Is there evidence to support PRU or platelet reactivity monitoring for cangrelor bridging for neurovascular indications?

Comment by InpharmD Researcher

A 2021 review suggests that low-dose cangrelor demonstrated significant variability in platelet reactivity unit (PRU) response in patients undergoing neuroendovascular stent placement. From other tertiary sources, there appears to be a consensus within most literature that PRU levels under 200 or 150 were considered appropriate targets for antiplatelet activity with cangrelor during neurovascular procedures. This PRU-guided approach does seem to report positive outcomes primarily derived from observational studies. But these investigations generally do not directly determine whether use of PRU was appropriate, nor try to establish the optimal PRU range.

Background

A 2024 systematic review discussed the use of cangrelor for neurointerventional procedures. Oftentimes, cangrelor infusion is used to maintain antiplatelet activity with a short onset and quick reversal. The most commonly reported infusion protocol is a 30 μg/kg bolus followed by a 4 µg/kg/min infusion. In the studies that reported intra- or postoperative platelet reactivity units (PRU) values, levels were consistently maintained below 200, and were less than 150 in the majority of cases. Patients were subsequently bridged to oral antiplatelet therapy 30 minutes to 4 hours before discontinuing the cangrelor infusion. This PRU-guided approach was associated with positive outcomes, including a 97.5% rate of adequate vessel reperfusion in ischemic stroke patients and favorable functional outcomes (modified Rankin Scale score 0-2) in 62.7% of patients at three-month follow-up. Though primarily from observational studies, the evidence suggests PRU can be used to guide cangrelor dosing and bridging for neurovascular indications by maintaining levels below 200 or 150 PRU. However, the included studies did not specifically investigate the appropriateness of PRU monitoring, and additional studies are needed. [1]

A 2023 study Investigated the use of intravenous cangrelor for neuroendovascular procedures through a retrospective analysis conducted across two centers. This investigation included a cohort of 76 patients, whose mean age was approximately 57 years, with a significant proportion being males and predominantly Black. Cangrelor was administered primarily for embolization and intracranial stent placement at a bolus dose of 15-30 mcg/kg followed by 2-4 mcg/kg/min infusion titrated to a PRU of 50-150. Results revealed that about 44% of the patients achieved a favorable outcome marked by a modified Rankin Scale score of 0 to 2 at 90 days (see Table 2). Additionally, the occurrence of recurrent or new strokes within one year was 8%, while symptomatic intracranial hemorrhage was observed in 6% of patients. The author’s updated systematic review and meta-analysis, suggests that intravenous cangrelor might be a viable option during neuroendovascular procedures, given its rapid onset and short duration, which facilitate precise platelet inhibition. However, the evidence remains preliminary, and the authors note that real-time PRU testing is not yet widely available. [2]

References:

[1] Coulibaly NJ, Elgouhari MH, Arshad MH, Waqas M, Shallwani H, Shakir HJ. Cangrelor for neurointerventional procedures: A systematic review. Interv Neuroradiol. Published online April 13, 2024. doi:10.1177/15910199241247255
[2] Desai H, Al-Salihi MM, Morsi RZ, et al. Intravenous cangrelor use for neuroendovascular procedures: a two-center experience and updated systematic review. Front Neurol. 2023;14:1304599. Published 2023 Dec 5. doi:10.3389/fneur.2023.1304599
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there evidence to support PRU or platelet reactivity monitoring for cangrelor bridging for neurovascular indications?

Level of evidence

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


Please see Tables 1-3 for your response.

Characterization of antiplatelet response to low-dose cangrelor utilizing platelet function testing in neuroendovascular patients
Design

Retrospective review

N= 72
Objective To characterize the dose response of low dose cangrelor (<2 mcg/kg/min) with the utilization of platelet function testing (PFT)
Study Groups All patients (n= 72)
Inclusion Criteria Patients 18 years or older who were administered cangrelor during neuroendovascular stent placement or for bridging when unable to tolerate oral antiplatelet agents
Exclusion Criteria Not specified
Methods

Patients undergoing procedural stenting received a cangrelor bolus of 5 mcg/kg and an initial infusion rate of either 0.75 mcg/kg/min or 1 mcg/kg/min. Bridging patients received an initial infusion rate of 0.75 mcg/kg/min or 1 mcg/kg/min. Doses were titrated to achieve a platelet reactivity unit (PRU) between 50–150. PFT was used to guide dosing adjustments.
Duration January 1, 2019 to October 31, 2020
Outcome Measures

Primary: Dose response of cangrelor at low doses with PFT

Secondary: PRU results in desired and acceptable ranges
Baseline Characteristics   All patients (n= 72)
Sex - Male 40 (56%)
Sex - Female 32 (44%)
Age, median years 64
Age range 37–95
Indication for procedure - Aneurysm 21
Indication for procedure - Stroke 37
Indication for procedure - Other 6
Indication for procedure - Bridging 8
Results   0.75 mcg/kg/min 1 mcg/kg/min p-value
Acceptable range (10–180) 69% 80% 0.268
Desired range (50–150) 45% 56% 0.353
Mean PRU (standard deviation) 117 (66) 80 (58) 0.017
Adverse Events Not specified
Study Author Conclusions

Utilizing low doses of cangrelor with platelet function testing is an option during emergent neuroendovascular stenting and bridging. Cangrelor demonstrates significant variability in response at low doses and exhibits a dose response relationship when PFT is utilized.
Critique

The study provides valuable insights into the dose response of cangrelor at low doses using PFT, but the retrospective design and lack of a control group limit the ability to draw definitive conclusions. The variability in PRU results highlights the challenges in standardizing treatment protocols. Further prospective studies are needed to validate these findings and optimize dosing strategies.

 

References:

Holden DN, Entezami P, Bush MC, et al. Characterization of antiplatelet response to low-dose cangrelor utilizing platelet function testing in neuroendovascular patients. Pharmacotherapy. 2021;41(10):811-819. doi:10.1002/phar.2619

Intravenous cangrelor use for neuroendovascular procedures: a two-center experience and updated systematic review
Design

Two-center retrospective study and updated systematic review and meta-analysis

N= 76 (retrospective study)
Objective To investigate the safety and feasibility of intravenous cangrelor in patients undergoing acute neuroendovascular interventions and to compare two different dosing titration regimens
Study Groups

Protocol A (n= 66)

Protocol B (n= 10)
Inclusion Criteria Age ≥18 years; patients underwent neuroendovascular procedures such as endovascular thrombectomy, intracranial or carotid stenting, or aneurysm embolization using various techniques; use of intravenous cangrelor regardless of duration
Exclusion Criteria Not specified
Methods Retrospective chart review of patients on intravenous cangrelor for neuroendovascular procedures. Cangrelor protocol involved an IV bolus of 15 to 30 mcg/kg followed by a maintenance infusion of 2 to 4 mcg/kg/min. Titration to goal P2Y12 reaction unit (PRU) level of 50 to 150.
Duration September 1, 2020, to March 13, 2022 (retrospective study) Systematic review up to February 22, 2023
Outcome Measures

Primary: Safety and feasibility of intravenous cangrelor

Secondary: Comparison of different dosing titration regimens, rates of symptomatic intracranial hemorrhage, major extracranial bleeding events, and gastrointestinal bleeding
Baseline Characteristics   Cangrelor use (n= 76)
Age (mean, SD) 57.2 ± 18.2
Sex – n (%)  
Male 39 (51)
Female 37 (49)
Race – n (%)  
Black or African American 49 (66)
White 9 (12)
Other 1 (1)
Asian 2 (3)
Unknown 15 (20)
Active smoking status – n (%)  
Yes 19 (25)
No 38 (50)
Unknown 19 (25)
Hypertension – n (%)  
Yes 35 (46)
No 30 (40)
Unknown 11 (15)
Previous ischemic stroke – n (%)  
Yes 16 (21)
No 49 (65)
Unknown 11 (15)
Type of neurovascular pathology – n (%)  
Stroke/carotid disease 44 (58)
Aneurysm (ruptured or unruptured) 19 (25)
Carotid cavernous fistula 6 (8)
Traumatic vessel injury 5 (7)
Carotid blowout syndrome 1 (1)
Idiopathic intracranial hypertension 1 (1)
Location of lesion – n (%)  
Anterior circulation 61 (80)
Posterior circulation 13 (17)
Both 1 (1)
Unknown 1 (1)
Presence of tandem lesiona – n (%)  
Yes 15 (30)
No 35 (70)
Baseline NIHSS score - n (%)  
Median (IQR) 12 (7–20)
0–10 20 (26)
11–20 20 (26)
21–30+ 11 (15)
Unknown 25 (33)
Results   Protocol A (n= 66) Protocol B (n= 10) p value
Safety outcomes – n (%)      
Mortality at discharge 5 (8) 2 (20) 0.24
Mortality at 90 days 12 (26) 2 (20) 0.65
Symptomatic intracranial hemorrhage 4 (7) 0 (0) N/A
Asymptomatic intracranial hemorrhage 4 (7.3) 0 (0) N/A
Major extracranial bleeding 1 (2) 1 (10) 0.29
Gastrointestinal bleeding 1 (2) 1 (10) 0.29
Efficacy outcomes – n (%)      
Favorable functional outcome (mRS 0 to 2) at discharge 31 (49) 5 (50) 0.82
Favorable functional outcome (mRS 0 to 2) at 90 days 19 (40) 6 (60) 0.31
New or recurrent strokes 5 (9) 0 (0) N/A
In-stent thrombosis 1 (2) 0 (0) N/A
Disposition location – n (%)      
Home 23 (35) 5 (50) 0.34
Subacute rehabilitation/Skilled nursing facility 4 (6) 1 (10) 0.51
Acute rehabilitation facility 24 (36) 2 (20) 0.48
Hospice/Death 9 (14) 2 (20) 0.63
Other 6 (9) N/A N/A
Adverse Events Symptomatic intracranial hemorrhage (7%); major extracranial bleeding (3%); gastrointestinal bleeding (3%)
Study Author Conclusions Intravenous cangrelor appears to be safe and effective in neuroendovascular procedures, with low rates of bleeding and ischemic events. Further research is needed to compare different dosing and titration protocols of cangrelor and other intravenous agents.
Critique The study provides valuable insights into the use of intravenous cangrelor for neuroendovascular procedures, highlighting its safety and efficacy. However, the retrospective design and small sample size limit the generalizability of the findings. The study's reliance on observational data and the lack of standardized treatment protocols across institutions may also contribute to potential biases. Larger, prospective studies are needed to validate these findings and explore optimal dosing strategies.

 

References:

Desai H, Al-Salihi MM, Morsi RZ, et al. Intravenous cangrelor use for neuroendovascular procedures: a two-center experience and updated systematic review. Front Neurol. 2023;14:1304599. Published 2023 Dec 5. doi:10.3389/fneur.2023.1304599

The use of cangrelor in neurovascular interventions: a multicenter experience
Design

Retrospective analysis of data from four cerebrovascular interventional centers

N= 66
Objective To evaluate the safety and effectiveness of IV cangrelor in neurovascular intervention
Study Groups

Ischemic group (IG) (n= 42)

Aneurysm group (AG) (n= 24)
Inclusion Criteria Adult patients (≥18 years old) who underwent neurovascular intervention and received cangrelor as part of their optimum care
Exclusion Criteria Not specified
Methods

Retrospective review at 4 centers between 2016 and 2019. Patients received a cangrelor loading dose of 15–30 μg/kg, followed by a 2–4-μg/kg/min maintenance dose. Transition to ticagrelor occurred before or immediately after stopping cangrelor infusion. VerifyNow P2Y12 assay was used to quantify antiplatelet therapy response with values were reported between 60 and 200 were considered ideal.
Duration 2016 to 2019
Outcome Measures

Primary: Safety and effectiveness of cangrelor in neurovascular interventions

Secondary: Periprocedural thromboembolic events, hemorrhagic complications, and clinical outcomes
Baseline Characteristics   Ischemic group (n= 42) Aneurysm group (n= 24)
Gender, female 24 (57.1%) 17 (70.8%)
Age median, y (range) 68.5 (34–88) 57 (28–86)
Hypertension 31 (73.8%) 13 (59%)
Hyperlipidemia 21 (50%) 5 (22.7%)
Diabetes mellitus 16 (38.1%) 2 (9.1%)
Previous stroke 12 (28.6%) 2 (9.1%)
Smoking 17 (40.5%) 5 (22.7%)
Results   Ischemic group (n= 42) Aneurysm group (n= 24)
Periprocedural symptomatic complication rate 9.5% 4.2%
Favorable outcome at discharge 47.6% 66.7%
Mortality rate 2.4% 8.3%
Mean PRU 139.45 ± 49.97 (n= 22) 54.43 ± 36.25 (n= 7)
Adverse Events

In the ischemic group, 9.5% experienced periprocedural symptomatic complications, including intracranial hemorrhages and retroperitoneal hematoma. In the aneurysm group, 4.2% had complications, including intracranial hemorrhage
Study Author Conclusions

Cangrelor may be a feasible alternative for patients requiring immediate intervention with endoluminal devices, allowing secure transition to long-term ticagrelor and progression to surgery in unexpected complications.
Critique

Interestingly, the PRU levels for the aneurysm group was below the ideal range as denoted by the authors. However, this was not further elaborated upon by the authors, and the aneurysm group concluded with higher favorable outcome rates compared to the ischemic group. Notably, only a subset of patients had platelet testings available post-surgery.

 

References:

Cortez GM, Monteiro A, Sourour N, et al. The use of cangrelor in neurovascular interventions: a multicenter experience. Neuroradiology. 2021;63(6):925-934. doi:10.1007/s00234-020-02599-2