Does ticagrelor need to bridge to cangrelor IV prior to urology procedure? Or can ticagrelor simply be on hold prior to procedure?

Comment by InpharmD Researcher

The decision of whether to simply hold ticagrelor or to engage in bridge therapy with cangrelor likely depends on a variety of factors including cardiovascular risk of the individual patient and invasiveness of the urologic procedure. When possible, non-urgent procedures should be delayed until dual-antiplatelet therapy (DAPT) is complete. If a planned urological procedure is deemed necessary during DAPT, ticagrelor should be held for approximately 5 days before a major urology procedure such as a biopsy or surgery. The majority of evidence for cangrelor bridging is in cardiac procedures with the usual P2Y12 receptor inhibitor being clopidogrel. However, bridging any antiplatelet therapy may be warranted for a variety of procedures to minimize ischemic and bleeding events. When bridging with cangrelor, a consensus statement published in the journal Circulation recommends waiting up to 2 -3 days after ticagrelor discontinuation to minimize the duration of cangrelor infusion. Cangrelor can be initiated at the dose of 0.75 mcg/kg/minute through IV administration until 1 to 6 hours before surgery. Signs and symptoms of bleeding should be monitored during therapy and the procedure. Reinitiate DAPT as soon as possible post-surgery. Product labeling for ticagrelor recommends restarting with a 180 mg oral loading dose.

Background

An International Expert Consensus on Switching Platelet P2Y12 Receptor–Inhibiting Therapies from American Heart Association strategically addressed bridging from oral agent to cangrelor intravenous (IV) therapy. For patients undergoing noncardiac procedures, the decision to hold and bridge P2Y12-inhibiting therapy should involve the timing and bleeding risk associated with the specific procedures in each individual. If bridging with cangrelor is indicated, it is reasonable to wait up to 2 to 3 days after ticagrelor discontinuation to minimize the duration of cangrelor infusion. If necessary, platelet function testing may be considered as guidance for cangrelor bridging initiation. Unlike that observed with thienopyridines, no interaction was shown for the transition from cangrelor to ticagrelor, allowing more versatile use of ticagrelor with respect to the timing of administration in relation to the start of cangrelor therapy. Ticagrelor reversibly binds the P2Y12 receptor at a site distinct from the ADP-binding site and has a half-life of 6 to 12 hours. Although it is unknown whether ticagrelor can bind with the P2Y12 receptor during cangrelor infusion, its half-life (which exceeds that of the duration of cangrelor infusion) is such that drug is still systemically available to bind with the P2Y12 receptor after discontinuation of cangrelor infusion. On the basis of these observations, ticagrelor can be administered before, during, or after cangrelor infusion. After noncardiac surgery, to minimize the risk of severe postoperative bleeding events, restarting oral antiplatelet (preferably clopidogrel) with a loading dose is recommended as soon as oral administration is possible. Authors also note ticagrelor administration should be discouraged after noncardiac surgery when ongoing risk of serious bleeding is suspected. [1]

Although ticagrelor binds reversibly to platelets, it must be discontinued 3-7 days prior to procedures due to its high potency for platelet inhibition. Until relatively recently, eptifibatide and tirofiban have been the mainstay of bridging therapy prior to procedures. Even though cangrelor is not FDA-approved for bridge therapy, it has become a promising alternative, especially in high-risk, peri-procedural patients. Studies have shown cangrelor failed to demonstrate a significant increase in bleeding risk when P2Y12 inhibitors were stopped and IV cangrelor bridge therapy was used between five and seven days pre-procedurally. Due to cangrelor’s ability to achieve a 90% level of platelet inhibition within 5 minutes and reach steady-state within 15 minutes, it is an ideal option as a bridging agent. [2]

Relevant Prescribing Information

Cangrelor (KENGREAL): [3]

Transitioning Patients to Oral P2Y12 Therapy

To maintain platelet inhibition after discontinuation of cangrelor infusion, administer an oral P2Y12 platelet inhibitor, as described below:

Ticagrelor: 180 mg at any time during cangrelor infusion or immediately after discontinuation

In clinical trials cangrelor has been co-administered with bivalirudin, low molecular weight heparin, clopidogrel, prasugrel, and ticagrelor without clinically detectable interactions.

The antiplatelet effect of a 180 mg ticagrelor loading dose was not altered significantly when ticagrelor was administered during cangrelor infusion. Administration of ticagrelor, a reversible P2Y12 platelet inhibitor, during the cangrelor infusion led to minimal decrease in platelet inhibition for approximately 0.5 hour following discontinuation of the cangrelor infusion. Administering ticagrelor during cangrelor infusion does not attenuate the anti-platelet effect of ticagrelor.

Ticagrelor (BRILINTA): [4]
Discontinuation of Ticagrelor will increase the risk of myocardial infarction, stroke, and death in patients being treated for coronary artery disease. If BRILINTA must be temporarily discontinued (e.g., to treat bleeding or for significant surgery), restart it as soon as possible. When possible, interrupt therapy with BRILINTA for five days prior to surgery that has a major risk of bleeding. Resume BRILINTA as soon as hemostasis is achieved.

Literature Review

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

Does Brilinta need to bridge to Cangrelor IV prior to urology procedure? Or can Brilinta simply be on hold prior to procedure?

Level of evidence

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

Please see Tables 1-2 for your response.

Bridging Antiplatelet Therapy with Cangrelor in Patients Undergoing Cardiac Surgery: a Randomized Controlled Trial
Design	Prospective, randomized, double-blind, placebo-controlled, multicenter trial N= 210
Objective	To evaluate the use of cangrelor, an intravenous, reversible P2Y12 platelet inhibitor for bridging thienopyridine-treated patients to coronary artery bypass grafting (CABG) surgery
Study Groups	Cangrelor (n= 106) Placebo (n= 101)
Inclusion Criteria	Patients at least 18 years of age planned to undergo nonemergency CABG surgery were eligible to be enrolled. All patients had to have 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, or bare-metal stents. Coronary artery bypass grafting surgery, either on-pump or off-pump, had to occur no sooner than 48 hours but no longer than 7 days from randomization, with patients hospitalized until planned CABG surgery.
Exclusion Criteria	Unverifiable factors for inclusion. Patients who did not receive study drug or primary outcome test (measured in P2Y12 reaction units [PRUs]) and unblinded participants were excluded from efficacy endpoint but not safety endpoints.
Methods	Thienopyridines (at least 500 mg ticlopidine, 75 mg of clopidogrel, or 10 mg of prasugrel) were stopped and patients were administered cangrelor or placebo for at least 48 hours, which was discontinued 1 to 6 hours before CABG surgery. The study was conducted in two stages. The first aimed to identify the dose of cangrelor that would achieve 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 predetermined doses (0.5 µg/kg, 0.75 µg/kg, 1.0 µg/kg, and 1.5 µg/kg per minute) until percent platelet inhibition as measured by VerifyNow P2Y12 (Accumetrics) was greater than 60% in 80% of daily samples or a dose of 2.0 µg/kg per minute was reached. Stage 2 was a prospective, randomized, double-blind, placebo-controlled phase of the study enrolling patients independent of stage 1 conducted between October 2009 and April 2011. The aim was to assess whether a cangrelor IV infusion (at the dose determined in stage I) would maintain levels of platelet reactivity of less than 240 P2Y12 Reaction Units (PRUs) throughout the preoperative period as measured by the VerifyNow P2Y12 assay. This level approximated the levels of platelet reactivity expected to be maintained if a thienopyridine had not been discontinued. Patients generally waited 5 days after discontinuation of ticlopidine and clopidogrel, and 7 days after prasugrel, before undergoing surgery in accordance with practice guidelines. However, the timing of surgery was left to the discretion of the investigator with a minimum of 48 hours and an allowed maximum of 7 days of study drug infusion.
Duration	January 2009 - April 2011. Patients were observed for up to 30 days post-surgery for some safety endpoints (death, myocardial infarction [MI], stroke, drug discontinuation)
Outcome Measures	The primary efficacy endpoint was platelet reactivity (measured in P2Y12 reaction units [PRUs]), assessed daily. The main safety endpoint was excessive CABG surgery-related bleeding.
Baseline Characteristics		Cangrelor	Placebo
	Age, median (IQR), years	65.0 (42-84)	62.0 (39-89)
	Female (%)	26 (24.5)	27 (26.7)
	White (%)	93 (87.7)	94 (93.1)
	Last thienopyridine therapy (%) Clopidogrel Prasugrel Ticlopidine	105 (99.1) 1 (0.9) 0 (0.0)	93 (92.1) 8 (7.9) 0 (0.0)
	The median time from thienopyridine discontinuation to study drug infusion was 29.1 hours (interquartile range [IQR], 11-38 hours) in the cangrelor group and 29.5 hours (IQR, 14-39 hours) in the placebo group (Wilcoxon, P= 0.80) The median duration of infusion was 2.8 days (IQR, 2.5-3.8 days) for cangrelor vs 3.4 days (IQR, 2.6-4.7 days) for placebo (Wilcoxon, P= 0.046). The median time from discontinuation of study drug infusion to surgical incision was 3.2 hours (IQR, 2-5 hours) in the cangrelor group and 3.2 hours (IQR, 2-5 hours) in the placebo group (Wilcoxon, P= 0.82).
Results	Endpoint	Cangrelor	Placebo	p-Value
	Platelet reactivity PRU< 240	98.8% (83 of 84)	19.0% (16 of 84)	Relative risk [RR], 5.2 [95% CI, 3.3-8.1] P< 0.001)
	Excessive CABG surgery–related bleeding	11.8% (12 of 102)	10.4% (10 of 96)	RR, 1.1 [95% CI, 0.5-2.5] P= 0.763)
	Note: The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 µg/kg per minute.
Adverse Events	Adverse Events: There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.
	Serious Adverse Events: Authors report adverse events were similar between groups (raw data not disclosed)
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	In this trial, cangrelor achieved and maintained target levels of platelet inhibition known to be associated with a low risk of thrombotic events compared with placebo, without a significant excess in bleeding complications. Our data support the hypothesis that intravenous cangrelor is a feasible management strategy in patients waiting for cardiac surgery who require prolonged platelet P2Y12 inhibition after thienopyridine discontinuation.
InpharmD Researcher Critique	This trial only enrolled patients undergoing open-heart surgery and did not assess the strategy for common noncardiac surgical procedures as different noncardiac operations have variable bleeding risk. Furthermore, whether similar outcomes would be achieved with cangrelor in patients with prior exposure to ticagrelor cannot be extrapolated from this analysis.

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

Antiplatelet Therapy with Cangrelor in Patients Undergoing Surgery after Coronary Stent Implantation: A Real-World Bridging Protocol Experience
Design	Prospective, observational, multicenter registry N= 24
Objective	To describe the real-world use of the P2Y12 inhibitor cangrelor as a bridging strategy in patients at high thrombotic risk after percutaneous coronary intervention (PCI) and referred to surgery requiring perioperative withdrawal of dual antiplatelet therapy (DAPT)
Study Groups	DAPT agent before bridge therapy. (Note: No comparative statistics between groups were attempted in study.) Ticagrelor (n= 14) Clopidogrel (n= 9) Prasugrel (n= 1)
Inclusion Criteria	Collected data from nine Italian centers on patients with previous PCI who were still on DAPT and undergoing nondeferrable surgery requiring DAPT discontinuation.
Exclusion Criteria	N/A
Methods	A standardized bridging protocol using cangrelor infusion before and eventually after surgery was reserved for patients deemed at high thrombotic risk undergoing nondeferrable surgery at intermediate to high risk of bleeding, which requires a predictable interruption of platelet inhibition at the time of surgery. Clopidogrel and ticagrelor were discontinued for 5 days before surgery, while prasugrel was discontinued for 7 days. In line with expert consensus recommendation, cangrelor at a bridging dose regimen (0.75 μg/kg/min infusion without a bolus) was initiated 2 to 3 days following clopidogrel and ticagrelor discontinuation and 3 to 4 days after prasugrel discontinuation. Cangrelor infusion was discontinued up 1 to 10 hours before surgery. Since thrombotic complications occur most frequently soon after surgery, close clinical and electrocardiographic monitoring in an intensive care unit was emphasized in the postoperative period. Complete blood count assessments were performed daily to monitor hemoglobin levels. Once successful hemostasis was achieved, oral P2Y12 inhibiting therapy was resumed within 24 to 48 hours. Clopidogrel was preferred over prasugrel or ticagrelor in this setting of increased bleeding risk patients. Clinical events during the perioperative phase (up to 48 hours from surgery) and at 30-days follow-up were prospectively collected.
Duration	Study ran from December 2017 to April 2019. All efficacy and safety endpoints were collected during the perioperative phase (evaluated within 48 hours from surgery) and at 30 days follow-up.
Outcome Measures	Average time of P2Y12 inhibitor discontinuation, start of cangrelor infusion (0.75 µg/kg/min), discontinuation of cangrelor infusion
Baseline Characteristics	Mean age, years	72 ± 9
	Male	79%
	Average time from PCI to surgery, days	80 ± 136
	DAPT agent (%) Ticagrelor Clopidogrel Prasugrel	58% (n= 14) 38% (n= 9) 4% (n= 1)
	All patients (100%) were also on aspirin 100 mg daily. Approximately 60% of patients were undergoing a non-cardiac procedure.
Results	Endpoint	p-Value
	Average time of P2Y12 inhibitor discontinuation	4.5 ± 1.7 days prior to surgery
	Start of cangrelor infusion (0.75 µg/kg/min)	2.9 ± 0.9 days before planned surgery
	Discontinuation of cangrelor infusion	6.6 ±1.5 hours prior to surgical incision
	In 55% of patients, cangrelor was resumed within 24 hours from surgery (mean time 8.6 6.1 hours) for a mean of 39 38 hours.
Adverse Events	Common Adverse Events: The average hemoglobin drop was 1.8 g/dL. Nine patients required periprocedural blood transfusions which was consistent with the type of surgery performed. One-third of patients experienced periprocedural moderate bleeding events.
	Serious Adverse Events: One cardiac death occurred due to fatal ST-elevation MI at 3 hours after cangrelor discontinuation.
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	Perioperative bridging therapy with cangrelor is a feasible approach for stented patients at high thrombotic risk and referred to surgery requiring DAPT discontinuation. Larger studies are warranted to support the safety of this strategy.
InpharmD Researcher Critique	The nonexperimental design, especially without a control, is a substantial limitation. However, this study is one of the few to include patients on ticagrelor and detail a potential approach to bridge therapy. Approximately 20% of patients underwent a urologic procedure (prostatectomy, bladder surgery). However small sample size (and even small subgroups of ticagrelor with urologic procedures), as well as an international setting, may hinder applicability to U.S. facilities or to the specific population in question.

References:

Rossini R, Masiero G, Fruttero C, et al. Antiplatelet Therapy with Cangrelor in Patients Undergoing Surgery after Coronary Stent Implantation: A Real-World Bridging Protocol Experience. TH Open. 2020;4(4):e437-e445. doi:10.1055/s-0040-1721504