Effect of pretreatment with a P2Y12 inhibitor in patients with non-ST-elevation acute coronary syndrome: a systematic review and network meta-analysis

Background This study aimed to systematically evaluate the effects of different types and doses of pretreatment with P2Y12 inhibitors in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). Methods Electronic databases were searched for studies comparing pretreatment with different types and doses of P2Y12 inhibitors or comparison between P2Y12 inhibitor pretreatment and nonpretreatment. Electronic databases included the Cochrane Library, PubMed, EMBASE, and Web of Science. Literature was obtained from the establishment of each database until June 2022. The patients included in the study had pretreatment with P2Y12 inhibitors with long-term oral or loading doses, or conventional aspirin treatment (non-pretreatment). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) during follow-up within 30 days after PCI, which included determining the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, and stroke. The safety endpoint was a major bleeding event. Results A total of 119,014 patients from 21 studies were enrolled, including 13 RCTs and eight observational studies. A total of six types of interventions were included—nonpretreatment (placebo), clopidogrel pretreatment, ticagrelor pretreatment, prasugrel pretreatment, double loading pretreatment (double loading dose of clopidogrel, ticagrelor, prasugrel) and P2Y12 inhibitors pretreatment (the included studies did not distinguish the types of P2Y12 inhibitors, including clopidogrel, ticagrelor, and prasugrel). The network meta-analysis results showed that compared to patients without pretreatment, patients receiving clopidogrel pretreatment (RR = 0.78, 95% CI:0.66, 0.91, P < 0.05) and double-loading pretreatment (RR = 0.62, 95% CI:0.41, 0.95, P < 0.05) had a lower incidence of MACCEs. There was no statistically significant difference in the incidence of major bleeding events among the six pretreatments (P > 0.05). Conclusions In patients with NSTE-ACS, pretreatment with P2Y12 inhibitors before percutaneous intervention reduced the incidence of recurrent ischemic events without increasing the risk of major bleeding after PCI compared with nonpretreatment. Clopidogrel or double loading dose P2Y12 inhibitors can be considered for the selection of pretreatment drugs.


Introduction
In patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), undergoing percutaneous coronary intervention (PCI), platelets are activated during the perioperative period, increasing the risk of stent thrombosis and coronary noreflow (1). Early oral antiplatelet loading doses can improve prognosis with similar safety (2). In these patients, dual antiplatelet therapy with aspirin and P2Y 12 inhibitors after PCI was effective in preventing the recurrence of thrombosis and ischemic events (3), also reducing the occurrence of major adverse cardiovascular events (MACEs) (4,5). However, whether patients with NSTE-ACS should be pretreated with oral P2Y 12 inhibitors before PCI remains controversial. With the widespread clinical application of new P2Y 12 inhibitors, data from 20 years ago supported the use of pretreatment (4,5). Therefore, the long-term efficacy of pretreatment with these drugs remains uncertain (6,7). The 2020 European Society of Cardiology (ESC) guidelines recommend that pretreatment with a P2Y 12 receptor inhibitor should be considered in patients with NSTE-ACS who do not plan to undergo an early invasive strategy and do not have a high bleeding risk (HBR) (IIb, C). Routine pretreatment with a P2Y 12 receptor inhibitor is not recommended in patients whose coronary anatomy is unknown, and early invasive management is planned (III, A). The effects of pretreatment with P2Y 12 inhibitors on bleeding and recurrent ischemic events in patients with NSTE-ACS undergoing PCI remain controversial. Therefore, we performed a network meta-analysis to assess the efficacy and safety of these therapies.

Inclusion and exclusion criteria
Studies were included for the following reasons: (1) randomized controlled trials and observational studies that compared P2Y 12 inhibitor pretreatment (intervention group or control group) in patients with NSTE-ACS following PCI; (2) patients were clearly diagnosed with NSTE-ACS (8); and (3) patients were administered oral P2Y 12 inhibitors before PCI. Additionally, the other treatments and nursing measures in the control group were the same as those in the intervention group and included conventional aspirin treatment.
Studies were excluded for the following reasons: (1) patients had other diseases that affected platelets and blood coagulation, such as severe hematological diseases or immune system diseases; (2) there was a combination of pretreatment and other interventions; and (3) the studies were duplicates.

Outcomes, definitions, and follow-up
The prognostic indicators synthesized in this study were the results of follow-up 30 days after PCI in patients with NSTE-ACS. The clinical endpoints analyzed included the following: The primary endpoint was major adverse cardiovascular and cerebrovascular event (MACCE) during follow-up within 30 days after PCI, and these MACCEs included the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, and stroke. The MACCEs in this study were reported in a single study and were not recalculated. The safety endpoint was a major bleeding event.

Data sources and search strategy
Electronic databases were searched for studies related to pretreatment with P2Y 12 inhibitors before PCI in patients with NSTE-ACS. The databases included the Cochrane Library, PubMed, EMBASE, and Web of Science. Literature retrieval, literature screening, data extraction, and data analysis were performed in accordance with the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines. Literatures were obtained from the establishment of each database until June 2022.
The search strategy was determined after multiple pre-searches using a combination of MeSH terms and free words, and fine adjustments were made based on a specific database. To reduce publication bias, manual queries were performed for relevant conference papers, academic reports, and dissertations to supplement the search results.
Duplicate literatures were removed using the Endnote software. Literatures were excluded by reading the title and abstract, based on the inclusion and exclusion criteria. Finally, related literatures were excluded by reading the full text. The selected studies were independently checked and cross-checked by two researchers. If the opinions of the two researchers were inconsistent, a third researcher negotiated to reach a consensus.

Data extraction and assessment of quality
Data extraction and quality evaluation were independently completed by two researchers using the quality evaluation criteria, and a cross-check was performed. If any disagreement occurred Li et al. 10.3389/fcvm.2023.1191777 Frontiers in Cardiovascular Medicine about the inclusion of certain data, a third researcher was included to conduct the discussion and reach a consensus. The data extracted from the articles included basic information, inclusion and exclusion criteria, type of research, sample size, type and dosage of P2Y 12 inhibitors, and outcome indicators. Quality was independently evaluated according to the method recommended in the Cochrane Handbook 5.1.0 (9). The evaluation included seven areas of the randomization method-allocation concealment, blindness of the participants and interveners, blindness of the measurement process, completeness of the outcome indicators (missing data), selective reporting, and other biases. The risk of bias for each area was judged as low, high, or unclear. Grade A included studies that fully met the abovementioned standards and had the lowest possibility of various deviations. Studies that partially met the above-mentioned criteria and had a moderate probability of bias were classified as grade B. Studies with a high probability of bias that did not meet the abovementioned criteria were grade C. The risk of bias in nonrandom studies of interventions (ROBINS-1) was used to evaluate the included cohort studies (10).

Statistical analysis
Stata software (version 17.0) was used for the data metaanalysis. Descriptive analyses were used for data that could not be quantitatively synthesized. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated for categorical variables. In the presence of a closed loop, the consistency between the direct and indirect comparisons was judged using the node-splitting method. When P < 0.05, the inconsistency was evident. The area under the cumulative ranking (SUCRA) showed the possibility of each intervention being the best.

Ranking result of pretreatment for MACCEs
The higher the SUCRA value of the pretreatment method, the fewer the MACCEs that occurred in patients receiving the pretreatment method. The SUCRA values of the six pretreatment methods were ranked from highest to lowest as follows: doubleloading pretreatment (SUCRA = 89.9), P2Y 12 inhibitor pretreatment (SUCRA = 69.1), clopidogrel pretreatment (SUCRA = 68.5), prasugrel pretreatment (SUCRA = 29.7), placebo (SUCRA = 23.8), and ticagrelor pretreatment (SUCRA = 18.9). The SUCRA curves for the different pretreatment methods are shown in Figure 4. Compared to the patients who did not receive pretreatment, those who received clopidogrel pretreatment (RR = 0.78, 95% CI: 0.66, 0.91, P < 0.05) and double-loading pretreatment (RR = 0.62, 95% CI: 0.41, 0.95, P < 0.05) had a lower incidence of MACCEs. Compared Li et al. 10.3389/fcvm.2023.1191777 Frontiers in Cardiovascular Medicine to the patients who received ticagrelor pretreatment, those who received double-loading pretreatment (RR = 0.60, 95% CI: 0.36, 0.99, P < 0.05) had a lower incidence of MACCEs ( Figure 3B). There were no significant differences in the other pairwise comparisons. Therefore, for MACCEs, it is better for patients to receive clopidogrel pretreatment and double-loading pretreatment than no pretreatment; it is better for patients to receive double-loading pretreatment than ticagrelor pretreatment.

Major bleeding events
Meta-analysis results for major bleeding events Sixteen studies with major bleeding events were included in the subgroup analysis (52,056 patients with NSTE-ACS) (4, 5, 11-13, 15-17, 19, 21-26, 28). The results of the inconsistency test showed that the inconsistency was not significant (I 2 = 0.04, P = 0.851); therefore, the consistency model was used for the analysis. The network plots are shown in Figure 5. The results of the loop inconsistency test showed that loop inconsistency was not significant (P > 0.05). The results of the direct meta-analysis are shown in Figure 6A. The network meta-analysis results showed no statistically significant differences in the incidence of major bleeding events among the six interventions ( Figure 6B).

Ranking result of pretreatment for major bleeding events
The higher the SUCRA value of the pretreatment method, the fewer major bleeding events occurred in the patients who received the pretreatment method. The SUCRA values of the six   Figure 7. There were no significant differences in the pairwise comparisons.

Publication bias and contribution plot
Funnel plots were constructed to test for publication bias (Figures 8A,B). Funnel plots showed that there was a publication bias in this study. A total of 21 studies were included in the metaanalysis. However, the number of studies included was insufficient for each comparison between the two groups. According to the Cochrane Handbook, funnel plots should only be used when the number of studies included is not less than 10 for each outcome indicator. With an extremely small number of included studies, the test efficiency was too low to distinguish between opportunity and true asymmetry. However, two retrieval methods were used to reduce publication bias. Duplicate published studies were excluded to avoid the use of the same data. A contribution plot was constructed for the network (Figures 9A,B).

Discussion
Twenty-one studies involving 119,014 patients with NSTE-ACS were included in this network meta-analysis. We compared different pretreatment strategies for P2Y 12 inhibitors to analyze the impact of P2Y 12 inhibitor pretreatment on the incidence of MACCEs and major bleeding events in patients with NSTE-ACS. The results were as follows: 1) pretreatment with a P2Y 12 inhibitor before PCI in patients with NSTE-ACS reduced the incidence of MACCEs without increasing the risk of major bleeding events; 2) clopidogrel or a P2Y 12 inhibitor with a double-loading dose could be selected as the pretreatment scheme; and 3) compared with pretreatment with ticagrelor, a P2Y 12 inhibitor with a double loading dose could reduce MACCEs.
Current guidelines recommend that patients with ST-elevation myocardial infarction be administered P2Y 12 inhibitors orally before PCI (30). However, whether P2Y 12 inhibitor pretreatment should be administered to patients with NSTE-ACS remains controversial (31). In addition, several meta-analyses have discussed P2Y 12 inhibitor pretreatment (32-37), but there were differences in the types of objects in these meta-analyses. Some studies focused on patients with ACS or all patients receiving PCI (32-35) and did not distinguish between NSTE-ACS patients. Two meta-analyses discussed P2Y 12 inhibitor pretreatment in patients with NSTE-ACS, and one meta-analysis included patients with NSTE-ACS (36). However, considering that there are many methods for P2Y 12 inhibitor pretreatment (different drug types and timings), if the methods of P2Y 12 inhibitor pretreatment are not differentiated, this may lead to Frontiers in Cardiovascular Medicine some heterogeneity in the meta-analysis. Another network metaanalysis divided the interventions into six groups: early clopidogrel, delayed clopidogrel, early prasugrel, delayed prasugrel, early ticagrelor, and delayed ticagrelor (37). The duration of follow-up was between 1 and 12 months in the nine included studies, which may also lead to some heterogeneity in the meta-analysis. In addition, we believe that the risks and benefits of P2Y 12 inhibitor pretreatment are mainly shown within 1-month of PCI. Therefore, we systematically reviewed all direct and indirect evidence from randomized controlled trials and observational cohort studies to establish this network metaanalysis, clarify the potential risks and benefits of P2Y 12 inhibitor pretreatment in patients with NSTE-ACS, and compare the differences between pretreatment schemes. Based on the type, dosage, and timing of P2Y 12 inhibitors, the interventions were divided into placebo, clopidogrel, ticagrelor, prasugrel, P2Y 12 inhibitors, and double-loading pretreatment. We ranked all potential combinations of P2Y 12 inhibitor pretreatments for MACCEs and bleeding events in patients with NSTE-ACS. For MACCEs, the SUCRA values indicated that the priority of the selected pretreatment scheme was double-loading pretreatment, P2Y 12 inhibitor pretreatment, clopidogrel pretreatment, prasugrel pretreatment, placebo, and ticagrelor pretreatment. The network meta-analysis results showed that, compared with patients without pretreatment, patients who received clopidogrel pretreatment (P < 0.05) and double-loading pretreatment (P < 0.05) had a lower incidence of MACCEs. Compared to patients who received ticagrelor pretreatment, those who received double-loading pretreatment (P < 0.05) had a lower incidence of MACCEs. For major bleeding events, the SUCRA values suggested that the priority of the selected pretreatment scheme was P2Y 12 pretreatment, double-loading, ticagretor, placebo, clopidogrel, and prasugrel pretreatment. Therefore, pretreatment with P2Y 12 inhibitors significantly reduced the number of recurrent ischemic events without increasing the  Network plots (MACCEs). 1 = placebo, 2 = clopidogrel pretreatment, 3 = ticagrelor pretreatment, 4 = prasugrel pretreatment, 5 = P2Y 12 inhibitor pretreatment, 6 = double pretreatment.
Li et al. 10.3389/fcvm.2023.1191777 Frontiers in Cardiovascular Medicine occurrence of major bleeding events. Clopidogrel or P2Y 12 inhibitors (clopidogrel, ticagrelor and prasugrel) with a doubleloading dose should be selected as the pretreatment protocols for patients with NSTE-ACS. Clopidogrel was the main pretreatment drug in the early studies. Clopidogrel was used as a pretreatment drug in 13 of the 21 studies included in our study. Compared with no pretreatment, the incidence of MACCEs within 30 days of PCI was lower. However, compared to a single loading dose (300 mg) of clopidogrel, a double-loading dose (600 mg) of clopidogrel did not show an advantage. The pretreatment method included a maintenance dose of 75 mg clopidogrel for 5 days or a loading  Frontiers in Cardiovascular Medicine dose of 300 mg clopidogrel before PCI. An early CURE study showed that the incidence of MACEs in patients with NSTE-ACS in the clopidogrel group was significantly reduced (9.3% vs. 11.4%, P < 0.001); however, the number of major bleeding events was significantly higher in patients with NSTE-ACS than in those in the control group (3.7% vs. 2.7%, P = 0.001) (4). Additionally, there was no significant difference in the number of fatal bleeding events between the two groups (2.1% vs. 1.8%, RR = 0.80, P = 0.13). Also, there were different research results regarding the timing of pretreatment. The onset of clopidogrel administration was relatively slow. Compared with patients who received clopidogrel pretreatment >6 h before PCI, those who received clopidogrel pretreatment <6 h before PCI had significantly fewer primary ischemic events (14). The pretreatment clopidogrel dose can be doubled in patients requiring rapid platelet inhibition within 6 h (18). With the gradual development and popularization of PCI, the emergence of new and more powerful antiplatelet drugs, and extensive application of drug-eluting stents in clinical practice, research on the application of new P2Y 12 inhibitors in the pretreatment of patients with NSTE-ACS before PCI has gradually increased. This meta-analysis included eight studies on ticagrelor and prasugrel, but two studies supported double-loading dose P2Y 12 inhibitors (24, 26), including ticagrelor and prasugrel, which were superior to pretreatment with ticagrelor in terms of the incidence of MACCEs, which may be related to the rapid inhibition of platelet activity. However, there are few studies, and the results may be inconsistent. Similarly, compared with a placebo, the use of a P2Y 12 inhibitor with a double-loading dose can inhibit platelet activity more quickly and reduce the occurrence of MACCEs.
Our network meta-analysis has increased our understanding of the existing evidence related to P2Y 12 receptor inhibitor pretreatment and clarified that P2Y 12 inhibitor pretreatment can reduce MACCEs within 30 days after PCI without increasing the number of bleeding events. However, more researches are needed to compare different P2Y 12 receptor inhibitor pretreatment schemes and determine the optimal P2Y 12 inhibitor pretreatment program for patients with NSTE-ACS. Compared with previous meta-analyses (32-37), our study showed some differences and advantages-this meta-analysis fully considered the differences in drug types, dosage, and administration timing of P2Y 12 inhibitors to evaluate the different pretreatment schemes; it summarizes all available information, including direct evidence and indirect estimates and provides the potential benefits and risks of each pretreatment method, and the age range of the patients included in the study was wide, ensuring the external validity of the results.
In summary, this study supports the use of pretreatment with P2Y 12 inhibitors in patients with NSTE-ACS. The suggested timing of pretreatment is when NSTE-ACS is diagnosed or before angiography. The pretreatment protocol is suggested to be clopidogrel [including 75 mg daily maintenance ≥5 days or loading dose (300 mg) before PCI] or a double-loading dose of a Network plots (major bleeding). 1 = placebo, 2 = clopidogrel pretreatment, 3 = ticagrelor pretreatment, 4 = prasugrel pretreatment, 5 = P2Y 12 inhibitor pretreatment, 6 = double pretreatment.   SUCRA curve (major bleeding). Frontiers in Cardiovascular Medicine and delayed CABG. If the patient needs to undergo coronary artery bypass grafting after angiography, ticagrelor should be discontinued for at least 3 days, clopidogrel for at least 5 days, and prasugrel for at least 1 week (38). Therefore, routine pre-treatment may cause high platelet inhibition and increase the risk of bleeding in some patients during the perioperative period. We observed that prasugrel alone increased the risk of major bleeding. In addition, pretreatment with clopidogrel and ticagrelor did not increase the risk of major bleeding (5,24). Some patients refused coronary artery bypass therapy after coronary angiography because of socioeconomic factors. These patients require long-term antiplatelet therapy to improve ischemia; therefore, there is no need to discontinue P2Y 12 inhibitors.

Limitation
However, this study has some limitations. First, the outcome indicators in this study were based on follow-up 30 days after PCI, which lacked laboratory-related indicators (platelet aggregation) and in-hospital bleeding. Future investigations of the perioperative period and related laboratory indicators should be performed. Second, the 21 studies included in our analysis comprised 13 randomized controlled trials and eight observational studies. In addition, the current research on P2Y 12 inhibitor pretreatment in patients with NSTE-ACS before PCI mainly included clopidogrel pretreatment. Third, for the definition of some endpoints, there were differences between the studies, especially TIMI bleeding, GUSTO bleeding, and MACCEs, which may lead to heterogeneity in this indicator. Fourth, it included open-label randomized controlled trials because it is difficult to use double-blind P2Y 12 inhibitor strategies and timing. Finally, the comparison between the use of a P2Y 12 inhibitor with a double loading dose and ticagrelor included only three studies, with a confidence interval of 0.36-0.99. Therefore, the results of this study need to be interpreted carefully.

Conclusions
For patients with NSTE-ACS, pretreatment with P2Y 12 inhibitors before PCI reduced the incidence of recurrent ischemic events without increasing the risk of major bleeding events after PCI compared with nonpretreatment. Clopidogrel or double loading dose P2Y 12 inhibitors can be considered for the selection of pretreatment drugs.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author contributions
ZX performed the main research. YL and ML conducted a literature search. ZZ and YY analysed the data. LA, JW, XS, and CL prepared the tables and figures. YL and ML wrote the main (A) contribution plot (MACCEs). Contribution plot for the network. The size of each square is proportional to the weight attached to each direct summary effect (horizontal axis) for the estimation of each network summary effect (vertical axis). The numbers re-express the weights as percentages. (A = placebo, B = clopidogrel pretreatment, C = ticagrelor pretreatment, D = prasugrel pretreatment, E = P2Y 12 inhibitor pretreatment, F = double pretreatment). (B) Contribution plot (major bleeding). Contribution plot for the network. The size of each square is proportional to the weight attached to each direct summary effect (horizontal axis) for the estimation of each network summary effect (vertical axis). The numbers re-express the weights as percentages. (A = placebo, B = clopidogrel pretreatment, C = ticagrelor pretreatment, D = prasugrel pretreatment, E = P2Y 12 inhibitor pretreatment, F = double pretreatment).
Li et al. 10.3389/fcvm.2023.1191777 Frontiers in Cardiovascular Medicine article. ZX critically reviewed and revised the article. All authors contributed to the article and approved the submitted version.