Comparison of VerifyNow, thromboelastography, and PL-12 in patients with minor ischemic stroke or transient ischemic attack

Results

Baseline characteristics

Among 675 patients enrolled in the PRINCE trial, 276 patients were included in this analysis. The baseline characteristics of patients included and excluded in the subgroup analysis were shown in Supplementary Table 1. The median age of the participants included in the subgroup analysis was 61 years, and 28.9% of them were women. The index event was a minor stroke in 231 patients (83.7%) and a TIA in 45 patients (16.3%). The baseline laboratory characteristics were also compared between these two groups (Supplementary Table 1).

Platelet function results

About 44 patients (15.94%) were detected to have HOPR-ADP via VerifyNow. TEG showed 39 patients (14.13%) with HOPR-ADP. About 14 patients (5.07) were detected to have HOPR-ADP by PL-12. Twenty-five patients (9.10%) showed HOPR-AA via VerifyNow. A number of 36 patients (13.04%) showed HOPR-AA via TEG, and 8 patients (2.90%) was found HOPR-AA in the PL-12.

Comparison of different tests in assessing HOPR-ADP

The correlation between VerifyNow and TEG is highest in our study (r=0.64, p<0.001; Table 1). The kappa value is 0.31 (Table 2). The receiver operating characteristic (ROC) curve analysis suggests that 49.2% should be the cutoff value for PL-12, with 98% sensitivity and 16% specificity (Supplementary Table 2). A limited correlation was found between VerifyNow and TEG (r=0.09, p=0.14; Table 1), and the kappa value was 0.03 (Table 2). The ROC analysis suggested that the cutoff value of ADPI should be 58.8% for TEG, with a sensitivity of 68.1% and a specificity of 81.8% (Supplementary Table 2). The correlation between VerifyNow and PL-12 was also obvious (r=0.47, p<0.001; Table 1). The kappa value was 0.22 (Table 2). The cutoff value of MAR_ADP should be 28.6% with 95.5% sensitivity and 67.7% specificity (Supplementary Table 2). TEG and PL-12 showed a moderate correlation (r=0.25, p<0.001; Table 1). The kappa value was 0.08 (Table 3). The comparison of these three methods is shown in Figure 1.

Table 1. Correlation between VerifyNow, thromboelastography (TEG), and PL-12 for HOPR-ADP.

Methods	PL-12		TEG
	r	p Value	r	p Value
VerifyNow	0.47	< 0.001	-0.64	< 0.001
TEG	-0.25	< 0.001
Because HOPR-ADP in the TEG test was defined as ADP inhibition < 30%, which was contrary to the trends of other tests, the r value was negative.

Table 2. Comparison between VerifyNow, thromboelastography (TEG), and PL-12 in identifying HOPR.

Method (agonist)	Definition of HOPR	Patients with HOPR n (%)	Kappa
VerifyNow (ADP)	PRU > 208	44 (15.9)	- (reference method)
TEG (ADP)	ADPI < 30%	39 (14.1)	0.31
PL-12 (ADP)	MARADP ≥ 55%	14 (5.1)	0.22
VerifyNow (AA)	ARU ≥ 550	25 (9.1)	- (reference method)
TEG (AA)	AAI < 50%	36 (13.0)	0.03
PL-12 (AA)	MARA > 50 %	8 (2.9)	0.14
HOPR, high on-treatment platelet reactivity; AA, arachidonic acid; ARU, aspirin reaction units; PRU, P2Y12 reaction units; AAI, arachidonic acid inhibition; ADPI, ADP inhibition; MARAA, maximal platelet aggregation ratio of arachidonic acid-stimulated platelets; MARADP, maximal platelet aggregation ratio of ADP-stimulated platelets.

Table 3. Comparison between thromboelastography (TEG) and PL-12 in identifying HOPR.

Method (agonist)	Definition of HOPR	Patients with HOPR n (%)	Kappa
TEG (ADP)	ADPI < 30%	39 (14.1)	0.08
PL-12 (ADP)	MARADP ≥ 55%	14 (5.1)
TEG (AA)	AAI < 50%	36 (13.0)	0.05
PL-12 (AA)	MARA > 50 %	8 (2.9)
HOPR, high on-treatment platelet reactivity; AA, arachidonic acid; AAI, arachidonic acid inhibition; ADPI, ADP inhibition; MARAA, maximal platelet aggregation ratio of arachidonic acid-stimulated platelets; MARADP, maximal platelet aggregation ratio of ADP-stimulated platelets.

Figure 1. Comparison of platelet function analyzers to assessing HOPR-ADP/AA. (A) The comparison between VerifyNow and TEG in assessing HOPR-ADP. (B) The comparison between VerifyNow and PL-12 in assessing HOPR-ADP. (C) The comparison between TEG and PL-12 in assessing HOPR-ADP. (D) The comparison between VerifyNow and TEG in assessing HOPR-AA. (E) The comparison between VerifyNow and PL-12 in assessing HOPR-AA. (F) The comparison between TEG and PL-12 in assessing HOPR-AA.

Comparison of different tests in assessing HOPR-AA

HOPR-AA was limited among VerifyNow, TEG and PL-12. VerifyNow and PL-12 got a weak correlation (r=0.15, p=0.01; Table 4), and the kappa value was 0.14 (Table 2). The ROC analysis suggested that 49.2% should be the cutoff value for PL-12, with 98% sensitivity and 16% specificity (Supplementary Table 2). A limited correlation was found between VerifyNow and TEG (r=0.09, p=0.14; Table 4), and the kappa value was 0.03 (Table 2). The ROC analysis suggested that the cutoff value of TEG-AA inhibition should be 97.4% for PL-12, with 76% sensitivity and 56% specificity (Supplementary Table 2). The correlation between PL-12 and TEG was also limited (r=0.10, p=0.09; Table 4), and the kappa value was 0.05 (Table 3). The comparison of these three methods is shown in Figure 1.

Table 4. Correlation between VerifyNow, thromboelastography (TEG), and PL-12 for HOPR-AA.

Methods	PL-12		TEG
	r	p Value	r	p Value
VerifyNow	0.15	0.01	-0.09	0.14
TEG	-0.10	0.09
Because HOPR-AA in the TEG test was defined as arachidonic acid inhibition < 50%, which was contrary to the trends of other tests, the r value was negative.

Relationships between HOPR detected by platelet function analyzers and clinical outcomes

Table 5 showed the relationship between HOPR and clinical outcomes. The proportions of stroke recurrence and composite events in patients with HOPR-ADP assessing by PL-12 were higher than VerifyNow and TEG. At 3 months, 2 patients (14.3%) who were found HOPR-ADP by VerifyNow got stroke recurrence and composite events, but no significant correlation was found (p=0.26). Compared with VerifyNow, TEG/PL-12 had lower proportion of stroke among patients with HOPA-ADP (VerifyNow: 13.6%, p=0.05; TEG: 7.7%, p=0.83). Two patients (25.00%) with HOPR-AA assessed by PL-12 were found stroke recurrence and composite events, and 2 (8.0%) were found in VerifyNow. TEG found that three patients (8.3%) with HOPR-AA got recurrent stroke.

Table 5. The association between HOPR and clinical outcomes in patients with HOPR monitored by VerifyNow, TEG and PL-12.

		Stroke recurrence		Composite events
		N (%)	P value	N (%)	P value
HOPR-ADP	VerifyNow	6 (13.6)	0.05	6 (13.6)	0.13
	TEG	3 (7.7)	0.83	3 (7.7)	0.94
	PL-12	2 (14.3)	0.26	2 (14.3)	0.37
HOPR-AA	VerifyNow	2 (8.0)	0.82	2 (8.0)	0.99
	TEG	3 (8.3)	0.71	3 (8.3)	0.93
	PL-12	2 (25.0)	0.04	2 (25.0)	0.07
HOPR-AA, high on-treatment platelet reactivity of AA; HOPR-ADP, high on-treatment platelet reactivity of ADP.

Materials and Methods

Overview of the PRINCE trial and the platelet function test substudy

The PRINCE (Effect of Ticagrelor with Clopidogrel on High On-treatment Platelet Reactivity in Acute Stroke or Transient Ischemic Attack) trial was designed as a prospective, multicenter, randomized, open-label, active-controlled, and blind-endpoint, phase IIb trial [1, 22]. The details of the design, rationale, and major results have been previously described. The data of the present subgroup analysis were derived from the prespecified platelet function test substudy of the PRINCE trial. The substudy involved three visits: 2 hours after taking the first agents, 24 hours after taking the first agents, and day 7 + 2 days. The blood samples of this subgroup were collected at 2–4 hours after taking the investigational drugs. Patients without all three platelet function tests at 7 days were excluded from the present analysis. Of the 26 centers included in the PRINCE trial, a total of 276 participants in 11 centers voluntarily participated in this analysis, in which the platelet reactivity was evaluated by VerifyNow, TEG, and PL-12 (Figure 2).

Figure 2. Flow diagram for the enrollment process of this study from the PRINCE trial.

Standard protocol approvals, registrations, and patient consents

The PRINCE trial was registered in ClinicalTrials.gov (NCT02506140) and approved by the ethics committee of Beijing Tiantan Hospital and all centers. Written informed consent was obtained from all participants or their legal representatives before being entered into the study.

Blood sampling

Six tubes of peripheral venous blood samples were collected at 2–4 hours after taking the investigational drugs. The first 2 mL of blood was discarded. A 3.2% sodium citrate tube (Greiner Bio-One Vacuette North America Inc., Monroe, NC) was used for VerifyNow analysis. A heparin tube (Becton-Dickinson, Franklin Lakes, NJ) was used for the TEG test, and two 3.2% sodium citrate tubes (Becton-Dickinson, Franklin Lakes, NJ) were used for the TEG and PL-12 tests, respectively. The tubes were gently inverted 10 times to ensure complete mixing of the blood sample with the anticoagulant. Blood samples were kept at 27° C before testing. The whole procedure needed to be performed within 2 hours after sampling.

Platelet function tests

VerifyNow analysis

The VerifyNow system (Accumetrics, San Diego, CA, USA) is a point-of-care test based on the optical change in whole blood samples to identifying platelet function [4, 23]. The whole blood sample was decanted into the reaction cartridge after being inserted into the apparatus. We used the aspirin- and P2Y12-specific cartridges to identify platelet dysfunction caused by aspirin and clopidogrel, respectively. Arachidonic acid (AA) was the platelet activation agent used in the aspirin test. If aspirin was not effective, cyclooxygenase-1 was activated to transform AA to thromboxane A2, leading to platelet aggregation. The degree of aggregation is reported in aspirin reaction units (ARU). A value ≥ 550 ARU indicates HOPR-AA [24, 25]. In the P2Y12-specific cartridge, the P2Y12 receptor was specially suppressed by ADP, and the changes in light transmission was measured as P2Y12 reaction units (PRU). A value > 208 PRU was defined as HOPR-ADP [23, 26, 27].

TEG platelet mapping™ assay

TEG (Heamoscope Corporation, Niles, IL) is a noninvasive assay that tests platelet function [28]. Different agonists and anticoagulant venous blood samples were placed into a special cup. The concentration of the activator added to the whole blood was 1 mmol/L AA or 2 mmol/L ADP. A special cup containing venous blood was rotated at 4° 45′, with each rotation lasting 10 s. The fibrin-platelet complex cohered to the cup, and the rotary torque of the cup was transferred to the pin immersed in the blood sample. The rotation of the pin was converted to electrical signals by electromechanical sensors, which were monitored by a computer. Maximum amplitude (MA) directly reflects the maximal clot strength that facilitates the formation of the cross-linked fibrin clot. The MA of the cyclooxygenase-1 pathway and P2Y12 was measured as MA_AA and MA_ADP, respectively. We defined a<50% and<30% inhibition of AA- and ADP-induced clot formation (i.e., TEG-AA inhibition, TEG-ADP inhibition [ADPI]) as HOPR-AA and HOPR-ADP, respectively [6, 29]. AA/ADPI was calculated using the following formula:

$\text{AA}\text{or}\text{ADP}\text{Inhibition}=100-100\times \left[\frac{\left({\text{MA}}_{\text{AA or ADP}}-{\text{MA}}_{\text{fibrin}}\right)}{\left({\text{MA}}_{\text{thromb}}-{\text{MA}}_{\text{fibrin}}\right)}\right]$

PL-12 analysis

The PL-12 platelet function analyzer (SINOWA Medical Science and Technology Co., Nanjing, China) is a new point-of-care platelet function analysis tool based on the SPCM [12]. SPCM was used to determine platelet parameters such as number and volume, and to calculate the platelet aggregation rate by using the change of platelet number before and after the agent was induced, thus allowing to dynamically evaluate the platelet function. The blood sample was gently mixed in a constant temperature for 10 min. Thereafter, 500 mL citrated blood sample was transferred to the detecting position. The whole analysis procedure was performed automatically. When the aggregated platelets were too large to be counted, they were dropped from the single platelet counting. PL-12 counted several times until the lowest level was detected. A value of MAR_AA > 50% was defined as HOPR-AA, and a value of MAR_ADP ≥ 55% was defined as HOPR-ADP. The maximal platelet aggregation ratio (MAR) was calculated using the following formula:

$$\begin{array}{l}\text{Percentage}\text{of}\text{MAR}\left(\%MAR\right)=\\ \{100-[\frac{\left(1^{\text{st}}\text{platelet count}+2^{\text{nd}}\text{platelet count}\right)}{2}\\ -\text{lowest platelet count}]\}\times 100\%\end{array}$$

Outcomes assessment

The study’s primary outcome was the proportion of patients with HOPR at 7 days. Secondary outcomes were clinical outcomes at 90 ± 7 days. The clinical outcomes included ischemic stroke and composite clinical vascular events (ischemic/hemorrhagic stroke, TIA, myocardial infarction, or vascular death) at 90 ± 7 days.

Statistical analysis

Continuous variables are presented as means with standard deviations or medians with interquartile ranges, and categorical variables are presented as percentages. The baseline characteristics were compared between the included group and the excluded group, using Student’s t-test or the Wilcoxon test for continuous variables, and the χ² test for categorical variables. Kappa analysis was used to assess the classification consistency of HOPR among the three methods. Pearson’s correlation coefficient was adopted to evaluate the relationships among methods when the data were in a normal distribution. The χ² test was used to compared HOPR and clinical outcomes. Two-sided p values<0.05 were considered statistically significant. All analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). Anonymized data are available to researchers on request for reproducing the results or replicating the procedures by contacting the corresponding author.

Author Contributions

Dr Yilong Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Ma, Chen, Yongjun Wang, Yilong Wang. Acquisition, analysis, or interpretation of data: Ma, Chen, Pan, Yan, Meng, Yilong Wang. Drafting of the manuscript: Ma, Chen. Critical revision of the manuscript and important intellectual contribution: Yongjun Wang, Yilong Wang. Statistical analysis: Pan, Yan, Li, Meng. Obtained funding: Yongjun Wang, Yilong Wang. Administrative, technical, or material support: Yilong Wang. Study supervision: Yongjun Wang, Yilong Wang.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81901177, 81825007, and 81971091); Beijing Outstanding Young Scientist Program (no. BJJWZYJH01201910025030); the “Thirteenth-Five” Key Development and Research Plan by the Ministry of Science and Technology of the People’s Republic of China (no. 2017YFC1307900); Beijing Hospitals Authority Youth Programme (QML20190501); Beijing Science and Technology Plan by Beijing Municipal Science and Technology Commission (no. D171100003017001); Beijing Tiantan Hospital, Capital Medical University (2018-YQN-1, 2020MP01); Beijing Excellent Talents Training and Supporting - Top Youth Team by Beijing Municipal Science and Technology Commission (no. 2016000021223TD03); Youth Beijing Scholar Program; and Beijing Talent Project - Class A: Innovation and Development (no. 2018A12).

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