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Effect of preoperative loading dose ticagrelor and clopidogrel on no-reflow phenomenon during intervention in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis

Background Previous studies have shown that ticagrelor is more effective than clopidogrel in platelet inhibition. However, this conclusion remains controversial. Therefore, we performed this meta-analysis to assess the effect of preoperative loading dose ticagrelor and clopidogrel on no-reflow (NRF) during intervention in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). Materials and methods Randomized controlled trials and observational studies were reviewed. The retrieval time was limited from inception to October 1, 2017. The retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database, and the Wang Fang database. RevMan 5.3 software was used for data analysis. Results Fourteen randomized controlled trials and one observational study, including 4,162 patients, were included. In these articles, 1,521 patients were in the ticagrelor group (180 mg) and 2,641 patients were in the clopidogrel group (600 mg). The meta-analysis showed that compared with clopidogrel group, preoperative loading dose ticagrelor: 1) significantly reduced the incidence of NRF during PPCI (95% confidence interval [CI]: 0.15, 0.39, P<0.05) as well as the level of postoperative corrected thrombolysis in myocardial infarction frame count (95% CI: −8.89, −6.91, P<0.05); 2) significantly reduced the incidence of major adverse cardiovascular events during hospitalization, including 30 and 180 days after PPCI (95% CI: 0.41, 0.82, P<0.05; 95% CI: 0.15, 0.46, P<0.05, respectively); and 3) significantly improved thrombolysis in myocardial infarction flow after PPCI (95% CI: 1.40, 2.45, P<0.05). No significant difference was observed in terms of bleeding events within 30 and 180 days after PPCI (95% CI: 0.71, 1.54, P=0.82; 95% CI: 0.81, 3.19, P=0.18, respectively). Conclusion Compared with clopidogrel, loading dose ticagrelor effectively reduced both the occurrence of NRF during PPCI and the incidence of major adverse cardiovascular event in patients with ST-segment elevation myocardial infarction undergoing PPCI. Furthermore, it did not increase the risk of bleeding after PPCI.


Introduction
Currently, with the improvement in living standards and the changes in diet and living environments, the incidence of coronary heart disease (CHD) has increased. 1 Acute STsegment elevation myocardial infarction (STEMI), a type of CHD, is a common global disease with a high mortality rate that is caused by a sharp reduction of coronary blood supply from an infarct-related artery (IRA). In general, the blockage, based on unstable coronary atherosclerotic plaque rupture and thrombosis, results in decreased blood flow in the IRA. As a consequence, some cardiac muscle is unable to function properly, and if the myocardium remains ischemic for a few hours, it becomes necrotic. Thus, recovering the blood flow in the IRA and performing revascularization as soon as possible are the most important treatments to improve the prognosis of patients with STEMI. Primary percutaneous coronary intervention (PPCI) is an important means of treating patients with STEMI, so that the IRA can be opened quickly and effectively. In addition, before PPCI, effective antiplatelet therapy is of critical importance in patients with STEMI. The newest European and American guidelines for STEMI both recommend that it is necessary for patients with STEMI undergoing PPCI to take one kind of P2Y12 receptor antagonist combined with aspirin as soon as possible for antiplatelet therapy.
Previous studies have demonstrated that the loading dose ticagrelor, a new P2Y12 receptor antagonist, is more effective and has a faster antiplatelet effect than clopidogrel. 2,3 This superior antiplatelet effect allows ticagrelor to effectively reduce thrombosis and prevent ischemic events. In addition, the global multicenter, double-blind, randomized controlled PLATO trial suggested that ticagrelor is effective in improving the prognosis of patients with acute coronary syndrome (ACS), and that the same improvement was demonstrated in the subgroup of patients with STEMI in PLTAO trial. 4 The no-reflow (NRF) phenomenon occurs when, although the revascularization of IRA has been completed, the blood flow of IRA in angiography is still obstructed and cannot restore thrombolysis in myocardial infarction (TIMI) flow 3 (TIMI3), excluding the cause of coronary spasm, dissection, thrombosis, and other external factors. NRF causes myocardium ineffective perfusion and significantly affects the prognosis of patients with STEMI. 5 Some studies have shown that the incidence of NRF in patients undergoing PPCI is higher than that in patients undergoing selective PCI; this incidence is ~10%-30%, depending on the incomplete statistics. 6 Although there are many mechanisms that lead to the occurrence of NRF, the predominant cause is that the debris from fissured or ruptured atherosclerotic plaque during PCI moves downstream and forms a microembolism, which can mechanically block the distal blood vessels. 7 Therefore, strengthening antiplatelet therapy and reducing the formation of microembolisms may be ways to prevent the occurrence of NRF during PPCI.
Some studies found that the administration of preoperative loading dose ticagrelor can reduce the incidence of NRF during PPCI and effectively improve coronary blood reperfusion. 8,[10][11][12] However, the conclusions have been inconsistent. The ATLANTIC study reported that prehospital ticagrelor did not improve early coronary reperfusion more than in-hospital ticagrelor did in patients with new STEMI undergoing PPCI. 9 In addition, some of these trials had small samples, resulting in poor clinical reliability. A few scholars have directly compared the efficacy of ticagrelor to clopidogrel with respect to the incidence of NRF phenomenon during interventions in patients with STEMI undergoing PPCI. Therefore, we performed this meta-analysis to assess the effect of preoperative loading dose ticagrelor and clopidogrel on NRF during interventions in patients with STEMI undergoing PPCI to provide a guide for clinical application.

Materials and methods literature search
According to the guidelines of the preferred reporting items for systematic reviews and meta-analyses, two researchers independently searched for published articles investigating the effects of preoperative loading dose ticagrelor and clopidogrel on NRF phenomenon during intervention in patients with STEMI undergoing PPCI. The retrieved databases included PubMed, Embase, the Cochrane Library, Web of Science, CBM, CNKI, the VIP database, and the Wang Fang database. The retrieval time was limited from inception to October 1, 2017. The search was performed using the keywords "(Ticagrelor) and (STEMI) and (no-reflow) and (PPCI)" for all articles available. Relevant keywords related to ticagrelor in combination with MeSH terms and text words ("Brilinta" or "AZD 6140" or "AZD6140") were used in combination with words related to ST-segment elevation myocardial infarction ("STEMI" or "ST Elevated Myocardial Infarction") and words related to the NRF phenomenon ("Slow-Flow Phenomenon" or "Slow-Flow" or "Slow Flow Phenomenon"). Articles written in English and Chinese were chosen, and the references of the extracted articles were retrieved. When the same study was reported by multiple journals, we used the most recent article. Because this analysis was based on previously published studies, there was no requirement for ethical approval or patient consent. We identified studies that assessed the effect of preoperative loading dose ticagrelor and clopidogrel on NRF during interventions in patients with STEMI undergoing PPCI. In the literature review, we first read the text and summary to exclude irrelevant literature, and we then read the full text to determine the final studies for inclusion according to the inclusion/exclusion criteria. inclusion criteria 1) All patients met the STEMI diagnostic criteria recommended by the newest American College of Cardiology/ American Heart Association guideline and underwent PPCI treatment to complete revascularization; 2) the studies were limited to randomized controlled trials (RCTs) and observational studies; 3) patients with chest pain ,12 h; 4) the experimental group used ticagrelor 180 mg combined with aspirin for antiplatelet therapy, and the control group used clopidogrel 600 mg combined with aspirin for antiplatelet therapy; 5) the duration of use for each P2Y12 receptor antagonist was limited before PPCI; 6) coronary angiography confirmed the IRA of each patient based on thrombotic infarction, and all patients completed PPCI treatment; 7) patients were older than 18 years; and 8) article provided sufficient data for analysis. exclusion criteria 1) Articles with incomplete or erroneous data; 2) patients were allergic to ticagrelor or clopidogrel; 3) patients had a history of recent major bleeding, malignant tumor, pulmonary infraction, serious infections, coagulation dysfunction, platelet abnormalities, or other hemorrhagic blood system diseases; 4) over the past 6 months, patients had a history of cerebral hemorrhage, surgery, or trauma; 5) patients were diagnosed with cardiogenic shock or cardiac function $Killip III; 6) patients were suspected of aortic dissection; and 7) dysfunctional patients.

Data extraction
The contents of the retrieved studies that were selected according to the prior search methods were scanned and extracted by two reviewers independently. Homemade data extraction tables were used to extract the data. Then, two reviewers cross-checked the data. If there were any discrepancies, the extracted data were subjected to thirdparty decision. The extracted data included basic data of the subjects (first author, year of publication, country, mean age, male/female ratio), intervention measure, and observation index. If there was a lack of necessary information in the article, we made every effort to contact the author and acquire complete data, and we excluded the article if the necessary data remained unavailable.

statistical analysis
We used Review Manager 5.3 software for data analysis. Odds ratio and mean difference were used as the effect index. Pooled results were presented with 95% confidence intervals (CIs) with two-sided P-values. P,0.05 indicated that the difference was statistically significant. Heterogeneity of the inclusion study was assessed using the I 2 test to assess the appropriateness of pooling the individual study results. When I 2 ,50%, the heterogeneity of the study was considered small; when I 2 .50%, the heterogeneity of the study was considered substantial. Funnel plots were used to investigate the sources of heterogeneity.

Results
We searched the relevant articles that were written in Chinese or English and that were published from inception to October 1, 2017. In total, 14 RCTs and one observational comparative study, including 4,162 patients, were included in our metaanalysis. 8,[10][11][12][13][14][15][16][17][18][19][20][21][22][23] The literature screening process and results are shown in Figure 1. Among these articles, 1,521 patients were placed in the ticagrelor (180 mg) group, and 2,641 patients were placed in the clopidogrel (600 mg) group. The basic information of the included studies is summarized in Table 1.

Discussion
The most important treatment for acute STEMI is the timely completion of IRA reperfusion. Under conditions of a mature interventional technique and necessary medical equipment, primary PCI is considered the first-choice treatment for patients with STEMI. 24 PPCI can quickly and effectively open the IRA and complete IRA reperfusion to avoid myocardial ischemia. After the completion of PPCI, most symptoms related to STEMI can improve immediately, and coronary blood flow can be restored to TIMI3. However, in a small proportion of patients, coronary blood flow continues to exhibit overt obstruction or slow flow despite the successful opening of IRA, after excluding vessel spasm, dissection, and other external causes. This phenomenon is called NRF.

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Ticagrelor and clopidogrel on no-reflow phenomenon Some studies have shown that PPCI is more likely to occur with the NRF phenomenon during intervention, with an incidence of ~10%-30%. 25 Simultaneously, compared with patients without NRF phenomenon during PPCI, the mortality of the NRF group was higher at 30 days and 6 months. 26 In addition, Ndrepepa et al found that when patients with NRF achieved normal blood flow, their left ventricular ejection fraction was higher than before and that the occurrence of NRF could be used as an independent predictor of death. 27 It is generally believed that the main mechanism of NRF is thrombus and plaque debris caused by stenting or balloon dilatation moving downstream, leading to distal vascular mechanical microembolization. 28 The treatment of NRF often returned poor results, and prevention is more important than treatment. 29 Thus, strengthening dual antiplatelet therapy, which is the preoperative basic treatment of PPCI, may inhibit platelet function and reduce the formation of microembolization by decreasing platelet adhesion to debris. This may be the key treatment for preventing NRF during PPCI. A new P2Y12 receptor inhibitor, ticagrelor, provides better outcomes compared with clopidogrel, as demonstrated in patients with ACS in the PLATO trial. However, few large clinical trials have investigated the influence of preoperative loading dose ticagrelor on the NRF phenomenon during PPCI in patients with STEMI.
In our current meta-analysis, we found that compared with the clopidogrel group, preoperative loading dose ticagrelor significantly reduced the incidence of the NRF phenomenon during PPCI (χ 2 =2.54, I 2 =0%, 95% CI: 0.15, 0.39, P,0.05), suggesting that preoperative loading dose ticagrelor may reduce the formation of microembolization resulting in NRF, improving reperfusion more effectively than did loading dose clopidogrel. This effect may occur via more potent platelet inhibition or other effects of ticagrelor that could provide potential benefits in patients with ACSs.
Clopidogrel is a thiophene pyridine antiplatelet active drug precursor that requires the metabolic activation of liver enzymes to produce active drugs and before taking effect. However, ticagrelor, which belongs to the cyclopentyltriazolol-pyrimidine family, directly reversibly inhibits the P2Y12-ADP receptor. Thus, the theoretical onset time is shorter than that of clopidogrel. 30 In the ONSET/OFFSET study, patients with stable coronary disease were selected as research objects and were randomly assigned to receive treatment with loading dose ticagrelor (180 mg, n=57) or clopidogrel (600 mg, n=54). 31 The mean time to maximal platelet inhibition was ~2 hours in the ticagrelor group and 7.8 hours in the clopidogrel group. In particular, platelet inhibition was higher in the ticagrelor group at 0.5 hour (41% vs 8%, P,0.0001), indicating that the onset time of ticagrelor was very short. Another study used a VerifyNow device to detect changes in P2Y12 reaction units (PRUs) after loading dose ticagrelor and clopidogrel in patients with ACS undergoing PCI who were low-risk, troponin-negative, and had not used P2Y12 receptor inhibitor previously. 32 After 2 hours of loading dose, the PRU of the ticagrelor group was significantly lower than that of the clopidogrel group (98.4 vs 257.5, P,0.001). This experimental design ruled out the impact of previous use of P2Y12 receptor antagonist and probably reflected the rapid effect of antiplatelet of ticagrelor.
Despite the potent and fast platelet inhibition of the P2Y12 receptor inhibitor ticagrelor, other effects associated with NRF were also found. Adenosine, as a common metabolite, increases coronary flow velocity and inhibits platelet activation by the A2A and A2B receptors. 33 However, adenosine is usually taken up rapidly by erythrocytes in vivo and thus cannot maintain the effect of inhibiting platelets for a long time. 34 Bonello et al designed a study in which 60 patients with ACS were randomized to a ticagrelor group or a clopidogrel group, and the results showed that the patients in the ticagrelor group had higher plasma levels of adenosine, suggesting that ticagrelor increased the plasma concentration of adenosine. 35 The mechanisms explaining this result could be that ticagrelor not only promoted the ATP that came from the degradation of erythrocytes into adenosine 36 but also inhibited the ENT1 pathway on the erythrocyte membranes to reduce the uptake of adenosine by erythrocytes. 37 This effect of higher levels of adenosine provides ticagrelor with an additional antiplatelet function that other P2Y12 receptor inhibitors do not have. Moreover, the adenosine-mediated antiplatelet pathway enhanced the antiplatelet effect of ticagrelor and possibly reduced the formation of microembolization that was associated with the mechanical occlusion of microvessels, resulting in the NRF phenomenon and the activation of the coagulation and inflammation pathways. 7,38 In addition, other studies have shown that adenosine acted on vascular endothelium A2A receptor to dilate coronary arteries, 39 increase coronary blood flow, 33 reduce myocardial infarct size, 40 and reduce ischemia and reperfusion injury. 41 Therefore, adenosine can play a role in protecting the heart. In another study, 42 by using adenosine receptor antagonists, the myocardial protective effect of ticagrelor was reversed. Thus, it demonstrated that this protective effect was mediated by increasing adenosine not by P2Y12 receptor antagonism.
By contrast, the results of our meta-analysis showed that preoperative loading dose ticagrelor significantly increased the number of patients whose coronary blood flow of IRA restored TIMI3 after PPCI (P,0.05), suggesting that the ticagrelor group had better IRA reperfusion after PPCI. In addition, the level of cTFC was more precise than TIMI blood flow for evaluating the reperfusion of coronary blood flow. As we know, the lower the cTFC level is, the faster the blood flow reaches the distal portion of the coronary vessel. In our study, the level of cTFC in the preoperative loading dose ticagrelor group after PPCI was significantly lower than that of the clopidogrel group (χ 2 =9.75, I 2 =69%, 95% CI: -9.89, -6.91, P,0.05). Although the I 2 test was .50%, according to the funnel plot ( Figure 5) of the cTFC levels, we found that all four articles were in the funnel, suggesting that the heterogeneity remained in acceptable range. Simultaneously, we found that preoperative loading dose ticagrelor significantly reduced the number of patients who suffered MACE during hospitalization or within 30 days after PPCI (95% CI: 0.41, 0.82, P,0.05) and within 180 days after PPCI (95% CI: 0.15, 0.46, P,0.05) without an increased number of bleeding events within 30 days after PPCI (95% CI: 0.71, 1.54, P=0.82) and within 180 days after PPCI (95% CI: 0.81, 3.19, P=0.18). This result suggested that in the ticagrelor group, patients with STEMI after PPCI obtained more clinical benefits without a higher risk of bleeding compared with the clopidogrel group. This consequence was consistent with the results of the PPCI subgroup in the PLATO trial, 4 including 7,544 patients with STEMI.
There are several limitations of our meta-analysis. First, the subjects in most of the included studies were Chinese. Thus, the conclusions obtained from this meta-analysis may be suitable only for Chinese populations. These findings might change in studies of various races and nationalities. In addition, the CYP2C19 gene polymorphism, which has an influence on the effect of clopidogrel, was not considered. However, the incidence of carriers with CYP2C19*2 and *3 alleles, which leads to the lower reaction of clopidogrel, in the Asian population was higher than that of the European and African populations, [43][44][45] suggesting that the antiplatelet effect of clopidogrel was underestimated if the included patients had alleles leading to low response to clopidogrel in Asia. Second, some of the studies included in our metaanalysis had their own limitations, especially in describing the randomization method, allocation method, and inclusion criteria. In addition, our study included an observational study that is weaker than RCTs in terms of strength of evidence. Third, only four articles described the onset of chest pain to opening of the IRA, and three articles described the time to loading and PCI. It is generally believed that the duration of ischemia is positively correlated with the degree of myocardial necrosis, resulting in different prognoses. Nevertheless, there was no difference between the groups in the reported studies. However, it was unclear whether the time to loading and PCI in other studies made a difference that would cause heterogeneity or produce effects on the final analysis. Finally, most of the studies included in our meta-analysis were published in Chinese journals, so the quality of the articles may not be as high as the quality of those published in Englishlanguage journals.

Conclusion
Our meta-analysis suggests that compared with clopidogrel, treatment with preoperative loading dose ticagrelor in patients with STEMI effectively reduces the occurrence of the NRF phenomenon during PPCI and near-term MACE. At the same time, loading dose ticagrelor does not increase the risk of bleeding, either in the hospital or within 180 days after PPCI. Due to the limitations in the quantity and quality of studies included in this article, these conclusions need to be confirmed by more high-quality multicenter clinical trials.