3%) 19 (21.6%) 0.71

Definite acute stent thrombosis

2 (2.3%) 2 (2.3%) 1.00

TIMI flow improvement

At least 1 grade

At least 2 grades

 

69/85 (81.2%)

57/85 (67.1%)

 

78/84 (92.9%)

68/84 (81.0%)

 

0.02

0.04

No differences were reported for other in-hospital complications, including renal replacement therapy, sepsis, and 12-month stroke.

Adverse Events

N/A

Study Author Conclusions

Cangrelor treatment was associated with similar bleeding risk and significantly better TIMI flow improvement compared with oral P2Y12 inhibitors in CS patients undergoing PCI. The use of cangrelor in CS offers a potentially safe and effective antiplatelet option and should be evaluated in randomized trials.

InpharmD Researcher Critique

Due to the non-randomized study design and potential for bias, the results of this study are limited to hypothesis-generating for future investigations. 



References:

Droppa M, Vaduganathan M, Venkateswaran RV, et al. Cangrelor in cardiogenic shock and after cardiopulmonary resuscitation: A global, multicenter, matched pair analysis with oral P2Y12 inhibition from the IABP-SHOCK II trial. Resuscitation. 2019;137:205-212. doi:10.1016/j.resuscitation.2019.02.008

 

Cangrelor Use in Cardiogenic Shock: A Single-Center Real-World Experience

Design

Descriptive, single-center retrospective chart review

N= 38

Objective

To report patterns of use and periprocedural outcomes in patients in clinical shock who received cangrelor

Study Groups

Cangrelor-receiving patients (N= 38)

Inclusion Criteria

Patients presenting with clinical shock, treated with cangrelor

Exclusion Criteria

N/A

Methods

The presence of clinical shock was defined as requiring vasopressors, inotropes, or mechanical circulatory support immediately before or during cangrelor administration. Dosing of cangrelor varied per the attending physician.

Duration

November 2015 to April 2017

Outcome Measures

Stent thrombosis, bleeding event, deaths

Baseline Characteristics

 

Cangrelor-receiving patients (N= 38)

Age (range), years

65.5 (55.5 to 75.5)

Male

63.2%

Medical history

Diabetes

Hypertension

Prior stroke or transient ischemic attack

Prior myocardial infarction

Prior coronary artery bypass graft (CABG)

 

34.2%

60.5%

7.9%

31.6%

10.5%

Type of shock

Cardiogenic shock

Mixed/distributive shock

 

37 (97.4%)

1 (2.6%)

Shock presentation

Left ventricular ejection fraction

Cardiac arrest

Ventricular tachycardia/fibrillation

Pulseless electrical activity/asystole

 

43%

42.1%

31.6%

10.5%

Received concomitant glycoprotein IIb/IIIa inhibitor

0

Results

Endpoint

Cangrelor-receiving patients (N= 38)

Stent thrombosis at 48 hours

0

Bleeding event

Required ≥ 1 blood transfusion

Access-site related

Gastrointestinal

Genitourinary

Multiple sites

11 (29%)

5

2

2

2

4

Deaths

5

Adverse Events

All bleeding events were classified as mild or moderate

Study Author Conclusions

The initial data suggest that cangrelor may offer a potent, parenteral strategy in patients in cardiogenic shock and seems to be well-tolerated with low rates of clinically significant ischemic or bleeding events.

InpharmD Researcher Critique

As a descriptive report of a study, there is limited information available. No formal statistical analysis was performed to determine the magnitude of the benefit. Patients who suffered from ST-segment elevation myocardial infarction (STEMI) were not reported.



References:

Vaduganathan M, Qamar A, Badreldin HA, Faxon DP, Bhatt DL. Cangrelor Use in Cardiogenic Shock: A Single-Center Real-World Experience. JACC Cardiovasc Interv. 2017 Aug 28;10(16):1712-1714. doi: 10.1016/j.jcin.2017.07.009. PMID: 28838482.

 

Stenting in Acute Ischemic Stroke: Monocentric Case Series

Design

Retrospective, observational case series

N= 12

Objective

To present a preliminary experience regarding the safety and effectiveness of using cangrelor, in combination with aspirin, in acute ischemic stroke (AIS) patients requiring acute stenting

Study Groups

Extracranial stenting (n= 4)

Intracranial stenting (n= 6)

Combined extracranial and intracranial stenting (n= 2)

Inclusion Criteria

Patients requiring acute stenting due to causative tandem occlusion or intracranial occlusive disease, such as atherosclerosis or arterial dissection 

Exclusion Criteria

Patients not exposed to cangrelor or patients treated for another cause than AIS

Methods

Patients received intravenous thrombolytic therapy (IVT) if they met the criteria for intravenous thrombolysis within 4.5 h of stroke symptoms’ onset. Blood tests were performed for all patients before cangrelor infusion. The patients received cangrelor 30 mcg/kg bolus at least 10 min before the stent deployment plus an IV bolus of 250mg aspirin. Then, cangrelor infusion was continued at 4 mcg/kg/minute IV infusion for 12–48 h. The patients underwent CT scan to rule out any hemorrhagic complications, then switching to ticagrelor.

A loading dose of 180mg of ticagrelor was started 2 h before stoppage of cangrelor infusion. Consequently, patients were maintained on standard dual antiplatelet therapy. It consisted of a standard regular dose of 90mg twice daily for 6 months in addition to aspirin 75mg once daily for at least 1 year.

In cases of postprocedural emergency surgery or asymptomatic hemorrhagic complications, the cangrelor infusion dose was modified to 0.75 mcg/kg/min, while it was stopped if symptomatic hemorrhagic complications occurred. In case of surgery, the cangrelor was stopped just 1h before the intervention. No platelet aggregometry testing the P2Y12 response for cangrelor was performed before administration because all the procedures were performed in emergency, at the acute phase of the AIS.

Duration

April 2018 to September 2019

Outcome Measures

Primary: incidence of intraprocedural thromboembolic complications and intraprocedural in-stent thrombosis

Secondary: incidence of postprocedural stent thrombosis, symptomatic intracranial hemorrhage (ICH) according to the ECASS II criteria, asymptomatic ICH

Baseline Characteristics

 Subject

Age (years)

Sex

Vascular risk factors

Baseline NIHSS

Pretreatment DWI-ASPECTS

NIHSS discharge

mRS at 3 months Complications

1

65 M

HTN IHD Dyslipidemia Peripheral Vascular disease Previous ischemic stroke COPD Smoker

12 6 11 4  No
2 51 F DM Dyslipidemia Smoker 18 9 2 1  No
3 65 F HTN Dyslipidemia Asthma HBV Smoker 15 6 14 4  ASICH

4

85 F DM Dyslipidemia Previous ischemic stroke 16 8 4 1 ASICH
5 54 M HTN 14 4 16 3 Malignant infarction and mass effect
6 88 F

HTN DM Dyslipidemia Asthma Alcoholic

4 8 1 1 No

7

70 HTN Smoker Alcoholic 0 9 0 0 Retroperitoneal hematoma

8

58 M HTN 8 8 0 0 No
9 44 F Smoker Alcoholic 22 7 2 2 Asymptomatic dissection of infrapetrous segment of left ICA
10 63 F HTN IHD Dyslipidemia Peripheral Vascular disease Smoker 9 8 3 0 No
11 74 F Smoker Alcoholic 22 6 6 3 No
12 86 F AF Previous ischemic stroke 10 6 4 5 SICH

NIHSS National Institutes of Health Stroke Score, DWI-ASPECTS diffusion-weighted image – Alberta stroke program early CT score, mRS modified Rankin scale, HTN hypertension, IHD ischemic heart disease, COPD chronic obstructive pulmonary disease, DM diabetes mellitus, HBV hepatitis B virus, ASICH asymptomatic intracranial hemorrhage, ICA internal carotid artery, AF atrial fibrillation, SICH symptomatic intracranial hemorrhage

Results

Endpoint

Number of patients (%)

 

         

 

Intraprocedural thromboembolic complications

 0              

Incidence of postprocedural stent thrombosis

 1 (8%)              
Asymptomatic intracranial hemorrhage 2 (17%)              

Symptomatic intracranial hemorrhage 

1 (8%)               

Retroperitoneal hematoma

1 (8%)              

Adverse Events

See above

Study Author Conclusions

Cangrelor might be a safe and effective antiplatelet medication owing to its on/off activity for acute stenting in the setting of acute ischemic stroke. Further investigations through randomized studies with larger samples are necessary.

InpharmD Researcher Critique

This study demonstrates evidence for cangrelor in patients requiring acute stenting. While promising, these results will need to be duplicated in a larger population under experimental conditions before incorporating into regular practice.



References:

Elhorany M, Lenck S, Degos V, Sourour NA, Frasca Polara G, Shotar E, Godier A, Drir M, Mahtout J, Premat K, Alamowitch S, Samson Y, Clarençon F. Cangrelor and Stenting in Acute Ischemic Stroke : Monocentric Case Series. Clin Neuroradiol. 2021;31(2):439-448. doi: 10.1007/s00062-020-00907-0.

 

Bridging Anti-Platelet Therapy With the Intravenous Agent Cangrelor In Patients Undergoing Cardiac Surgery

Design

Prospective, randomized, double-blind, placebo-controlled, multicenter trial

N= 207

Objective

To evaluate the use of cangrelor, an intravenous, reversible P2Y12 platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG)

Study Groups

Cangrelor (n= 106)

Placebo (n= 101)

Inclusion Criteria

Aged ≥18 years; planned to undergo non-emergent CABG; received a thienopyridine (at least 500 mg ticlopidine, 75 mg of clopidogrel or 10 mg of prasugrel) within at least 72 hours prior to randomization either for the treatment of an ACS or for long-term preventive therapy following coronary stent implantation, drug-eluting stents (DES) or bare-metal stents; received CABG surgery no sooner than 48 hours but no longer than 7 days from randomization; hospitalized until planned CABG

Exclusion Criteria

Need for urgent CABG; confirmed or suspected pregnancy (in woman of child-bearing potential) or lactating females; cerebrovascular accident within the previous year; intracranial neoplasm or history of intracranial surgery; history of bleeding diathesis, thrombocytopenia; International Normalized Ratio (INR) >1.5; requirement for dialysis treatment; estimated glomerular filtration rate (GFR) <30 ml/min; administration of abciximab within 24 hours of randomization or administration of eptifibatide or tirofiban within 12 hours of randomization; plans to continue oral anticoagulant, thienopyridine or glycoprotein (GP) IIb/IIIa antagonist therapy in the pre-operative period; known or suspected coagulopathy

Methods

The BRIDGE trial consisted of two independent stages. Stage I represented an open-label phase of the study aimed to identify the dose of cangrelor that achieved a desired antiplatelet effect after thienopyridine discontinuation. Specifically, cangrelor IV infusion was to be administered to cohorts of 5 patients at a time in a step-wise fashion at pre-determined doses (0.5 mcg/kg/min, 0.75 mcg/kg/min, 1.0 mcg/kg/min, and 1.5 mcg/kg/min) until percent platelet inhibition as measured by VerifyNowTM P2Y12 was > 60% in 80% of daily samples or a dose of 2.0 mcg/kg/min was reached.

In Stage II, eligible patients were randomly assigned (1:1) to receive cangrelor infusion plus standard of care or placebo infusion plus standard of care, using the cangrelor dose determined in Stage I. Platelet reactivity was defined as <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNowTM P2Y12 assay.

Duration

Stage I: January 2009 through August 2009

Stage II: October 2009 through April 2011

Outcome Measures

Primary efficacy: platelet reactivity 

Primary safety: excessive CABG-related bleeding

Baseline Characteristics*

 

Cangrelor (n= 106)

Placebo (n= 101)

   

Age, years

65 (42, 84) 62 (39, 89)    

Female

26 (24.5%)

27 (26.7%)

   

White

93 (87.7%)

94 (93.1%)

   

Medical history

Stroke/TIA

Family history of CAD

Prior MI

Prior PCI

Prior CABG

Congestive HF

PAD

 

9 (8.5%)

47 (44.3%)

46 (43.4%)

53 (50.0%)

3 (2.8%)

16 (15.1%)

14 (13.2%)

 

4 (4.0%)

49 (48.5%)

36 (35.6%)

46 (45.5%)

1 (1.0%)

6 (5.9%)

12 (11.9%)

   

Last Thienopyridine therapy

Clopidogrel

Prasugrel

Unknown 

 

105 (99.1%)

1 (0.9%)

0 / 1 (0.0)

 

93 (92.1%)

8 (7.9%)

1 / 8 (12.5%)

   

Other Antithrombotic Medications (Pre Surgery)

Aspirin

Low molecular weight heparin

Unfractionated heparin

Bivalirudin

Fondaparinux

 

105 (99.1%)

38 (35.8%)

51 (48.1%)

0 (0)

3 (2.8%)

 

97 (96.0%)

43 (42.6%)

49 (48.5%)

1 (1.0%)

4 (4.0%)

   

*Variables are presented as median (25th, 75th) 

CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; HF, heart failure; MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; TIA, transient ischemic attack

Results

Endpoint

Cangrelor (n= 106)

Placebo (n= 101)

Relative risk (95% confidence interval)

p-value

Platelet reactivity 

83/84 (98.8%) 16/84 (19.0%) 5.2 (3.3 to 8.1) <0.001 

Excessive CABG-related bleeding

12/102 (11.8%)  10/96 (10.4%) 1.1 (0.5 to 2.5) 0.763

There were no significant differences in major bleeding prior to CABG, although minor bleeding was numerically higher with cangrelor.

Adverse Events

See results

Study Author Conclusions

Among patients who must wait for cardiac surgery after thienopyridine discontinuation, the use of cangrelor compared with placebo resulted in a higher rate of maintenance of platelet inhibition. 

InpharmD Researcher Critique

As the primary efficacy outcome of the study (platelet reactivity) was a surrogate marker, the results may be misleading. Moreover, this study was not powered to assess the outcomes leading to underestimating the bleeding event rates.



References:

Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307(3):265-274. doi:10.1001/jama.2011.2002

 

Safety and Efficacy of Cangrelor, an Intravenous, Short-Acting Platelet Inhibitor in Patients Requiring Coronary Artery Bypass Surgery

Design

Randomized, open-label, multicenter, double-blinded trial 

N= 210

Objective

To assess the effects of preoperative cangrelor on the incidence of perioperative complications in patients who are awaiting coronary artery bypass grafting (CABG) and require P2Y12 inhibition

Study Groups

Cangrelor (n= 102)

Placebo (n= 96)

Inclusion Criteria

Patients aged ≥ 18 years planned to undergo non-emergent CABG; received a thienopyridine (at least 500 mg ticlopidine, 75 mg of clopidogrel, or 10 mg of prasugrel) within at least 72 hours prior to randomization either for the treatment of an ACS or for long-term preventive therapy following coronary stent implantation, drug-eluting stent (DES) or bare-metal stent; CABG scheduled 48 hours to 7 days from randomization 

Exclusion Criteria

Need for urgent CABG; cerebrovascular accident within the previous year; intracranial neoplasm or history of intracranial surgery;  history of bleeding diathesis; thrombocytopenia (platelet count of < 100,000/µL); known International Normalized Ratio (INR) ≥ 1.5; requirement for dialysis; estimated glomerular filtration rate (GFR) <30 ml/min; administration of abciximab within 24 hours of randomization or administration of eptifibatide or tirofiban within 12 hours of randomization; plans to continue oral anticoagulant, thienopyridine, or glycoprotein (GP) IIb/IIIa antagonist therapy in the pre-operative period; suspected coagulopathy

Methods

Eligible patients were randomized to receive either a continuous intravenous (IV) infusion of cangrelor 0.75 µg/kg/min or placebo for a minimum of 48 hours and a maximum of 7 days. Intravenous cangrelor was discontinued 1 to 6 hours before the planned CABG. All patients received aspirin during the study period and all other perioperative management decisions (ie, heparin infusions, transfusion decisions, need for reoperation, and surgical techniques) were at the discretion of the primary teams. 

Platelet reactivity, defined as < 240 platelet reaction units (PRU), was measured with serial point-of-care testing before infusion, every day preoperatively, immediately before discontinuation of the study drug, and at the time of surgical incision.

Duration

Intervention: 2-7 days

Outcome Measures

Efficacy: proportion of patients with a platelet reactivity of < 240 PRU for all samples assessed during infusion of the study drug before surgery

Safety: excessive CABG-related bleeding, rates of transfusion, and postoperative adverse events (AEs)

Baseline Characteristics

 

Cangrelor
(n = 106)

Placebo
(n= 101)

 

Age, years (range)

65.0 (42 to 84)

62.0 (39 to 89)  

Male

80 (75.5%) 74 (73.3%)  

White

93 (87.7%) 94 (93.1%)  

STEMI

16 (15.1%) 12 (11.9%)  

Medical history

Stroke/transient ischemic attack

Coronary artery disease

Previous myocardial infarction

Previous percutaneous coronary intervention 

Previous CABG

Peripheral vascular disease 

 

9/106 (8.5%)

47/106 (44.3%)

46/106 (43.4%)

53/106 (50.0%)

3/106 (2.8%)

14/106 (13.2%)

 

4/101 (4.0%)

49/101 (48.5%)

36/101 (35.6%)

46/101 (45.5%)

1/101 (1.0%)

12/101 (11.9%)

 

Last thienopyridine therapy

Clopidogrel 

Prasugrel

 

105 (99.1%)

1 (0.9%)

 

93 (92.1%)

8 (7.9%)

 

Time from last thienopyridine use to start of study drug, h (range)

29.1 (1 to 71) 29.5 (4 to 111)  

Infusion duration, h 

67.0 (1 to 161) 82.7 (2 to 306)  

CABG surgical characteristics

CABG type 

On pump

Off pump

CABG duration, h

Any concomitant surgeries

 

 

77/101 (76.2%)

24/101 (23.8%)

3.6 ± 1.2

4/102 (3.9%)

 

 

79/95 (83.2%)

16/95 (16.8%)

3.8 ± 1.0

6/96 (6.3%)

 

No significant differences were noted in patient demographic and surgical-procedure characteristics. 

Results

Endpoint

Cangrelor
(n= 106)

Placebo
(n= 101)

OR (95% CI)

Values < 240 PRU during the entire preoperative infusion period 

98.8% (83/84) 19.0% (16/84) (RR 5.2; 3.3 to 8.1)

CABG-related bleeding from CABG procedure through hospital discharge

Protocol defined

Surgical reexploration

Chest tube output (24 h) > 1.5 L

Incidence of PRBC transfusions > 4 units

BARC defined

Fatal bleeding

Perioperative intracranial bleeding within 48 h

Reoperation after sternotomy closure to control bleeding

Transfusion of 5 units of whole blood or PRBC within 48-h period

Chest tube output 2 L within 24-h period

 

12/102 (11.8%)

2/102 (2.0%)

8/102 (7.8%)

6/102 (5.9%)

10/102 (9.8%)

0/102 (0.0)

0/102 (0.0)

2/102 (2.0%)

7/102 (6.9%)

3/102 (2.9%)

 

10/96 (10.4%)

2/96 (2.1%)

5/96 (5.2%)

8/96 (8.3%)

10/96 (10.4%)

0/96 (0.0)

0/96 (0.0)

2/96 (2.1%)

8/96 (8.3%)

4/96 (4.2%)

 

1.15 (0.47-2.79)

0.94 (0.13-6.81)

1.55 (0.49-4.91)

0.69 (0.23-2.06)

0.93 (0.37-2.36)

NA

NA

0.94 (0.13-6.81)

0.81 (0.28-2.33)

0.70 (0.15-3.20)

Multivariate analyses of major and minor bleeding showed that the adjusted OR for the effect of cangrelor on preoperative major and minor bleeding was 2.12 (95% CI, 0.78-5.76; p= 0.139).

Commonly encountered postoperative cardiac, gastrointestinal, infection, pain, psychiatric, renal, and respiratory events were not significantly different between the two groups. 

BARC, Bleeding Academic Research Consortium; CI, confidence interval; OR, odds ratio; PRBC, packed red blood cells; RR, relative risk. 

Adverse Events

Common Adverse Events: any events (preprocedure 30.2% vs 28.7%, p= 0.816; postprocedure 57.8% vs 55.9%, p= 0.827); ischemic event (2.8% vs 4.0%) 

Serious Adverse Events: pre- and postprocedure (10.4% vs 8.9%, p= 0.721)

Percentage that Discontinued due to Adverse Events: pre- and postprocedure (5.7% vs 3%, p= 0.499)

Study Author Conclusions

Bridging patients with cangrelor before CABG effectively maintains platelet inhibition without significantly increasing pre- or postoperative bleeding, thrombotic or other complications, or perioperative transfusions. Use of cangrelor appears to be a viable clinical strategy for balancing the need for sustained platelet inhibition with minimizing any undue risk of bleeding or postoperative complications in patients awaiting surgery.

InpharmD Researcher Critique

Besides cangrelor, certain preoperative management was at treating physicians' discretion, which may confound the study results. Additionally, some patients in the placebo group also exhibited adequate platelet inhibition at the time of surgery, indicating an incomplete wash-out from previous antiplatelet regimens. 



References:

Firstenberg MS, Dyke CM, Angiolillo DJ, et al. Safety and efficacy of cangrelor, an intravenous, short-acting platelet inhibitor in patients requiring coronary artery bypass surgery. Heart Surg Forum. 2013;16(2):E60-E69. doi:10.1532/HSF98.20121103

 

Use of Cangrelor in Cervical and Intracranial Stenting for the Treatment of Acute Ischemic Stroke: A “Real Life” Single-Center Experience

Design

Single-center, retrospective chart review

N= 38

Objective

To report a single-center experience about the effects of periprocedural IV administration of this drug in patients with AIS due to intracranial or cervical artery occlusion, who needed stent placement

Study Groups

All patients (N= 38)

Inclusion Criteria

Having acute ischemic stroke (AIS); underwent an endovascular procedure requiring acute stent implantation; were treated with periprocedural administration of cangrelor; needed either extracranial or intracranial stent placement, both in the anterior and posterior circulations 

Exclusion Criteria

Not explicitly specified

Methods

If no intrastent thrombosis occurred, cangrelor administration was avoided. On the other hand, in the case of intrastent thrombosis, a 30-mcg/kg bolus of cangrelor was administered, followed by a 4.0-mcg/kg/min intravenous (IV) infusion, until the transition to the oral P2Y12 inhibitor ticagrelor was deemed possible according to the treating physician. A loading dose of ticagrelor, 180 mg, was administered 30 minutes before cangrelor infusion was discontinued.

The postprocedural dual-antiplatelet therapy was performed with ticagrelor 90 mg twice a day, and aspirin 100 mg except for individualized modifications.

Duration

Between January 2019 and April 2020

Outcome Measures

Occurrence of in-stent thrombosis, the evidence of intracerebral hemorrhage (ICH) 

Baseline Characteristics

 

All patients (N= 38)

Age (range), years

64 (26 to 85)

Male

25 (65.8%)

Carotid artery stent placement

Intracranial stent implantation

26 (68.4%)

12 (31.6%)

Results

Endpoint

All patients (N= 38)

Stent occlusion

1 (2.6%)

Intracerebral hemorrhage*

4 (10.5%)

*Basal ganglia reperfusion ICH occurred in 4 patients leading to switching to ticagrelor oral antiplatelet therapy.

No new hemorrhagic complications, either systemic or intracranial, occurred in the first postprocedural week.

In 2 patients (5.2%), a vessel perforation with minimal subsequent subarachnoid hemorrhage occurred, but it was stable after the end of the procedure.

Adverse Events

See results

Study Author Conclusions

Results are in line with other preliminary observations suggesting that cangrelor might be a valuable therapeutic option in the management of emergency neuroendovascular interventions, given its efficacy in rapid platelet function inhibition and its fast resolution in cases of hemorrhagic complications. 

InpharmD Researcher Critique

This study is limited based on its retrospective, single-center nature with a short follow-up period and lack of a comparator group. Additionally, the patients who were treated with oral anticoagulants were under-represented which limits the generalizability of the results.



References:

Cervo A, Ferrari F, Barchetti G, Quilici L, Piano M, Boccardi E, Pero G. Use of Cangrelor in Cervical and Intracranial Stenting for the Treatment of Acute Ischemic Stroke: A "Real Life" Single-Center Experience. AJNR Am J Neuroradiol. 2020 Nov;41(11):2094-2099. doi: 10.3174/ajnr.A6785. Epub 2020 Oct 8. PMID: 33033047; PMCID: PMC7658814.