Platelet Function Testing to Guide Cangrelor Dosing in Patients with Temporary Mechanical Circulatory Support or as a Bridge to Procedure

Abstract

Cangrelor is a rapid-acting, intravenous P2Y12 inhibitor that can be used in patients after percutaneous coronary intervention who require mechanical circulatory support or as a bridge to procedure. We retrospectively reviewed adult patients who received platelet function testing (PFT) with the VerifyNow P2Y12 assay while on cangrelor from March 2021 through November 2022. All patients were initiated on 0.75 mcg/kg/min of cangrelor with P2Y12 reaction unit (PRU) values collected 12–24 h after initiation. Cangrelor doses were adjusted per protocol to maintain PRU values of 85–208. A total of 42 patients were included. Thirty-eight patients (90.5%) required temporary mechanical circulatory support while on cangrelor, and 4 patients (9.5%) received cangrelor as a bridge to procedure. The median cangrelor maintenance dose was 0.5 (interquartile range [IQR]: 0.375–0.75) mcg/kg/min, and the median time in therapeutic range with a PRU value between 85 and 208 was 66.6% (IQR: 39.6%-100%). No patients experienced stent thrombosis. A composite major adverse cardiovascular event occurred in 4 patients (9.5%), and major bleeding occurred in 16 patients (38.1%). Compared to empiric cangrelor dosing of 0.75 mcg/kg/min, PFT-guided cangrelor dose adjustment was associated with a median drug cost savings of $1605.60 (IQR: $0-4281.56). Utilizing PFT with cangrelor may allow for lower, individualized dosing while preventing stent thrombosis.

Keywords

antiplatelets extracorporeal membrane oxygenation impella P2Y12 reaction unit bridging

Introduction

Cangrelor is an intravenous (IV), reversible P2Y12 inhibitor that is approved for use during percutaneous coronary intervention (PCI) to reduce the risk of ischemic events after stent implantation. Cangrelor has a short half-life of 3–6 min with normalized platelet function after 1 h of infusion discontinuation.¹ With IV administration, cangrelor potentially allows for more consistent absorption in critically ill patients who may have malabsorption or difficulties with enteral access.^2,3 Given its rapid offset of action, cangrelor also allows for discontinuation in the setting of procedures or bleeding.

Previous studies have evaluated the off-label use of low dose cangrelor in patients requiring temporary mechanical circulatory support (MCS) or in bridging cases before surgery or a procedure.^4–14 Additionally, small case series have assessed using platelet function testing (PFT) with the VerifyNow P2Y12 assay to guide cangrelor dosing in bridging situations or in patients with temporary MCS; however, these previous studies lacked a standardized protocol for dose adjustments based upon P2Y12 reaction units (PRU) and utilized different goal values for PRU.^12–14 Therefore, additional studies are needed to better evaluate the clinical utility of PFT to guide cangrelor dosing. The purpose of this study was to describe clinical outcomes using a standardized algorithm for PFT-guided cangrelor dose adjustments in patients with temporary MCS or as a bridge to procedure.

Methods

Study Design and Patient Population

This was a retrospective, single-center, observational study of patients who received cangrelor between March 1, 2021 and November 30, 2022 at Allegheny General Hospital. Patients were included if they were ≥ 18 years old, received PCI, and were administered cangrelor for ≥ 24 h with dose adjustments based on PFT. Indications for cangrelor use in this study included cardiogenic shock requiring temporary MCS or bridging for a procedure. Forms of MCS included intra-aortic balloon pump, Impella devices, and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Concomitant anticoagulation (unfractionated heparin or direct thrombin inhibitor) was administered in patients on MCS or with another clinical indication. The choice of anticoagulant and activated partial thromboplastin time goal range were at the discretion of the treating physician. The study was approved by the Institutional Review Board, and informed consent was waived due to the observational nature of the study.

Baseline demographics, past medical history, medication use, and laboratory values were collected from chart review using the electronic medical record. Additional data collection variables included indication for PCI as well as type, location, and number of stents placed. Duration of MCS and cangrelor were tracked. The dose of cangrelor, number of cangrelor dose adjustments, and time since oral P2Y12 inhibitor administration to cangrelor initiation were also collected. The cangrelor maintenance dose was defined as the dose that the patient received for the longest duration.

Cangrelor Dosing Protocol with Platelet Function Testing

For patients with recent administration of an oral P2Y12 inhibitor, cangrelor is initially dosed at 0.75 mcg/kg/min without a bolus. Per our institutional protocol, cangrelor is started 24–48 h after the last dose of clopidogrel or ticagrelor or 48–72 h after the last dose of prasugrel. In patients who received cangrelor during PCI, cangrelor is given as a 30 mcg/kg bolus followed by an infusion at 4 mcg/kg/min for the duration of PCI. Once patients are transferred to the intensive care unit or general floor, the dose of cangrelor is adjusted to 0.75 mcg/kg/min. Subsequent dose adjustments of cangrelor are made based upon PFT. PFT was performed using the VerifyNow P2Y12 assay (Accriva Diagnostics, owned by Instrumentation Laboratory, San Diego, CA) with results reported as PRU. PRU values are checked 12–24 h after cangrelor initiation. Based upon the initial PRU value, the dose of cangrelor may be adjusted (Table 1). If the dose of cangrelor is adjusted based upon the initial PRU value, a subsequent PRU is checked 24 h later with a goal range of 85–208. The goal range of 85–208 was selected based upon expert consensus cutoff values for low platelet reactivity and high platelet reactivity, respectively.¹⁵ The number and value of PRU were collected. The time in therapeutic range (TTR) for each patient was calculated using the following formula: number of PRU values within therapeutic range/total number of PRU tests performed × 100.

Table 1.

Cangrelor Dose Adjustments Based upon Platelet Function Testing.

PRU value	Initial Dose Adjustment
<85	Decrease dose to 0.375 mcg/kg/min, re-check PRU in 24 h
85–149	Decrease dose to 0.5 mcg/kg/min, re-check PRU in 24 h
150–208	Continue dose at 0.75 mcg/kg/min, consider additional PRU in 2–3 days
>208	Consider dose increase to 1 mcg/kg/min, re-check PRU in 24 h
PRU value	Subsequent Dose Adjustment
<85	Reduce dose to 0.125–0.25 mcg/kg/min, re-check PRU in 24 h
85–208	Continue current dosing; consider additional PRU in 2–3 days
>208	Increase dose by 0.125–0.25 mcg/kg/min, re-check PRU in 24 h

Abbreviation: PRU, P2Y12 reactivity unit.

Study End Points

The primary outcome was the incidence of stent thrombosis. Secondary outcomes included major bleeding events and major adverse cardiovascular events (MACE), defined as a composite of ischemic stroke, myocardial infarction, or coronary revascularization. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or greater, and minor bleeding was defined as BARC type 1 or 2 bleeding.¹⁶ Additional secondary objectives included in-hospital mortality, hospital and intensive care unit (ICU) length of stay (LOS), and packed red blood cell (PRBC) transfusions. Clinical outcomes were identified through chart review with corroborating imaging studies when available. Stent thrombosis, MACE, PRBC transfusions, and bleeding events were evaluated from the day of cangrelor initiation until death or 24 h after cangrelor discontinuation.

A drug cost-savings analysis was performed by comparing the difference in total cangrelor cost with dose adjustments using PFT and a standard 0.75 mcg/kg/min dose, using the patient's actual body weight. A total dose was calculated using the duration of cangrelor therapy, converted to vials, and rounded to the next whole number. The difference in vials between the standard 0.75 mg/kg/min dose and dose adjusted cangrelor using PFT was multiplied by the average wholesale price (AWP) of $1070.39.

Statistical Analysis

Continuous data are expressed as median (interquartile range [IQR] or range), and categorical variables are expressed as numbers and percentage. Comparisons between continuous data were evaluated by the Mann-Whitney U test. A P-value < 0.05 was considered statistically significant.

Results

Patient Characteristics

There were 42 patients included in this study, with 38 patients (90.5%) receiving cangrelor while supported on temporary MCS and 4 patients (9.5%) receiving cangrelor as a bridge to procedure. Two patients received cangrelor as a bridge to tracheostomy, with one patient on cangrelor prior to percutaneous endoscopic gastrostomy tube placement and the other prior to left ventricular assist device surgery. VA-ECMO was the most common temporary MCS and used in 25 patients (59.5%). The median duration of MCS was 7.5 (IQR: 5–11) days. Baseline characteristics are displayed in Table 2. Most patients were male (69%) and Caucasian (85.7%), and the median age of the study population was 62 years.

Table 2.

Baseline Demographics.

Characteristic	N = 42
Age (years), median (IQR)	62 (55–70)
Weight (kg), median (IQR)	84.5 (75–97)
Sex (male), n (%)	29 (69)
Race, n (%)
Caucasian	36 (85.7)
Black	5 (11.9)
Other	1 (2.4)
Past medical history, n (%)
Coronary artery disease	20 (47.6)
Hypertension	31 (73.8)
Diabetes	16 (38.1)
Heart failure	11 (26.2)
Atrial fibrillation	4 (9.5)
Chronic kidney disease	5 (11.9)
Baseline laboratory values, median (IQR)
Hemoglobin, g/dL	8.6 (7.8–9.9)
INR	1.4 (1.3–1.8)
Platelets, 10³/µL	133.5 (82.8–243.3)
Type of PCI, n (%)
DES	39 (92.9)
BMS	3 (7.1)
Indication for PCI, n (%)
STEMI	27 (64.3)
NSTEMI	14 (33.3)
Elective PCI	1 (2.4)
Number of stents, median (IQR)	1 (1–2)
Location of stents, n (%)
LAD	13 (31)
Circumflex	5 (11.9)
RCA	9 (21.4)
Left main	2 (4.8)
Ramus	1 (2.4)
Vein graft	1 (2.4)
Multiple vessels	11 (26.2)
Mechanical circulatory support, n (%)
VA-ECMO + Impella CP	15 (35.7)
VA-ECMO + IABP	10 (23.8)
Impella CP or 5.5	6 (14.3)
IABP	7 (16.7)
None	4 (9.5)
Concomitant anticoagulant, n (%)	41 (97.6)
Concomitant aspirin, n (%)	41 (97.6)
Oral P2Y12 inhibitor use prior to cangrelor initiation, n (%)
Clopidogrel	12 (28.6)
Ticagrelor	11 (26.2)
Prasugrel	1 (2.4)
None	18 (42.9)

Abbreviations: BMS, bare-metal stent; DES, drug-eluting stent; IABP, intra-aortic balloon pump; INR, international normalized ratio; IQR, interquartile range; LAD, left anterior descending artery; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction; VA-ECMO, venoarterial extracorporeal membrane oxygenation.

Cangrelor Characteristics and Platelet Function Testing

The median maintenance dose of cangrelor was 0.5 (IQR: 0.375–0.75) mcg/kg/min (Table 3). The median number of dose adjustments was 1 (IQR: 1–2). Fourteen patients (33.3%) required ≥ 2 dose adjustments with cangrelor. In 26 patients (61.9%), cangrelor was used during PCI, and patients were continued on cangrelor afterwards. For the remaining 16 patients (38.1%), cangrelor was started a median of 24 h (range: 24–60 h) after the last oral P2Y12 inhibitor dose. The median duration of cangrelor use was 6.1 (IQR: 2.8–11.8) days.

Table 3.

Cangrelor Maintenance Dose Following Platelet Function Testing Adjustment.

Cangrelor Dose	N = 42
0.25 mcg/kg/min	1 (2.4)
0.375 mcg/kg/min	12 (28.6)
0.5 mcg/kg/min	15 (35.7)
0.75 mcg/kg/min	13 (31)
1 mcg/kg/min	1 (2.4)

Data are displayed as n (%). The cangrelor maintenance dose was defined as the dose that the patient received for the longest duration.

The first documented PRU value while patients received the initial 0.75 mg/kg/min dose of cangrelor is shown in Figure 1. The median initial PRU was 103.5 (IQR: 82.5–117.3). There was no significant difference in initial PRU value comparing patients on VA-ECMO to patients who were not on VA-ECMO (P = 0.25). In 11 patients (26.2%), no dose adjustment was made based upon the initial PRU, which included five patients with an initial PRU value above 208. In these five patients, dosing was continued at 0.75 mcg/kg/min due to concern with high bleeding risk. One patient with an initial PRU value > 208 was maintained at higher dosing of 1 mcg/kg/min. In the 31 patients (73.8%) with dose adjustments after the initial PRU, the subsequent PRU value is displayed in Figure 2. One patient had a dose increase to 1 mcg/kg/min while the remaining 30 patients had a cangrelor dose reduction (18 patients received 0.5 mcg/kg/min and 12 patients received 0.375 mcg/kg/min). The median number of PRU values per patient was 3 (IQR: 2–4), and the median TTR was 66.6% (IQR: 39.6%-100%).

Figure 1.

Initial PRU value. All patients (n = 42) were receiving a cangrelor dose of 0.75 mg/kg/min at the time of first PRU.

Figure 2.

Subsequent PRU value in 31 patients with cangrelor dose changes after initial PRU. Eighteen patients were receiving cangrelor at a dose of 0.5 mcg/kg/min, 12 patients were receiving cangrelor at a dose of 0.375 mcg/kg/min, and one patient was receiving cangrelor at a dose of 1 mcg/kg/min.

Cost Analysis

Compared to a standard dose of 0.75 mcg/kg/min, dose-adjusted cangrelor using PFT led to a median drug cost savings of $1605.60 (IQR: $0–4281.56). A majority of patients (64.3%) had drug cost savings with PFT-adjusted cangrelor dosing. Fourteen patients (33.3%) had neutral cost savings with PFT-adjusted cangrelor dosing, and one patient had higher drug costs due to receiving a dose of 1 mcg/kg/min.

Clinical Outcomes

No patients had stent thrombosis. Composite MACE was low with two patients experiencing an ischemic stroke and requiring coronary revascularization, respectively (Table 4). Bleeding events were frequent, with 16 patients (38.1%) experiencing a major bleed (Table 4). There was no significant difference in initial PRU value between patients with a bleeding event compared to patients who did not have a bleeding event (P = 0.91). Most patients (92.9%) received at least 1 unit of packed red blood cell transfusion. In-hospital death occurred in 13 patients (31%).

Table 4.

Clinical Outcomes.

Outcome	N = 42
Stent thrombosis, n (%)	0 (0)
Composite MACE, n (%)	4 (9.5)
Ischemic Stroke	2 (4.8)
Myocardial Infarction	0 (0)
Revascularization	2 (4.8)
Major bleeding, n (%)	16 (38.1)
Minor bleeding, n (%)	8 (19)
Major or minor bleeding, n (%)	24 (57.1)
PRBC transfusion, n (%)	39 (92.9)
Total units of PRBC, median (IQR)	5 (2–9.8)
In-hospital mortality, n (%)	13 (31)
ICU LOS (days), median (IQR)	15 (10.3–23)
Hospital LOS (days), median (IQR)	20.5 (11.3–30.3)

Abbreviations: ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; MACE, major adverse cardiovascular events; PRBC, packed red blood cell.

Discussion

Our study is the first to evaluate PFT-guided dose adjustments with cangrelor in patients with temporary MCS or as a bridge to procedure using a standardized protocol. No patients had a stent thrombosis event, and a composite MACE was low at 9.5% in our study. Despite a reduced median cangrelor dose of 0.5 mcg/kg/min in this study, major bleeding events were common and occurred in 38% of patients. Our protocol aimed for a goal PRU between 85 and 208. Two-thirds of patients had a subsequent PRU within goal range after initial dose adjustment with a median TTR of 66.6% during the study period.

Most patients in this study received IV cangrelor while on temporary MCS with approximately 60% of patients receiving VA-ECMO. Patients supported with temporary MCS are at high risk of both bleeding and thrombotic events, and the balance between these events becomes more difficult to manage in patients who have received PCI, due to the need for dual antiplatelet therapy. Cangrelor allows for more consistent antiplatelet therapy in patients with cardiogenic shock and organ dysfunction, and the rapid onset and fast offset of action allows for ease of use to discontinue antiplatelet therapy for procedures or with a bleeding event.^1–3 In our study, major bleeding occurred in 38% of patients, and the composite MACE occurred in 9.5% of patients. Similar to our study, previous studies in patients with MCS on cangrelor have demonstrated higher bleeding events than thrombotic events with major bleeding occurring in 21–77% of patients and thrombotic events in 10–35% of patients.^4–6,12 Therefore, additional focus is needed to better reduce bleeding events while preventing thrombotic events. Utilizing PFT-guided cangrelor dosing in our study allowed for lower cangrelor dosing while maintaining adequate antiplatelet activity, which may reduce bleeding risk. While most of our patients were on triple antithrombotic therapy with aspirin, cangrelor, and an IV anticoagulant, discontinuation of aspirin after a short period of triple therapy may also be considered in these patients to reduce bleeding risk.^6,17

The optimal dosing of cangrelor in patients supported with MCS or as bridging therapy remains controversial. Several previous studies in patients supported with VA-ECMO or as bridging therapy used empiric cangrelor dosing of 0.75 mcg/kg/min based on similar dosing used in the BRIDGE trial.^4,5,7–11 Other studies allowed for lower cangrelor doses between 0.5 and 0.75 mcg/kg/min^12,13 with PRU monitoring or empiric dosing as low as 0.125 mcg/kg/min in one study of patients supported on VA-ECMO.⁶ In our study, we utilized an initial dose of 0.75 mcg/kg/min with subsequent dose adjustments based upon PRU values. While lower empiric dosing could be considered, this would likely lead to significant number of patients with high platelet reactivity based upon our results, which may predispose patients to stent thrombosis. Therefore, we believe an initial dose of 0.75 mcg/kg/min is most appropriate with subsequent individualized dose adjustments made based upon PRU values.

We utilized the VerifyNow P2Y12 assay for PFT in our study due to ease of use and clinical validation in patients receiving oral P2Y12 inhibitors after PCI.¹⁵ However, data on using the VerifyNow P2Y12 assay in patients supported with MCS on IV cangrelor is limited. The VerifyNow manufacturer packaging states that results have not been validated in patients with thrombocytopenia (platelet count < 119,000/µL) which frequently occurs in patients supported on MCS.^18–20 Additionally, PRU results are known to be impacted in patients with anemia which is also common in these patients.^21,22 Despite these known limitations, several previous studies have also utilized the VerifyNow P2Y12 assay in patients receiving IV cangrelor, including patients on temporary MCS.^11–13 Additional studies are warranted to better characterize the accuracy of the VerifyNow P2Y12 assay in patients supported with temporary MCS on cangrelor or if alternative PFT assays provide a more accurate assessment of antiplatelet response.

For dose adjustments with cangrelor in our study, we selected a goal PRU range between 85–208, which is based upon expert consensus values for low and high platelet reactivity.¹⁵ We hypothesized that maintaining the PRU in this range would reduce the risk of bleeding by avoiding excessive antiplatelet activity while maintaining adequate antiplatelet therapy to prevent thrombosis. This PRU goal range has not been externally validated in patients on cangrelor, and previous studies have used a variety of PRU goals in patients on cangrelor. In the BRIDGE trial, a goal PRU value of < 240 was used, with 98.8% of patients achieving this goal value throughout the study period on a cangrelor dose of 0.75 mcg/kg/min.¹¹ The mean PRU of the last sample was 68.9 in this study, which is below the 85 threshold for low platelet reactivity used in our study. Katz et al evaluated 17 patients on temporary MCS, and they did not have a standardized dose adjustment with cangrelor.¹² They utilized a goal PRU of 50–194 in this case series. In a case series of 11 patients on cangrelor for bridging therapy, a PRU goal of ≤ 208 was utilized to adjust the cangrelor dose.¹³ The median cangrelor dose was 0.5 mcg/kg/min, with 81.6% of PRU values falling within goal range. In our study, there was significant interpatient variability with PRU values on a cangrelor dose of 0.75 mcg/kg/min, and the median PRU value was 103.5 on this dose. A total of 29% of patients had PRU values < 85, and 14% of patients had values above 208 on 0.75 mcg/kg/min dosing. The median TTR with our dose-adjustment algorithm was 66.6%, which is less than previous studies, although our goal PRU range was much narrower than previous studies.

Use of PFT-guided cangrelor dosing was associated with a median drug cost savings of $1605.60 in our study compared to empiric dosing of 0.75 mcg/kg/min. We acknowledge that this analysis does not include the cost of the VerifyNow P2Y12 assay, which is a limitation. However, given the high cost of cangrelor, the impact of laboratory costs is expected to be minimal. In previous analyses, cangrelor has been demonstrated to reduce drug costs compared to other alternative therapy, such as eptifibatide, in bridging cases.^7,13

There are several limitations to this study. First, this study was conducted at a single center with a small number of patients, limiting overall generalizability. Additionally, our study was retrospective and observational in nature and, therefore, is susceptible to residual confounding variables. Without a comparator group, we are unable to make definitive conclusions on the impact of PFT-guided cangrelor dosing on clinical outcomes, such as bleeding and thrombotic events. Our PFT-guided protocol used initial PRU values within 12–24 h after cangrelor initiation and daily thereafter; so, it remains unclear how a more rapid cangrelor adjustment protocol may impact clinical outcomes. We did not evaluate anticoagulation control in our study, which may have impacted clinical outcomes. Even with a protocol for dose adjustment, several patients with PRU values above 208 did not receive subsequent dosing adjustments out of concern for bleeding risk. This limits evaluation of our dose adjustment protocol with cangrelor. Despite these limitations, our study provides real world evidence on clinical outcomes with the use of PFT-guided cangrelor dosing.

Conclusion

Utilizing PFT-guided cangrelor dosing successfully prevented stent thrombosis and resulted in comparable bleeding events to those previously reported. The cangrelor dosing protocol with a goal PRU of 85–208 led to a TTR of 66.6% and was associated with drug cost savings. Further studies are needed to determine if PFT-guided cangrelor dosing improves clinical outcomes compared to empiric dosing and clarify the optimal PFT to utilize in these patients.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Nathan J. Verlinden

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