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Original research
Intravenous cangrelor and oral ticagrelor as an alternative to clopidogrel in acute intervention
  1. Italo Linfante1,2,
  2. Kaushik Ravipati3,
  3. Amy Kathryn Starosciak2,3,
  4. Dennys Reyes1,2,
  5. Guilherme Dabus1,2
  1. 1 Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, Florida, USA
  2. 2 Miami Neuroscience Institute, Baptist Health South Florida, Miami, Florida, USA
  3. 3 Translational Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, Florida, USA
  1. Correspondence to Dr Italo Linfante, Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, FL 33176, USA; linfante.italo{at}gmail.com

Abstract

Background Dual antiplatelet therapy (DAP) is necessary to prevent thromboembolic events during carotid stenting, stent-assisted coil embolization, and implant of flow diverters (FD). However, DAP in the acute phase may be challenging. An intravenous alternative, cangrelor, has rapid onset, short plasma half-life, and more reliable antiplatelet action for acute interventions. The study objective was to evaluate feasibility and safety of IV cangrelor during acute neuroendovascular surgery procedures.

Methods We performed a retrospective analysis of our database of patients treated with stent-assisted coil embolization, FD placement for aneurysmal subarachnoid hemorrhage (aSAH), or stenting for acute internal carotid artery (ICA) occlusion where IV cangrelor was used. Morbidity, mortality, incidence of thromboembolic events, hemorrhages, and 90-day outcomes were reported.

Results Ten patients were found in our database from June 2018 through January 2019. Four patients had aSAH, four had middle cerebral artery strokes with tandem lesions, one had an ICA occlusion, and one had a vertebral artery aneurysm. One of the ten patients experienced a thrombotic event. One patient developed new post-procedural bleeding and two had worsening intracranial hemorrhage. Five patients were discharged home in stable condition, two to acute rehabilitation, one to a nursing facility, and two others expired (likely the result of the severe and evolving strokes). Of the eight who were discharged, six (75%) had a good 90-day functional outcome (modified Rankin Scale 0–2).

Conclusion Acute administration of IV cangrelor with or without oral ticagrelor is a feasible antiplatelet treatment option for acute neuroendovascular procedures.

  • stroke
  • thrombectomy
  • stent
  • flow diverter
  • aneurysm

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Background

Cangrelor is a rapidly acting, reversible, IV P2Y12 receptor antagonist with a half-life of just 3–6 min and a virtually instant onset of action. In percutaneous coronary intervention (PCI), cangrelor has been shown to reduce ischemic events such as myocardial infarction (MI), ischemia-driven revascularization, in-stent thrombosis, and reduce death from these events without an increase in moderate to severe bleeding compared with clopidogrel.1–3 Therefore, cangrelor is currently FDA-approved as an adjunct to reduce the risk of peri-procedural MI, repeat coronary revascularization, and stent thrombosis.4

Stent-assisted coil embolization and implant of flow diverters (FD) have been reported as an effective option in selected cases to secure the aneurysm in aneurysmal subarachnoid hemorrhage (aSAH).5 6 Angioplasty and stenting for an acute internal carotid artery (ICA) and middle cerebral artery (MCA) tandem occlusions has been reported to be feasible, safe, and effective .7 8 However, in these cases, acute stent thrombosis is a complication of inadequate acute antiplatelet activity at the time of stent implant in the extracranial ICA.9 10 Clopidogrel is an oral antiplatelet agent with a half-life of 5–6 days and may need up to 2 hours to exert its antiplatelet aggregation effect.11 Because of this slow onset of action, it may not be the best option in the acute setting.12 13 Clopidogrel also has the issue of non-responsiveness in a small to modest proportion of people undergoing neurovascular stenting and stent-assisted coil embolization procedures.14–18 Because of cangrelor’s fast and reliable onset of action and reversible platelet inhibition without evidence of resistance, it might be a viable alternative to oral clopidogrel in the acute setting.19 Recently, cangrelor has been reported as a possible alternative in acute stenting procedures to treat cerebrovascular pathology such as acute ischemic stroke (AIS) or intracranial aneurysms.20–23

We investigated feasibility and safety of IV cangrelor as an antiplatelet agent in acute neuroendovascular procedures where a stent or FD is implanted acutely.

Methods

The current analysis was approved by the Institutional Review Board of Baptist Health South Florida. Informed consent for the procedure was obtained from each patient. The patients included in this analysis were obtained from a retrospective review of our database of intracranial aneurysms treated endovascularly with an FD and acute tandem ICA–MCA occlusions treated by stenting between June 2018 and January 2019.

All patients had a conventional digital subtraction angiography (DSA) including three-dimensional reconstructed images at the time of admission. The treatment approach for each aSAH case to determine whether an endovascular or open surgery was a better option was discussed between the NeuroEndovascular Surgery (NES) Attending and the open surgical Neurosurgery Attending.

Treatment options for acute tandem ICA–MCA occlusions were discussed between the NES Attending and the Stroke Neurology Attending.

Treatment was based on each operator’s preference, including device selection, administration and dose of antiplatelet agents such as aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors; and peri-operative management of the patients. Position and immediate angiographic result was recorded with conventional DSA images with or without XPER CT (Philips Healthcare, Best, Netherlands) and Low Contrast Imaging (LCI) (Toshiba Medical Systems, Japan). Cangrelor infusion lasted 2 hours, after which patients were transitioned to dual antiplatelet therapy (DAPT). For those patients who did not pass a swallow evaluation, DAPT was administered through nasogastric tube. Patients were admitted to ICU following treatment for further observation and management. Timing and modality of follow-up post-operative imaging also were dependent on the operator’s preference and the clinical status of the patient, though typically a non-contrast brain CT was done at 24 hours. A carotid ultrasound during the hospitalization was completed in those who received carotid stenting to confirm stent patency. All patients had a DSA at 6 months post-treatment.

We retrospectively collected basic patient demographics, diagnosis, and procedure-related outcomes and complications from individual patient chart review. Main outcomes of interest were peri-procedural complications such as thrombotic or bleeding events. Additional relevant outcomes were discharge disposition, and functional condition at discharge and 90-days using the modified Rankin Scale (mRS).

Results

In our database we found 10 patients in whom IV cangrelor (with or without oral ticagrelor) was administered acutely for NES procedures during June 2018 through January 2019. Four patients presented with SAH due to a ruptured cerebral aneurysm, four had tandem ICA–MCA occlusion, one had a vertebral artery dissecting aneurysm, and one had an ICA occlusion (table 1). The average age was 62±18 (range 41–88) years and 40% of cases were female.

Table 1

Patient demographics and clinical diagnosis

All patients received a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min infusion of cangrelor) followed by 81 mg aspirin and 180 mg ticagrelor orally. All patients were switched to an oral antiplatelet agent, post-procedure.

All endovascular procedures were successful, with mechanical thrombectomy resulting in complete recanalization of the involved artery. There was one thrombotic event in which the patient developed a large infarct, a likely evolution of the index stroke without evidence of in-stent thrombosis. Two cases had some extension of the previous hemorrhage distribution (Case 1 developed a small, asymptomatic subdural hemorrhage and Case 2 had increased intraventricular hemorrhage (IVH), but already was in poor clinical condition), and one had a transient gastrointestinal (GI) bleed noted post-procedure (table 2). Five patients were discharged home in stable condition, two to acute rehabilitation, one to a nursing facility, and two others expired. Of those who expired, Case 2 presented with extensive SAH with IVH and obstructive hydrocephalus and Case 3 with sequelae from the initial right MCA stroke due to embolic event from right ICA occlusion.

Table 2

Patient outcomes and discharge

Discussion

In our early experience, IV cangrelor and oral ticagrelor as an alternative to clopidogrel for acute neuroendovascular procedures seem to be feasible. Overall, there was one minor thrombotic event reported in Case 3. In addition, there were three reported bleeding events, two extensions of existing SAH into the fourth ventricle, and a transient episode of GI bleeding post-thrombectomy which resolved spontaneously within 24 hours.

Studies in post-PCI patients have shown that bleeding is a more common complication than thrombosis, although thrombosis carries a greater risk of death.24–26 Previous literature also has shown that most of the advantage that cangrelor has over clopidogrel in preventing thrombosis was peri-procedurally in the first 2 hours following PCI.1 Because cangrelor is an ATP analog that is biologically active without any need for GI absorption or first-pass metabolism and reversibly inhibits the P2Y12 subunit of the ADP receptor, it inhibits platelets immediately on the start of its infusion.19 In fact, unlike the oral P2Y12 inhibitors, such as ticlopidine, clopidogrel, prasugrel, and ticagrelor, which have plasma half-lives between 7 and 8.5 hours, cangrelor’s plasma half-life is 3 min, and its antiplatelet effect lasts less than 30 min after the infusion is stopped.26 These characteristics make cangrelor a possible treatment option in an acute setting.

In a recent case series reported by Aguilar-Salinas (2019), cangrelor was used as an alternative to clopidogrel in seven patients with AIS and one patient with an unruptured left superior hypophoseal aneurysm.20 Patients were treated with a loading dose of 325 mg aspirin, along with a 15 mcg/kg bolus of cangrelor, followed by a cangrelor infusion at 2 mcg/kg/min. In this case, Aguilar-Salinas and colleagues selected a cangrelor dose at half of the cardiac protocol. The authors did not find in-stent thrombosis, thromboembolic complications, or further ischemic or hemorrhagic strokes in those patients treated with peri-procedureal cangrelor. They also found that five out of their seven stroke patients (71%) were discharged with a modified Rankin Scale (mRS) of 0–2.20 In our study, which included five patients with AIS, four with aSAH, and one with unruptured aneurysm, cangrelor dosing was selected to be the same as the dose used in cardiac procedures. Similar to Aguilar-Salinas and colleagues, we did not find any in-stent thrombosis, but there was one minor thrombotic event. However, we did have three bleeding events, including two cases where the initial intracranial bleed spread, and in an AIS patient a transient GI bleed. It is unclear whether the intracranial bleeding events are related to cangrelor use or the natural history of the disease. For functional outcomes in our cases (which included aSAH) five out of 10 (50%) had an mRS 0–2 at discharge, and of those who were discharged from the hospital, six of eight (75%) had an mRS of 0–2 at 90 days. In fact, seven of eight cases (88%) had an improved mRS at 90 days compared to discharge and one remained the same.

Considering that Aguilar-Salinas et al used a half cardiac dose of cangrelor for AIS and unruptured aneurysm without thrombotic or hemorrhagic events, compared with our use of the full cardiac dose for AIS, aSAH, and an unruptured aneurysm, with one minor thrombotic event and three bleeding events, it is imperative to determine optimal dosage in AIS, aSAH, and unruptured aneurysm cases through clinical trial. A comparison of the two doses or multiple doses between the half and full cardiac doses would be valuable to balance thrombotic and hemorrhagic events based on presenting diagnosis.

Limitation of the study

This case series was a retrospective examination of consecutive cases treated at a single facility. Therefore, there was no opportunity to compare outcomes in patients who received cangrelor to those of patients who received clopidogrel. Patient selection criteria such as prior antiplatelet therapy or especially emergent cases, and further fine-tuning of cangrelor dosing based on clinical presentation (AIS vs aSAH), may be achieved by developing a standardized protocol.

Conclusion

In conclusion, IV cangrelor with oral ticagrelor maybe a feasible option in acute NES procedures where DAP is needed.

Acknowledgments

The authors would like to acknowledge the critical review of cases by Radhan Gopalani, Pharm.D. and Andrea Marr-Peralto, APRN from a hospital quality assurance perspective.

References

Footnotes

  • Twitter @italolinfante

  • Contributors IL and GD conceptualized the retrospective case review and provided data. AKS and KR reviewed the cases and drafted the manuscript. All authors reviewed and contributed to interpretation of data, revised the manuscript, approved the final version for publication, and agree to be accountable for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests IL discloses that he is a proctor, consultant, and speaker for Medtronic, he is a consultant and speaker for Stryker, and holds stock in InNeuroCo, and Three Rivers, outside the submitted work. GD discloses that he is a consultant, proctor, and speaker for Medtronic, is a consultant and speaker for Microvention and Penumbra, is a consultant for Cerenovus, and a shareholder for Surpass, outside the submitted work.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Baptist Health South Florida Institutional Review Board (10-060). This was a retrospective review of cases, and a waiver of consent was obtained. Patients did provide informed consent for the standard care medical procedures.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.