Use of intravenous cangrelor and stenting in acute ischemic stroke interventions: a new single center analysis and pooled-analysis of current studies

Abstract

Introduction

Emergent stenting of both extra- and intracranial occlusions during acute ischemic stroke procedures is complicated by the need for immediate platelet inhibition to prevent thromboembolic complications. IV cangrelor is a relatively new antiplatelet that was initially approved for coronary interventions. Five prior case series have been published evaluating the results of IV cangrelor in neurointerventional procedures. We sought to combine the data from all prior studies and analyze only ischemic stroke interventions.

Methods

A prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during acute ischemic stroke intervention. Nine additional patients were identified who have not been previously published. In addition, a literature search was performed to identify five prior publications of cangrelor in neurointervention. The data from these was combined with our institution in a pooled-analysis.

Results

Overall, 129 patients who received IV cangrelor during an acute ischemic stroke intervention were identified. The asymptomatic intracranial hemorrhage rate was 12.6%(11/87). The symptomatic intracranial hemorrhage rate was 6.2% (8/129). The rate of retroperitoneal hematoma and gastrointestinal bleeding were also low (1.5% and 0.8%, 2/129 and 1/129). There was one case of intraprocedural thromboembolic complication (0.8%) and no cases of intraprocedural in-stent thrombosis(0%).

Conclusions

IV cangrelor during acute ischemic stroke intervention appears to be safe, with a symptomatic intracranial hemorrhage rate of 6.2%. More research is needed to determine the ideal dosing regimen.

Introduction

Emergent stenting of both extra- and intracranial occlusions during acute ischemic stroke procedures is complicated by the need for immediate platelet inhibition to prevent thromboembolic complications. Dual antiplatelet therapy with aspirin and an oral P2Y12 receptor inhibitor has become the standard medication regimen for non-emergent procedures. Previously, intravenous (IV) glycoprotein IIb/IIIa receptor antagonists, such as abciximab (Reopro), eptifibatide (Integrilin) and tirofiban (Aggrastat) have been used. These agents all have different onset and offset of action as well as varied platelet inhibition efficacies. ¹ Tandem occlusions have been noted to occur in 10% of ischemic stroke cases and may require cervical internal carotid artery (ICA) stenting. ² In addition, intracranial atherosclerotic disease may be present in up to 16% of cases which may require intracranial stent placement. ³

Cangrelor (Kangreal, Chiesi, Cary, NC, USA) is a relatively new IV antiplatelet agent that was initially approved for percutaneous coronary intervention (PCI) in 2015. ⁴ Cangrelor has been found to decrease myocardial infarction and in-stent thrombosis in PCI without any increase in moderate to severe bleeding when compared to clopidogrel.^5,6 Cangrelor is a direct and reversible inhibitor of the P2Y12 receptor and is typically given as a bolus followed by a maintenance infusion. Unlike clopidogrel, which is a pro-drug, cangrelor does not require transformation into active metabolites, resulting in immediate and constant platelet inhibition. Cangrelor is rapidly deactivated by dephosphorylation which results in a half-life of 3–6 minutes and platelet function is normalized within 1 hour after discontinuation.^7–9 It is typically given as a bolus followed by a maintenance infusion resulting in immediate and constant platelet inhibition. These unique pharmacodynamic features make cangrelor ideally suited for neurointerventional procedures where subsequent emergency surgery may necessitate the need to completely reverse platelet inhibition.

Five other series of IV cangrelor in neuro-intervention have previously been published, though they have all included mixed indications for cangrelor administration. We sought to clarify the results by focusing on a single indication of stenting in acute ischemic stroke and analyze all prior published data in a pooled-analysis.

Methods

A prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during acute stroke intervention. National Institute of Health Stroke Score (NIHSS) at admission and discharge were independently assessed by a vascular neurologist. The modified Rankin scale (mRS) was assessed at 90 days during follow up by a vascular neurologist or endovascular neurosurgeon.

Pre-procedure and post-procedure imaging

Our standard thrombectomy protocol includes a non-contrast brain computed tomography scan (CTH), CT angiography (CTA) of the head and neck and CT perfusion scans (CTP). Routine head CT was obtained 24 hours after tPA administration or prior to the transition to oral ticagrelor.

Stents utilized

All intracranial stenting was performed with the Enterprise (Codman & Shurtleff, Raynham, Massachusetts, USA) stent. Cervical carotid stenting was performed with the X-act stent (Abbott, Chicago, Illinois, USA) or Carotid Wall stent (Boston Scientific, Marlborough, Massachusetts, USA) with the exception of 1 case which used a Pipeline stent (Medtronic, Dublin, Ireland) and 1 case which required a Low-profile Visualized Intraluminal Support (LVIS; MicroVention, Tustin, California, USA) stent for distal lesions.

Cangrelor administration protocol

In all patients, cangrelor was administered as a 5 ug/kg bolus over 30 seconds followed by a maintenance infusion of 1.0 μg/kg/min. Our initial protocol used a maintenance dose of 0.75 μg/kg/min. However after evaluation of our preliminary results in 14 consecutive patients, the decision was made to increase the starting maintenance dose to 1 μg/kg/min. P2Y12 reactivity units (PRU) was checked at least one time during the procedure using the Verify Now assay (Accriva Diagnostics; San Diego, USA). Our institutional target ranges from 50–150. Cangrelor dose adjustments were made in 0.25 μg/kg/min increments as required with the intent to maintain the patients’ PRU within the aforementioned range. More information regarding cangrelor dose adjustments can be found in the series from Entezami et al. ¹⁰

After a CTH was obtained which did not demonstrate any hemorrhage and the patient passed their bedside swallow or had PO access, the patient was given a loading dose of oral or per tube crushed ticagrelor and the cangrelor infusion was discontinued 1 hour following administration of the loading dose. In addition, if aspirin had not been previously administered, the patient was started on 81 mg aspirin daily. Patients were maintained on oral ticagrelor and aspirin as per our usual protocol.

Primary endpoint

The primary endpoint was incidence of symptomatic intracranial hemorrhage (ICH). Secondary endpoints were intraprocedural thromboembolic complications, asymptomatic ICH, and groin puncture complications requiring surgical repair or blood transfusions.

Pooled-analysis

Two reviewers (N.F. and A.P.) independently searched PubMed database in February 2021 without restrictions on publication date or language. Search terms included “cangrelor”, “stroke”, “cerebrovascular” and “stent.” Search terms were combined using the Boolean operator “AND.”

Studies meeting the following criteria were eligible for inclusion: 1) studies with intraprocedural administration of cangrelor during a stroke intervention and 2) available data on periprocedural complications (Figure 1). We excluded studies which were duplicate reports of earlier trials (Supplement 1 includes studies that were not included).

Figure 1.

Method for selecting studies for pooled analysis.

The following information was extracted from the final set of included studies: first author’s name, year of publication, number of patients, asymptomatic intracranial hemorrhage, symptomatic intracranial hemorrhage, retroperitoneal hematoma, GI bleed, intraprocedural thromboembolic events, intraprocedural in-stent thrombosis, location of stent (i.e., intra or extra cranial), administration of IV tPA, bolus and drip rate of cangrelor, aspirin administration, P2Y12 response, and average PRU.

Results

Demographics

Twenty-five patients from our institution have received cangrelor during an acute ischemic stroke intervention. Sixteen of those cases have been previously published. ¹⁰ New data from our institution was available for 9 cases. The average age of the new patients was 56 ± 25; 68% of patients were male, and three patients (33.3%) received IV tissue plasminogen activator (tPA) prior to the endovascular intervention. Of all twenty five patients, ten (40%) had an unknown onset time. For those patients with a known symptom onset time, the median onset to puncture time was 4 hours and 20 minutes with a range from 1 hour 50 minutes to 22 hours 57 minutes. The average ASPECTS score was 8 with a range from 6 to 10. Two patients were treated for basilar occlusions and did not have an ASPECT score calculated. No resistance to cangrelor was experienced in our cohort.

Procedural details

All procedures were performed using femoral access. Of the 9 new patients, 6 underwent cervical ICA stenting and two patients had intracranial stenting (Table 1). One patient (#6) was started on cangrelor in anticipation of needing a cervical stent but did not require the stent to be placed. The cangrelor drip was maintained for several hours afterwards and she was transitioned to oral ticagrelor. This patient was included in the study because she was started on the cangrelor and remained on the medication similar to patients who did undergo stenting. In all patients, a satisfactory reperfusion (mTICI ≥ 2b) was obtained. The average PRU was 68 ± 46.

Table 1.

Demographic and complication details for 9 new patients who underwent ischemic stroke intervention and received IV cangrelor.

Subject	Age	IV tPA	Intervention	Procedural PRU	Asymptomatic ICH	Symptomatic ICH	Intraprocedural thromboembolic complication	Intraprocedural in-stent thrombosis
1	50s	No	Failed thrombectomy, rescue L M1 stent	87	No	No	No	No
2	40s	Yes	Right M1 thrombectomy, R CAS for tandem lesion	4	No	No	No	No
3	60s	Yes	L CAS for acute occlusion	161	No	No	No	No
4	70s	No	R M1 thrombectomy, R CAS for tandem lesion	37	Yes	No	No	No
5	40s	No	R CAS for dissection	27	No	No	No	No
6	30s	No	L M1 thrombectomy, L ICA occlusion	98	No	No	No	No
7	60s	No	R CAS following occlusion post CEA	42	No	No	No	No
8	70s	Yes	R CAS for dissection	8	No	No	No	No
9	60s	No	Failed thrombectomy, rescue basilar stent	5	No	No	No	No

CAS: carotid artery stenting.

Complications

No patients experienced symptomatic intracranial hemorrhage nor intraprocedural thromboembolic complications. One patient in the new series experienced asymptomatic ICH diagnosed on routine follow up CT. This patient did not receive IV tPA.

Pooled-analysis

The data from five prior studies was combined with our updated institutional data (Table 2). Overall, 129 patients who underwent an acute ischemic stroke intervention and cangrelor administration were included. There were 71 cervical carotid artery stents placed, 53 intracranial stents and 2 combined cases. IV tPA was administered in 23.4% (29/124) of reported cases. The asymptomatic intracranial hemorrhage (aSICH) rate was 12.6% (11/87). The symptomatic intracranial hemorrhage (SICH) rate was 6.2% (8/129). The rate of retroperitoneal (RP) hematoma was 1.5% (2/129) and the rate of gastrointestinal (GI) bleed was also 0.8% (1/129). There were one case of intraprocedural thromboembolic complication (0.8%) and no cases of intraprocedural in-stent thrombosis(0%). There was a trend towards higher rate of symptomatic intracranial hemorrhage in the group given the standard cardiac infusion of 4.0 ug/kg/min compared to the lower dose group (≤1 ug/kg/min), (0% vs 9% p = 0.1), (Table 3).

Table 2.

The results of a meta-analysis evaluating prior published studies of IV cangrelor in the setting of acute ischemic stroke.

	Total Patients	aSICH	SICH	RP Hematoma	GI Bleed	Intraprocedural Thromboembolic	Intraprocedural In-Stent Thrombosis	Cervical	Intracranial	Combined	IV tPA administered
Elhorany et al.	12	16.7% (2/12)	8% (1/12)	8% (1/12)	0% (0/12)	0% (0/12)	0% (0/12)	4	6	2	50% (6/12)
Linfante et al.	5	0% (0/5)	0% (0/5)	0% (0/5)	20% (1/5)	0% (0/5)	0% (0/5)	3	2	0	NR
Cervo et al.	38	15.8% (6/38)	10.5% (4/38)	0% (0/38)	0% (0/38)	0% (0/38)	0% (0/38)	26	12	0	0% (0/38)
Cortez et al.	42	NR	7.1% (3/42)	2% (1/42)	0% (0/42)	2.4% (1/42)	0% (0/42)	17	23	0	33.3% (14/42)
Aguilar-Salinas	7	0% (0/7)	0% (0/7)	0% (0/7)	0% (0/7)	0% (0/7)	0% (0/7)	6	1	0	29% (2/7)
Our institution	25	12% (3/25)	0% (0/25)	0% (0/25)	0% (0/25)	0% (0/25)	0% (0/25)	15	9	0	29% (7/25)
Combined	129	12.6% (11/87)	6.2% (8/129)	1.5% (2/129)	0.8% (1/129)	0.8% (1/129)	0% (0/129)	71	53	2	23.4% (29/124)

Table 3.

Rate of symptomatic hemorrhage (SICH) with regards to cangrelor dose.

Rate (ug/kg/min)	% SICH
4	9% (5/55)
2–4	7.1% (3/42)
2	0% (0/7)
0.75–1	0% (0/25)

Table 4.

Dosing regimens utilized in each individual study.

	Bolus (ug/kg)	Drip Rate (ug/kg/min)	Aspirin given	P2Y12 response checked	Average PRU
Elhorany et al.	30	4	250 mg	No	NR
Linfante et al.	30	4	Varied by provider	NR	NR
Cervo et al.	30	4	500 mg	No	NR
Cortez et al.	15–30	2–4	75mg–325 mg	Yes	139
Aguilar-Salinas	15	2	325 mg	Yes	109
Our institution	5	0.75 or 1	None	Yes	67

Discussion

This study adds to the growing body of evidence that IV cangrelor is safe in the setting of acute ischemic stroke. This study adds significant volume to the current literature on the safety of IV cangrelor. In addition, it is only the third study to report the platelet reactivity units following the administration of IV cangrelor in the neuroendovascular literature.

Combining the 104 patients from the Elhorany et al., Linfante et al., Aguilar-Salinas et al., Cortez et al., and Cervo et al., series with our own institutional data allowed for a total of 129 patients to be analyzed, all who underwent acute ischemic stroke intervention and were given IV cangrelor.^11–15 The overall rate of asymptomatic intracranial hemorrhage was 12.6% (11/87). This rate is consistent with the rate of hemorrhagic transformation without any stroke intervention. ¹⁴ The rate of symptomatic intracranial hemorrhage was 6.2% (8/129). There was one case of intraprocedural thromboembolic complication (0.8%) and no cases of in-stent thrombosis (0%). Other hemorrhagic complications were also low and consistent with the literature.

Dose

Several different dose regimens have now been published (Table 4). Four prior studies used the standard cardiac bolus of 30 ug/kg followed by an infusion of 4.0 ug/kg/min and did not check P2Y12 responsiveness.^11–13,15 Aguilar-Salinas et al. used a half cardiac dose of 15 ug/kg bolus followed by a 2.0 ug/kg/min IV infusion. The authors did use P2Y12 assays to evaluate for adequate response, with a goal <200. ¹⁴ In our series, a bolus of 5 ug/kg was given over 30 seconds and an infusion of either 0.75 or 1.0 ug/kg/min was given.

Conclusion

Use of IV cangrelor during acute ischemic stroke intervention has a low risk of symptomatic intracranial hemorrhage. The rate of intraprocedural thromboembolic complication was 0.8% and there were no reports of in-stent thrombosis. The use of IV tPA does not appear to increase the risk of hemorrhage. Further studies are needed to elucidate the best dosing regimen.