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. 2023 Oct;38(10):1218-1227.
doi: 10.1007/s00380-023-02279-0. Epub 2023 Jun 15.

Time-dependent changes in P2Y12 reaction unit values for predicting the different types of cardiovascular events in patients with ischemic heart disease

Takatoku Aizawa  1 , Yasunori Inoue  2 , Satoshi Ito  1 , Satoshi Morimoto  1 , Kazuo Ogawa  1 , Tomohisa Nagoshi  1 , Kosuke Minai  1 , Takayuki Ogawa  1 , Makoto Kawai  1 , Michihiro Yoshimura  1
Affiliations

Time-dependent changes in P2Y12 reaction unit values for predicting the different types of cardiovascular events in patients with ischemic heart disease

Takatoku Aizawa et al. Heart Vessels. 2023 Oct.

Abstract

Several studies have investigated the association between P2Y12 reaction unit (PRU) value and major adverse cardiovascular events (MACEs) in patients with ischemic heart disease, but there is no well-established consensus on the utility of PRU value. Furthermore, the optimal PRU cut-off value varied with studies. One reason may be that the endpoints and observation periods differed, depending on the study. This study aimed to investigate the optimal cut-off and predictive ability of the PRU value for predicting cardiovascular events, while considering different endpoints and observation periods. We surveyed a total of 338 patients receiving P2Y12 inhibitors and measured PRU during cardiac catheterization. Using time-dependent receiver operating characteristic analysis, we evaluated the cut-off and area under curve (AUC) of the PRU value for two MACEs (MACE ①: composite of death, myocardial infarction, stent thrombosis, and cerebral infarction; MACE ②: composite of MACE ① and target vessel revascularization) at 6, 12, 24 and 36 months after cardiac catheterization. MACE ① occurred in 18 cases and MACE ② in 32 cases. The PRU cut-off values at 6, 12, 24, and 36 months were 257, 238, 217, and 216, respectively, for MACE ① and 250, 238, 209, and 204, respectively, for MACE ②. The AUCs at 6, 12, 24, and 36 months were 0.753, 0.832, 0.718, and 0.717, respectively, for MACE ① and 0.724, 0.722, 0.664, and 0.682, respectively, for MACE ②. The optimal cut-off and predictive ability of PRU values for cardiovascular events varied depending on different endpoints and duration of the observation periods. A relatively high PRU value is effective for short-term event suppression, but a low value is required for long-term event suppression.

Keywords: Major adverse cardiovascular event; Optimal cut-off value; P2Y12 reaction unit; Time-dependent receiver-operating characteristic analysis.

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Conflict of interest statement

Takayuki Ogawa reports that there are no relevant conflicts of interest. Outside the submitted work, Takayuki Ogawa received personal fees from Terumo Co. and personal fees from Kaneka Co. Makoto Kawai has no conflict of interest and reports that there are no relevant conflicts of interest. Outside the submitted work, Makoto Kawai received scholarship donations from Daiichi Sankyo Co., Ltd. Michihiro Yoshimura reports that there are no relevant conflicts of interest. Outside the submitted work, Michihiro Yoshimura received lecture fees from Mochida Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Kowa Co., Ltd., and Astra Zeneca Plc., as well as scholarship donations from Teijin Pharma Ltd. and Shionogi & Co., Ltd. The other authors have no conflict of interest.

Figures

Fig. 1
Fig. 1
Incidence rates of MACE ① and MACE ②. A The cumulative incidence rates for MACE ① (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, and non-fatal cerebral infarction) at 6, 12, 24, and 36 months were 1.8%, 3.0%, 3.8%, and 5.3%, respectively. B The cumulative incidence rates for MACE ② (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, non-fatal cerebral infarction, and TVR) at 6, 12, 24, and 36 months were 2.4%, 5.0%, 8.0%, and 9.5%, respectively. MACE, major adverse cardiovascular event; TVR, target vessel revascularization
Fig. 2
Fig. 2
Time-dependent ROC curves of the PRU values for MACE ① and MACE ② at 6, 12, 24, and 36 months during follow-up. A Time-dependent ROC curve for MACE ① (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, and non-fatal cerebral infarction) at 6 months. B Time-dependent ROC curve for MACE ① at 12 months. C Time-dependent ROC curve for MACE ① at 24 months. D Time-dependent ROC curve for MACE ① at 36 months. E Time-dependent ROC curve for MACE ② (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, non-fatal cerebral infarction, and TVR) at 6 months. F Time-dependent ROC curve for MACE ② at 12 months. G Time-dependent ROC curve for MACE ② at 24 months. H Time-dependent ROC curve for MACE ② at 36 months. ROC, receiver operating characteristic; MACE, major adverse cardiovascular event; PRU, P2Y12 reaction unit; TVR, target vessel revascularization
Fig. 3
Fig. 3
Changes in AUC over time using time-dependent ROC analysis. The AUC of the PRU value for MACE ① (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, and non-fatal cerebral infarction) and MACE ② (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, non-fatal cerebral infarction, and TVR) were plotted monthly from the start of follow-up to 36 months. MACE, major adverse cardiovascular event; PRU, P2Y12 reaction unit; TVR, target vessel revascularization; ROC, receiver operating characteristic; AUC, area under the curve
Fig. 4
Fig. 4
Time-to event curves of MACE ① and MACE ②. By using the time-dependent ROC analysis, the optimal PRU cut-off value for predicting MACE ① (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, and non-fatal cerebral infarction) and MACE ② (composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, non-fatal cerebral infarction, and TVR) at 6, 12, 24, and 36 months was estimated. Furthermore, the target patients were divided into two groups based on the calculated optimal PRU cut-off value for each period, and the Kaplan–Meier curve was created. A Time-to-event curve of MACE ① from the start of follow-up to 6 months. B Time-to-event curve of MACE ① from the start of follow-up to 12 months. C Time-to-event curve of MACE ① from the start of follow-up to 24 months. D Time-to-event curve of MACE ① from the start of follow-up to 36 months. E Time-to-event curve of MACE ② from the start of follow-up to 6 months. F Time-to-event curve of MACE ② from the start of follow-up to 12 months. G Time-to-event curve of MACE ② from the start of follow-up to 24 months. H Time-to-event curve of MACE ② from the start of follow-up to 36 months. MACE, major adverse cardiovascular event; HR, hazard ratio; PRU, P2Y12 reaction unit; ROC, receiver operating characteristic; CI, confidence interval; TVR, target vessel revascularization
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