What is the evidence for using an IV IIb/IIIa inhibitor as bridge therapy while off oral P2Y12 inhibitors (in setting of very recent PCI <1 month)?

Comment by InpharmD Researcher

There is a paucity of data to support the use of GPIIb/IIa inhibitors as acute bridge therapy following PCI (<1 month) for patients not on oral P2Y12 inhibitor therapy. In general, data to support the use of GPIIb/IIa inhibitors in patients with myocardial infarction was established largely before the use of oral DAPT. Additionally, data evaluating their use in the setting of PCI is limited to administration either prior to or during PCI, rather than following the procedure, to ensure coverage during surgery; GPIIb/IIa inhibitors are typically discontinued 6 hours following surgery.

Background

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Guidelines for the management of ST-elevation myocardial infarction (STEMI), published in 2013, recommend treatment with an intravenous (IV) GPIIb/IIIa receptor antagonist such as abciximab, high-bolus-dose tirofiban, or double-bolus eptifibatide at the time of primary percutaneous coronary intervention (PCI), with or without stenting or clopidogrel pretreatment, in selected patients with STEMI who are receiving unfractionated heparin (UFH). In general, evidence to support the use of IV GPIIb/IIIa receptor antagonists in patients with STEMI was established largely before the use of oral dual antiplatelet therapy (DAPT). Although several studies have failed to show a benefit with the administration of “upstream” GP IIb/IIIa receptor antagonists before primary PCI in the setting of DAPT with either UFH or bivalirudin anticoagulation, a meta-analysis suggests abciximab may be useful in this setting. There is a lack of guidance regarding the use of GPIIb/IIa inhibitors in patients unable to tolerate oral medications immediately following PCI with drug-eluting stent (DES). [1]

According to the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of non-ST-elevation acute coronary syndromes, GP IIB/IIIa inhibitors are generally recommended to be administered at the time of PCIs. The use of GP IIb/IIIa directly after a PCI due to NPO status is not addressed. Their usefulness is based on the premise that patients may not be adequately treated with antiplatelets prior to PCI with the purpose of ensuring patients are adequately covered during surgery. [2]

The 2022 European Society of Cardiology (ESC) guidelines for management of patients undergoing non-cardiac surgery (NCS) state that bridging dual antiplatelet therapy (DAPT) with intravenous (IV) compounds (eptifibatide/tirofiban or cangrelor) is generally not recommended except in rare cases where DAPT cannot be interrupted in emergent or time-sensitive NCS. These include, but are not limited to, patients with very high risk of stent thrombosis, history of recurrent myocardial infarction (MI), or recent percutaneous coronary intervention (PCI). When bridging is indicated, tirofiban/eptifibatide should be initiated 3 days before NCS at the recommended doses: Tirofiban: 0.1 μg/kg/min IV; reduce to 0.05 mcg/kg/min if CrCl <50 mL/min; eptifibatide: 2.0 mcg/kg/min IV; reduce to 1.0 mcg/kg/min if CrCl <50 mL/min. Afterward, oral P2Y12 inhibitor may recommence, or IV infusion may continue until oral therapy is possible. Throughout the bridging, patients should remain on low-dose acetylsalicylic acid. [3]

In general, available literature in the setting of PCI appears to only discuss the use of GPIIb/IIa inhibitors with respect to pretreatment before the PCI. The evidence for GPIIb/IIa inhibitors predates use of routine oral DAPT and early invasive treatment. While early trials demonstrated a reduction in ischemic events in favor of GPIIb/IIa inhibitors in combination with UFH compared with UFH alone, a consistent major bleeding risk was seen. Overall, there is a lack of evidence to support the benefit of routine upstream GPIIb/IIa inhibitors in patients scheduled for PCI receiving DAPT treatment. Additionally, there is a lack of data to support the use of these agents in patients who cannot tolerate oral meds (i.e., DAPT) following PCI. [4], [5], [6]

Background References: [1] O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2013;82(1):E1-E27. doi:10.1002/ccd.24776
[2] Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2014 Dec 23;130(25):e433-4. Dosage error in article text]. Circulation. 2014;130(25):e344-e426. doi:10.1161/CIR.0000000000000134
[3] Halvorsen S, Mehilli J, Cassese S, et al. Linee guida ESC 2022 per la valutazione cardiovascolare e la gestione dei pazienti sottoposti a chirurgia non cardiaca elaborate dalla task force per la valutazione cardiovascolare e la gestione dei pazienti sottoposti a chirurgia non cardiaca della Società Europea di Cardiologia (ESC) con il patrocinio della European Society of Anaesthesiology and Intensive Care (ESAIC) [2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery Developed by the task force for cardiovascular assessment and management of patients undergoing non-cardiac surgery of the European Society of Cardiology (ESC) Endorsed by the European Society of Anaesthesiology and Intensive Care (ESAIC)]. G Ital Cardiol (Rome). 2023;24(1 Suppl 1):e1-e102. doi:10.1714/3956.39326
[4] Zaman AG, Aleem Q. Pharmacology before, during and after percutaneous coronary intervention. Heart. Published online November 4, 2020. doi:10.1136/heartjnl-2019-315090
[5] Howard JP, Jones DA, Gallagher S, et al. Glycoprotein IIb/IIIa inhibitors use and outcome after percutaneous coronary intervention for non-ST elevation myocardial infarction. Biomed Res Int. 2014;2014:643981. doi:10.1155/2014/643981
[6] Blanchart K, Heudel T, Ardouin P, et al. Glycoprotein IIb/IIIa inhibitors use in the setting of primary percutaneous coronary intervention for ST elevation myocardial infarction in patients pre-treated with newer P2Y12 inhibitors. Clin Cardiol. 2021;44(8):1080-1088. doi:10.1002/clc.23654
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for using an IV IIb/IIIa inhibitor as bridge therapy while off oral P2Y12 inhibitors (in setting of very recent PCI <1 month)?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

Safety and Efficacy of Periprocedural Bridging With Cangrelor Versus Eptifibatide

Design

Single-center retrospective chart review

N= 75

Objective

To assess the safety and efficacy of cangrelor compared with eptifibatide when used in a periprocedural setting

Study Groups

Cangrelor (n= 50)

Eptifibatide (n= 25)

Inclusion Criteria

Adult patients admitted to an inpatient unit who received cangrelor or eptifibatide as a bridge to a surgery or procedure; received at least 1 maintenance dose of an oral P2Y12 inhibitor for stent implantation within the past 12 months (e.g., 75 mg clopidogrel daily, 10 mg prasugrel daily, or 90 mg of ticagrelor BID)

Exclusion Criteria

Cangrelor or eptifibatide used for any indication outside of bridging for coronary stent implantation (e.g., treatment of acute coronary syndrome or substitution of oral therapy due to poor gastrointestinal absorption or strict nothing by mouth protocol); documented allergy to study medications; mechanical circulatory support devices, including extracorporeal membrane oxygenation, Impella devices, HeartMate 3 left ventricular assist device, or Tandemlife ProteKDuo devices

Methods

Electronic medical records were retrospectively reviewed to identify eligible patients and collect relevant baseline characteristics, pertinent information on use of P2Y12 inhibitors before bridging, and hours between oral agent discontinuation and bridging agent initiation. 

Specific bridging P2Y12 inhibitor protocol required discontinuation of clopidogrel or ticagrelor 5 days and prasugrel 7 days prior to procedure (s). Patients were then initiated on intravenous (IV) bridge agent 3 days prior to procedure(s). In patients with high risk of bleeding requiring rapid reversal and/or renal dysfunction, cangrelor was given as 0.75 mcg/kg/min IV infusion without a bolus. For those with low risk of bleeding not requiring rapid reversal and/or have normal renal function, eptifibatide was administered at 2 mcg/kg/min (max: 15 mg/hr) if creatinine clearance (CrCl) was ≥50 mL/min and at 1 mcg/kg/min (max: 7.5 mg/hr) if CrCl was 30-50 mL/min. Cangrelor and eptifibatide was discontinued 1 to 6 hours and 4 to 6 hours prior to surgeries. Reinitiation of oral P2Y12 inhibitors was based on oral administration status and surgical risks. 

Duration

Follow-up: During hospitalization

Outcome Measures

Primary: Incidence of bleeding as defined by the global use of strategies to open occluded coronary arteries (GUSTO) criteria

Severe: bleeding resulting in substantial hemodynamic compromise requiring treatment

Moderate: required blood transfusions without hemodynamic compromise

Mild: bleeding that did not meet the criteria for severe or moderate bleeding

Secondary: Transfusion requirements (units of packed red blood cells, fresh frozen plasma, and platelets) during preoperative, intraoperative, and postoperative time periods and in-hospital MACE (defined as coronary revascularization, definite stent thrombosis, MI, stroke, or death 

Baseline Characteristics

  

Cangrelor (n= 50)

Eptifibatide (n= 25)

  

Age, years

 67 67  

Female

18%  20%  

White

 80% 92%  

Weight, kg

 83.4 81.9  

Comorbidities 

Coronary artery disease

Stroke or TIA*

Surgery or major bleed (1 yr)

 

100%

16%

18%

 

100%

0

16%

  

CrCl, mL/min*

 71 93.4  

Renal replacement therapy*

 18% 0  

Oral antiplatelet 

Clopidogrel 

Prasugrel 

Ticargrelor 

Concomitant aspirin

 

62%

4%

34%

94%

 

48%

12%

40%

73%

  

Cardiac surgery planned 

CABG

Valve replacement

Device replacement

Heart transplant

 

16%

8%

4%

6 %

 

24%

20%

16%

0

  

Indication of stent 

STEMI

NSTE-ACS

 

32%

28%

 

40%

16%

  

Duration of DAPT <3 mo

 60% 73%  

Concomitant therapeutic anticoagulant 

 26% 24%  

CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; NSTE-ACS, non-ST-elevation acute coronary syndromes; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischemic attack 

*p< 0.05

Results

Endpoint

Cangrelor (n= 50)

Eptifibatide (n= 25)

p-value

GUSTO bleeding criteria

Mild 

Moderate 

Severe

 

4 (8%)

14 (28%)

4 (8%)

 

2 (8%)

12 (48%)

2 (8%)

 

0.68

0.07

0.25

Composite MACE

5 (10%)

2 (8%)

 0.78

Transfusion requirements

Perioperative 

Intraoperative 

Postoperative

 

6 (12%)

6 (12%)

13 (26%)

 

3 (12%)

8 (32%)

10 (40%)

 

N/A

< 0.05

0.22

Duration of bridging therapy, hrs

 77 ± 52 87 ± 47 0.42

Time from last oral dose to initiation of infusion, hr

 49 ± 31

36 ± 44

 0.18 

Length of stay, d 

 18 ± 20 20 ± 21 0.71 

Length of intensive care unit stay, d

 9 ± 14 11 ± 12  0.69 

A cost savings analysis in patients from the cangrelor cohort who could have been started on eptifibatide alternatively without clear contraindications to eptifibatide, such as renal dysfunction (CrCl <50 mL/min) or deemed high bleeding risk that required a shorter onset and offset of therapy, resulted in cost savings of approximately $5,824 per patient.

Adverse Events

 See results 

Study Author Conclusions

Cangrelor and eptifibatide were similar in terms of safety and efficacy when used as a bridge in patients with recent coronary stents, but considerable cost savings could be made if cangrelor was substituted for by eptifibatide in select patients. Further studies are needed to determine its applicability specifically in patients at high thrombotic and hemorrhagic risk.

InpharmD Researcher Critique

The findings are subject to inherent limitations of single-center and retrospective experiences, such as incomplete chart review. As the choice of one agent over the other is mainly based on providers' preferences, clinical rationale or use criteria is not clearly documented within the medical records. 

 

Table 1 References:
[7] Yun AN, Toyoda AY, Solomon EJ, Roberts RJ, Ji CS. Safety and Efficacy of Periprocedural Bridging With Cangrelor Versus Eptifibatide. J Cardiovasc Pharmacol. 2022;79(3):383-389. doi:10.1097/FJC.0000000000001192

Outcomes of a Preoperative “Bridging” Strategy with Glycoprotein IIb/IIIa Inhibitors to Prevent Perioperative Stent Thrombosis in Patients with Drug-Eluting Stents who Undergo Surgery Necessitating Interruption of Thienopyridine Administration

Design

Retrospective, observational, cohort study 

N= 67

Objective

To evaluate the outcomes of patients who underwent surgery after the implantation of drug-eluting stents (DES) and received preoperative "bridging" with a glycoprotein IIb/IIIa inhibitor

Study Groups

Non-cardiac surgery (n= 51)

Cardiac surgery (n= 16) 

Inclusion Criteria

Male patients who required surgery after DES implantation, high prevalence of atherosclerosis risk factors, and elevated risk for perioperative stent thrombosis

Exclusion Criteria

Not meeting the inclusion criteria 

Methods

Patients at elevated risk for perioperative stent thrombosis (recent stent placement within 12 months, specific coronary artery stenting, diabetes, bifurcation stenting, or prior stent thrombosis) underwent "bridging" with glycoprotein IIb/IIIa inhibitors. Before surgery, clopidogrel was stopped for 5 to 7 days. Patients then received intravenous (IV) glycoprotein IIb/IIIa inhibitors (eptifibatide or tirofiban), dosed based on renal function. Eptifibatide was administered as an IV bolus of 180 mcg/kg, followed by a continuous infusion of 2 mcg/kg/min. For patients with creatinine clearance < 50 ml/min, the infusion rate was reduced to 1 mcg/kg/min. Tirofiban was given at 0.4 mcg/kg/min over 30 minutes, followed by 0.1 mcg/kg/min for patients with normal renal function. In cases of creatinine clearance < 30 ml/min, the tirofiban dose was reduced by 50%. The infusion was discontinued 4 to 6 hours prior to surgery. 

Post-surgery, patients were given a 600 mg clopidogrel loading dose, followed by 75 mg daily. If clopidogrel couldn't be resumed, glycoprotein IIb/IIIa infusion recommenced for up to 6 hours after clopidogrel restart.

Continuous monitoring included cardiac and hemodynamic tracking. Electrocardiograms (ECGs) and cardiac biomarkers were assessed every 12 hours, or sooner if needed. Stent thrombosis used Academic Research Consortium criteria and significant bleeding employed Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria.

Duration

2008 to 2010 

Outcome Measures

Stent thrombosis proven by coronary angiography, probable stent thrombosis, blood loss, decrease in hemoglobin level, major bleeding using GUSTO criteria, in-hospital mortality, and time to hospital discharge 

Baseline Characteristics

  

Non-cardiac surgery (n= 51)

Cardiac surgery (n= 16) 

Age, years

 65 ± 1 64 ± 3

Men

 51 (100%) 16 (100%)

Hypertension

 46 (90%) 13 (81%)

Hyperlipidemia

 45 (88%) 13 (81%)

Diabetes mellitus

 22 (43%) 7 (44%)

Prior coronary artery bypass graft surgery

 11 (22%) 0

Indication for percutaneous coronary intervention (PCI)

Stable angina

Acute coronary syndrome 

Other 

 

12 (24%)

31 (61%)

8 (15%)

 

6 (38%)

9 (56%)

1 (6%)

Eptifibatide

 49 (96%) 13 (81%)

Tirofiban

 2 (4%) 3 (19%)

Duration of bridging, days

 7.1 ± 0.4  7.8 ± 0.7

Duration of clopidogrel interruption, days

 8.0 ± 0.4 11.8 ± 1.3

Aspirin continued perioperatively

 33 (65%) 15 (94%)

Results

Endpoint

Non-cardiac surgery (n= 51)

Cardiac surgery (n= 16) 

Stent thrombosis proven by coronary angiography

 2 (3.9%) 0

Probable stent thrombosis

 0 1 (6%)

Mean blood loss, mL

 132 ± 56  716 ± 109

Mean decrease in hemoglobin level, g/dL

 0.4 ± 0.1 1.7 ± 0.3

Major bleeding using the GUSTO criteria

 2 (4%) 0

In-hospital mortality

 2 (4%) 1 (6%)

Mean time to hospital discharge, days 

 2.0 ± 0.3  8.9 ± 0.8

Adverse Events

In the non-cardiac surgery group, four patients (7.8%) experienced bleeding complications (two moderate and two severe). Two patients had epistaxis, one before lung biopsy (did not require transfusion) and one following nasopharyngeal mass excision (required two units of red blood cells). The third patient had haemoperitoneum following a liver biopsy and was treated with a transfusion of three units of red blood cells; he expired after a prolonged hospital course secondary to sepsis. The fourth patient had gastrointestinal bleeding following sigmoidectomy and was treated with a transfusion of three units of red blood cells. 

Study Author Conclusions

In spite of preoperative “bridging” with a glycoprotein IIb/IIIa inhibitor, postoperative stent thrombosis can still occur in patients with prior DES undergoing surgery requiring antiplatelet medication interruption.

InpharmD Researcher Critique

One limitation of this study is the retrospective nature of the analysis, which might have introduced biases in data collection, patient selection, and outcome assessment. Additionally, this study was comprised of a relatively small number of patients, which could impact the generalizability of these findings.

 

 

Table 2 References:
[8] Alshawabkeh LI, Prasad A, Lenkovsky F, et al. Outcomes of a preoperative "bridging" strategy with glycoprotein IIb/IIIa inhibitors to prevent perioperative stent thrombosis in patients with drug-eluting stents who undergo surgery necessitating interruption of thienopyridine administration. EuroIntervention. 2013;9(2):204-211.